BMJ Open...In September 2012, the UK recommended providing Tdap vaccine for pregnant women ideally...
Transcript of BMJ Open...In September 2012, the UK recommended providing Tdap vaccine for pregnant women ideally...
For peer review only
Safety of Tdap vaccine in pregnant women— an observational study
Journal: BMJ Open
Manuscript ID bmjopen-2015-010911
Article Type: Research
Date Submitted by the Author: 18-Dec-2015
Complete List of Authors: Petousis-Harris, Helen; The University of Auckland, School of Population Health Walls, Tony; University of Otago, Christchurch, Department of Paediatrics; Watson, Donna ; University of Auckland, School of Population Health Private Bag 92019 Auckland 1149 Auckland, NZ 1149 +64 9 373 7599 Paynter, Janine; University of Auckland, School of Population Health Graham, Patricia; NICU, Christchurch Womens Hospital
Turner, Nikki; University of Auckland, General Practice and Primary Health Care
<b>Primary Subject Heading</b>:
Infectious diseases
Secondary Subject Heading: Paediatrics
Keywords: whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on A
pril 30, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2015-010911 on 18 April 2016. D
ownloaded from
For peer review only
1
Safety of Tdap vaccine in pregnant women— an observational study
Helen Petousis-Harris1, Senior Lecturer Tony Walls
2, Senior Lecturer, Donna Watson
1, Project
Manager, Janine Paynter1, Research Fellow, Patricia Graham
3, Research Nurse, Nikki Turner
1 ,
Associate Professor
1Immunisation Advisory Centre, Department of General Practice and Primary Care, The University
of Auckland, Auckland, New Zealand
2Department of Paediatrics, University of Otago, Christchurch, New Zealand
3Canterbury District Health Board, Christchurch, New Zealand
Correspondence to:
Helen Petousis-Harris
Department of General Practice and Primary Health Care
School of Population Health, Faculty of Medical and Health Sciences
University of Auckland, Private Bag 92019
Telephone: +64 9 9232078, Fax: +64 9 3737030.
Keywords: Whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
Word count: 3323
Page 1 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
2
ABSTRACT
Objectives: Actively recruit and intensively follow pregnant women receiving a booster dose of acellular
pertussis vaccine.
Design and settings: A prospective observational study conducted in two New Zealand centres.
Participants: Women in their 28th
–38th
week of pregnancy, recruited from primary care and antenatal clinics
at the time of Tdap administration. Telephone interviews were conducted at 48 hours and 4 weeks post
vaccination.
Main outcomes measures: Outcomes were injection site reactions, systemic symptoms and serious adverse
events (SAEs). Where available, data have been classified and reported according to Brighton Collaboration
definitions.
Results: 793 women participated with 27.9% receiving trivalent inactivated influenza vaccine concomitantly.
79% of participants reported mild or moderate pain and 2.6% severe pain. Any swelling was reported by
7.6%, induration by 12.0% (collected from one site only, n=326) and erythema 5.8% of participants. Fever
was reported by 17 (2.1%), for whom 14 occurred within 24 hours. Headache, dizziness, nausea, myalgia or
arthralgia were reported by <4% of participants respectively and fatigue by 8.4%. During the study period
there were 115 adverse events in 113 participants, most were minor. At the end of reporting 31 events were
classified as serious (e.g., obstetric bleeding, hypertension, infection, tachycardia, preterm labour,
exacerbation of pre-existing condition and preeclampsia). All had variable onset time from vaccination.
There were two perinatal deaths. Clinician assessment of all SAEs found none likely to be vaccine related.
Conclusion: Vaccination with Tdap in pregnant women was well tolerated with no SAE likely to be caused by
the vaccine.
Trial registration
WHO Universal Trial Number (UTN) (U1111-1148-0718). Australian New Zealand Clinical Trials Registry
(ACTRN12613001045707).
Page 2 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
3
STRENGTHS AND LIMITATIONS OF THIS STUDY
Strengths
• This is the largest number of pregnancy exposures to Tdap that have been individually followed
• We had close contact with all participants in this study and multiple modes of communication.
• There was intensive follow up of all serious adverse events.
• Our study allowed for close examination of common local and systemic vaccine reactions.
Limitations
• This is an observational study, there were no direct comparator groups. While our results add to the
body of evidence of safety for pregnant women the study population was not randomly selected.
• The women in our group were older (32 years) than the general NZ maternal population (29.2 years)
and more likely to be of NZ European ethnicity (73.5% vs 49.5%). This is likely a reflection of the
health seeking behaviour associated with these demographics.
Page 3 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
4
INTRODUCTION
In 2011, the United States Advisory Committee on Immunization Practices (ACIP) recommended that
acellular pertussis-containing vaccine (Tdap) be given to any person, including pregnant women, likely to be
in contact with infants under the age of 12 months. In September 2012, the UK recommended providing
Tdap vaccine for pregnant women ideally between 28–38 weeks of pregnancy.1,2
Vaccine administration in
pregnancy not only offers maternal protection against pertussis, but also provides for maternal antibody to
be passed to the infant, which has been demonstrated to be protective in their first months of life.3,4
There
are no theoretical safety concerns with administering subunit vaccines in pregnancy and some vaccines, in
particular tetanus, have been used widely in pregnant women. In October 2012, in response to a pertussis
epidemic, the New Zealand (NZ) Ministry of Health began funding Tdap vaccine for all women from 28–38
weeks gestation.
At the time of this study, the USA ACIP committee acknowledged that the safety of Tdap immunisation
during pregnancy had not been systematically studied, with the only data available coming from small
studies, post-marketing surveillance, and the US Vaccine Adverse Event Reporting System.1
Our aim was to intensively monitor the safety of Tdap vaccine in a larger group of pregnant women for a
period up to 4 weeks post vaccination.
METHODS
Study design, setting and participants
This was a prospective observational study conducted in two different geographical areas of NZ using the
same outcome measures and database. There was some difference in recruitment and data collection
methods. The Northern arm of the study was conducted primarily in Auckland and included other North
Island centres. Auckland is a culturally diverse metropolitan city of 1.42 million in the North Island. Women
being administered Tdap between 28–38 weeks gestation were identified by staff from 21 out of 24
participating general practices and the maternity clinics of three district health boards (DHBs) and referrals
faxed to the study team from 30 January–30 June, 2014.
Page 4 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
5
The other arm was conducted in Canterbury, a more ethnically homogenous South Island region of just over
half a million. Recruitment for this arm began earlier, from late September 2012--late June, 2014.
Participants aged 18-40 years and administered Tdap between 30–36 weeks gestation were identified via
claims submitted by general practices (within 1 week of vaccination) for reimbursement from the local DHB
for each vaccination service delivered.
In both study arms, consent to be contacted by members of the research team was sought at the time of
vaccination.
Women who had given birth prior to being contacted by study team memberswere originally to be excluded
from both arms of the study; however, due to concern that this may lead to overlooked serious adverse
events (SAEs) (i.e, premature birth) early in the study, after the first exclusion subsequent women in the
Northern arm who had birthed prior to contact but met other inclusion criteria were included.
Vaccines
The pertussis-containing vaccine (Tdap) funded for pregnant women in NZ is Boostrix®. The Boostrix®
formulation used in NZ has 0.5mg aluminium as aluminium hydroxide and aluminium phosphate adjuvant
and the US formulation no more than 0.39mg aluminium as aluminium hydroxide.
Influenza (TIV) vaccine is given at the start of the winter season and funded for all pregnant women
regardless of gestational age. Where this time coincides with the gestation age for delivery of the Tdap
providers are encouraged to deliver both vaccines together.
Data collection and main outcomes
Page 5 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
6
Figure 1: Participant recruitment and data collection
Northern participants leaving the practice/clinic after their vaccination, were given a study envelope
containing an information sheet, consent form, clear plastic measuring tool (to measure any local reaction)
and a 3-day diary card to record any symptoms or events. At the first phone contact 48–72 hours post-
vaccine administration, verbal consent was obtained then an interview undertaken. The second phone
interview was conducted at 4 weeks post administration (see Figure 1).
For Canterbury participants, a research team member made phone contact with potential participants within
2 weeks of identification, obtained consent and conducted the first interview. A follow-up questionnaire was
mailed at 4 weeks post vaccination.
For both groups, consent to follow up with their Lead Maternity Carer (LMC) (either a midwife or
obstetrician) or General Practitioner was sought from all women who reported a SAE or any birth
complication. As per national protocols,5 any adverse events (AEs) were also reported to the Centre for
Adverse Reaction Monitoring (CARM), the official regulatory body in charge of receiving all AE reports in NZ.
Page 6 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
7
An AE is any untoward medical occurrence temporally associated with administration of the vaccine and
does not include common injection site reactions. Anonymised data for any SAEs were also reported to the
Marketing Authorisation Holder (the vaccine manufacturer) as part of global drug safety surveillance.
To ensure consistency in our classifications of SAEs we used an algorithm based on the International
Conference on Harmonisation definitions for SAEs.6,7
We separated events occurring in the mother during
pregnancy (Figure 2) and those triggered by indications of non-reassuring fetal status (Figure 3).
A SAE is defined as any untoward medical occurrence that: results in death; is life-threatening; requires
inpatient hospitalisation or causes prolongation of existing hospitalisation; results in persistent or significant
disability/incapacity; is a congenital anomaly/birth defect, or; requires intervention to prevent permanent
impairment or damage.
The term "life-threatening" used here refers to an event in which the patient was at risk of death at the time
of the event; it does not refer to an event, which hypothetically might have caused death if it were more
severe.8
All SAEs were followed up by a study clinician.
Page 7 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
8
Figure 2 Classification of maternal adverse events
Figure 3 Classification of labour, delivery and infant-related adverse events
Page 8 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
9
Solicited and unsolicited outcomes
The diary card (Northern arm) allowed recording of injection site reactions, fever and unsolicited events over
3 days (Day 0, 1 and 2). Response categories were consistent with Brighton Collaboration definitions and
guidelines for events following immunisation.9-12
The 48-hour post-vaccination telephone interview (Northern arm) asked about nausea, vomiting, diarrhoea,
headache, fatigue, and contact with health care services. Participants were also asked if they had any other
concerns after the vaccination. The telephone interview conducted by the Canterbury team, sought the
same information retrospectively for up to 7 days post vaccination.
The 4-week post-vaccination telephone interview (Northern arm) and mailed questionnaire (Canterbury
arm) asked if any events, including contact with health professionals, had occurred since the last interview.
Canterbury participants were phoned if their questionnaire was not returned.
Statistical analysis
The size of our sample was based on the number of births in the study regions, estimated uptake of pertussis
vaccine in pregnancy and the number of women available for follow up over the study timeframe.
As the two regions recruited and collected data in different ways we have not attempted to analyse any
differences.
Frequencies, percentages and cross tabulations for demographic and outcome variables were produced
using SAS Enterprise Guide version 6. Results are summarised as counts and percentages for each outcome.
Values within outcome variables (e.g., pain, redness, swelling and induration), are based on Brighton
collaboration definitions of outcomes. Other outcomes such as fever, nausea, myalgia, are summarised as
presence or absence (i.e., yes or no). Missing values are reported in the tables where relevant.
Page 9 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
10
RESULTS
Twenty-four general practices out of 34 invited (70.6%) and three invited DHB maternity clinics were
recruited to the Northern arm. Twenty-one of the practices recruited participants. Practices who declined
said they were too busy or had too few patients who met the required criteria. In the Canterbury arm, claim
forms for financial reimbursement of delivery of the vaccine for 1,212 women were received. Attempts to
contact women within 2 weeks of their claim form being received by the study team meant 710 women
were contacted by phone, of which 467 consented (65.8%). Participant flow is presented in Figure 4.
Figure 4: Participant flow Of those who were contacted but ineligible were two males, four women who delivered prior to being contacted and 84 women who
received Tdap outside the specified inclusion criteria.
In total, there were 793 participants across both arms, predominantly of NZ European ethnicity (73.5%). The
mean age was 32, with 61.4% of participants aged between 25 and 35 years. Just over one quarter (27.9%)
were co-administered influenza vaccine. A range of pre-existing conditions were present among 18% of
Page 10 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
11
participants, including pregnancy-related conditions (2.0%) including pre-eclampsia (PET), symphysis pubis
dysfunction, low lying placenta, shortening cervix and poor fetal growth. Participant demographics are
presented in Table 1.
Table 1: Demographic characteristics of participants
Ethnicity (N = 793) n (%)
NZ European 583 (73.5)
Māori (indigenous NZ) 55 (6.9)
Pacific Island 34 (4.3)
Asian 103 (13.0)
Middle Eastern, Latin American or African 18 (2.3)
Age
<20 years 12 (1.5)
20–24 years 65 (8.2)
25–29 years 180 (22.7)
30–34 years 307 (38.7)
35–39 years 180 (22.7)
40 years or more 49 (6.6)
Coadministered flu vaccine
Yes 218 (27.5)
Medical history/pre-existing conditions
None noted 651 (82.1)
Asthma 24 (3.0)
Atopy 4 (0.5)
Cancer 2 (0.3)
Cardiovascular 12 (1.5)
Chronic Renal Disease 1 (0.1)
Chronic Respiratory Disease 1 (0.1)
Diabetes 29 (3.7)
Other 52 (6.6)
Pregnancy related conditions 16 (2.0)
Unanswered 1 (0.1)
Approximately one half of Northern participants were co-administered influenza vaccine and 13% of
Canterbury participants; this was due to the differences in timing for the influenza season with recruitment.
Injection site reactions
Pain was the most commonly reported reaction to the Tdap injection with 79.0% of participants overall
reporting mild or moderate pain in total. Severe pain was reported by 2.6%. Onset of pain occurred within
24 hours in 83.9% of participants. There were differences in the intensity, onset and resolution. Northern
Page 11 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
12
study participants reported higher intensity pain, later onset and longer time until resolution (Table 2). The
proportion reporting no pain was similar for both groups.
Table 2: Number and percentage (n/%) of participants from respective study arms reporting pain after Tdap injection
Pain
Northern arm
(N = 326)
Canterbury arm
(N = 467)
Total
(N = 793)
None 56 (17.2) 90 (19.3) 146 (18.4)
Mild, still able to move arm normally 163 (50.0) 184 (39.4) 347 (43.8)
Moderate, hurts to move or to touch 90 (27.6) 189 (40.5) 279 (35.2)
Severe, unable to move arm 17 (5.2) 4 (0.9) 21 (2.6)
Onset of pain (n = 270) (n = 377) (n = 647)
0–24 hours 201 (74.4) 342 (90.7) 543 (83.9)
25–48 hours 68 (25.2) 35 (9.3) 103 (15.9)
49–72 hours 1 (0.4) - 1 (0.2)
Pain resolved by
0–24 hours 30 (11.1) 131 (34.7) 161 (25.1)
25–48 hours 86 (31.9) 141 (37.4) 227 (35.4)
>49 hours 154 (57.0) 99 (26.3) 253 (39.5)
Missing - 6 (1.6) 6 (0.9)
Swelling at the injection site was uncommon with 7.6% of participants reporting any swelling and three
participants (0.4%) reporting swelling greater than 5 centimetres. All cases of swelling had an onset within
48 hours with half unresolved after 48 hours (Table 3).
Erythema was reported by 5.8% of participants with 0.4% reporting erythema of greater than 5 centimetres.
Onset was generally within 48 hours and resolution over 48 hours for half of these (Table 3).
Induration as an injection site reaction was collected in the Northern but not the Canterbury arm. Any
induration was reported by 12% of participants, in whom half took more than 48 hours to resolve. No
indurations events measured greater than 5 centimetres. (Table 3).
Table 3: Total number and percent (n/%) of participants reporting swelling, erythema or induration after Tdap
injection
Swelling
(N = 793)
Erythema
(N = 793)
Induration�
(N = 326)
None 733 (92.4) 747 (94.2) 287 (88.0)
Circumference of event (n = 60) (n = 46) (n = 39)
>0.0–<1.0 cm 33 (4.2) 25 (3.2) 21 (6.4)
>1.0–<2.5cm 12 (1.5) 10 (1.3) 12 (3.7)
>2.5–<5.0cm 12 (1.5) 8 (1.0) 6 (1.8)
>5.0–<10.0cm 2 (0.3) 3 (0.4) -
>10.0–<15.0cm 1 (0.1) - -
Onset of event after injection (n = 60) (n = 46) (n = 39)
0–24 hours 44 (73.3) 27 (58.7) 15 (38.5)
25–48 hours 16 (26.7) 16 (34.8) 22 (56.4)
Page 12 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
13
>49 hours - 3 (6.5) 2 (5.1)
Resolution of event (n = 60) (n = 46) (n = 39)
0–24 hours 14 (23.3) 13 (28.3) 6 (15.4)
25–48 hours 15 (25.0) 10 (21.7) 11 (28.2)
>49 hours 31 (51.7) 23 (50.0) 22 (56.4) �Northern study data only
Systemic events
Fever was reported by 17 (2.1%) participants, 14 of whom reported this occurring within 24 hours. Of those
reporting fever within 24 hours, 6 (35%) had been co-administered influenza vaccine (Table 4).
Table 4: Numbers and percentage (n/%) of participants reporting fever and taking antipyretics or pain medication
following Tdap injection
Fever (N = 793)
No reported fever 776 (97.9)
Fever 17 (2.1)
Onset of fever (n = 17)
0–24 hours 14 (82.3)
25–48 hours 2 (11.8)
49–72 hours 1 (5.9)
Antipyretic or pain medication taken (N = 793)
No 762 (96.1)
Yes 31 (3.9)
Fever within 24 hrs and co-administered influenza vaccine (n = 17)
Yes 6 (43)
Other systemic events included headache and dizziness, nausea and vomiting, fatigue and myalgia or
arthralgia. All were uncommon and reported by fewer than 4% of participants with the exception of fatigue,
which was reported by 8.4% (Table 5). Thirty-two participants reported more than one of these outcomes
occurring together. Around one quarter to one third of those who reported a systemic event also received
the influenza vaccine at the same time (Table 5).
Table 5: Number and percentage of participants reporting systemic events following Tdap Injection
Systemic events
(N = 793) n (%)
Onset within 24 hrs
n (%)
Coadministered flu vaccine
n (%) of sample
experiencing event
n (%) of sample with
24-hour onset
Headache/Dizzy 31 (3.9) 27 (87) 13 (42) 11 (41)
Nausea/Vomiting 22 (2.8) 19 (86) 5 (23) 5 (26)
Fatigue 67 (8.4) 58 (86) 17 (25) 13 (22)
Myalgia/Arthralgia 24 (3.0) 21 (88) 6 (25) 6 (29)
Page 13 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
14
AEs and SAEs
During the study period there were 115 AEs and SAEs in 113 participants (two events each for two
participants) reported to CARM, in accordance with local guidelines. CARM reports submitted for events not
considered SAEs were mostly minor in nature and for a range of issues including a stiff neck on the same side
as the injection, itching, changes in baby movements and combinations of systemic events such as
headaches, nausea, fatigue and fever (see Tables 4 and 5). Additionally, 25 reports were for diagnosed non-
injection site infections (e.g., chest, urine and throat).
We have reported SAEs according to whether they occurred or were triggered during pregnancy; during
labour and delivery; or occurred in the infant after delivery.
Of the 31 events deemed to be serious (3.9%) there were 23 hospitalisations following immunisation that
occurred during pregnancy. Reasons for these were: obstetric bleeding (4), hypertension (2), infection (4),
tachycardia (1), preterm labour (9), exacerbation of pre-existing condition (2) and preeclampsia (1). All had
variable onset time from vaccination (Table 6).
Additionally, there were a total of eight SAEs that occurred during labour and delivery: six reported in the
Northern arm and two in the Canterbury arm (note different methodologies). Of these eight SAEs,
two were perinatal deaths, one of which was due to a congenital abnormality, the other unexplained. There
was one cyanotic episode and five cases where concern for fetal wellbeing resulted in health service
intervention (Table 7).
Table 6. SAEs reported among pregnant women following immunisation in 793 pregnant women vaccinated with
Tdap
Participant Event SAE definition Onset post
Tdap
Gestation at
time of event
(wks)
1 PV bleeding Required hospitalisation 11d 30w
2 Hypertension in pregnancy Required hospitalisation 27d 40+w
3 Pelvic pain, bacterial
vaginitis
Required hospitalisation 9d 34w
4 Cellulitis Required hospitalisation 6d 38w
5 Hypertension in pregnancy Required hospitalisation 11d 34w
6 Threatened labour and
Group A strep infection
Required hospitalisation 20d 31w
7 Bleeding Required hospitalisation 24d 36w
8 Maternal tachycardia Required hospitalisation 16d 34w
Page 14 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
15
9 Gestational diabetes &
antenatal partum
haemorrhage
Required hospitalisation 29d 34w
10 Preterm labour Required hospitalisation 1d 36w
11 Preterm labour Required hospitalisation 24d 36w
12 Preterm labour Required hospitalisation 7d 33w
13 Exacerbation of pre-
existing condition
Required hospitalisation 17d 36w
14 Exacerbation of pre-
existing condition
Required hospitalisation 7d 19w
15 Preeclampsia Required hospitalisation 8d 36w
16 Preterm labour Required hospitalisation 16d 36w
17 Preterm labour Required hospitalisation 19d 36w
18 Preterm labour Required hospitalisation 11d 33w
19 Preterm labour Required hospitalisation 19d 36w
20 Vaginal bleeding Required hospitalisation 21d 34w
21 Preterm labour Required hospitalisation 9d 34w
22 Preterm labour Required hospitalisation ~15d* 36w
23 Infection (coronavirus) Required hospitalisation 1d 34w
Note: d= days; w=weeks; *No delivery date was recorded for this participant.
Table 7. SAEs during labour in and among infants of 793 pregnant women vaccinated with Tdap
Participant Event SAE Definition Onset post
Tdap
Gestation at time
of event (wks)
24 Cyanotic episodes in infant Prolongation of existing
hospitalisation
31d 39w
25 Fetal death (trisomy 11q) Resulted in death 10d 36w
26 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
11d 38w
27 Non-reassuring fetal status Hospitalisation 23d 39w
28 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
37d 41w
29 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
18d 39w
30 Non-reassuring fetal status Admission to NICU and
CPAP
28d 37w
31 Perinatal death (stillbirth) Resulted in death 53d 40w
Clinician review and assessment of each of these cases found none were likely to be vaccine related.
DISCUSSION
Reduced-antigen-content tetanus–diphtheria–acellular pertussis (Tdap) vaccines have been shown to be
highly effective in pregnancy for reducing infant pertussis morbidity,3,4
and are being increasingly
recommended on national schedules, particularly during epidemics. While there have been no safety
concerns to date using these vaccines in pregnancy, data on safety in pregnancy are relatively limited. This
study intensively followed 793 women vaccinated in pregnancy with Tdap for solicited and unsolicited
Page 15 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
16
outcomes and is the largest number of pregnancy exposures to Tdap that have been individually followed.
Our sample included pregnant women regardless of underlying conditions, including women with
comorbidities. Injection site reactions were common, minor and self-limiting. Systemic reactions were
uncommon. Differences in pain reporting between the study groups is likely due to both demographic
differences and differences in data collection methods. Previous NZ studies have shown vaccine
reactogenicity varies by ethnic group.13,14
SAEs occurred in our study population during the study period.
None were likely to have been caused by the exposure to Tdap vaccine.
As this is an observational study, there were no direct comparator groups. While our results add to the body
of evidence of safety for pregnant women the study population was not randomly selected. The women in
our group were older (32 vs 29.2 years) and more likely to be of NZ European ethnicity (73.5% vs 49.5%) than
the general NZ maternal population. This is likely a reflection of the health seeking behaviour associated with
these demographics. While pregnancy complications increase with age, in contrast, NZ European ethnicity is
associated with lower risk pregnancies.15
The reactogenicity of acellular pertussis-containing vaccines in adults was reviewed in 2012.16
Data on the
reactogenicity of Tdap are derived from clinical trials and prospective studies; however, the results are not
presented in a standardised way that allows comparison. Generally participants record symptoms, both
solicited and unsolicited, on diary cards for 4–15 days after vaccination. Events are graded by subjects as 0–3
with 0 being not present and 3 defined as symptoms that prevent normal activity. Grade 3 fever is axillary
temperature greater than 39°C and grade 3 swelling or redness is variably described as >20mm, >30mm or
≥50mm in diameter. There is insufficient information in the study manuscripts to determine in more detail
how events are measured or classified. However severe local pain ranges from less than 1%–30% and severe
local redness or swelling (≥50mm) ranges from 2%–18%.17-23
Although most of these studies were published
after 2007 when definitions were published by the Brighton Collaboration none have provided information
about induration.
A small US randomised trial including 33 pregnant women assessed the immunogenicity and safety of Tdap
during pregnancy. Safety outcomes were collected with a 7-day diary. How these were defined is not
Page 16 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
17
described. Pain was reported by 25 (75.8%) participants while erythema and induration/swelling was each
reported by three (9.1%) participants. These were the same rates as reported by the non-pregnant women in
the study.24
The rates of injection site pain in our study are consistent with most other studies that report
less than 10% experiencing severe pain.9,18,19,21
Rates of swelling with a diameter of more than 50mm ranged
from 1% to 18% in clinical studies. In our study population just 0.4% recorded swelling of more than 50mm
and fewer than 8% reported any. 9,17-21,23
Our outcomes are lower than these other reports; however, this
could be because we have differentiated between swelling and induration. Overall both events were
infrequent and mild. Erythema (redness) was relatively uncommon in our study with fewer than 6% of
participants reporting any and 1.4% reporting a diameter greater than 50mm. In clinical studies severe
erythema has been reported to range from 2% to 17%17-21,23
Our rates are consistent with those recently
reported in the US trial in pregnant women.24
It should be noted that the aluminium content of the NZ
Boostrix® formulation is higher than that of the US formulation, and higher aluminium content may be linked
to greater local reactogenicity.25
In the Northern arm of our study we collected information about swelling and induration according to
Brighton Collaboration definitions10,11
and are able to report induration separately from swelling. Induration
occurred more frequently than swelling and appeared to have a later temporal onset than swelling. More
than half of the cases of induration occurred 25–48 hours later compared with around a quarter of all
swelling, supporting the likelihood each have different aetiologies.
While in previous clinical studies headache has tended to be reported by around a third of
participants,17,18,20-23
fewer than 3.9% of our subjects reported either headache or feeling dizzy. Also, few of
our participants reported any gastrointestinal symptoms (2.8%). Almost all systemic events in our study
occurred in the 24 hours following immunisation as opposed to later and we consider them likely to be
vaccine related. Overall there were few systemic events reported and the rates of the most common
aconsistent with those reported in the US study with 33 participants.24
SAEs occurred in our study population during the study period. None were considered by clinical review
likely to be caused by the exposure to Tdap vaccine. In NZ, up to 15% of pregnancies have obstetric
Page 17 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
18
complications and approximately 1 per 10 infants are born preterm or low birth weight.26,27
Annually there
are approximately 600 perinatal deaths (~1% of births) of which 14% are unexplained. These figures have
remained consistent over time.15
Based on NZ data the rates of SAEs in our study were not higher than the
expected background rate for such a cohort. Reports to the US Vaccine Adverse Event Reporting System of
pregnant women inadvertently given Tdap have been summarised.28
Between January 2005 and June 2010
there were 132 reports identified, 20 following Boostrix® with no non-pregnancy SAEs reported. In the US
trial SAEs occurred in 7/33 pregnant women, without known risks to pregnancy at enrolment, followed to 4
months post-partum, none of these were non-pregnancy SAEs. The events occurred at variable time periods
following immunisation and none were considered attributable to the vaccine. More recently, obstetric
events and birth outcomes for 123,494 women from two Californian Vaccine Safety Datalink sites were
evaluated; 26,229 women received Tdap with no increased risk for hypertensive disorders of pregnancy or
preterm or small for gestational age birth found. There was a small increased risk of chorioamnionitis
diagnosis.29
Further investigations have not found an association.30,31
A matched case control study from the
UK in 20,074 pregnant women and matched historical unvaccinated control group found no evidence of any
increase for predefined pregnancy related AEs including stillbirth.32
These all support the safety of Tdap in
pregnancy.
In conclusion, we found a Tdap vaccination was well tolerated in pregnant women. Our findings are
consistent with data from studies involving non-pregnant women. There were no SAEs in this study that
were likely to have been caused by the vaccine. This is reassuring for pregnant women, vaccinators and
policy makers.
Section 1: What is already known on this subject
Tdap vaccines have a well-established safety profile in adults. Recent large data-linking
studies have evaluated obstetric and birth outcomes and found no concerning patterns.
This study intensively followed 793 pregnant women, recording solicited local injection
site reactions, systemic events and all events that occurred within 4 weeks of
vaccination.
Section 2: What this study adds
This is the largest number of pregnancy exposures to Tdap that have been actively
followed for safety outcomes. Injection site reactions were common, minor and self-
limiting and systemic reactions were uncommon. Our findings are consistent with the
data from studies involving non-pregnant women. Serious Adverse Events occurred in
our study population during the study period. None were likely to be caused by the
exposure to Tdap vaccine. Our study supports the safety of Tdap in pregnant women.
Page 18 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
19
ACKNOWLEDGEMENTS
We acknowledge the general practice and DHB antenatal clinic staff involved in the study, for their
assistance in referring eligible women to the study team. We also thank the pregnant women and mothers
who contributed to the study. Our colleagues Angela Chong, Trish Graham, Nicky Ellis , Barbara McArdle,
Tracey Poole and Jane Stephen assisted in various ways, such as recruiting general practices, database set-up
and data collection.
FUNDING
The Northern study was funded by GlaxoSmithKline Biologicals SA, the manufacturer of Boostrix® and
sponsored by Auckland UniServices Ltd. However they had no role in study design, conduct or data
interpretation. The Southern study was funded by the Canterbury District Health Board.
COMPETING INTERESTS
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and
declare: Financial support for the submitted work from GlaxoSmithKline. HPH has served on advisory panels
and/or DSMB for GlaxoSmithKline, Pfizer, CSL Biotherapies and Merck but does receive personal honorarium
or payment. She has also served on investigator led studies funded but not sponsored by GlaxoSmithKline,
CSL and sanofi pasteur.
CONTRIBUTORS
HPH and TW were responsible for the study concept and design, DW acquired the data for the Northern arm
of the study, PG acquired the data for the Canterbury arm of the study. JP managed and analysed the data
for this study, NT collected clinical data for the SAEs. All authors drafted the manuscript and critically revised
it for important intellectual content.
ETHICAL APPROVAL
Page 19 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
20
Ethics approval was obtained from the University of Auckland Human Participants Ethics Committee
(010656) and from the Upper South A Regional Ethics Committee (URA/12/EXP/021).
TRANSPARENCY
HPH (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent
account of the study being reported; that no important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered) have been explained.
DATA SHARING
All adverse events were shared with the local pharmacovigilance centre, which is also shared with the WHO
Programme for International Drug Monitoring in Uppsala, Sweden. All Northern arm deidentified data and
consenting participant data from the Canterbury arm were shared with the Market Authoriser
(GlaxoSmithKline Biologicals SA). No additional data are available from the authors.
EXCLUSIVE LICENCE
HPH has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive
licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd
to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and
sublicences such use and exploit all subsidiary rights, as set out in our licence
Page 20 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
21
REFERENCES
1. Advisory Committee on Immunization Practices (ACIP). Summary Report February 23-24, 2011.
Atlanta, Georgia2011.
2. Temporary programme of pertussis (whooping cough) vaccination of pregnant women. Sept 28,
2012. Department of Health,, 2012.
3. Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis vaccination in
England: an observational study. The Lancet 2014;384:1521-8.
4. Dabrera G, Amirthalingam G, Andrews N, et al. A Case-Control Study to Estimate the Effectiveness of
Maternal Pertussis Vaccination in Protecting Newborn Infants in England and Wales, 2012–2013. Clinical
Infectious Diseases 2015;60:333-7.
5. Ministry of Health. Processes for safe immunisation. In: Ministry of Health, ed. Immunisation
Handbook 2014. Wellington: Ministry of Health,; 2014:75.
6. International Conference on Harmonisation. Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting E2A. International Conference on Harmonisation,; 1994.
7. International Conference on Harmonisation. Post-Approval SAfety Data Management: Definitions
and Standards for Expedited Reporting E2D. International Conference on Harmonisation,; 2003.
8. Working Group on Vaccine Pharmacovigilance. Definition and Application of Terms for Vaccine
Pharmacovigilance. Geneva, Switzerland: World Health Organization,; 2012.
9. Gidudu J, Kohl KS, Halperin S, et al. A local reaction at or near injection site: case definition and
guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2008;26:6800-13.
10. Kohl KS, Walop W, Gidudu J, et al. Swelling at or near injection site: case definition and guidelines for
collection, analysis and presentation of immunization safety data. Vaccine 2007;25:5858-74.
11. Kohl KS, Walop W, Gidudu J, et al. Induration at or near injection site: case definition and guidelines
for collection, analysis, and presentation of immunization safety data. Vaccine 2007;25:5839-57.
Page 21 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
22
12. Michael Marcy S, Kohl KS, Dagan R, et al. Fever as an adverse event following immunization: case
definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22:551-6.
13. Petousis-Harris H, Jackson C, Stewart J, et al. Factors associated with reported pain on injection and
reactogenicity to an OMV meningococcal B vaccine in children and adolescents. Human vaccines &
immunotherapeutics 2015;11:1875-80.
14. Petousis-Harris H, Poole T, Turner N, Reynolds G. Febrile events including convulsions following the
administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and
children: the importance of routine active safety surveillance. Vaccine 2012;30:4945-52.
15. Perinatal and Maternal Mortality Review Committee. Eighth Annual Report of the Perinatal and
Maternal Mortality Review Committee. Reporting mortality 2012. Wellington2014.
16. McCormack PL. Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine,
adsorbed (boostrix ®): A review of its properties and use as a single-dose booster immunization. Drugs
2012;72:1765-91.
17. Abarca K, Valdivieso F, Potin M, Ibanez I, Vial P. [Immunogenicity and reactogenicity of a reduced
antigen content diphtheria, tetanus and acellular pertussis vaccine dTpa) in 10 to 11 years old children and in
adults]. Rev Med Chil 2002;130:502-10.
18. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid,
reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19-64 years of age.
Vaccine 2009;27:765-72.
19. Booy R, Van Der Meeren O, Ng S-P, Celzo F, Ramakrishnan G, Jacquet J-M. A decennial booster dose
of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (< i> Boostrix</i>™) is
immunogenic and well tolerated in adults. Vaccine 2010;29:45-50.
20. Chan S, Tan P, Han H, Bock H. Immunogenicity and reactogenicity of a reduced-antigen-content
diphtheria-tetanus-acellular pertussis vaccine as a single-dose booster in Singaporean adults. Singapore
medical journal 2006;47:286-90.
Page 22 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
23
21. Mertsola J, Van Der Meeren O, He Q, et al. Decennial administration of a reduced antigen content
diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. Clinical infectious diseases
2010;51:656-62.
22. Turnbull FM, Heath TC, Jalaludin BB, Burgess MA, Ramalho AC. A randomized trial of two acellular
pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults. Vaccine
2000;19:628-36.
23. Van der Wielen M, Van Damme P, Joossens E, Francois G, Meurice F, Ramalho A. A randomised
controlled trial with a diphtheria–tetanus–acellular pertussis (dTpa) vaccine in adults. Vaccine 2000;18:2075-
82.
24. Munoz F, Bond N, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular
pertussis (tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA:
the journal of the American Medical Association 2014;311:1760.
25. Lindblad EB. Aluminium adjuvants--in retrospect and prospect. Vaccine 2004;22:3658-68.
26. Ministry of Health. New Zealand Maternity Clinical Indicators 2013. Wellington: Ministry of Health;
2015.
27. Ministry of Health. Hospital-based Maternity Events 2007. Wellington: Ministry of Health,; 2010.
28. Zheteyeva YA, Moro PL, Tepper NK, et al. Adverse event reports after tetanus toxoid, reduced
diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol 2012;207:59 e1-
7.
29. Kharbanda EO, Vazquez-Benitez G, Lipkind HS, et al. Evaluation of the association of maternal
pertussis vaccination with obstetric events and birth outcomes. Jama 2014;312:1897-904.
30. Datwani H, Moro PL, Harrington T, Broder KR. Chorioamnionitis following vaccination in the Vaccine
Adverse Event Reporting System. Vaccine 2015;33:3110-3.
Page 23 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
24
31. Morgan JL, Baggari SR, McIntire DD, Sheffield JS. Pregnancy Outcomes After Antepartum Tetanus,
Diphtheria, and Acellular Pertussis Vaccination. Obstetrics & Gynecology 2015;125:1433-8.
32. Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational
study. BMJ 2014;349:g4219.
Page 24 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross‐sectional studies
Section/Topic Item #
Recommendation Reported on page #
(a) Indicate the study’s design with a commonly used term in the title or the abstract 1 and 2 Title and abstract 1
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4
Objectives 3 State specific objectives, including any prespecified hypotheses 4
Methods
Study design 4 Present key elements of study design early in the paper 4 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow‐up, and data
collection
4 - 9
Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants 4 and 5
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
5 - 7
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
6 and 7
Bias 9 Describe any efforts to address potential sources of bias n/a Study size 10 Explain how the study size was arrived at 9 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
9
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9
(b) Describe any methods used to examine subgroups and interactions n/a
(c) Explain how missing data were addressed 9 (d) If applicable, describe analytical methods taking account of sampling strategy n/a
(e) Describe any sensitivity analyses n/a
Results
Page 25 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from
For peer review only
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow‐up, and analysed
10
(b) Give reasons for non‐participation at each stage 10(c) Consider use of a flow diagram Figure 4
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
Table 1
(b) Indicate number of participants with missing data for each variable of interest Tables 1, 2 Outcome data 15* Report numbers of outcome events or summary measures Tables 2-7 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder‐adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
n/a
(b) Report category boundaries when continuous variables were categorized 6, 7 and 9 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period n/a
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses n/a
Discussion
Key results 18 Summarise key results with reference to study objectives 15-16 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
18
Generalisability 21 Discuss the generalisability (external validity) of the study results 16
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
19
*Give information separately for cases and controls in case‐control studies and, if applicable, for exposed and unexposed groups in cohort and cross‐sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe‐statement.org.
Page 26 of 26
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from
For peer review only
Safety of Tdap vaccine in pregnant women— an observational study
Journal: BMJ Open
Manuscript ID bmjopen-2015-010911.R1
Article Type: Research
Date Submitted by the Author: 25-Jan-2016
Complete List of Authors: Petousis-Harris, Helen; The University of Auckland, School of Population Health Walls, Tony; University of Otago, Christchurch, Department of Paediatrics; Watson, Donna ; University of Auckland, School of Population Health Private Bag 92019 Auckland 1149 Auckland, NZ 1149 +64 9 373 7599 Paynter, Janine; University of Auckland, School of Population Health Graham, Patricia; NICU, Christchurch Womens Hospital
Turner, Nikki; University of Auckland, General Practice and Primary Health Care
<b>Primary Subject Heading</b>:
Infectious diseases
Secondary Subject Heading: Paediatrics
Keywords: whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on A
pril 30, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2015-010911 on 18 April 2016. D
ownloaded from
For peer review only
1
Safety of Tdap vaccine in pregnant women— an observational study
Helen Petousis-Harris1, Senior Lecturer Tony Walls
2, Senior Lecturer, Donna Watson
1, Project
Manager, Janine Paynter1, Research Fellow, Patricia Graham
3, Research Nurse, Nikki Turner
1 ,
Associate Professor
1Immunisation Advisory Centre, Department of General Practice and Primary Care, The University
of Auckland, Auckland, New Zealand
2Department of Paediatrics, University of Otago, Christchurch, New Zealand
3Canterbury District Health Board, Christchurch, New Zealand
Correspondence to:
Helen Petousis-Harris
Department of General Practice and Primary Health Care
School of Population Health, Faculty of Medical and Health Sciences
University of Auckland, Private Bag 92019
Telephone: +64 9 9232078, Fax: +64 9 3737030.
Keywords: Whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
Word count: 3507
Page 1 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
2
ABSTRACT
Objectives: Actively recruit and intensively follow pregnant women receiving a dose of acellular pertussis
vaccine for 4 weeks after vaccination.
Design and settings: A prospective observational study conducted in two New Zealand regions.
Participants: Women in their 28th
–38th
week of pregnancy, recruited from primary care and antenatal clinics
at the time of Tdap administration. Telephone interviews were conducted at 48 hours and 4 weeks post
vaccination.
Main outcomes measures: Outcomes were injection site reactions, systemic symptoms and serious adverse
events (SAEs). Where available, data have been classified and reported according to Brighton Collaboration
definitions.
Results: 793 women participated with 27.9% receiving trivalent inactivated influenza vaccine concomitantly.
79% of participants reported mild or moderate pain and 2.6% severe pain. Any swelling was reported by
7.6%, induration by 12.0% (collected from one site only, n=326) and erythema 5.8% of participants. Fever
was reported by 17 (2.1%), for whom 14 occurred within 24 hours. Headache, dizziness, nausea, myalgia or
arthralgia were reported by <4% of participants respectively and fatigue by 8.4%. During the study period
there were 115 adverse events in 113 participants, most were minor. At the end of reporting 31 events were
classified as serious (e.g., obstetric bleeding, hypertension, infection, tachycardia, preterm labour,
exacerbation of pre-existing condition and preeclampsia). All had variable onset time from vaccination.
There were two perinatal deaths. Clinician assessment of all SAEs found none likely to be vaccine related.
Conclusion: Vaccination with Tdap in pregnant women was well tolerated with no SAE likely to be caused by
the vaccine.
Trial registration
WHO Universal Trial Number (UTN) (U1111-1148-0718). Australian New Zealand Clinical Trials Registry
(ACTRN12613001045707).
Page 2 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
3
STRENGTHS AND LIMITATIONS OF THIS STUDY
Strengths
• This is the largest number of pregnancy exposures to Tdap that have been individually followed
• We had close contact with all participants in this study and multiple modes of communication.
• There was intensive follow up of all serious adverse events.
• Our study allowed for close examination of common local and systemic vaccine reactions.
Limitations
• This is an observational study, there were no direct comparator groups. While our results add to the
body of evidence of safety for pregnant women the study population was not randomly selected.
The study was not large enough to explore SAEs.
• There were differences between our two study populations in terms of recruitment and data
collection.
• The women in our group were older (32 years) than the general NZ maternal population (29.2 years)
and more likely to be of NZ European ethnicity (73.5% vs 49.5%). This is likely a reflection of the
health seeking behaviour associated with these demographics.
Page 3 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
4
INTRODUCTION
In 2011, the United States Advisory Committee on Immunization Practices (ACIP) recommended that
acellular pertussis-containing vaccine (Tdap) be given to any person, including pregnant women, likely to be
in contact with infants under the age of 12 months.1 In September 2012, the UK recommended providing
Tdap vaccine for pregnant women ideally between 28–38 weeks of pregnancy.2 Vaccine administration in
pregnancy not only offers maternal protection against pertussis, but also provides for maternal antibody to
be passed to the infant, which has been demonstrated to be protective in their first months of life.3,4
There
are no theoretical safety concerns with administering subunit vaccines in pregnancy and some vaccines, in
particular tetanus, have been used widely in pregnant women.5 In October 2012, in response to a pertussis
epidemic, the New Zealand (NZ) Ministry of Health began funding Tdap vaccine for all women from 28–38
weeks gestation.
While there are now several large studies published,6-10
at the time of this study, the USA ACIP committee
acknowledged that the safety of Tdap immunisation during pregnancy had not been systematically studied,
with the only data available coming from small studies, post-marketing surveillance, and the US Vaccine
Adverse Event Reporting System.1,11
Our aim was to intensively monitor the safety of Tdap vaccine in a larger group of pregnant women for a
period up to 4 weeks post vaccination.
METHODS
Study design, setting and participants
This was a prospective observational study conducted in two different geographical areas of NZ using the
same outcome measures and database. There was some difference in recruitment and data collection
methods. The Northern arm of the study was conducted primarily in Auckland and included other North
Island centres. Auckland is a culturally diverse metropolitan city of 1.42 million in the North Island. Women
being administered Tdap between 28–38 weeks gestation were identified by staff from 21 out of 24
Page 4 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
5
participating general practices and the maternity clinics of three district health boards (DHBs) and referrals
faxed to the study team from 30 January–30 June, 2014.
The other arm was conducted in Canterbury, a more ethnically homogenous South Island region of just over
half a million. Recruitment for this arm began earlier, from late September 2012--late June, 2014.
Participants aged 18-40 years and administered Tdap between 30–36 weeks gestation were identified via
claims submitted by general practices (within 1 week of vaccination) for reimbursement from the local DHB
for each vaccination service delivered.
In both study arms, consent to be contacted by members of the research team was sought at the time of
vaccination.
Inclusion criteria was compliance with routine antenatal care, including at least one ultrasound early in
pregnancy. Women who had given birth prior to being contacted by study team members were originally to
be excluded from both arms of the study; however, due to concern that this may lead to overlooked serious
adverse events (SAEs) (i.e, premature birth) early in the study, after the first exclusion subsequent women in
the Northern arm who had birthed prior to contact but met other inclusion criteria were included.
Vaccines
The pertussis-containing vaccine (Tdap) funded for pregnant women in NZ is Boostrix®. The Boostrix®
formulation used in NZ has 0.5mg aluminium as aluminium hydroxide and aluminium phosphate adjuvant
and the US formulation no more than 0.39mg aluminium as aluminium hydroxide.
Influenza (TIV) vaccine is given at the start of the winter season and funded for all pregnant women
regardless of gestational age. Where this time coincides with the gestation age for delivery of the Tdap
providers are encouraged to deliver both vaccines together.
Data collection and main outcomes
Page 5 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
6
Northern participants leaving the practice/clinic after their vaccination, were given a study envelope
containing an information sheet, consent form, clear plastic measuring tool (to measure any local reaction)
and a 3-day diary card to record any symptoms or events. At the first phone contact 48–72 hours post-
vaccine administration, verbal consent was obtained then an interview undertaken. The second phone
interview was conducted at 4 weeks post administration (see Figure 1).
Figure 1: Participant recruitment and data collection
For Canterbury participants, a research team member made phone contact with potential participants within
2 weeks of identification, obtained consent and conducted the first interview. A follow-up questionnaire was
mailed at 4 weeks post vaccination.
For both groups, consent to follow up with their Lead Maternity Carer (LMC) (either a midwife or
obstetrician) or General Practitioner was sought from all women who reported a SAE or any birth
complication. As per national protocols,12
any adverse events (AEs) were also reported to the Centre for
Adverse Reaction Monitoring (CARM), the official regulatory body in charge of receiving all AE reports in NZ.
An AE is any untoward medical occurrence temporally associated with administration of the vaccine and
does not include common injection site reactions. In NZ, AEFI (adverse events following immunisation)
reporting is encouraged if the event is serious or unexpected. Anonymised data for any SAEs were also
reported to the Marketing Authorisation Holder (the vaccine manufacturer) as part of global drug safety
surveillance.
To ensure consistency in our classifications of SAEs we used an algorithm based on the International
Conference on Harmonisation definitions for SAEs.13,14
We separated events occurring in the mother during
pregnancy (Figure 2) and those triggered by indications of non-reassuring fetal status (Figure 3).
Figure 2: Classification of maternal adverse events
Figure 3: Classification of labour, delivery and infant-related adverse events
Page 6 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
7
A SAE is defined as any untoward medical occurrence that: results in death; is life-threatening; requires
inpatient hospitalisation or causes prolongation of existing hospitalisation; results in persistent or significant
disability/incapacity; is a congenital anomaly/birth defect, or; requires intervention to prevent permanent
impairment or damage.
The term "life-threatening" used here refers to an event in which the patient was at risk of death at the time
of the event; it does not refer to an event, which hypothetically might have caused death if it were more
severe.15
All SAEs were followed up by a study clinician.
Solicited and unsolicited outcomes
The diary card (Northern arm) allowed recording of injection site reactions, fever and unsolicited events over
3 days (Day 0, 1 and 2). Response categories were consistent with Brighton Collaboration definitions and
guidelines for events following immunisation.16-19
The 48-hour post-vaccination telephone interview (Northern arm) asked about nausea, vomiting, diarrhoea,
headache, fatigue, and contact with health care services. Participants were also asked if they had any other
concerns after the vaccination. The telephone interview conducted by the Canterbury team, sought the
same information retrospectively for up to 7 days post vaccination.
The 4-week post-vaccination telephone interview (Northern arm) and mailed questionnaire (Canterbury
arm) asked if any events, including contact with health professionals, had occurred since the last interview.
Canterbury participants were phoned if their questionnaire was not returned.
Statistical analysis
The size of our sample was based on the number of births in the study regions (28,000 per annum),
estimated uptake of pertussis vaccine in pregnancy and the number of women available for follow up over
the study timeframe.
Page 7 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
8
As the two regions recruited and collected data in different ways we have not attempted to analyse any
differences.
Frequencies, percentages and cross tabulations for demographic and outcome variables were produced
using SAS Enterprise Guide version 6. Results are summarised as counts and percentages for each outcome.
Values within outcome variables (e.g., pain, redness, swelling and induration), are based on Brighton
Collaboration definitions of outcomes. Other outcomes such as fever, nausea, myalgia, are summarised as
presence or absence (i.e., yes or no). Missing values are reported in the tables where relevant.
RESULTS
Twenty-four general practices out of 34 invited (70.6%) and three invited DHB maternity clinics were
recruited to the Northern arm. Twenty-one of the practices recruited participants. Practices who declined
said they were too busy or had too few patients who met the required criteria. In the Canterbury arm, claim
forms for financial reimbursement of delivery of the vaccine for 1,212 women were received. Attempts to
contact women within 2 weeks of their claim form being received by the study team meant 710 women
were contacted by phone, of which 467 consented (65.8%). Participant flow is presented in Figure 4.
Figure 4: Participant flow
In total, there were 793 participants across both arms, predominantly of NZ European ethnicity (73.5%). The
mean age was 32, with 61.4% of participants aged between 25 and 35 years. Just over one quarter (27.9%)
were co-administered influenza vaccine. A range of pre-existing conditions were present among 18% of
participants, including pregnancy-related conditions (2.0%) including pre-eclampsia (PET), symphysis pubis
dysfunction, low lying placenta, shortening cervix and poor fetal growth. Participant demographics are
presented in Table 1.
Table 1: Demographic characteristics of participants
Ethnicity (N = 793) n (%)
NZ European 583 (73.5)
Māori (indigenous NZ) 55 (6.9)
Pacific Island 34 (4.3)
Asian 103 (13.0)
Page 8 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
9
Middle Eastern, Latin American or African 18 (2.3)
Age
<20 years 12 (1.5)
20–24 years 65 (8.2)
25–29 years 180 (22.7)
30–34 years 307 (38.7)
35–39 years 180 (22.7)
40 years or more 49 (6.6)
Coadministered flu vaccine
Yes 218 (27.5)
Medical history/pre-existing conditions
None noted 651 (82.1)
Asthma 24 (3.0)
Atopy 4 (0.5)
Cancer 2 (0.3)
Cardiovascular 12 (1.5)
Chronic Renal Disease 1 (0.1)
Chronic Respiratory Disease 1 (0.1)
Diabetes 29 (3.7)
Other 52 (6.6)
Pregnancy related conditions 16 (2.0)
Unanswered 1 (0.1)
Approximately one half of Northern participants were co-administered influenza vaccine and 13% of
Canterbury participants; this was due to the differences in timing for the influenza season with recruitment.
Injection site reactions
Pain was the most commonly reported reaction to the Tdap injection with 79.0% of participants overall
reporting mild or moderate pain in total. Severe pain was reported by 2.6%. Onset of pain occurred within
24 hours in 83.9% of participants. There were differences in the intensity, onset and resolution. Northern
study participants reported higher intensity pain, later onset and longer time until resolution (Table 2). The
proportion reporting no pain was similar for both groups.
Table 2: Number and percentage (n/%) of participants from respective study arms reporting pain after Tdap injection
Pain
Northern arm
(N = 326)
Canterbury arm
(N = 467)
Total
(N = 793)
None 56 (17.2) 90 (19.3) 146 (18.4)
Mild, still able to move arm normally 163 (50.0) 184 (39.4) 347 (43.8)
Moderate, hurts to move or to touch 90 (27.6) 189 (40.5) 279 (35.2)
Severe, unable to move arm 17 (5.2) 4 (0.9) 21 (2.6)
Onset of pain (n = 270) (n = 377) (n = 647)
0–24 hours 201 (74.4) 342 (90.7) 543 (83.9)
25–48 hours 68 (25.2) 35 (9.3) 103 (15.9)
Page 9 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
10
Pain
Northern arm
(N = 326)
Canterbury arm
(N = 467)
Total
(N = 793)
49–72 hours 1 (0.4) - 1 (0.2)
Pain resolved by
0–24 hours 30 (11.1) 131 (34.7) 161 (25.1)
25–48 hours 86 (31.9) 141 (37.4) 227 (35.4)
>49 hours 154 (57.0) 99 (26.3) 253 (39.5)
Missing - 6 (1.6) 6 (0.9)
Swelling at the injection site was uncommon with 7.6% of participants reporting any swelling and three
participants (0.4%) reporting swelling greater than 5 centimetres. All cases of swelling had an onset within
48 hours with half unresolved after 48 hours (Table 3). The timing of onset of swelling reported was different
between the two study populations with 94% of the Southern population reporting the onset of swelling
within 24 hours compared with 48% of the Northern population. The time to resolution was the same in
both groups with 49% resolving within 48 hours (not shown).
Erythema was reported by 5.8% of participants with 0.4% reporting erythema of greater than 5 centimetres.
Onset was generally within 48 hours and resolution over 48 hours for half of these (Table 3). While there
were 37 reports of erythema for the Northern participants there were nine for the Southern participants.
Induration as an injection site reaction was collected in the Northern but not the Canterbury arm. Any
induration was reported by 12% of participants, in whom half took more than 48 hours to resolve. No
indurations events measured greater than 5 centimetres. (Table 3).
Table 3: Total number and percent (n/%) of participants reporting swelling, erythema or induration after Tdap
injection
Swelling
(N = 793)
Erythema
(N = 793)
Induration�
(N = 326)
None 733 (92.4) 747 (94.2) 287 (88.0)
Circumference of event (n = 60) (n = 46) (n = 39)
>0.0–<1.0 cm 33 (4.2) 25 (3.2) 21 (6.4)
>1.0–<2.5cm 12 (1.5) 10 (1.3) 12 (3.7)
>2.5–<5.0cm 12 (1.5) 8 (1.0) 6 (1.8)
>5.0–<10.0cm 2 (0.3) 3 (0.4) -
>10.0–<15.0cm 1 (0.1) - -
Onset of event after injection (n = 60) (n = 46) (n = 39)
0–24 hours 44 (73.3) 27 (58.7) 15 (38.5)
25–48 hours 16 (26.7) 16 (34.8) 22 (56.4)
>49 hours - 3 (6.5) 2 (5.1)
Resolution of event (n = 60) (n = 46) (n = 39)
0–24 hours 14 (23.3) 13 (28.3) 6 (15.4)
25–48 hours 15 (25.0) 10 (21.7) 11 (28.2)
Page 10 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
11
>49 hours 31 (51.7) 23 (50.0) 22 (56.4) �Northern study data only
Systemic events
Fever was reported by 17 (2.1%) participants, 14 of whom reported this occurring within 24 hours. Of those
reporting fever within 24 hours, 6 (35%) had been co-administered influenza vaccine (Table 4). There were
10 reports of fever in the Northern participants and seven reports in the Southern participants, and 6/10
Northern participants were co-administered influenza vaccine and 0/7 Southern participants.
Table 4: Numbers and percentage (n/%) of participants reporting fever and taking antipyretics or pain medication
following Tdap injection
Fever (N = 793)
No reported fever 776 (97.9)
Fever 17 (2.1)
Onset of fever (n = 17)
0–24 hours 14 (82.3)
25–48 hours 2 (11.8)
49–72 hours 1 (5.9)
Antipyretic or pain medication taken (N = 793)
No 762 (96.1)
Yes 31 (3.9)
Fever within 24 hrs and co-administered influenza vaccine (n = 17)
Yes 6 (43)
Other systemic events included headache and dizziness, nausea and vomiting, fatigue and myalgia or
arthralgia. All were uncommon and reported by fewer than 4% of participants with the exception of fatigue,
which was reported by 8.4% (Table 5). Thirty-two participants reported more than one of these outcomes
occurring together. Around one quarter to one third of those who reported a systemic event also received
the influenza vaccine at the same time (Table 5).
Table 5: Number and percentage of participants reporting systemic events following Tdap Injection
Systemic events
(N = 793) n (%)
Onset within 24 hrs
n (%)
Coadministered flu vaccine
n (%) of sample
experiencing event
n (%) of sample with
24-hour onset
Headache/Dizzy 31 (3.9) 27 (87) 13 (42) 11 (41)
Nausea/Vomiting 22 (2.8) 19 (86) 5 (23) 5 (26)
Fatigue 67 (8.4) 58 (86) 17 (25) 13 (22)
Myalgia/Arthralgia 24 (3.0) 21 (88) 6 (25) 6 (29)
AEs and SAEs
Page 11 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
12
During the study period there were 115 AEs and SAEs in 113 participants (two events each for two
participants) reported to CARM, in accordance with local guidelines. CARM reports submitted for events not
considered SAEs were mostly minor in nature and for a range of issues including a stiff neck on the same side
as the injection, itching, changes in baby movements and combinations of systemic events such as
headaches, nausea, fatigue and fever (see Tables 4 and 5). Additionally, 25 reports were for diagnosed non-
injection site infections (e.g., chest, urine and throat).
We have reported SAEs according to whether they occurred or were triggered during pregnancy; during
labour and delivery; or occurred in the infant after delivery.
Of the 31 events deemed to be serious (3.9%) there were 23 hospitalisations following immunisation that
occurred during pregnancy. Reasons for these were: obstetric bleeding (4), hypertension (2), infection (4),
tachycardia (1), preterm labour (9), exacerbation of pre-existing condition (2) and preeclampsia (1). All had
variable onset time from vaccination (Table 6).
Additionally, there were a total of eight SAEs that occurred during labour and delivery: six reported in the
Northern arm and two in the Canterbury arm (note different methodologies). Of these eight SAEs,
two were perinatal deaths, one of which was due to a congenital abnormality, the other unexplained. There
was one cyanotic episode and five cases where concern for fetal wellbeing resulted in health service
intervention (Table 7).
Table 6: SAEs reported among pregnant women following immunisation in 793 pregnant women vaccinated with
Tdap
Participant Event SAE definition Onset post
Tdap
Gestation at
time of event
(wks)
1 PV bleeding Required hospitalisation 11d 30w
2 Hypertension in pregnancy Required hospitalisation 27d 40+w
3 Pelvic pain, bacterial
vaginitis
Required hospitalisation 9d 34w
4 Cellulitis Required hospitalisation 6d 38w
5 Hypertension in pregnancy Required hospitalisation 11d 34w
6 Threatened labour and
Group A strep infection
Required hospitalisation 20d 31w
7 Bleeding Required hospitalisation 24d 36w
8 Maternal tachycardia Required hospitalisation 16d 34w
9 Gestational diabetes &
antenatal partum
Required hospitalisation 29d 34w
Page 12 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
13
haemorrhage
10 Preterm labour Required hospitalisation 1d 36w
11 Preterm labour Required hospitalisation 24d 36w
12 Preterm labour Required hospitalisation 7d 33w
13 Exacerbation of pre-
existing condition
Required hospitalisation 17d 36w
14 Exacerbation of pre-
existing condition
Required hospitalisation 7d 19w
15 Preeclampsia Required hospitalisation 8d 36w
16 Preterm labour Required hospitalisation 16d 36w
17 Preterm labour Required hospitalisation 19d 36w
18 Preterm labour Required hospitalisation 11d 33w
19 Preterm labour Required hospitalisation 19d 36w
20 Vaginal bleeding Required hospitalisation 21d 34w
21 Preterm labour Required hospitalisation 9d 34w
22 Preterm labour Required hospitalisation ~15d* 36w
23 Infection (coronavirus) Required hospitalisation 1d 34w
Note: d= days; w=weeks; *No delivery date was recorded for this participant.
Table 7: SAEs during labour in and among infants of 793 pregnant women vaccinated with Tdap
Participant Event SAE Definition Onset post
Tdap
Gestation at time
of event (wks)
24 Cyanotic episodes in infant Prolongation of existing
hospitalisation
31d 39w
25 Fetal death (trisomy 11q) Resulted in death 10d 36w
26 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
11d 38w
27 Non-reassuring fetal status Hospitalisation 23d 39w
28 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
37d 41w
29 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
18d 39w
30 Non-reassuring fetal status Admission to NICU and
CPAP
28d 37w
31 Perinatal death (stillbirth) Resulted in death 53d 40w
Clinician review and assessment of each of these cases found none were likely to be vaccine related.
DISCUSSION
Reduced-antigen-content tetanus–diphtheria–acellular pertussis (Tdap) vaccines have been shown to be
highly effective in pregnancy for reducing infant pertussis morbidity,3,4
and are being increasingly
recommended on national schedules, particularly during epidemics. While there have been no safety
concerns to date using these vaccines in pregnancy, data on safety in pregnancy are relatively limited. This
study intensively followed 793 women vaccinated in pregnancy with Tdap for solicited and unsolicited
outcomes. Our sample included pregnant women regardless of underlying conditions, including women with
Page 13 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
14
comorbidities. Injection site reactions were common, minor and self-limiting. Systemic reactions were
uncommon. Differences in pain reporting between the study groups is likely due to both demographic
differences and differences in data collection methods. As there was delay in interviewing the Southern
participants and no participant-held diary, minor events are possibly prone to recall bias. Previous NZ studies
have shown vaccine reactogenicity varies by ethnic group.20,21
SAEs occurred in our study population during
the study period. None were likely to have been caused by the exposure to Tdap vaccine.
As this is an observational study, with no direct comparator groups. The size of the study has limited power
to detect SAEs. Data collection methods and periods for each region were different and the Northern region
included a wider gestational age band. While our results add to the body of evidence of safety for pregnant
women the study population was not randomly selected. The women in our group were older (32 vs 29.2
years) and more likely to be of NZ European ethnicity (73.5% vs 49.5%) than the general NZ maternal
population. This is likely a reflection of the health seeking behaviour associated with these demographics.
While pregnancy complications increase with age, in contrast, NZ European ethnicity is associated with lower
risk pregnancies.22
In addition
The reactogenicity of acellular pertussis-containing vaccines in adults was reviewed in 2012.23
Data on the
reactogenicity of Tdap are derived from clinical trials and prospective studies; however, the results are not
presented in a standardised way that allows comparison. Generally participants record symptoms, both
solicited and unsolicited, on diary cards for 4–15 days after vaccination. Events are graded by subjects as 0–3
with 0 being not present and 3 defined as symptoms that prevent normal activity. Grade 3 fever is axillary
temperature greater than 39°C and grade 3 swelling or redness is variably described as >20mm, >30mm or
≥50mm in diameter. There is insufficient information in the study manuscripts to determine in more detail
how events are measured or classified. However severe local pain ranges from less than 1%–30% and severe
local redness or swelling (≥50mm) ranges from 2%–18%.24-30
Although most of these studies were published
after 2007 when definitions were published by the Brighton Collaboration none have provided information
about induration.
Page 14 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
15
A small US randomised trial including 33 pregnant women assessed the immunogenicity and safety of Tdap
during pregnancy. Safety outcomes were collected with a 7-day diary. How these were defined is not
described. Pain was reported by 25 (75.8%) participants while erythema and induration/swelling was each
reported by three (9.1%) participants. These were the same rates as reported by the non-pregnant women in
the study.31
The rates of injection site pain in our study are consistent with most other studies that report
less than 10% experiencing severe pain.16,25,26,28
Rates of swelling with a diameter of more than 50mm
ranged from 1% to 18% in clinical studies. In our study population just 0.4% recorded swelling of more than
50mm and fewer than 8% reported any. 16,24-28,30
Our outcomes are lower than these other reports;
however, this could be because we have differentiated between swelling and induration. Overall both events
were infrequent and mild. Erythema (redness) was relatively uncommon in our study with fewer than 6% of
participants reporting any and 1.4% reporting a diameter greater than 50mm. In clinical studies severe
erythema has been reported to range from 2% to 17%24-28,30
Our rates are consistent with those recently
reported in the US trial in pregnant women.31
It should be noted that the aluminium content of the NZ
Boostrix® formulation is higher than that of the US formulation, and higher aluminium content may be linked
to greater local reactogenicity.32
In the Northern arm of our study we collected information about swelling and induration according to
Brighton Collaboration definitions17,18
and are able to report induration separately from swelling. Induration
occurred more frequently than swelling and appeared to have a later temporal onset than swelling. More
than half of the cases of induration occurred 25–48 hours later compared with around a quarter of all
swelling, supporting the likelihood each have different aetiologies. It is likely that some of the swelling
reported in the Southern participants was in fact induration misclassified.
We found differences in the reporting of swelling and erythema between our groups. There were fewer
reports of erythema in the Southern group and while there were similar numbers of reports of swelling the
timing for onset may have been more imprecise. Given the differences in the reported pain onset and
resolution between the groups, it is likely that recall for details of minor local reactions became more prone
to recall bias as time progressed and in the absence of a diary to record the details.
Page 15 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
16
While in previous clinical studies headache has tended to be reported by around a third of
participants,24,25,27-30
fewer than 3.9% of our subjects reported either headache or feeling dizzy. Also, few of
our participants reported any gastrointestinal symptoms (2.8%). Almost all systemic events in our study
occurred in the 24 hours following immunisation as opposed to later and we consider them likely to be
vaccine related. Overall there were few systemic events reported and the rates of the most common
aconsistent with those reported in the US study with 33 participants.31
In our study, one third to one quarter
of those who reported systemic events had also received the influenza vaccine at the same time. Northern
participants reporting systemic events were consistently more likely to have received co-administered
influenza vaccine than Southern participants. Most of the reported fevers in our Northern participants also
occurred after co-administration with influenza vaccine. Some influenza vaccines are known to be more
pyrogenic than others so it is possible that influenza vaccine was the cause of these excess reports,
particularly as the fevers occurred within 24 hours after vaccination.21
The safety of co-administration of
influenza vaccine and Tdap in pregnancy has been assessed by the Vaccine Safety Datalink Project and no
excess medically attended events occurred among women receiving both vaccines together compared with
sequential vaccination.6 However, it cannot be assumed that these vaccines have the same reactogenicity
profiles.
SAEs occurred in our study population during the study period. None were considered by clinical review
likely to be caused by the exposure to Tdap vaccine. In NZ, up to 15% of pregnancies have obstetric
complications and approximately 1 per 10 infants are born preterm or low birth weight.33,34
Annually there
are approximately 600 perinatal deaths (~1% of births) of which 14% are unexplained. These figures have
remained consistent over time.22
Based on NZ data the rates of SAEs in our study were not higher than the
expected background rate for such a cohort. Reports to the US Vaccine Adverse Event Reporting System of
pregnant women inadvertently given Tdap have been summarised.35
Between January 2005 and June 2010
there were 132 reports identified, 20 following Boostrix® with no non-pregnancy SAEs reported. In the US
trial31
SAEs occurred in 7/33 pregnant women, without known risks to pregnancy at enrolment, followed to 4
months post-partum, none of these were non-pregnancy SAEs. The events occurred at variable time periods
Page 16 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
17
following immunisation and none were considered attributable to the vaccine. More recently, obstetric
events and birth outcomes for 123,494 women from two Californian Vaccine Safety Datalink sites were
evaluated; 26,229 women received Tdap with no increased risk for hypertensive disorders of pregnancy or
preterm or small for gestational age birth found. There was a small increased risk of chorioamnionitis
diagnosis.9 Further investigations have not found an association.
7,8 A matched cohort study from the UK in
20,074 pregnant women and matched historical unvaccinated control group found no evidence of any
increase for predefined pregnancy related AEs including stillbirth.10
These all support the safety of Tdap in
pregnancy.
In conclusion, we found a Tdap vaccination was well tolerated in pregnant women. Our findings are
consistent with data from studies involving non-pregnant women.23
There were no SAEs in this study that
were likely to have been caused by the vaccine. This is reassuring for pregnant women, vaccinators and
policy makers.
Section 1: What is already known on this subject
Tdap vaccines have a well-established safety profile in adults. Recent large data-linking
studies have evaluated obstetric and birth outcomes and found no concerning patterns.
This study intensively followed 793 pregnant women, recording solicited local injection
site reactions, systemic events and all events that occurred within 4 weeks of
vaccination.
Section 2: What this study adds
This is the largest number of pregnancy exposures to Tdap that have been actively
followed for safety outcomes. Injection site reactions were common, minor and self-
limiting and systemic reactions were uncommon. Our findings are consistent with the
data from studies involving non-pregnant women. Serious Adverse Events occurred in
our study population during the study period. None were likely to be caused by the
exposure to Tdap vaccine. Our study supports the safety of Tdap in pregnant women.
Page 17 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
18
ACKNOWLEDGEMENTS
We acknowledge the general practice and DHB antenatal clinic staff involved in the study, for their
assistance in referring eligible women to the study team. We also thank the pregnant women and mothers
who contributed to the study. Our colleagues Angela Chong, Trish Graham, Nicky Ellis , Barbara McArdle,
Tracey Poole and Jane Stephen assisted in various ways, such as recruiting general practices, database set-up
and data collection.
FUNDING
The Northern study was funded by GlaxoSmithKline Biologicals SA, the manufacturer of Boostrix® and
sponsored by Auckland UniServices Ltd. However they had no role in study design, conduct or data
interpretation. The Southern study was funded by the Canterbury District Health Board.
COMPETING INTERESTS
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and
declare: Financial support for the submitted work from GlaxoSmithKline. HPH has served on advisory panels
and/or DSMB for GlaxoSmithKline, Pfizer, CSL Biotherapies and Merck but does receive personal honorarium
or payment. She has also served on investigator led studies funded but not sponsored by GlaxoSmithKline,
CSL and sanofi pasteur.
CONTRIBUTORS
HPH and TW were responsible for the study concept and design, DW acquired the data for the Northern arm
of the study, PG acquired the data for the Canterbury arm of the study. JP managed and analysed the data
for this study, NT collected clinical data for the SAEs. All authors drafted the manuscript and critically revised
it for important intellectual content.
ETHICAL APPROVAL
Page 18 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
19
Ethics approval was obtained from the University of Auckland Human Participants Ethics Committee
(010656) and from the Upper South A Regional Ethics Committee (URA/12/EXP/021).
TRANSPARENCY
HPH (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent
account of the study being reported; that no important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered) have been explained.
DATA SHARING
No additional data available.
EXCLUSIVE LICENCE
HPH has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive
licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd
to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and
sublicences such use and exploit all subsidiary rights, as set out in our licence
Page 19 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
20
REFERENCES
1. Advisory Committee on Immunization Practices (ACIP). Summary Report February 23-24, 2011.
Atlanta, Georgia2011.
2. Temporary programme of pertussis (whooping cough) vaccination of pregnant women. Sept 28,
2012. Department of Health,, 2012.
3. Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis vaccination in
England: an observational study. The Lancet 2014;384:1521-8.
4. Dabrera G, Amirthalingam G, Andrews N, et al. A Case-Control Study to Estimate the Effectiveness of
Maternal Pertussis Vaccination in Protecting Newborn Infants in England and Wales, 2012–2013. Clinical
Infectious Diseases 2015;60:333-7.
5. Englund JA. Maternal immunization – Promises and concerns. Vaccine 2015;33:6372-3.
6. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Safety of Tetanus Toxoid, Reduced Diphtheria
Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. Obstetrics & Gynecology
2015;126:1069-74.
7. Morgan JL, Baggari SR, McIntire DD, Sheffield JS. Pregnancy Outcomes After Antepartum Tetanus,
Diphtheria, and Acellular Pertussis Vaccination. Obstetrics & Gynecology 2015;125:1433-8.
8. Datwani H, Moro PL, Harrington T, Broder KR. Chorioamnionitis following vaccination in the Vaccine
Adverse Event Reporting System. Vaccine 2015;33:3110-3.
9. Kharbanda EO, Vazquez-Benitez G, Lipkind HS, et al. Evaluation of the association of maternal
pertussis vaccination with obstetric events and birth outcomes. Jama 2014;312:1897-904.
10. Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational
study. BMJ 2014;349:g4219.
11. Moro PL, McNeil MM, Sukumaran L, Broder KR. The Centers for Disease Control and Prevention's
public health response to monitoring Tdap safety in pregnant women in the United States. Human vaccines
& immunotherapeutics 2015:1-8.
12. Ministry of Health. Processes for safe immunisation. In: Ministry of Health, ed. Immunisation
Handbook 2014. Wellington: Ministry of Health,; 2014:75.
13. International Conference on Harmonisation. Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting E2A. International Conference on Harmonisation,; 1994.
14. International Conference on Harmonisation. Post-Approval SAfety Data Management: Definitions
and Standards for Expedited Reporting E2D. International Conference on Harmonisation,; 2003.
15. Working Group on Vaccine Pharmacovigilance. Definition and Application of Terms for Vaccine
Pharmacovigilance. Geneva, Switzerland: World Health Organization,; 2012.
16. Gidudu J, Kohl KS, Halperin S, et al. A local reaction at or near injection site: case definition and
guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2008;26:6800-13.
17. Kohl KS, Walop W, Gidudu J, et al. Swelling at or near injection site: case definition and guidelines for
collection, analysis and presentation of immunization safety data. Vaccine 2007;25:5858-74.
18. Kohl KS, Walop W, Gidudu J, et al. Induration at or near injection site: case definition and guidelines
for collection, analysis, and presentation of immunization safety data. Vaccine 2007;25:5839-57.
19. Michael Marcy S, Kohl KS, Dagan R, et al. Fever as an adverse event following immunization: case
definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22:551-6.
Page 20 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
21
20. Petousis-Harris H, Jackson C, Stewart J, et al. Factors associated with reported pain on injection and
reactogenicity to an OMV meningococcal B vaccine in children and adolescents. Human vaccines &
immunotherapeutics 2015;11:1875-80.
21. Petousis-Harris H, Poole T, Turner N, Reynolds G. Febrile events including convulsions following the
administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and
children: the importance of routine active safety surveillance. Vaccine 2012;30:4945-52.
22. Perinatal and Maternal Mortality Review Committee. Eighth Annual Report of the Perinatal and
Maternal Mortality Review Committee. Reporting mortality 2012. Wellington2014.
23. McCormack PL. Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine,
adsorbed (boostrix ®): A review of its properties and use as a single-dose booster immunization. Drugs
2012;72:1765-91.
24. Abarca K, Valdivieso F, Potin M, Ibanez I, Vial P. [Immunogenicity and reactogenicity of a reduced
antigen content diphtheria, tetanus and acellular pertussis vaccine dTpa) in 10 to 11 years old children and in
adults]. Rev Med Chil 2002;130:502-10.
25. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid,
reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19-64 years of age.
Vaccine 2009;27:765-72.
26. Booy R, Van Der Meeren O, Ng S-P, Celzo F, Ramakrishnan G, Jacquet J-M. A decennial booster dose
of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (< i> Boostrix</i>™) is
immunogenic and well tolerated in adults. Vaccine 2010;29:45-50.
27. Chan S, Tan P, Han H, Bock H. Immunogenicity and reactogenicity of a reduced-antigen-content
diphtheria-tetanus-acellular pertussis vaccine as a single-dose booster in Singaporean adults. Singapore
medical journal 2006;47:286-90.
28. Mertsola J, Van Der Meeren O, He Q, et al. Decennial administration of a reduced antigen content
diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. Clinical infectious diseases
2010;51:656-62.
29. Turnbull FM, Heath TC, Jalaludin BB, Burgess MA, Ramalho AC. A randomized trial of two acellular
pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults. Vaccine
2000;19:628-36.
30. Van der Wielen M, Van Damme P, Joossens E, Francois G, Meurice F, Ramalho A. A randomised
controlled trial with a diphtheria–tetanus–acellular pertussis (dTpa) vaccine in adults. Vaccine 2000;18:2075-
82.
31. Munoz F, Bond N, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular
pertussis (tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA:
the journal of the American Medical Association 2014;311:1760.
32. Lindblad EB. Aluminium adjuvants--in retrospect and prospect. Vaccine 2004;22:3658-68.
33. Ministry of Health. New Zealand Maternity Clinical Indicators 2013. Wellington: Ministry of Health;
2015.
34. Ministry of Health. Hospital-based Maternity Events 2007. Wellington: Ministry of Health,; 2010.
35. Zheteyeva YA, Moro PL, Tepper NK, et al. Adverse event reports after tetanus toxoid, reduced
diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol 2012;207:59 e1-
7.
Page 21 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 1: Participant recruitment and data collection
195x276mm (300 x 300 DPI)
Page 22 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 2: Classification of maternal adverse events 127x109mm (300 x 300 DPI)
Page 23 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 3: Classification of labour, delivery and infant related adverse events 84x64mm (300 x 300 DPI)
Page 24 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 4 Participant flow 146x106mm (300 x 300 DPI)
Page 25 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross‐sectional studies
Section/Topic Item #
Recommendation Reported on page #
(a) Indicate the study’s design with a commonly used term in the title or the abstract 1 and 2 Title and abstract 1
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4
Objectives 3 State specific objectives, including any prespecified hypotheses 4
Methods
Study design 4 Present key elements of study design early in the paper 4 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow‐up, and data
collection
4 - 9
Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants 4 and 5
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
5 - 7
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
6 and 7
Bias 9 Describe any efforts to address potential sources of bias n/a Study size 10 Explain how the study size was arrived at 9 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
9
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9
(b) Describe any methods used to examine subgroups and interactions n/a
(c) Explain how missing data were addressed 9 (d) If applicable, describe analytical methods taking account of sampling strategy n/a
(e) Describe any sensitivity analyses n/a
Results
Page 26 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from
For peer review only
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow‐up, and analysed
10
(b) Give reasons for non‐participation at each stage 10(c) Consider use of a flow diagram Figure 4
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
Table 1
(b) Indicate number of participants with missing data for each variable of interest Tables 1, 2 Outcome data 15* Report numbers of outcome events or summary measures Tables 2-7 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder‐adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
n/a
(b) Report category boundaries when continuous variables were categorized 6, 7 and 9 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period n/a
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses n/a
Discussion
Key results 18 Summarise key results with reference to study objectives 15-16 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
18
Generalisability 21 Discuss the generalisability (external validity) of the study results 16
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
19
*Give information separately for cases and controls in case‐control studies and, if applicable, for exposed and unexposed groups in cohort and cross‐sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe‐statement.org.
Page 27 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from
For peer review only
Safety of Tdap vaccine in pregnant women— an observational study
Journal: BMJ Open
Manuscript ID bmjopen-2015-010911.R2
Article Type: Research
Date Submitted by the Author: 29-Feb-2016
Complete List of Authors: Petousis-Harris, Helen; The University of Auckland, School of Population Health Walls, Tony; University of Otago, Christchurch, Department of Paediatrics; Watson, Donna ; University of Auckland, School of Population Health Private Bag 92019 Auckland 1149 Auckland, NZ 1149 +64 9 373 7599 Paynter, Janine; University of Auckland, School of Population Health Graham, Patricia; NICU, Christchurch Womens Hospital
Turner, Nikki; University of Auckland, General Practice and Primary Health Care
<b>Primary Subject Heading</b>:
Infectious diseases
Secondary Subject Heading: Paediatrics
Keywords: whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on A
pril 30, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2015-010911 on 18 April 2016. D
ownloaded from
For peer review only
1
Safety of Tdap vaccine in pregnant women— an observational study
Helen Petousis-Harris1, Senior Lecturer Tony Walls
2, Senior Lecturer, Donna Watson
1, Project
Manager, Janine Paynter1, Research Fellow, Patricia Graham
3, Research Nurse, Nikki Turner
1 ,
Associate Professor
1Immunisation Advisory Centre, Department of General Practice and Primary Care, The University
of Auckland, Auckland, New Zealand
2Department of Paediatrics, University of Otago, Christchurch, New Zealand
3Canterbury District Health Board, Christchurch, New Zealand
Correspondence to:
Helen Petousis-Harris
Department of General Practice and Primary Health Care
School of Population Health, Faculty of Medical and Health Sciences
University of Auckland, Private Bag 92019
Telephone: +64 9 9232078, Fax: +64 9 3737030.
Keywords: Whooping cough, acellular pertussis vaccine, safety, vaccination, pregnancy
Word count: 3507
Page 1 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
2
ABSTRACT
Objectives: Actively recruit and intensively follow pregnant women receiving a dose of acellular pertussis
vaccine for 4 weeks after vaccination.
Design and settings: A prospective observational study conducted in two New Zealand regions.
Participants: Women in their 28th
–38th
week of pregnancy, recruited from primary care and antenatal clinics
at the time of Tdap administration. Telephone interviews were conducted at 48 hours and 4 weeks post
vaccination.
Main outcomes measures: Outcomes were injection site reactions, systemic symptoms and serious adverse
events (SAEs). Where available, data have been classified and reported according to Brighton Collaboration
definitions.
Results: 793 women participated with 27.9% receiving trivalent inactivated influenza vaccine concomitantly.
79% of participants reported mild or moderate pain and 2.6% severe pain. Any swelling was reported by
7.6%, induration by 12.0% (collected from one site only, n=326) and erythema 5.8% of participants. Fever
was reported by 17 (2.1%), for whom 14 occurred within 24 hours. Headache, dizziness, nausea, myalgia or
arthralgia were reported by <4% of participants respectively and fatigue by 8.4%. During the study period
there were 115 adverse events in 113 participants, most were minor. At the end of reporting 31 events were
classified as serious (e.g., obstetric bleeding, hypertension, infection, tachycardia, preterm labour,
exacerbation of pre-existing condition and preeclampsia). All had variable onset time from vaccination.
There were two perinatal deaths. Clinician assessment of all SAEs found none likely to be vaccine related.
Conclusion: Vaccination with Tdap in pregnant women was well tolerated with no SAE likely to be caused by
the vaccine.
Trial registration
WHO Universal Trial Number (UTN) (U1111-1148-0718). Australian New Zealand Clinical Trials Registry
(ACTRN12613001045707).
Page 2 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
3
STRENGTHS AND LIMITATIONS OF THIS STUDY
Strengths
• This is the largest number of pregnancy exposures to Tdap that have been actively followed up for
safety outcomes.
• Our study allows for close examination of common local and systemic vaccine reactions.
Limitations
• This is an observational study with no direct comparator groups.
• The study is not large enough to explore SAEs.
• The women in our group were older (32 years) than the general NZ maternal population (29.2 years)
and more likely to be of NZ European ethnicity (73.5% vs 49.5%). This is likely a reflection of the
health seeking behaviour associated with these demographics.
Page 3 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
4
INTRODUCTION
In 2011, the United States Advisory Committee on Immunization Practices (ACIP) recommended that
acellular pertussis-containing vaccine (Tdap) be given to any person, including pregnant women, likely to be
in contact with infants under the age of 12 months.1 In September 2012, the UK recommended providing
Tdap vaccine for pregnant women ideally between 28–38 weeks of pregnancy.2 Vaccine administration in
pregnancy not only offers maternal protection against pertussis, but also provides for maternal antibody to
be passed to the infant, which has been demonstrated to be protective in their first months of life.3,4
There
are no theoretical safety concerns with administering subunit vaccines in pregnancy and some vaccines, in
particular tetanus, have been used widely in pregnant women.5 In October 2012, in response to a pertussis
epidemic, the New Zealand (NZ) Ministry of Health began funding Tdap vaccine for all women from 28–38
weeks gestation.
While there are now several large studies published,6-10
at the time of this study, the USA ACIP committee
acknowledged that the safety of Tdap immunisation during pregnancy had not been systematically studied,
with the only data available coming from small studies, post-marketing surveillance, and the US Vaccine
Adverse Event Reporting System.1,11
Our aim was to intensively monitor the safety of Tdap vaccine in a larger group of pregnant women for a
period up to 4 weeks post vaccination.
METHODS
Study design, setting and participants
This was a prospective observational study conducted in two different geographical areas of NZ using the
same outcome measures and database. There was some difference in recruitment and data collection
methods. The Northern arm of the study was conducted primarily in Auckland and included other North
Island centres. Auckland is a culturally diverse metropolitan city of 1.42 million in the North Island. Women
being administered Tdap between 28–38 weeks gestation were identified by staff from 21 out of 24
Page 4 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
5
participating general practices and the maternity clinics of three district health boards (DHBs) and referrals
faxed to the study team from 30 January–30 June, 2014.
The other arm was conducted in Canterbury, a more ethnically homogenous South Island region of just over
half a million. Recruitment for this arm began earlier, from late September 2012--late June, 2014.
Participants aged 18-40 years and administered Tdap between 30–36 weeks gestation were identified via
claims submitted by general practices (within 1 week of vaccination) for reimbursement from the local DHB
for each vaccination service delivered.
In both study arms, consent to be contacted by members of the research team was sought at the time of
vaccination.
Inclusion criteria was compliance with routine antenatal care, including at least one ultrasound early in
pregnancy. Women who had given birth prior to being contacted by study team members were originally to
be excluded from both arms of the study; however, due to concern that this may lead to overlooked serious
adverse events (SAEs) (i.e, premature birth) early in the study, after the first exclusion subsequent women in
the Northern arm who had birthed prior to contact but met other inclusion criteria were included.
Vaccines
The pertussis-containing vaccine (Tdap) funded for pregnant women in NZ is Boostrix®. The Boostrix®
formulation used in NZ has 0.5mg aluminium as aluminium hydroxide and aluminium phosphate adjuvant
and the US formulation no more than 0.39mg aluminium as aluminium hydroxide.
Influenza (TIV) vaccine is given at the start of the winter season and funded for all pregnant women
regardless of gestational age. Where this time coincides with the gestation age for delivery of the Tdap
providers are encouraged to deliver both vaccines together.
Data collection and main outcomes
Page 5 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
6
Northern participants leaving the practice/clinic after their vaccination, were given a study envelope
containing an information sheet, consent form, clear plastic measuring tool (to measure any local reaction)
and a 3-day diary card to record any symptoms or events. At the first phone contact 48–72 hours post-
vaccine administration, verbal consent was obtained then an interview undertaken. The second phone
interview was conducted at 4 weeks post administration (see Figure 1).
Figure 1: Participant recruitment and data collection
For Canterbury participants, a research team member made phone contact with potential participants within
2 weeks of identification, obtained consent and conducted the first interview. A follow-up questionnaire was
mailed at 4 weeks post vaccination.
For both groups, consent to follow up with their Lead Maternity Carer (LMC) (either a midwife or
obstetrician) or General Practitioner was sought from all women who reported a SAE or any birth
complication. As per national protocols,12
any adverse events (AEs) were also reported to the Centre for
Adverse Reaction Monitoring (CARM), the official regulatory body in charge of receiving all AE reports in NZ.
An AE is any untoward medical occurrence temporally associated with administration of the vaccine and
does not include common injection site reactions. In NZ, AEFI (adverse events following immunisation)
reporting is encouraged if the event is serious or unexpected. Anonymised data for any SAEs were also
reported to the Marketing Authorisation Holder (the vaccine manufacturer) as part of global drug safety
surveillance.
To ensure consistency in our classifications of SAEs we used an algorithm based on the International
Conference on Harmonisation definitions for SAEs.13,14
We separated events occurring in the mother during
pregnancy (Figure 2) and those triggered by indications of non-reassuring fetal status (Figure 3).
Figure 2: Classification of maternal adverse events
Figure 3: Classification of labour, delivery and infant-related adverse events
Page 6 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
7
A SAE is defined as any untoward medical occurrence that: results in death; is life-threatening; requires
inpatient hospitalisation or causes prolongation of existing hospitalisation; results in persistent or significant
disability/incapacity; is a congenital anomaly/birth defect, or; requires intervention to prevent permanent
impairment or damage.
The term "life-threatening" used here refers to an event in which the patient was at risk of death at the time
of the event; it does not refer to an event, which hypothetically might have caused death if it were more
severe.15
All SAEs were followed up by a study clinician.
Solicited and unsolicited outcomes
The diary card (Northern arm) allowed recording of injection site reactions, fever and unsolicited events over
3 days (Day 0, 1 and 2). Response categories were consistent with Brighton Collaboration definitions and
guidelines for events following immunisation.16-19
The 48-hour post-vaccination telephone interview (Northern arm) asked about nausea, vomiting, diarrhoea,
headache, fatigue, and contact with health care services. Participants were also asked if they had any other
concerns after the vaccination. The telephone interview conducted by the Canterbury team, sought the
same information retrospectively for up to 7 days post vaccination.
The 4-week post-vaccination telephone interview (Northern arm) and mailed questionnaire (Canterbury
arm) asked if any events, including contact with health professionals, had occurred since the last interview.
Canterbury participants were phoned if their questionnaire was not returned.
Statistical analysis
The size of our sample was based on the number of births in the study regions (28,000 per annum),
estimated uptake of pertussis vaccine in pregnancy and the number of women available for follow up over
the study timeframe.
Page 7 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
8
As the two regions recruited and collected data in different ways we have not attempted to analyse any
differences.
Frequencies, percentages and cross tabulations for demographic and outcome variables were produced
using SAS Enterprise Guide version 6. Results are summarised as counts and percentages for each outcome.
Values within outcome variables (e.g., pain, redness, swelling and induration), are based on Brighton
Collaboration definitions of outcomes. Other outcomes such as fever, nausea, myalgia, are summarised as
presence or absence (i.e., yes or no). Missing values are reported in the tables where relevant.
RESULTS
Twenty-four general practices out of 34 invited (70.6%) and three invited DHB maternity clinics were
recruited to the Northern arm. Twenty-one of the practices recruited participants. Practices who declined
said they were too busy or had too few patients who met the required criteria. In the Canterbury arm, claim
forms for financial reimbursement of delivery of the vaccine for 1,212 women were received. Attempts to
contact women within 2 weeks of their claim form being received by the study team meant 710 women
were contacted by phone, of which 467 consented (65.8%). Participant flow is presented in Figure 4.
Figure 4: Participant flow
In total, there were 793 participants across both arms, predominantly of NZ European ethnicity (73.5%). The
mean age was 32, with 61.4% of participants aged between 25 and 35 years. Just over one quarter (27.9%)
were co-administered influenza vaccine. A range of pre-existing conditions were present among 18% of
participants, including pregnancy-related conditions (2.0%) including pre-eclampsia (PET), symphysis pubis
dysfunction, low lying placenta, shortening cervix and poor fetal growth. Participant demographics are
presented in Table 1.
Table 1: Demographic characteristics of participants
Ethnicity (N = 793) n (%)
NZ European 583 (73.5)
Māori (indigenous NZ) 55 (6.9)
Pacific Island 34 (4.3)
Asian 103 (13.0)
Page 8 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
9
Middle Eastern, Latin American or African 18 (2.3)
Age
<20 years 12 (1.5)
20–24 years 65 (8.2)
25–29 years 180 (22.7)
30–34 years 307 (38.7)
35–39 years 180 (22.7)
40 years or more 49 (6.6)
Coadministered flu vaccine
Yes 218 (27.5)
Medical history/pre-existing conditions
None noted 651 (82.1)
Asthma 24 (3.0)
Atopy 4 (0.5)
Cancer 2 (0.3)
Cardiovascular 12 (1.5)
Chronic Renal Disease 1 (0.1)
Chronic Respiratory Disease 1 (0.1)
Diabetes 29 (3.7)
Other 52 (6.6)
Pregnancy related conditions 16 (2.0)
Unanswered 1 (0.1)
Approximately one half of Northern participants were co-administered influenza vaccine and 13% of
Canterbury participants; this was due to the differences in timing for the influenza season with recruitment.
Injection site reactions
Pain was the most commonly reported reaction to the Tdap injection with 79.0% of participants overall
reporting mild or moderate pain in total. Severe pain was reported by 2.6%. Onset of pain occurred within
24 hours in 83.9% of participants. There were differences in the intensity, onset and resolution. Northern
study participants reported higher intensity pain, later onset and longer time until resolution (Table 2). The
proportion reporting no pain was similar for both groups.
Table 2: Number and percentage (n/%) of participants from respective study arms reporting pain after Tdap injection
Pain
Northern arm
(N = 326)
Canterbury arm
(N = 467)
Total
(N = 793)
None 56 (17.2) 90 (19.3) 146 (18.4)
Mild, still able to move arm normally 163 (50.0) 184 (39.4) 347 (43.8)
Moderate, hurts to move or to touch 90 (27.6) 189 (40.5) 279 (35.2)
Severe, unable to move arm 17 (5.2) 4 (0.9) 21 (2.6)
Onset of pain (n = 270) (n = 377) (n = 647)
0–24 hours 201 (74.4) 342 (90.7) 543 (83.9)
25–48 hours 68 (25.2) 35 (9.3) 103 (15.9)
Page 9 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
10
Pain
Northern arm
(N = 326)
Canterbury arm
(N = 467)
Total
(N = 793)
49–72 hours 1 (0.4) - 1 (0.2)
Pain resolved by
0–24 hours 30 (11.1) 131 (34.7) 161 (25.1)
25–48 hours 86 (31.9) 141 (37.4) 227 (35.4)
>49 hours 154 (57.0) 99 (26.3) 253 (39.5)
Missing - 6 (1.6) 6 (0.9)
Swelling at the injection site was uncommon with 7.6% of participants reporting any swelling and three
participants (0.4%) reporting swelling greater than 5 centimetres. All cases of swelling had an onset within
48 hours with half unresolved after 48 hours (Table 3). The timing of onset of swelling reported was different
between the two study populations with 94% of the Southern population reporting the onset of swelling
within 24 hours compared with 48% of the Northern population. The time to resolution was the same in
both groups with 49% resolving within 48 hours (not shown).
Erythema was reported by 5.8% of participants with 0.4% reporting erythema of greater than 5 centimetres.
Onset was generally within 48 hours and resolution over 48 hours for half of these (Table 3). While there
were 37 reports of erythema for the Northern participants there were nine for the Southern participants.
Induration as an injection site reaction was collected in the Northern but not the Canterbury arm. Any
induration was reported by 12% of participants, in whom half took more than 48 hours to resolve. No
indurations events measured greater than 5 centimetres. (Table 3).
Table 3: Total number and percent (n/%) of participants reporting swelling, erythema or induration after Tdap
injection
Swelling
(N = 793)
Erythema
(N = 793)
Induration�
(N = 326)
None 733 (92.4) 747 (94.2) 287 (88.0)
Circumference of event (n = 60) (n = 46) (n = 39)
>0.0–<1.0 cm 33 (4.2) 25 (3.2) 21 (6.4)
>1.0–<2.5cm 12 (1.5) 10 (1.3) 12 (3.7)
>2.5–<5.0cm 12 (1.5) 8 (1.0) 6 (1.8)
>5.0–<10.0cm 2 (0.3) 3 (0.4) -
>10.0–<15.0cm 1 (0.1) - -
Onset of event after injection (n = 60) (n = 46) (n = 39)
0–24 hours 44 (73.3) 27 (58.7) 15 (38.5)
25–48 hours 16 (26.7) 16 (34.8) 22 (56.4)
>49 hours - 3 (6.5) 2 (5.1)
Resolution of event (n = 60) (n = 46) (n = 39)
0–24 hours 14 (23.3) 13 (28.3) 6 (15.4)
25–48 hours 15 (25.0) 10 (21.7) 11 (28.2)
Page 10 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
11
>49 hours 31 (51.7) 23 (50.0) 22 (56.4) �Northern study data only
Systemic events
Fever was reported by 17 (2.1%) participants, 14 of whom reported this occurring within 24 hours. Of those
reporting fever within 24 hours, 6 (35%) had been co-administered influenza vaccine (Table 4). There were
10 reports of fever in the Northern participants and seven reports in the Southern participants, and 6/10
Northern participants were co-administered influenza vaccine and 0/7 Southern participants.
Table 4: Numbers and percentage (n/%) of participants reporting fever and taking antipyretics or pain medication
following Tdap injection
Fever (N = 793)
No reported fever 776 (97.9)
Fever 17 (2.1)
Onset of fever (n = 17)
0–24 hours 14 (82.3)
25–48 hours 2 (11.8)
49–72 hours 1 (5.9)
Antipyretic or pain medication taken (N = 793)
No 762 (96.1)
Yes 31 (3.9)
Fever within 24 hrs and co-administered influenza vaccine (n = 17)
Yes 6 (43)
Other systemic events included headache and dizziness, nausea and vomiting, fatigue and myalgia or
arthralgia. All were uncommon and reported by fewer than 4% of participants with the exception of fatigue,
which was reported by 8.4% (Table 5). Thirty-two participants reported more than one of these outcomes
occurring together. Around one quarter to one third of those who reported a systemic event also received
the influenza vaccine at the same time (Table 5).
Table 5: Number and percentage of participants reporting systemic events following Tdap Injection
Systemic events
(N = 793) n (%)
Onset within 24 hrs
n (%)
Coadministered flu vaccine
n (%) of sample
experiencing event
n (%) of sample with
24-hour onset
Headache/Dizzy 31 (3.9) 27 (87) 13 (42) 11 (41)
Nausea/Vomiting 22 (2.8) 19 (86) 5 (23) 5 (26)
Fatigue 67 (8.4) 58 (86) 17 (25) 13 (22)
Myalgia/Arthralgia 24 (3.0) 21 (88) 6 (25) 6 (29)
AEs and SAEs
Page 11 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
12
During the study period there were 115 AEs and SAEs in 113 participants (two events each for two
participants) reported to CARM, in accordance with local guidelines. CARM reports submitted for events not
considered SAEs were mostly minor in nature and for a range of issues including a stiff neck on the same side
as the injection, itching, changes in baby movements and combinations of systemic events such as
headaches, nausea, fatigue and fever (see Tables 4 and 5). Additionally, 25 reports were for diagnosed non-
injection site infections (e.g., chest, urine and throat).
We have reported SAEs according to whether they occurred or were triggered during pregnancy; during
labour and delivery; or occurred in the infant after delivery.
Of the 31 events deemed to be serious (3.9%) there were 23 hospitalisations following immunisation that
occurred during pregnancy. Reasons for these were: obstetric bleeding (4), hypertension (2), infection (4),
tachycardia (1), preterm labour (9), exacerbation of pre-existing condition (2) and preeclampsia (1). All had
variable onset time from vaccination (Table 6).
Additionally, there were a total of eight SAEs that occurred during labour and delivery: six reported in the
Northern arm and two in the Canterbury arm (note different methodologies). Of these eight SAEs,
two were perinatal deaths, one of which was due to a congenital abnormality, the other unexplained. There
was one cyanotic episode and five cases where concern for fetal wellbeing resulted in health service
intervention (Table 7).
Table 6: SAEs reported among pregnant women following immunisation in 793 pregnant women vaccinated with
Tdap
Participant Event SAE definition Onset post
Tdap
Gestation at
time of event
(wks)
1 PV bleeding Required hospitalisation 11d 30w
2 Hypertension in pregnancy Required hospitalisation 27d 40+w
3 Pelvic pain, bacterial
vaginitis
Required hospitalisation 9d 34w
4 Cellulitis Required hospitalisation 6d 38w
5 Hypertension in pregnancy Required hospitalisation 11d 34w
6 Threatened labour and
Group A strep infection
Required hospitalisation 20d 31w
7 Bleeding Required hospitalisation 24d 36w
8 Maternal tachycardia Required hospitalisation 16d 34w
9 Gestational diabetes &
antenatal partum
Required hospitalisation 29d 34w
Page 12 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
13
haemorrhage
10 Preterm labour Required hospitalisation 1d 36w
11 Preterm labour Required hospitalisation 24d 36w
12 Preterm labour Required hospitalisation 7d 33w
13 Exacerbation of pre-
existing condition
Required hospitalisation 17d 36w
14 Exacerbation of pre-
existing condition
Required hospitalisation 7d 19w
15 Preeclampsia Required hospitalisation 8d 36w
16 Preterm labour Required hospitalisation 16d 36w
17 Preterm labour Required hospitalisation 19d 36w
18 Preterm labour Required hospitalisation 11d 33w
19 Preterm labour Required hospitalisation 19d 36w
20 Vaginal bleeding Required hospitalisation 21d 34w
21 Preterm labour Required hospitalisation 9d 34w
22 Preterm labour Required hospitalisation ~15d* 36w
23 Infection (coronavirus) Required hospitalisation 1d 34w
Note: d= days; w=weeks; *No delivery date was recorded for this participant.
Table 7: SAEs during labour in and among infants of 793 pregnant women vaccinated with Tdap
Participant Event SAE Definition Onset post
Tdap
Gestation at time
of event (wks)
24 Cyanotic episodes in infant Prolongation of existing
hospitalisation
31d 39w
25 Fetal death (trisomy 11q) Resulted in death 10d 36w
26 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
11d 38w
27 Non-reassuring fetal status Hospitalisation 23d 39w
28 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
37d 41w
29 Non-reassuring fetal status Intervention to prevent
permanent damage or
death
18d 39w
30 Non-reassuring fetal status Admission to NICU and
CPAP
28d 37w
31 Perinatal death (stillbirth) Resulted in death 53d 40w
Clinician review and assessment of each of these cases found none were likely to be vaccine related.
DISCUSSION
Reduced-antigen-content tetanus–diphtheria–acellular pertussis (Tdap) vaccines have been shown to be
highly effective in pregnancy for reducing infant pertussis morbidity,3,4
and are being increasingly
recommended on national schedules, particularly during epidemics. While there have been no safety
concerns to date using these vaccines in pregnancy, data on safety in pregnancy are relatively limited. This
study intensively followed 793 women vaccinated in pregnancy with Tdap for solicited and unsolicited
outcomes. Our sample included pregnant women regardless of underlying conditions, including women with
Page 13 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
14
comorbidities. Injection site reactions were common, minor and self-limiting. Systemic reactions were
uncommon. Differences in pain reporting between the study groups is likely due to both demographic
differences and differences in data collection methods. As there was delay in interviewing the Southern
participants and no participant-held diary, minor events are possibly prone to recall bias. Previous NZ studies
have shown vaccine reactogenicity varies by ethnic group.20,21
SAEs occurred in our study population during
the study period. None were likely to have been caused by the exposure to Tdap vaccine.
As this is an observational study, with no direct comparator groups. The size of the study has limited power
to detect SAEs. Data collection methods and periods for each region were different and the Northern region
included a wider gestational age band. While our results add to the body of evidence of safety for pregnant
women the study population was not randomly selected. The women in our group were older (32 vs 29.2
years) and more likely to be of NZ European ethnicity (73.5% vs 49.5%) than the general NZ maternal
population. This is likely a reflection of the health seeking behaviour associated with these demographics.
While pregnancy complications increase with age, in contrast, NZ European ethnicity is associated with lower
risk pregnancies.22
The reactogenicity of acellular pertussis-containing vaccines in adults was reviewed in 2012.23
Data on the
reactogenicity of Tdap are derived from clinical trials and prospective studies; however, the results are not
presented in a standardised way that allows comparison. There is insufficient information in the study
manuscripts to determine in more detail how events are measured or classified. However severe local pain
ranges from less than 1%–30% and severe local redness or swelling (≥50mm) ranges from 2%–18%.24-30
Although most of these studies were published after 2007 when definitions were published by the Brighton
Collaboration none have provided information about induration.
A small US randomised trial including 33 pregnant women assessed the immunogenicity and safety of Tdap
during pregnancy. Safety outcomes were collected with a 7-day diary. How these were defined is not
described. Pain was reported by 25 (75.8%) participants while erythema and induration/swelling was each
reported by three (9.1%) participants. These were the same rates as reported by the non-pregnant women in
the study.31
The rates of injection site pain in our study are consistent with most other studies that report
Page 14 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
15
less than 10% experiencing severe pain.16,25,26,28
Rates of swelling with a diameter of more than 50mm
ranged from 1% to 18% in clinical studies. In our study population just 0.4% recorded swelling of more than
50mm and fewer than 8% reported any. 16,24-28,30
Our outcomes are lower than these other reports;
however, this could be because we have differentiated between swelling and induration. Overall both events
were infrequent and mild. Erythema (redness) was relatively uncommon in our study with fewer than 6% of
participants reporting any and 1.4% reporting a diameter greater than 50mm. In clinical studies severe
erythema has been reported to range from 2% to 17%24-28,30
Our rates are consistent with those recently
reported in the US trial in pregnant women.31
It should be noted that the aluminium content of the NZ
Boostrix® formulation is higher than that of the US formulation, and higher aluminium content may be linked
to greater local reactogenicity.32
In the Northern arm of our study we collected information about swelling and induration according to
Brighton Collaboration definitions17,18
and are able to report induration separately from swelling. Induration
occurred more frequently than swelling and appeared to have a later temporal onset than swelling. More
than half of the cases of induration occurred 25–48 hours later compared with around a quarter of all
swelling, supporting the likelihood each have different aetiologies. It is likely that some of the swelling
reported in the Southern participants was in fact induration misclassified.
We found differences in the reporting of swelling and erythema between our groups. There were fewer
reports of erythema in the Southern group and while there were similar numbers of reports of swelling the
timing for onset may have been more imprecise. Given the differences in the reported pain onset and
resolution between the groups, it is likely that recall for details of minor local reactions became more prone
to recall bias as time progressed and in the absence of a diary to record the details.
While in previous clinical studies headache has tended to be reported by around a third of
participants,24,25,27-30
fewer than 3.9% of our subjects reported either headache or feeling dizzy. Also, few of
our participants reported any gastrointestinal symptoms (2.8%). Almost all systemic events in our study
occurred in the 24 hours following immunisation as opposed to later and we consider them likely to be
vaccine related. Overall there were few systemic events reported and the rates of the most common
Page 15 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
16
aconsistent with those reported in the US study with 33 participants.31
In our study, one third to one quarter
of those who reported systemic events had also received the influenza vaccine at the same time. Northern
participants reporting systemic events were consistently more likely to have received co-administered
influenza vaccine than Southern participants. Most of the reported fevers in our Northern participants also
occurred after co-administration with influenza vaccine. Some influenza vaccines are known to be more
pyrogenic than others so it is possible that influenza vaccine was the cause of these excess reports,
particularly as the fevers occurred within 24 hours after vaccination.21
The safety of co-administration of
influenza vaccine and Tdap in pregnancy has been assessed by the Vaccine Safety Datalink Project and no
excess medically attended events occurred among women receiving both vaccines together compared with
sequential vaccination.6 However, it cannot be assumed that these vaccines have the same reactogenicity
profiles.
SAEs occurred in our study population during the study period. None were considered by clinical review
likely to be caused by the exposure to Tdap vaccine. In NZ, up to 15% of pregnancies have obstetric
complications and approximately 1 per 10 infants are born preterm or low birth weight.33,34
Annually there
are approximately 600 perinatal deaths (~1% of births) of which 14% are unexplained. These figures have
remained consistent over time.22
Based on NZ data the rates of SAEs in our study were not higher than the
expected background rate for such a cohort. Reports to the US Vaccine Adverse Event Reporting System of
pregnant women inadvertently given Tdap have been summarised.35
Between January 2005 and June 2010
there were 132 reports identified, 20 following Boostrix® with no non-pregnancy SAEs reported. In the US
trial31
SAEs occurred in 7/33 pregnant women, without known risks to pregnancy at enrolment, followed to 4
months post-partum, none of these were non-pregnancy SAEs. The events occurred at variable time periods
following immunisation and none were considered attributable to the vaccine. More recently, obstetric
events and birth outcomes for 123,494 women from two Californian Vaccine Safety Datalink sites were
evaluated; 26,229 women received Tdap with no increased risk for hypertensive disorders of pregnancy or
preterm or small for gestational age birth found. There was a small increased risk of chorioamnionitis
diagnosis.9 Further investigations have not found an association.
7,8 A matched cohort study from the UK in
Page 16 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
17
20,074 pregnant women and matched historical unvaccinated control group found no evidence of any
increase for predefined pregnancy related AEs including stillbirth.10
These all support the safety of Tdap in
pregnancy.
In conclusion, we found a Tdap vaccination was well tolerated in pregnant women. Our findings are
consistent with data from studies involving non-pregnant women.23
There were no SAEs in this study that
were likely to have been caused by the vaccine. This is reassuring for pregnant women, vaccinators and
policy makers.
Section 1: What is already known on this subject
Tdap vaccines have a well-established safety profile in adults. Recent large data-linking
studies have evaluated obstetric and birth outcomes and found no concerning patterns.
This study intensively followed 793 pregnant women, recording solicited local injection
site reactions, systemic events and all events that occurred within 4 weeks of
vaccination.
Section 2: What this study adds
This is the largest number of pregnancy exposures to Tdap that have been actively
followed for safety outcomes. Injection site reactions were common, minor and self-
limiting and systemic reactions were uncommon. Our findings are consistent with the
data from studies involving non-pregnant women. Serious Adverse Events occurred in
our study population during the study period. None were likely to be caused by the
exposure to Tdap vaccine. Our study supports the safety of Tdap in pregnant women.
Page 17 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
18
ACKNOWLEDGEMENTS
We acknowledge the general practice and DHB antenatal clinic staff involved in the study, for their
assistance in referring eligible women to the study team. We also thank the pregnant women and mothers
who contributed to the study. Our colleagues Angela Chong, Trish Graham, Nicky Ellis , Barbara McArdle,
Tracey Poole and Jane Stephen assisted in various ways, such as recruiting general practices, database set-up
and data collection.
FUNDING
The Northern study was funded by GlaxoSmithKline Biologicals SA, the manufacturer of Boostrix® and
sponsored by Auckland UniServices Ltd. However they had no role in study design, conduct or data
interpretation. The Southern study was funded by the Canterbury District Health Board.
COMPETING INTERESTS
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and
declare: Financial support for the submitted work from GlaxoSmithKline. HPH has served on advisory panels
and/or DSMB for GlaxoSmithKline, Pfizer, CSL Biotherapies and Merck but does receive personal honorarium
or payment. She has also served on investigator led studies funded but not sponsored by GlaxoSmithKline,
CSL and sanofi pasteur.
CONTRIBUTORS
HPH and TW were responsible for the study concept and design, DW acquired the data for the Northern arm
of the study, PG acquired the data for the Canterbury arm of the study. JP managed and analysed the data
for this study, NT collected clinical data for the SAEs. All authors drafted the manuscript and critically revised
it for important intellectual content.
ETHICAL APPROVAL
Page 18 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
19
Ethics approval was obtained from the University of Auckland Human Participants Ethics Committee
(010656) and from the Upper South A Regional Ethics Committee (URA/12/EXP/021).
TRANSPARENCY
HPH (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent
account of the study being reported; that no important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered) have been explained.
DATA SHARING
No additional data are available.
EXCLUSIVE LICENCE
HPH has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive
licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd
to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and
sublicences such use and exploit all subsidiary rights, as set out in our licence.
Page 19 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
20
REFERENCES
1. Advisory Committee on Immunization Practices (ACIP). Summary Report February 23-24, 2011.
Atlanta, Georgia2011.
2. Temporary programme of pertussis (whooping cough) vaccination of pregnant women. Sept 28,
2012. Department of Health,, 2012.
3. Amirthalingam G, Andrews N, Campbell H, et al. Effectiveness of maternal pertussis vaccination in
England: an observational study. The Lancet 2014;384:1521-8.
4. Dabrera G, Amirthalingam G, Andrews N, et al. A Case-Control Study to Estimate the Effectiveness of
Maternal Pertussis Vaccination in Protecting Newborn Infants in England and Wales, 2012–2013. Clinical
Infectious Diseases 2015;60:333-7.
5. Englund JA. Maternal immunization – Promises and concerns. Vaccine 2015;33:6372-3.
6. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Safety of Tetanus Toxoid, Reduced Diphtheria
Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. Obstetrics & Gynecology
2015;126:1069-74.
7. Morgan JL, Baggari SR, McIntire DD, Sheffield JS. Pregnancy Outcomes After Antepartum Tetanus,
Diphtheria, and Acellular Pertussis Vaccination. Obstetrics & Gynecology 2015;125:1433-8.
8. Datwani H, Moro PL, Harrington T, Broder KR. Chorioamnionitis following vaccination in the Vaccine
Adverse Event Reporting System. Vaccine 2015;33:3110-3.
9. Kharbanda EO, Vazquez-Benitez G, Lipkind HS, et al. Evaluation of the association of maternal
pertussis vaccination with obstetric events and birth outcomes. Jama 2014;312:1897-904.
10. Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational
study. BMJ 2014;349:g4219.
11. Moro PL, McNeil MM, Sukumaran L, Broder KR. The Centers for Disease Control and Prevention's
public health response to monitoring Tdap safety in pregnant women in the United States. Human vaccines
& immunotherapeutics 2015:1-8.
12. Ministry of Health. Processes for safe immunisation. In: Ministry of Health, ed. Immunisation
Handbook 2014. Wellington: Ministry of Health,; 2014:75.
13. International Conference on Harmonisation. Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting E2A. International Conference on Harmonisation,; 1994.
14. International Conference on Harmonisation. Post-Approval SAfety Data Management: Definitions
and Standards for Expedited Reporting E2D. International Conference on Harmonisation,; 2003.
15. Working Group on Vaccine Pharmacovigilance. Definition and Application of Terms for Vaccine
Pharmacovigilance. Geneva, Switzerland: World Health Organization,; 2012.
16. Gidudu J, Kohl KS, Halperin S, et al. A local reaction at or near injection site: case definition and
guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 2008;26:6800-13.
17. Kohl KS, Walop W, Gidudu J, et al. Swelling at or near injection site: case definition and guidelines for
collection, analysis and presentation of immunization safety data. Vaccine 2007;25:5858-74.
18. Kohl KS, Walop W, Gidudu J, et al. Induration at or near injection site: case definition and guidelines
for collection, analysis, and presentation of immunization safety data. Vaccine 2007;25:5839-57.
19. Michael Marcy S, Kohl KS, Dagan R, et al. Fever as an adverse event following immunization: case
definition and guidelines of data collection, analysis, and presentation. Vaccine 2004;22:551-6.
Page 20 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
21
20. Petousis-Harris H, Jackson C, Stewart J, et al. Factors associated with reported pain on injection and
reactogenicity to an OMV meningococcal B vaccine in children and adolescents. Human vaccines &
immunotherapeutics 2015;11:1875-80.
21. Petousis-Harris H, Poole T, Turner N, Reynolds G. Febrile events including convulsions following the
administration of four brands of 2010 and 2011 inactivated seasonal influenza vaccine in NZ infants and
children: the importance of routine active safety surveillance. Vaccine 2012;30:4945-52.
22. Perinatal and Maternal Mortality Review Committee. Eighth Annual Report of the Perinatal and
Maternal Mortality Review Committee. Reporting mortality 2012. Wellington2014.
23. McCormack PL. Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine,
adsorbed (boostrix ®): A review of its properties and use as a single-dose booster immunization. Drugs
2012;72:1765-91.
24. Abarca K, Valdivieso F, Potin M, Ibanez I, Vial P. [Immunogenicity and reactogenicity of a reduced
antigen content diphtheria, tetanus and acellular pertussis vaccine dTpa) in 10 to 11 years old children and in
adults]. Rev Med Chil 2002;130:502-10.
25. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid,
reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19-64 years of age.
Vaccine 2009;27:765-72.
26. Booy R, Van Der Meeren O, Ng S-P, Celzo F, Ramakrishnan G, Jacquet J-M. A decennial booster dose
of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (< i> Boostrix</i>™) is
immunogenic and well tolerated in adults. Vaccine 2010;29:45-50.
27. Chan S, Tan P, Han H, Bock H. Immunogenicity and reactogenicity of a reduced-antigen-content
diphtheria-tetanus-acellular pertussis vaccine as a single-dose booster in Singaporean adults. Singapore
medical journal 2006;47:286-90.
28. Mertsola J, Van Der Meeren O, He Q, et al. Decennial administration of a reduced antigen content
diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. Clinical infectious diseases
2010;51:656-62.
29. Turnbull FM, Heath TC, Jalaludin BB, Burgess MA, Ramalho AC. A randomized trial of two acellular
pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults. Vaccine
2000;19:628-36.
30. Van der Wielen M, Van Damme P, Joossens E, Francois G, Meurice F, Ramalho A. A randomised
controlled trial with a diphtheria–tetanus–acellular pertussis (dTpa) vaccine in adults. Vaccine 2000;18:2075-
82.
31. Munoz F, Bond N, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular
pertussis (tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA:
the journal of the American Medical Association 2014;311:1760.
32. Lindblad EB. Aluminium adjuvants--in retrospect and prospect. Vaccine 2004;22:3658-68.
33. Ministry of Health. New Zealand Maternity Clinical Indicators 2013. Wellington: Ministry of Health;
2015.
34. Ministry of Health. Hospital-based Maternity Events 2007. Wellington: Ministry of Health,; 2010.
35. Zheteyeva YA, Moro PL, Tepper NK, et al. Adverse event reports after tetanus toxoid, reduced
diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol 2012;207:59 e1-
7.
Page 21 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 1: Participant recruitment and data collection
195x276mm (300 x 300 DPI)
Page 22 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 2: Classification of maternal adverse events 127x109mm (300 x 300 DPI)
Page 23 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 3: Classification of labour, delivery and infant related adverse events 90x68mm (300 x 300 DPI)
Page 24 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
Figure 4 Participant flow 146x106mm (300 x 300 DPI)
Page 25 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010911 on 18 A
pril 2016. Dow
nloaded from
For peer review only
STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross‐sectional studies
Section/Topic Item #
Recommendation Reported on page #
(a) Indicate the study’s design with a commonly used term in the title or the abstract 1 and 2 Title and abstract 1
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4
Objectives 3 State specific objectives, including any prespecified hypotheses 4
Methods
Study design 4 Present key elements of study design early in the paper 4 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow‐up, and data
collection
4 - 9
Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants 4 and 5
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
5 - 7
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
6 and 7
Bias 9 Describe any efforts to address potential sources of bias n/a Study size 10 Explain how the study size was arrived at 9 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
9
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9
(b) Describe any methods used to examine subgroups and interactions n/a
(c) Explain how missing data were addressed 9 (d) If applicable, describe analytical methods taking account of sampling strategy n/a
(e) Describe any sensitivity analyses n/a
Results
Page 26 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from
For peer review only
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow‐up, and analysed
10
(b) Give reasons for non‐participation at each stage 10(c) Consider use of a flow diagram Figure 4
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
Table 1
(b) Indicate number of participants with missing data for each variable of interest Tables 1, 2 Outcome data 15* Report numbers of outcome events or summary measures Tables 2-7 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder‐adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
n/a
(b) Report category boundaries when continuous variables were categorized 6, 7 and 9 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period n/a
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses n/a
Discussion
Key results 18 Summarise key results with reference to study objectives 15-16 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
18
Generalisability 21 Discuss the generalisability (external validity) of the study results 16
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
19
*Give information separately for cases and controls in case‐control studies and, if applicable, for exposed and unexposed groups in cohort and cross‐sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe‐statement.org.
Page 27 of 27
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on April 30, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010911 on 18 April 2016. Downloaded from