A Dissertation on

DIAGNOSTIC PERFORMANCE AND DISCRIMINATIVE VALUE

OF SERUM FERRITIN IN PRETERM LABOUR AND PPROM

Dissertation submitted to

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

CHENNAI-600032

With partial fulfillment of the requirements for the award of

M.S.DEGREE IN

OBSTETRICS AND GYNECOLOGY

(BRANCH VI)

COIMBATORE MEDICAL COLLEGE, COIMBATORE

MAY 2020

UNIVERSITY REGISTER NUMBER : 221716306

DECLARATION

I Dr. SABARENAA THARINI.N solemnly declare that the

dissertation entitled “DIAGNOSTIC PERFORMANCE AND

DISCRIMINATIVE VALUE OF SERUM FERRITIN IN

PRETERM LABOUR AND PPROM” is a bonafide work done by

me at Coimbatore Medical College Hospital during the period of

January 2018 to December 2018 under the guidance & supervision of

Dr.R.MANONMANI M.D., DGO., Professor & Head of

Department, Department of Obstetrics and Gynecology, Coimbatore

Medical College & Hospital. The dissertation is submitted to Dr.MGR

Medical University towards partial fulfillment of requirements for the

award of MS degree branch VI Obstetrics and Gynecology.

Place: Coimbatore Dr. SABARENAA THARINI. N

Date:

CERTIFICATE

This is to certify that the dissertation entitled “DIAGNOSTIC

PERFORMANCE AND DISCRIMINATIVE VALUE OF

SERUM FERRITIN IN PRETERM LABOUR AND PPROM” is

a bonafide original work done by Dr. SABARENAA THARINI. N

Postgraduate student in the Department of Obstetrics and Gynecology,

Coimbatore Medical College Hospital, Coimbatore under the

guidance of Dr.R.MANONMANI M.D., DGO., Professor & Head of

Department, Department of Obstetrics and Gynecology, Coimbatore

Medical College Hospital, Coimbatore in partial fulfillment of the

regulations for the Tamilnadu DR.M.G.R Medical University,

Chennai towards the award of MS., degree (Branch VI.) in Obstetrics

and Gynecology.

Date : Prof.Dr.R.MANONMANI M.D DGO.,

Guide and HOD

Department of Obstetrics and Gynecology

Date : Dr.B.Asokan, M.S., Mch.,

The Dean

Coimbatore Medical College & Hospital

Coimbatore

COPYRIGHT

Declaration by the Candidate

I hereby declare that The Tamilnadu DR.M.G.R Medical University,

Chennai shall have the rights to preserve, use and disseminate this

dissertation/thesis in print or electronic format for academic/research

purposes.

Place: Coimbatore Dr. SABARENAA THARINI. N

Date:

ACKNOWLEDGEMENT

I solicit my humble thanks to the Dean Dr.B.ASOKAN, M.S.,

Mch., Coimbatore Medical College Hospital, for allowing me to conduct

the study in this hospital.

I am also immensely thankful to my guide Prof.

Dr.R.MANONMANI M.D., DGO., Professor & Head of Department,

Department of Obstetrics and Gynecology, for her invaluable guidance,

motivation and help throughout the study.

I express my earnest gratitude to all the Associate and Assistant

Professors, Department of Obstetrics and Gynecology, without their help

and guidance this work would not have been possible.

I owe a lot to my parents, my spouse Dr. M. Deepan Chakravarthy

and other family members who have always been my pillar of support in

all stages of my life.

My sincere thanks to my fellow post graduates who have been of

immense help throughout the study period.

I am very grateful to all patients for their cooperation and participation in

the study.

ABBREVIATION

PTB - Preterm Labour

PPROM - Preterm Premature Rupture of Membranes

NICU - Neonatal Intensive Care Unit

17P - 17 Alpha Hydroxyprogesterone Caproate

AN OP - Antenatal outpatient department

IUD - IntraUterine death

GDM - Gestational Diabetes Melitus

PIH - Pregnancy Induced Hypertension

Hb - Hemoglobin

WHO - World Health Organization

SGA - Small for Gestational Age

CRP - C-Reactive Protein

IL 6,2 - InterLeukin

TNF - Tumour Necrosis Factor

RR - Relative Risk

BMI - Body Mass Index

fFN - Fetal Fibronectin

TVS - Trans Vaginal Sonography

CDC - Center of Disease Control

C/I - Contra Indication

ADR - Adverse Drug Reaction

GBS - Group B Streptococcal Infection

LIST OF FIGURES

S.No Figures Page

1 Features of preterm child 8

2 Outcome of preterm birth 10

3 Phenotypic components of preterm birth syndrome 13

4 Risk factors of preterm birth 14

5 Pathogenesis of infection leading to PTB 16

6 Mechanism of preterm birth 18

7 Cervical Malformations 21

8 Comparison of normal and short cervix 26

9 Fetal fibronectin 27

10 Fetal fibronectin levels throughout pregnancy 29

11 Intrauterine infection 30

12 Structure of ferritin 31

13 Amniotic fluid sludge 35

14 Secondary prevention of PTB 37

15 Cervical cerclage procedure 38

16 Cervical pessary 40

LIST OF TABLES

S.No Tables Page

1 Subcategories of preterm birth, based on gestational age

1

2 Progesterone formulation and dose for the prevention of PTB

42

3 CDC recommendations for clindamycin treatment of bacterial vaginosis in pregnancy

43

4 Pharmaceutical agents for tocolysis 45

5 Antenatal steroids for fetal lung maturation 47

6 Magnesium sulphate for neuroprotection 48

7 Antibiotic therapy in PPROM 51

8 Mean Age 53

9 Age distribution 53

10 Parity distribution 55

11 Distribution of Multi gravida among study group 56

12 Parity distribution among different age groups 57

13 Socio economic status 58

14 Distribution of multigravida in study group based on previous delivery

59

15 Distribution of PPROM 60

16 Association of Hemoglobin with parity 61

17 Association of Serum Ferritin with parity 62

18 Association of Gestational age with Hemoglobin 63

19 Association of Gestational age with serum ferritin 64

20 Association of Hemoglobin with PPROM 65

21 Association of Serum Ferritin with PPROM 66

22 Association of Hemoglobin with Socio economic status

67

23 Association of Serum Ferritin with Socio economic status

68

24 Association of Gestational age of present delivery with previous delivery

69

25 Association of multigravida in study group with Gestational age at present delivery

70

26 Association of multigravida in study group with previous delivery

71

TABLE OF CONTENTS

S.No Contents Page

1 Introduction 1

2 Aim and Objective of the study 4

3 Materials and methods 5

4 Review of literature 7

5 Observations and Results 53

6 Discussion 72

7 Limitations 76

8 Conclusion 77

9 Bibliography

10 Annexures

A – Proforma B – Master chart C – Consent form

ABSTRACT

TITLE

DIAGNOSTIC PERFORMANCE AND DISCRIMINATIVE VALUE

OF SERUM FERRITIN IN PRETERM LABOUR AND PPROM

BACKGROUND AND OBJECTIVES

Preterm labour is defined as regular uterine contractions leading

to cervical changes before 37 completed weeks of gestation. PTB

should be distinguished from ‘prematurity’ which constitutes the

deficiency of various system development at the time of birth. Preterm

birth is responsible for 30-40% of neonatal mortality worldwide.

Almost 1 million children die each year due to complications of

preterm birth. Survivors are left with lifetime disabilities such as

learning and hearing disabilities. Identifying pregnant women at risk

of preterm delivery will enable them an early access to tertiary care

centres for the management of infections and respiratory distress. An

action plan to avoid preventable newborn death includes World wide

access to newborn resuscitation, low cost corticosteroids, Kangaroo

mother care in place of incubator. Preterm premature rupture of

membranes (PPROM) is defined as amniorrhexis before the onset of

preterm labour.It is the leading cause of preterm birth. Rupture of

membranes is caused due to activation of enzymes such as

collagenase and other mechanical factors. But PPROM and preterm

labor appears to be linked to pathologic processes such as

inflammation and infection of membranes. Many biomarkers are in

study to predict preterm labour. Serum ferritin is one such marker . It

is an intracellular protein that is involved in iron storage. It is also an

acute phase reactant which gets elevated in acute and chronic

infections. This study is directed in finding the relationship between

serum ferritin and preterm labour

METHODOLOGY

This is a prospective study conducted in the Department of

Obstetrics and Gynecology, Coimbatore Medical College Hospital,

Coimbatore during the period of January 2018 to December 2018.

This study includes100 antenatal mothers who attended Antenatal OP

between 20 to 24 weeks of gestation.

After getting approval from ethical committee, patients were

selected according to inclusion and exclusion criteria. Study was done

after explaining the details and getting written consent from the

patients. Informed written consent is obtained from them. Pregnant

women with Hb levels >10 gm% are enrolled in this study.

Data regarding patient age, parity, height, weight, period of

gestation are obtained.

Maternal serum samples are obtained and sent for serum ferritin

estimation.

Pregnant women are followed till delivery and ferritin levels of

women who deliver preterm are compared with ferritin levels of

pregnant women delivered at term.

After attaining serum ferritin from all the patients , ferritin of patients

with preterm labour and term delivery were compared. By using mean

and standard deviation data were compared using ‘independent t test’.

Other data were analysed using chi square test. P value of <0.01 was

accepted as statistically significant.

RESULTS

In this study the mean values of serum ferritin taken at

Coimbatore Medical College Hospital in PPROM , preterm labour and

term labour were 44.4, 43.21, 21.96 and respectively. The standard

deviation of serum ferritin in PPROM, preterm labour and term labour

are 14.31, 15.23 and 9.12 respectively. There is significant statistical

increase in serum ferritin in the PPROM and preterm group when

compared with term delivery (P < 0.05). The high values of ferritin

levels in preterm labour and PPROM cases could be due to infections

associated with them. In this study most women with preterm delivery

in past pregnancy had preterm delivery in this current pregnancy also.

About 58.3% who had previous preterm delivery had preterm delivery

in this delivery. All these data indicate that preterm delivery is

multifactorial and influenced by number of factors. Anemia during the

second trimester is shown to be positively linked with preterm labour

although anemia later in pregnancy has a negative association. Hence

in our study to overcome this variable women with anemia

(hemoglobin < 10.5gm/dl) were not included.

CONCLUSION

Our Study found significant difference in serum ferritin levels

between preterm labour, PPROM and normal pregnant women with

same gestational age, possibly because that subclinical infection is

associated with preterm delivery. Elevated ferritin concentration

associated with spontaneous delivery more than 43ng/ml in second

trimester as cut off point could be derived from this study. Thus from

the present study serum ferritin can be used as marker in predicting

the pregnant women at risk for preterm delivery and thus help

obstetricians to identify pregnant women at risk and advice them for a

higher centre neonatal care . The results of this study can be used for

promoting further studies of ferritin in relationship with pregnancy

complication.

1

INTRODUCTION

Preterm labour is defined as regular uterine contractions leading to

cervical changes before 37 completed weeks of gestation 6.

Table No 1. Subcategories of preterm birth, based on gestational age

PTB should be distinguished from ‘prematurity’ which constitutes

the deficiency of various system development at the time of birth.

Preterm birth is responsible for 30-40% of neonatal mortality worldwide

7. Almost 1 million children die each year due to complications of

preterm birth. Survivors are left with lifetime disabilities such as learning

and hearing disabilities. Identifying pregnant women at risk of preterm

delivery will enable them an early access to tertiary care centres for the

management of infections and respiratory distress.

Low- income countries lack the resources required for prevention and

treatment of preterm labour. Babies born preterm may die of respiratory

distress due to surfactant unavailability or lack of infrastructure to transport

rapidly to a tertiary care facility.

2

An action plan to avoid preventable newborn death includes

1. World wide access to newborn resuscitation

2. Low cost corticosteroids

3. Kangaroo mother care in place of incubator

Preterm premature rupture of membranes (PPROM) is defined as

amniorrhexis before the onset of preterm labour. It the leading cause of

preterm birth. Rupture of membranes is caused due to activation of

enzymes such as collagenase and other mechanical factors. But PPROM

and preterm labor appears to be linked to pathologic processes such as

inflammation and infection of membranes.

Administration of antenatal corticosteroids remains an important

intervention to improve neonatal outcome in women presenting with

preterm labour. Tocolytic agents administration provide time for the

administration of antenatal steroids or transfer to a facility with NICU.

Very low birth weight neonates whose mothers were given magnesium

sulphate for preterm labour or preeclampsia were found to have reduced

incidence of cerebral palsy at 3 years.

Interventions such as vaginal progesterone , intramuscular 17

alpha-hydroxyprogesterone caproate (17P) and use of cervical cerclage

are used to reduce the rate of preterm delivery.

3

Many biomarkers are in study to predict preterm labour2. Serum

ferritin is one such marker . It is an intracellular protein that is involved in

iron storage. It is also an acute phase reactant which gets elevated in acute

and chronic infections.

This study is directed in finding the relationship between serum

ferritin and preterm labour.

4

AIM OF STUDY

1. To study the role of maternal serum ferritin in predicting preterm

labour

2. To estimate the optimal cut off point of ferritin in identifying

between preterm labour and term birth.

5

MATERIALS AND METHODS

This study was conducted in the Department of Obstetrics and

Gynecology, Coimbatore medical college hospital, Coimbatore during the

period of January 2018 to December 2018.

Type of study

Prospective study

Study population

This study includes 100 antenatal mothers who attended Antenatal

OP between 20 to 24 weeks of gestation.

Inclusion criteria

Age 18-40

Singleton pregnancy

Conceived spontaneously

Healthy pregnant women attending AN OP between 20 and 24 weeks

of gestation.

Exclusion criteria

Age >40 yrs

Multiple pregnancy

Pregnant women with signs of infection –fever, pain, vaginal

discharge

Antenatal woman with any chronic systemic disease pertaining to

cardiovascular, urogenital, oncological, endocrinological systems

Pregnant mother with any complications of pregnancy like

IUD,GDM,PIH.

6

After getting approval from ethical committee ,patients were selected

according to inclusion and exclusion criteria listed above. Study was

done after explaining the details and getting written consent from the

patients.

Methodology

● Pregnant women meeting the inclusion and exclusion criteria are

enrolled in this study.

● Informed written consent is obtained from them.

● Pregnant women with Hb levels >10 gm% are enrolled in this

study.

● Data regarding patient age,parity, height,weight, period of

gestation are obtained.

● Maternal serum samples are obtained and sent for serum ferritin

estimation.

● Pregnant women are followed till delivery and ferritin levels of women

who deliver preterm are compared with ferritin levels of pregnant women

delivered at term.

After attaining serum ferritin from all the patients , ferritin of patients

with preterm labour and term delivery were compared. By using mean and

standard deviation ,data were compared using ‘independent t test’. Other data

were analysed using chi square test. P value of <0.01 was accepted as

statistically significant.

7

REVIEW OF LITERATURE

In a study by Abdel-Malek K et al , serum ferritin appears to be

raised in preterm labor and a cut off point of 31ng/ml between preterm

labor and term labor.

In another study by Hazem F. El-Shahawy et al, there was a

statistical significance in ferritin levels between term and preterm labor

patients. This study concluded that serum ferritin can be used as a marker

for preterm labour.

In another study by Sanoop Adathila Valappil there is significant

increase in serum ferritin in PPROM cases as compared to the control

group. But no significant increase in spontaneous preterm labour cases as

compared to the control group.

Definition of Preterm

Preterm procured its source from Latin as prae (before) and terma

(limit) from Greek 10% of the babies born around the world are preterm.

After Pneumonia, preterm is the major cause of neonatal mortality and

death less than 5 years of age. The short and long term morbidity due to

preterm are wide. The World Health Organisation (WHO) defines

preterm as birth before 37 completed weeks of gestation or less than 259

days from the 1st day of last menstrual period .1

8

Fig No 1. Features of preterm child

Incidence and Prevalence

WHO calculated the incidence of PTB as 9.6% which accounts for

13 million annually in 2005. In 2010 the rate of PTB raised to 11.1%

accounting for 14.9 million 1. The major proportion of PTB is distributed

among Asia and Africa which contributed to 60 to 85% of all PTB.

The major reason for PTB in developing countries is mainly linked

to higher number of deliveries, infection, poor maternal conditions, lack

9

of availability of tocolytic drugs, heavy physical activity, lack of basic

neonatal and obstetric care.1

Data across Europe for the last 10 years shows that PTB rate before

32 weeks of gestation is unchanged at 1 - 2%. The rise in PTB rate

globally can be associated with increased age pregnant women, increased

multiple pregnancy rate and assisted reproductive techniques, increase in

iatrogenic preterm delivery and changes in registration 1. Cutting edge

technologies and combined efforts of obstetricians and neonatologists

has reduced PTB and its complication respectively in the last decade.

Short-term outcomes

Preterm Birth is a disruption of fetal maturation process and thus

the preterm child experiences the extra uterine surroundings before its

organs are fully formed. They are exposed to complications such as brain,

GIT, lungs and circulatory systems immaturity 15.

Complications such as apnoea, necrotizing enterocolitis,

hypoglycemia, respiratory distress, feeding difficulties, poor temperature

regulation and bacterial infections are encountered by preterm babies

compared with term babies 16. The risks of neonatal complications,

morbidity and mortality increase with lower gestational age.

10

Long-term outcomes

There exists an exponential relationship between immaturity and

neonatal mortality. Preterm babies have long term disabilities with low

gestational age at birth. They are risk of cerebral palsy, vision and hearing

defects, impaired mental function, asthma, epilepsy, behavioural and

psychological disorders and learning disabilities 4. Children born

extremely premature are at risk of early development of COPD. When the

become adults they have lower educational levels 14, fewer children,

lower income and are less often married. Most babies born preterm are

healthy and have a normal level of function. Data from EPICure study

indicates that PTB children have serious risk of disability throughout their

upcoming years 13.

Fig No 2. Outcome of preterm birth

11

Classification

PTB is classified into following categories based on gestational age,

clinical presentation and birth weight.

Based On Gestation Age 5

Extremely preterm: < 28 weeks

Very preterm: 28 - 31+6 weeks

The majority of PTBs occur between 32-36 weeks.

Subdivided as moderate preterm - 32 to 33+6 weeks

Late preterm (or near term) 34-36+6 weeks

Mild preterm accounts for the great majority of all PTBs

Based on Clinical Presentation

According to its clinical presentation 1

Medically indicated PTB (iatrogenic or elective)

Spontaneous preterm birth

Medically indicated PTB (iatrogenic or elective)

Major reasons are

antepartum haemorrhage

pregnancy-induced hypertension or preeclampsia

intrauterine growth restriction

12

non reassuring tests of foetal well-being

small for gestational age - SGA

obstetric care has become more interventional and aggressive in recent

times which has mainly led to iatrogenic PTB 2.

Spontaneous PTB

Spontaneous PTBs are referred as preterm birth which occur after

both prelabour rupture of the membranes (PPROM) and without rupture

(with membranes intact).

PPROM is defined as spontaneous rupture of the membranes prior

to 37 weeks with at least 1 hour before the start of regular uterine

contractions.

Based on birth weight

Birth weight is subdivided into

1. Very low birth weight (<1500g, VlBW)

2. Low birth weight (<2500g, lBW)

3. Extremely low birth weight (<1000g, elBW).

Preterm babies may be SGA - small for gestational age - less than 10th

percentile.

A Prototype Phenotypic classification

The phenotypic subdivision includes situations which are present in the

index pregnancy only, but no risk factors and mode of delivery6. These

information are collected meticulously from clinical records. It is found

13

that - because of overlapping of clinical conditions and presentation there

exist more than one phenotype for any particular case 2,3.

This phenotypic classification helps us to understand the various causes

and enhance the surveillance globally by accepting other relevant

conditions to be included in the classification and doesn’t categorize a

specific case to a preformed phenotype2.

Fig No 3. Phenotypic components of preterm birth syndrome

14

Risk factors

Fig No 4. Risk factors of preterm birth

The accurate predictor of PTB is difficult and combination of

history of previous pregnancy events and maternal and fetal risk factors

has to be involved in determining the cause of Preterm. The exact

mechanism by which the risk factors are associated with PTB is unknown

but defining these risk factors is significant in finding the high risk

pregnant woman for initiation of prevention and interventional research

regarding mechanism leading to PTB.

PTB is a multi-factorial situation. Various risk factors have been

found. They are not sufficient enough to constitute bigger pool of PTBs.

15

Risk factors can be categorised into

1) Chronic stresses which includes maternal demographic risk factors

like race, socio-economic status, marital status, age and maternal

behavior (nutrition, smoking, etc.)

2) Acute stress like infection and immune dysregulation 17

3) Underlying genetic factors

Chronic Stress

Chronic stress is also a risk factor for PTB. Numerous chronically

stressful situations have been proposed as a cause of PTB such as

domestic violence, working conditions, low socioeconomic status and

depression. Various researches have proved that pregnant women with

features of depression and anxiousness have higher incidence of PTB.

Women who work for longer hours standing and night duties are found to

have chronic stress 17 and are linked to have higher rates of PTB.

Duration and intensity of physical exertion by the pregnant mother affects

pregnancy but it is difficult to quantify. Since it cannot be quantified, it

cannot be used to predict the risk of PTB.

16

Infection

Infection is closely related to PTB. The increasing trend of

chorioamnionitis with decreasing gestational age and increase in the rate

of infection found by examination of placenta from preterm birth have

proved this theory.

Fig No 5. Pathogenesis of infection leading to PTB

17

Bacterial vaginosis

Bacterial vaginosis is a frequently occurring lower genital tract

infection in pregnancy and linked with PTB. Studies have proved

bacterial vaginosis as an independent risk factor for PTB. However

predictive value of it is limited.

Antibiotic intervention using clindamycin for the treatment of

bacterial vaginosis during early pregnancy has shown some benefit in the

prevention of preterm Births. In some studies usage of antibiotics such as

Metronidazole in bacterial vaginosis has been found to be of less benefit

and have also been related to PTB 24.

Amsel’s criteria for diagnosis of bacterial vaginosis

Diagnosis requires 3 or 4 findings

1. Homogeneous, white, non-inflammatory discharge that smoothly

coats vaginal wall

2. Presence of clue cells on microscopic examination

3. pH of vaginal fluid more than 4.5

4. Fishy odour of vaginal discharge after the addition of 10% KOH

Asymptomatic bacteriuria

Another important infection leading to PTB is asymptomatic

bacteriuria which can lead to pyelonephritis. The incidence of

asymptomatic bacteriuria is 2 - 10% which accounts for less amount and

thus it cannot be used as an independent predictor of PTB. But treatment

of asymptomatic bacteriuria has reduced the incidence of PTB.

18

Periodontal disease

A final infectious process that has gained significant attention for its

relation with PTB is periodontal disease 25. Periodontal disease is a

marker that a pregnant woman is in a highly inflammatory state and may

have increased risk of PTB. But the treatment periodontal disease has

shown no major decrease in PTB26.

Fig No 6. Mechanism of preterm birth

19

Inflammation

Inflammation is a systematic pathway which includes many risk factors in

the causation of PTB. The two major types of inflammation that have

been associated with PTB are

systemic inflammation - measured in maternal serum

localized inflammation - measured in amniotic fluid or

cervicovaginal secretions

There is a huge array of markers for testing inflammation in maternal

serum, amninotic fluid and cervical secretion but only some has shown

constant association with PTB and they cannot be taken with a high

predictive value.

The most common inflammatory markers used for detection of PTB are

CRP

IL-6

Serum ferritin

IL-2, 8, 10

TNF-alpha

alkaline phosphatase

20

Genetic Risk

Genetic factors have also been associated with PTB in 25 - 40%.

These genetic risk factors are mainly of maternal origin. Pregnant

women who had PTB previously and have change in partner are still at

increased risk (RR = 5). But men have no increased risk for subsequent

offspring.

Maternal relative with a history of PTB has also been found to

increase the risk of having a PTB (RR = 1.5)18. This maternal genetic

factor is further enlightened in studies of monozygotic twins who show

similarities in pregnancy duration than monozygotic twins 19.

Cervical Malformations

Cervical abnormalities both congenital and iatrogenic such as

arcuate uterus, unification defects, canalization defects and cervical

insufficiency have been found to be associated with PTB. These women

have twice the risk of PTB than women with normal uterus 20.

Pathophysiology - Partially dilated or short cervix fails in retaining

intrauterine contents and allows bacteria to ascend up, where they act

through toll - like receptors and stimulate activation of prostaglandins,

cytokines and initiate an inflammatory response 21.

21

Fig No 7. Cervical Malformations

Women who have done uterine procedures such as cone excision,

Fothergills repair also have twice the risk of PTBs 20.

Multiple Pregnancies

Multiple Pregnancies have increased risk of PTB with increasing

number of fetuses 27.

Assisted reproductive therapy (ART) increase the rate of multiple

pregnancy which have contributed to PTB pool.

Multiple pregnancies which occur naturally cannot be prevented

but which occur due to ART leading to PTB can be reduced.

22

Weight, Diabetes and Metabolic Syndrome

Lifestyle factors such as Body Mass Index (BMI) influence the rate

of PTB. Previous studies have shown that pregnant women who are

underweight (BMI < 18.5) have increased risk of PTB (RR = 1.21) 28.

Women on the other end of the spectrum with higher BMI (BMI > 25 to

30, 30 - 35) have reduced rates of PTB indicating a protective role. On

the other hand, mothers with very high BMI of more than 35, 40 have

higher risk ratios (RR = 1.33 & 2.27 respectively) 29. Women with very

high BMI have increased PTB especially at 32 - 36 weeks. Meta analysis

shows BMI has increased risk for both spontaneous and induced PTBs.

Metabolic diseases such as diabetes mellitus usually occur concurrent

with high BMI and women with preexisting diabetes also have a high risk

for both spontaneous and induced PTB.

Socio Demographic Risk Factors

This includes factors such as

Maternal age

Marital status

Race/Ethnicity

Maternal Education

23

Maternal Age

It is one of obstetric risk factors associated with PTB. The average

age of first born child has been considerably increased and this increase is

most commonly seen in women around 35 - 39 years. Compared to

mothers between 20 - 35 years adolescent mothers and mothers more than

35 years have shown a greater risk for PTB. Teenage and older mothers

are reported to have a higher degree of low birth weight babies, still birth,

preterm birth and fetal death and hence they require more chances of

infant admission to NICU.

Marital Status

Unmarried mothers have lack of social emotional support and

hence they receive less antenatal care, poor nutrition and they have more

complications during pregnancy that lead to preterm delivery and low

birth weight.

Race/Ethnicity

The rate of PTB in black mothers is high but it has reduced over

time. Even after correcting the physiological and social risk factors racial

differences exist.

Maternal Education

Lower levels of education in pregnant mother is associated with

higher risk of preterm delivery. But some studies have shown no

relationship between maternal education and PTB.

24

Smoking

Among the behavioral risk factors smoking shows a consistent

association with PTB. There exists as a dose response relationship

between PTB and smoking. Increased smoking leads to increased risk31.

Thus smoking reduction programs have been introduced as a behavioural

intervention for the reduction of PTB. But smoking cannot be used as a

predictive tool for preterm Birth. Smoking 10 - 20 cigarettes per day has a

RR = 1.5 - 2. Researchers found that women who quit smoking before 15

weeks of gestation have equally comparable rates of PTB and SGA

compared to non smokers emphasizing that smoking is modifiable risk

factor31.

Idiopathic causes

Only 50% of PTBs have a known cause 17. Thus preventing them

with targeted therapies is difficult except in conditions like smoking and

infection 30. Hence preventive measures must be undertaken in a broad

spectrum.

Predicting PTB

A very important tool for prediction of PTB is previous obstetric

history. Mothers with previous history of one preterm birth have 14 -

20% risk of preterm in next pregnancy and with 2 PTBs have 28 - 42%

risk and those with 3 PTBs previously have 67% risk of preterm births.

25

Further multiple pregnancy complicate this scenario. Research have

contributed that prevalence of PTB in the first pregnancy is 10% and in

the second pregnancy is 9.6%. The positive predictive value (PPV) is

23%. In case of spontaneous PTBs the prevalence in first pregnancy is

8.3% and in second pregnancy is 7.8%. The PTB is 20.7%.

Cervical Length

An important predictor of PTB is the length of cervix measured

during pregnancy. Cervical length and strength contribute to retaining the

pregnancy. The most acceptable time to measure cervical length is

between 18 - 22 weeks. Measuring during early weeks and after 32 weeks

has less predictive value as cervical length decreases in later weeks. It is

best measured transvaginally as transabdominal measurements are not

replicable. Cervical length measured at the appropriate time using the

right procedure is predictive in both high risk and low risk women.

Average cervical length is 35mm. Length above 35mm is considered

normal and no further evaluation is needed. Women with cervical length

below 20mm have an increased risk of preterm birth 34.

26

Cervical factors scoring

Cervical length < 25 mm in TVS

Cervical score < 1.5 in digital cervical examination

Cervical score = cervical length in cm - cervical dilatation in cm at the

internal OS

Fig No 8. Comparison of normal and short cervix

Significance of cervical length (Limitations and advantages) 33

1. Best predictive accuracy

2. Different population show variation

3. Women with twin, triplet pregnancy

The earlier the short cervix the greater the risk of preterm birth.

27

Fetal Fibronectin

Fig No 9. Fetal fibronectin

Fetal Fibronectin (fFN) is a placental glycoprotein which is a

component of extracellular matrix of chorio decidual junction, mainly

produced by the trophoblast. fFN acts like a glue at the maternal - fetal

interface and mediates implantation and chorio decidual attachment

throughout pregnancy. fFN is normally present in cervico vaginal

secretion before 20 weeks gestation because of incomplete fusion

between decidua and fetal membranes. Hence the appropriate timing for

testing fFN is after 22 weeks, after the fusion of membranes.

28

fFN measured in the cervico vaginal fluid is a predictor for PTB. The

disruption of maternal - fetal interface by mechanical (uterine activity) or

localized inflammation may lead to release of fFN. It has become invalid

if the cervix is dilated, when there is bleeding per vaginum, recent sexual

intercourse (< 24 hours), ruptured membranes, recent cervical

examination (digital or ultrasound). Lubricants, creams, disinfectants and

soaps may give a false negative result. fFN concentration more than

50ng/mL is considered positive. Though it is an indicator of PTB, it has

low sensitivity in low risk population.

The American College of Obstetricians and Gynecologist (ACOG)

recommends testing fFN only in symptomatic women with high risk

pregnancy with following criteria; intact membranes, sampling between

24 - 34 weeks, minimum cervical dilatation (< 3cm).

The European association of perinatal medicine encourages testing

fFN as a routine assessment of PTB and recommends to withhold

tocolysis and prophylactic steroids when fFN is negative and cervical

length by TVS is more than 2.5 cm 10.

29

Fig No 10. Foetal fibronectin levels throughout pregnancy

Maternal Inflammatory response - Evaluation of biomarkers in

maternal serum

Pregnancy is a unique immunological state in which maternal

immune system changes to promote fetal allograft tolerance. The balance

between suppression and immune tolerance is strictly regulated by

cytokines in harmony with progesterone. Switch in the Th1:Th2 cytokine

ratio towards Th2 predominates in pregnancy. The aberrant Th1:Th2

profile is related to adverse pregnancy outcome such as miscarriage,

preterm labour, pre-eclampsia and fetal brain injury. Mainly activation of

Th1 rather than suppression of Th2 seems to be more in PTB.

30

Human labour is an inflammatory process characterized by an

influx of inflammatory cells in gestational tissues and increased

production of chemokines and cytokines. This inturn causes synthesis of

prostaglandins which stimulates uterine contractions and increases

expression of matrix metalloproteinases (MMP) leading to rupture of

membranes and cervical ripening. Although this mechanism is seen both

in term and preterm labour, preterm labour is characterized by

asynchronous inflammatory activation.

Intrauterine Infection (IUI)

Fig No 11. Intrauterine infection

31

Evidence suggests that most intrauterine infection are chronic and

subclinical and thus they are difficult to diagnose before labour or

membrane rupture. A diagnostic marker for identifying these subclinical

infection would be useful in PTB detection. Measurement of a single

biomarker lacks efficiency in predicting in PTB because of the complex

nature of PTB and the various pathway leading to PTB. Measurement of

inflammatory markers in mid trimester and detection of microbial

invasion of the amniotic cavity can predict PTB 4.

The various biomarkers involved in detection of PTB are described

below

Serum Ferritin

Fig No 12. Structure of ferritin

32

Ferritin is an acute phase reactant released by leukocytes in

response to infection. It has a role in iron homeostasis by binding and

sequestering intra cellular iron. It has a spherical cell with a central cavity

in which upto 4500 atoms of iron are oxidized and stored. Ferritin is a

multimer with 24H (heavy) and L (light) sub units in variable proportion

in different tissues, only the H subunit has feroxidize activity 45,47.

Action of ferritin as an acute phase reactant is of high importance

for protection against microbial proliferation, oxidative damage and

inflammation. The serum ferritin differs from intracellular protein that it

is glycated and contains little or no iron46. Serum ferritin has less heavy

chains and tissue ferritin has more heavy chains. It is the primary

intracellular storage of iron in both prokaryotes and eukaryotes and is a

diagnostic marker in a variety of acute phase reactions and inflammatory

condition in high serum levels. Extracellular ferritin has important role in

defence against bacteria by stimulating oxidative metabolism.

Phosphorylated insulin like growth factor binding protein 1

(PHIGFBP-1)

Insulin like growth factor produced by the liver and is involved in

fetal growth and development. It is a major protein of human decidua.

The phosphorylation status of IGFBP-1 differs in different sides and the

non phosphorylated isoform predominates in amniotic fluid. The highly

33

phosphorylated isoform is found in cervical secretion in first and early

second trimester (rarely after 23 - 37 weeks), during cervical ripening and

onset of labour, as it is secreted by the decidua.

Hence prediction of PTB by rapid bedside test for the detection of

PHIGFBP-1 in cervical secretion after 23 weeks can be advised.

Concentration of 30mcg/litre is required for a positive result.

Placental Alpha Macro Globulin-1 (PAMG-1) and Insulin like

growth factor binding protein-1 (IGFBP-1)

Very high concentration of IGFBP-1 and PAMG-1 are found in

amniotic fluid compared to blood and cervico vaginal secretions 11.

Detection of IGFBP-1 and PAMG-1 are indicative of PROM in few

studies. But the negative predictive value of PAMG-1 is 93.9% and

IGFBP-1 is 89.5% with accuracy of both being 95 and 93% respectively.

Rapid strip test are accurate than any single clinical method but the

accuracy is similar when compared with combined clinical approach

which includes vaginal pooling, nitrazine test and fenning pattern and the

test is also expensive. So these tests are useful in women with doubtful

diagnosis of PROM.

34

Amniotic Fluid Sludge

These are aggregates of particulate matter present in amniotic fluid

in close proximity to internal os. It indicates impending PTB, PPROM

and microbial invasion of the amniotic cavity. It is also present in

histologic chorioamnionitis in patients with spontaneous PTB and intact

membranes. Bacteria can form a microbial biofilm in case of intra-

amniotic infection in the form of sludge 4. Biofilms are embedded in a

hydrated matrix of extracellular polymeric substances and they are

implicated in 80% of chronic infections. These bacteria in biofilms are

resistant to antimicrobials and difficult to isolate in culture.

Prevalence of sludge in term normal pregnancy is 1% whereas in

patients with spontaneous PTB and intact membranes is 22%. In the

setting of short cervix this debris seems to be a marker of PTB but there

is no evidence that the management of short cervix should be altered in

the presence of debris.

35

Fig No 13. Amniotic fluid sludge

Prevention of Preterm Birth

The strategies involved in delaying PTB reduce the mortality and

morbidity of preterm. These interventions can be primary, secondary or

tertiary. Single intervention may not be effective in all cases of preterm

labour.

Primary Prevention

This is directed to all women before or during pregnancy to prevent

PTB. They focus on overall health and includes nutritional

supplementation, screening of low risk women, smoking cessation,

improved access to prenatal care, weight optimisation and avoidance of

late PTB due to elective cesarean section by doing cesarean section after

36

39 weeks. More than 50% of PTB does not have obvious risk factors and

many risk factors are difficult to modify (example: previous placenta

previa, previous PTB), few risk factors respond to targeted intervention

like smoking cessation, change in working conditions and BMI.

Nutritional supplementation role is controversial but nutritional and

lifestyle adjustments in pre pregnancy period is essential to ensure BMI

within normal range. Smoking cessation reduces PTB by 15% 30.

Increased awareness of PTB regarding the potential avoidable risk factors

and government or medical policies to limit the number of embryos

transferred may reduce the rate of PTB.

Secondary Prevention

These are directed against pregnant women who are under risk of

preterm labour either because of history of previous preterm delivery or

the present pregnancy has risk factors. They include interventions to

reduce,stop or reverse the progress of preterm labour.

37

Fig No 14. Secondary prevention of PTB

Secondary prevention includes

1. Cervical Cerclage

2. Cervical pessary

3. Antenatal Progesterone

4. Antibiotic treatment of infections

38

Cervical cerclage

Fig No 15. Cervical cerclage procedure

Cervical cerclage is a surgical procedure which involves placing

suture around cervix to give mechanical support to the cervix and

prevents its opening. The indications of cerclage are (a)history -indicated

cerclage: with previous history of PTB. It is offered between 12 and 14

weeks gestation in women with a history suggestive of cervical

insufficiency (b) ultrasound indicated cerclage: a short cervix

demonstrated in TVS before 24 weeks. It is performed at 14 - 24 weeks

(c) physical examination-indicated cerclage : in emergency situations

when pregnant women present with more than 1cm cervical dilation and

39

membranes have prolapsed. (d) Emergency cerclage: Indicated in women

who present with cervical dilation with <4 cm with bulging membranes.

Rupture of membranes, dilatation > 4 cm and evidence of infection are

contraindication to this procedure. Reduction in PTB after cerclage was

mainly observed in women with previous history of PTB or second

trimester losses and in women with short cervix 43.

Techniques for cervical cerclage

1. Transvaginal cerclage

a. McDonald suture

b. Shirodkar procedure

2. Transabdominal cerclage

McDonalds procedure is the procedure of choice for cerclage. It is

done under spinal or general anesthesia. Shirodkar procedure is indicated

in women with previous failed McDonalds suture. A mersilene tape is

used which is passed around the cervix using a specially designed

Shirodkar needle

Cervical cerclage carries risks to pregnancy such that ,it causes

myometrial contractions, infection or bleeding which inturn may lead to

preterm labour. Hence the benefits should be carefully explained along

with the risks. Studies show that there is no role for cerclage in multiple

pregnancy 44.

40

Cervical pessary

Fig No 16. Cervical pessary

Cervical pessaries such as Arabin pessary have been used from the

past as an effective intervention for the prevention of PTB. most

commonly used is the arabin pessary . It is a flexible ring-like silicon

device present in different sizes. Smaller diameter of pessary is fitted

around the cervix and larger diameter faces the pelvic floor. This causes

rotation of cervix towards posterior vaginal wall ,thus correcting the

cervical angle. It is an out-patient procedure which is operator-

independent and cost effective. This procedure does not require

anesthesia and can be removed when necessary. It is not routinely used.

41

Antenatal progesterone

Mechanism of progesterone in preventing preterm labour is by

reducing gap junction formation, maintaining cervical integrity, oxytocin

antagonism and anti-inflammation. Role of progesterone in multiple

pregnancies is less clear. Role of progesterone in threatened preterm

labour is also less. Progesterone administration is beneficial in women

with previous history of PTB and vaginal progesterone has shown to

reduce the risk of PTB in women with short cervix36.

Women with a history of spontaneous PTB can be given

intramuscular 17P weekly. After 17P is started ,it should not be

discontinued as it increases the risk of recurrent preterm delivery.

Cervical length is evaluated by TVS every two weeks from 16 - 24

weeks in women with a history of PTB 32. If cervical length is less than

25mm at < 24 weeks cervical cerclage is offered. In women without a

history of PTB but with short cervix should receive vaginal progesterone

from the period of diagnosis till 36 weeks. Studies have shown this

decreased the incidence of PTB and neonatal morbidity and mortality

with this intervention 35.

42

Table No 2. Progesterone formulation and dose for the prevention of

PTB

Indication Progestogen Dosing

Prior PTB 17 alpha -

hydroxyprogesterone

caproate

250mg IM weekly

from 16 - 36 weeks

No prior PTB, cervical

length < 25mm at <24

weeks

Vaginal progesterone

gel 90mg

Vaginal progesterone

capsule 200 mg

Daily from diagnosis

of short cervix till 36

weeks

The OPPTIMUM study - dOes Progesterone Prophylaxis To

prevent preterm labour IMprove oUtcoMe - is a randomized trial vaginal

progesterone 200mg daily from 22 - 24 to 34 weeks of gestation. Primary

outcome of this study was to assess the immediate obstetrical and

childhood outcomes. The results were that vaginal progesterone was not

associated with lower risk of preterm birth or composite neonatal adverse

outcomes 37,38,39.

Management of Infection

Routine screening and treatment of bacterial vaginosis to reduce

PTB does not significantly reduce the risk of PTB. Possible reasons for

antibiotic failure are

43

Antibiotic might not effectively treat or prevent chorioamnionitis

Host factors such as diet, smoking might influence the risk of PTB

irrespective of antibiotics

Treatment protocol differs in many aspects such as methods of

diagnosing, timing, dosing and choice of antibiotic.

However, some studies have shown that administration of clindamycin to

women (<22 weeks) reduce the rate of PTB compared to placebo 24.

Table No 3. CDC recommendations for clindamycin treatment of

bacterial vaginosis in pregnancy

Treatment Dosage

Clindamycin cream 2% 1 full applicator (5g) intravaginally at

bed time - 7 days

Alternative Regimens

Clindamycin 300mg Orally twice daily - 7 days

Clindamycin ovules 100mg Intravaginally once at bedtime - 3 days

Routine screening of asymptomatic bacteriuria with urine culture is

recommended at 12 - 16 weeks gestation which will identify 80% of

women with infection. Currently the gold standard for diagnosis is

quantitative culture of mid stream or clean catch urine. Criteria for

44

diagnosis of asymptomatic bacteriuria is 2 (or more) consecutive clean

catch urine samples both giving positive cultures of the same bacterial

strain in quantitative counts of at least 105 colony forming units (cfu) per

ml. Escherichia coli is the most common causative organism identified

other than gram negative bacteria and group B streptococci. Various

antibiotics are available for the treatment of asymptomatic bacteriuria in

pregnancy and the treatment should depend upon antimicrobial

susceptibility testing. Periodontal disease is associated with PTB but

antenatal treatment does not affect the pregnancy outcome.

Tertiary Prevention

Most interventions are aimed at tertiary prevention - prevention

after symptoms develops. It includes antenatal transfer, regionalized

perinatal care, tocolytic agents, antenatal administration of

corticosteroids.

Tocolysis

Tocolytic drugs are used for short term prolongation of pregnancy

(upto 48 hours) with the goal of allowing time for administration of

antenatal steroids, magnesium sulphate for neuroprotection, antibiotics

for group B streptococcal infection and maternal transfer if needed. After

cessation of labour there is evidence of long term tocolysis benefits for

the prolongation of the pregnancy. Wide variety of tocolytic agents have

been used for suppressing uterine contraction - beta agonists, oxytocin

45

receptor antagonists, calcium channel blockers, prostaglandin synthetase

inhibitor and magnesium sulphate. The ideal tocolytic agent must be

inexpensive, easy to administer, without maternal, fetal or neonatal side

effects and effective in delaying PTB long enough for the administration

of antenatal steroids 40,41.

Table No 4. Pharmaceutical agents for tocolysis

Drug (class) Dose Comments Contra indication and

adverse effects

Nifedipine

(calcium channel

blocker)

30mg oral loading

dose, 10 - 20mg

every 4-6 hours

Decreased

incidence of

neonatal

respiratory

distress syndrome,

necrotising

enterocolitis,

intraventricular

hemorrhage,

jaundice

C/I - maternal

hypotension

ADR - flushing,

dizziness, headache,

transient hypotension.

No fetal adverse

effects

Terbutaline (beta

mimetic)

0.25mg

subcutaneously

every 20min -

upto 3 doses

Neonatal

outcomes are

variable and

maternal adverse

effects are

common

C/I - heart disease,

thyrotoxicosis, purely

controlled diabetes

ADR - Cardiac

arrhythmia,

pulmonary edema,

hypotension,

46

tachycardia,

hyperglycemia,

hyperinsulinemia,

hypokalemia,

hallucination, tremor.

Fetal and neonatal

ADR - tachycardia,

hyperglycemia,

hypocalcemia,

intraventricular

haemorrhage.

Indomethacin

(NSAID)

50mg rectally/50 -

100mg orally -

loading dose

25 - 50 mg orally

every 4 hours - for

48 hours -

maintenance dose

Efficacy appears

similar to other

agents. Other

NSAIDs -

ketorolac,

sulindac may also

be used

C/I - Renal or hepatic

impairment, active

peptic ulcer disease,

oligohydramnios

Maternal ADR -

heartburn, nausea

Fetal ADR -

Constriction of ductus

arteriosus, pulmonary

hypertension,

intraventricular

haemorrhage,

hyperbilirubinemia,

necrotizing

enterocolitis.

47

Antenatal Administration of corticosteroids

Trials confirmed that treatment with steroids reduces the risk of

respiratory distress syndrome (RDS), intraventricular hemorrhage,

necrotizing enterocolitis, early sepsis, need for respiratory support, NICU

admission and neonatal death. Antenatal steroids enhances the benefit of

postnatal surfactant and reduces the need for blood pressure support.

They are administered routinely to accelerate fetal lung maturation in

pregnant women at risk of PTB 48,49.

Table No 5. Antenatal steroids for fetal lung maturation

Corticosteroid Dose

Betamethasone Two Doses - 12mg IM given 24 hours apart

Dexamethasone 4 doses - 6mg IM given every 6 hours

In general both betamethasone and dexamethasone shows similar results

in terms of respiratory distress and perinatal mortality. But 1 meta -

analysis showed that dexamethasone has decreased in intraventricular

hemorrhage and NICU stay when compared to betamethasone. Evidence

shows that even a single dose of either gives benefit, so it is

recommended that the first dose be given even if it is unlikely that patient

will receive the following doses. However there is no evidence of

improved outcome with accelerated dosing.

48

Magnesium sulphate for neuroprotection

Magnesium sulphate can be administered immediately before and

at the time of delivery of a preterm infant. It decreases the rate of cerebral

palsy (RR = 0.68) 50. Various trials have proved its benefits but have

varied in regimens used. A 2012 Cochrane review showed that no

superiority of any regimen over the other. It is administered to women

between 24 - 32 weeks at high risk of delivery within 24 hours.

Table No 6. Magnesium sulphate for neuroprotection

Loading Dose Maintenance Dose Repeat Treatment

4gm over 20-30 min 1gm/hr till birth or 24

hours

No immediate repeat

doses

BEAM study - Beneficial Effects of Antenatal Magnesium

sulphate - A placebo controlled trial in 2 - 41 women at imminent risk of

preterm birth between 24 and 31 week. A 2 year follow up was done

which concluded that magnesium sulphate infusion prevents cerebral

palsy regardless of the gestational age at which therapy is given.

Neonatal GBS prophylaxis

The incidents of neonatal GBS infection and its mortality has

decreased significantly after the acceptance of CDC guidelines for the

prevention of GBS disease. GBS reminds the leading cause of neonatal

49

mortality due to infection. Use of clindamycin and cefazolin in penicillin

allergic patients for treatment of PTB and PPROM is recommended. A

vaginal - rectal swab for GBS culture should be obtained when a woman

presents with PPROM or preterm labour if results from last 5 weeks

testing is not available. Intrapartum antibiotics (Penicillin or ampicillin)

should be started on admission until birth or until it is confirmed that

women is not in true preterm labour or a negative GBS culture is

available. Clindamycin and vancomycin are used as a last resort for

women with serious penicillin allergy. It is not routinely practised in

india.

Preterm rupture of membranes (PPROM)

PPROM is the amniorrhexis before 37 completed weeks. 25 - 30%

of PTB are preceded by PPROM1.Collagen fibers contributed to the

tensile strength of membranes. Matrix metalloproteinase (collagenase

activity is increased due to the result of infection or inflammation and

leads to final common pathway ending in membrane rupture. Risk factors

for PPROM are similar to those of preterm labour with intact membranes.

Delivery is likely to occur within a week of rupture in 13 - 16% of cases

there is clinically evident intra-amniotic infection. Digital vaginal

examination increases the likelihood of this infection. Intrauterine

complications are abruption of the placenta, umbilical cord compression,

pulmonary developmental abnormalities and infection.

50

Evaluation of the patient with suspected PPROM includes accurate

dating, sterile speculum examination, ultrasound evaluation of

oligohydramnios, assessment of fetal lung maturity (by amniocentesis or

vaginal amniotic fluid testing for lamellar body count and

phosphatidylglycerol between 32-36 weeks), screening for infection and

fetal monitoring (electronic fetal heart rate and uterine contraction

monitoring).

Management of PPROM

The management of PPROM necessitates a balance between

advantage of delaying delivery and risk of prolonged fetal exposure to

potentially hostile environment.

1. Monitored for clinical infection - maternal fever, uterine tenderness

and fetal tachycardia are signs of infection

2. Antepartum fetal testing - the non - stress test and biophysical

profile are used to assess the fetal condition

3. Antibiotic therapy - management with antibiotics between 24 - 32

weeks prolonged pregnancy and decreases chorioamnionitis, fetal

morbidity and maternal infection

51

Table No 7. Antibiotic therapy in PPROM

Antibiotic Dosage

Initial therapy

Ampicillin 2gm IV every 6 hours for 48 hours

Erythromycin 250 mg IV every 6 hours for 48 hours

Follow up therapy

Amoxicillin 250mg orally every 8 hours for 5 days

Erythromycin base 333mg orally every 8 hours for 5 days

4. Cortical steroids - Antenatal corticosteroids administration in the

setting of PPROM decreases the risk of neonatal RDS, necrotising

enterocolitis and intraventricular haemorrhage. The incidence of

maternal and neonatal infection is not found to be increased.

5. Tocolysis - As opposed to antibiotics and steroid treatment,

tocolysis in view of PPROM lacks evidence of benefit

6. Magnesium sulphate for neuroprotection

52

Management of PPROM according to gestational age

1. 34 weeks or more - plan delivery - labour induction unless

contraindicated. Single cotico steroid course may be considered

upto 36+6 weeks in those who have not received a previous course

of steroids.

2. 32 - 33 completed weeks - expectant management, single

corticosteroids, antimicrobials to prolong latency

3. 24 - 31 completed weeks - expectant management, single

corticosteroids course, tocolytics, antimicrobial to prolong latency,

magnesium sulphate for neuroprotection

4. < 24 weeks - expectant management or induction of labour,

antimicrobials

53

OBSERVATIONS AND RESULTS

Table No 8. Mean Age

N Minimum Maximum Mean SD

Age 100 17 38 25.54 4.217

Study group consists of 100 patients who attended our AN OP for

routine second trimester antenatal check up. Most of the patients were

around the age of 25.

Table No 9. Age distribution

Groups Frequency Percent (%)

<20 years 12 12.0

21-25 years 40 40.0

26-30 years 37 37.0

>31 years 11 11.0

Total 100 100

Teenage pregnancy constituted about 12% of the study population.

Most of the patients were around 21 - 25 years which constitutes 40%.

Elderly gravida were around 11% and antenatal mothers between 26 and

30 years constituted about 37%

54

55

Table No 10. Parity distribution

Groups Frequency Percent (%)

PRIMI 48 48.0

MULTI 52 52.0

Total 100 100

This study has a combination of primigravida and multigravida.

Multigravida constituted most of the study population which is about

52% and primigravida constituted about the remaining 48%. Pregnant

women with previous history of abortion were classified according to

thier parity level as either primigravida or multigravida.

56

Table No 11. Distribution of Multi gravida among study group

Groups Frequency Percent (%)

L1 49 94.2

L2 2 3.8

L3 1 2

Total 52 100

Multigravida are further divided into L1,L1,L3 based on the

number of living children they have. Most multigravida were P1L1

occupying 94.2% of multigravida population.

57

Table No 12. Parity distribution among different age groups

Groups PRIMI MULTI P value

<20 years 5(41.7%) 7(58.3%)

.158 21-25 years 11(27.5%) 29(72.5%)

26-30 years 9(24.3%) 28(75.7%)

>31 years 3(27.3%) 8(72.7%)

Multigravida constituted most of the study population with 58.3%

in the teenage group. In 21 - 25 years group 72.5% were multi and 27.5%

were primigravida. In 26 - 30 year group 75.7% were multi and 24.3%

only were primi. In the elderly group majority were multi with 72.7% and

primigravida were only 27.3%.

58

Table No 13. Socio economic status

Groups Frequency Percent (%)

CLASS III 9 9.0

CLASS IV 50 50.0

CLASS V 41 41.0

Total 100 100

Pregnant women were grouped according to Kuppusamy modified

scale into different socioeconomic status. Most of the pregnant women

belong to class IV socio economic status which constitutes about 50%.

The remaining were distributed between class III and V.

59

Table No 14. Distribution of multigravida in study group based on

previous delivery

Groups Frequency Percent (%)

PREVIOUS TERM 40 76.9

PREVIOUS PRETERM 12 23.1

Total 52 100

The multigravida in study group were also classified based on previous

delivery as previous preterm and previous term. 23.1% multigravida had

previuos history of a preterm delivery.

60

Table No 15. distribution of PPROM

Groups Frequency Percent (%)

POSITIVE 31 31.0

NEGATIVE 69 69.0

Total 100 100

In our study, 31% of women had PPROM and the rest 69% did not have

PPROM.

61

Table No 16. Association of Hemoglobin with parity

Groups N Mean SD P value

HB PRIMI 28 11.74 .8437

.157

MULTI 72 12 .9468

The hemoglobin was estimated to 9.98 to 13.34gm/dl in the primi

group and 10 - 13.8gm/dl in the multigravida group. P- Value is >0.05

and it is not statistically significant.

62

Table No 17. Association of Serum Ferritin with parity

Groups N Mean SD P value

S.FERRITIN PRIMI 28 27.63 15.48

.598

MULTI 72 29.42 15.03

Average serum ferritin was around 26.6ng/ml in primigravida

group and 28.42ng/ml in multigravida. P- Value is >0.05 and it is not

statistically significant.

63

Table No 18. Association of Gestational age with Hemoglobin

Groups N Mean SD P value

HB

PRETERM<37

WEEKS 37 11.703 .8902

.147

TERM>37 WEEKS 63 11.981 .9355

P - Value is >0.05 and it is not statistically significant. Present

delivery as term or preterm is not influenced by hemoglobin in this study

group.

64

Table No 19. Association of Gestational age with serum ferritin

Groups N Mean SD P value

S.FERRITIN

PRETERM<37

WEEKS 37 43.21 15.23

.000*

TERM>37 WEEKS 63 20.52 6.00

Serum ferritin in the preterm group ranged between 13 - 73ng/ml

and in the term group it ranged between 8 - 32ng/ml. P- Value is <0.05

and it is statistically significant.

65

Table No 20. Association of Hemoglobin with PPROM

PPROM N Mean SD P value

HB POSITIVE 31 11.58 .99

.034* NEGATIVE 69 12.00 .86

66

Table No 21. Association of Serum Ferritin with PPROM

PPROM N Mean SD P value

S.FERRITIN

POSITIVE 31 44.40 14.31 .000*

NEGATIVE 69 21.96 9.12

Serum ferritin in the PPROM category ranged between 13 - 73ng/

ml and in the no PPROM group 3 - 39ng/ml. P - Value is <0.05 and it is

statistically significant.

67

Table No 22. Association of Hemoglobin with Socio economic status

Groups N Mean SD P value

HB

CLASS III 9 12.244 0.6146

.210 CLASS IV 50 11.952 1.0154

CLASS V 41 11.707 0.8421

P- Value is >0.05 and it is not statistically significant.

68

Table No 23. Association of Serum Ferritin with Socio economic

status

Groups N Mean SD P value

S.FERRITIN

CLASS III 9 23.61 5.10

.323 CLASS IV 50 30.92 17.26

CLASS V 41 27.64 13.45

P- Value is >0.05 and it is not statistically significant.

69

Table No 24. Association of Gestational age of present delivery with

previous delivery

PREVIOUS

TERM/PRETERM

Gestational age

P value PRETERM<37

WEEKS

TERM>37

WEEKS

PREVIOUS TERM 6(15%) 34(85%) .002*

PREVIOUS PRETERM 7(58.3%) 5(41.7%)

Among the previous preterm delivery ,7 women had preterm delivery in

this pregnancy also and 5 had term delivery. In previous term deliveries

group, most women delivered by term in current pregnancy also. P value

is <0.05, hence it is statistically significant.

70

Table No 25. Association of multigravida in study group with

Gestational age at present delivery

Gestational age Multi gravida P

value L1 L2 L3

PRETERM<37 WEEKS 12(92.3%) 1(7.7%) 0(0.0%) .801 TERM>37 WEEKS 36(92.3%) 2(5.1%) 1(2.6%)

Among the 52 multipara of study group, majority of multigravida with 1 live

child delivered at term- 92.3%. p value is more than 0.005 and hence parity

index as such is not an indicator for determining preterm birth.

71

Table No 26.Association of multigravida in study group with previous

delivery

PREVIOUS

TERM/PRETERM

Multi gravida P

value L1 L2 L3

PREVIOUS TERM 36(90%) 3(7.5%) 1(2.5%) .522

PREVIOUS PRETERM 12(100%) 0(0.0%) 0(0.0%)

Most multigravida in present study had previous term deliveries and only

12 had previous preterm delivery.

72

DISCUSSION

Preterm birth is one of the leading causes of neonatal mortality in

the absence of congenital anomalies in developing countries. Hence

measure should be taken to identify, prevent preterm deliveries and treat

this preterm neonates as early as possible. Present study was planned to

assay the serum ferritin levels in pregnant women with preterm labour,

PPROM and in normal pregnant women. The purpose of the analysis of

this study was to determine whether serum ferritin levels can be used as a

marker for preterm labour.

Serum ferritin is an acute phase reactant which is increased in

infection and inflammation. Preterm labour has many causes among

which infection plays a major role. Pregnancy predisposes to vagino

cervical infections due to alteration in vaginal pH. Also chorio - decidual

interface gets infiltrated by macrophages due to bacterial colonization.

High serum ferritin levels in apparently healthy pregnant women will

help the obstetrician to anticipate the preterm delivery and take

appropriate action.

Anemia during the second trimester is shown to be positively

linked with preterm labour although anemia later in pregnancy has a

negative association. Hence in our study to overcome this variable

women with anemia (hemoglobin < 10.5gm/dl) were not included.

73

In our study the mean values of serum ferritin taken at Coimbatore

Medical College Hospital in PPROM , preterm labour and term labour

were 44.4, 43.21, 21.96 and respectively. The standard deviation of serum

ferritin in PPROM, preterm labour and term labour are 14.31, 15.23 and

9.12 respectively. There is significant statistical increase in serum ferritin

in the PPROM and preterm group when compared with term delivery (P

< 0.05). The high values of ferritin levels in preterm labour and PPROM

cases could be due to infections associated with them. In this study most

women with preterm delivery in past pregnancy had preterm delivery in

this current pregnancy also. About 58.3% who had previous preterm

delivery had preterm delivery in this delivery. All these data indicate that

preterm delivery is multifactorial and influenced by number of factors.

Number of studies have been done to relate the incidence of infection

induced preterm labour. Brailesford proposed that high levels of

extracellular ferritin has an important role in host defence against

bacteremia by oxidative metabolism.

Thus the high levels of serum ferritin in preterm and PPROM in

most likely a part of acute phase reaction to subclinical genital infection

and inflammation. So serum ferritin may be used as a marker and help

physicians to anticipate preterm labour in such patients.

74

In our study there was no significant difference between preterm

and term with regard to age, parity, socioeconomic status. In our study

also there is significant difference in ferritin values between preterm and

term group. This agrees with the study done by Nandini et al., on 100

pregnant women divided into two groups of preterm and term delivery.

Their findings showed ferritin levels were high in preterm labour and its

value ranges from 4.4mcg/dl – 841.2mcg/dl and in term delivery from 9.8

- 67mcg/dl.

Another case control study by Movahedi on 220 pregnancy

concluded that women who delivered after 37 weeks had lower mean

serum ferritin than those who delivered before 37 weeks. In their

study,receiver operator characteristic curve was constructed which

yielded a sensitivity of 78.3%, a specificity of 83% positive predictive

value of 67.5% and negative predictive value of 89.4%, for the prediction

of preterm labour.

In the study by Saha et al., mean ferritin levels in control PPROM,

spontaneous preterm labour are 8.69±3.7, 29.4±28.4, 23.24±12.13mg/l

respectively. In that study there was a significant difference between

control group and preterm labour group.

However in retrospective study by Gopal et al., there is no relation

between serum ferritin levels and spontaneous labour. In the study by

Valappil et al., which compared the ferritin levels of 50 patients with

75

PPROM, 50 with spontaneous preterm labour and 50 normal pregnant

women with matching hemoglobin and gestational age reported that there

was significant difference in mean ferritin values between control group

and PPROM group. But there was no statistical difference in ferritin

values between control group and spontaneous preterm labour indicated

by a p value of 0.180. This lack of significant statistical difference may

be due to multifactorial cause of preterm labour.

76

LIMITATIONS

1. Patients were enrolled from a single medical center. So the results

cannot be generalized based on a small population.

2. Our study included women who were not in labour. The

significance of high ferritin levels during labour needs a larger

study population to reach any conclusion.

3. Factor such as cervical length, fetal fibronectin which are other

major factors in determining preterm labour were not included in

our study.

4. Single measurement of ferritin does not provide a time integrated

measurement of maternal inflammation status during the index

pregnancy. Thus a serial estimation of ferritin levels rather than a

single value may give a clue to the possibility of preterm delivery.

5. Spontaneous preterm labour delivery may be due to multifactorial

causes and cannot be attributed only to infection.

77

CONCLUSION

Our Study found significant difference in serum ferritin levels between

preterm labour, PPROM and normal pregnant women with same

gestational age, possibly because that subclinical infection is associated

with preterm delivery. Elevated ferritin concentration associated with

spontaneous delivery more than 43ng/ml in second trimester as cut off

point could be derived from this study. Thus from the present study

serum ferritin can be used as marker in predicting the pregnant women at

risk for preterm delivery and thus help obstetricians to identify pregnant

women at risk and advice them for a higher centre neonatal care . The

results of this study can be used for promoting further studies of ferritin

in relationship with pregnancy complication.

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ANNEXURE- A

PROFORMA

NAME: AGE:

OP NO: ADDRESS:

CONTACT NUMBER SOCIO ECONOMIC

STATUS: DATE:

PARITY: LMP : EDD :

MENSTRUAL HISTORY :

MARITAL HISTORY :

MEDICAL HISTORY:

DIABETES: HYPERTENSION : EPILEPSY :

RENAL DISEASE: HEART DISEASE :

PAST OBSTETRIC HISTORY:

H/O STILL BIRTHS : ABRUPTION: H/O PRETERM:

FAMILY HISTORY:

DIABETES: HYPERTENSION:

GESTATIONAL HYPERTENSION: TWINS :

ON GENERAL EXAMINATION BUILT - TEMPERATURE -

ANEMIA - PULSE RATE - BLOOD PRESSURE AT

SITTING POSTURE - PEDAL EDEMA - HEIGHT

- WEIGHT - BMI- BREAST -

THYROID

CVS :

RS:

PER ABDOMEN : FUNDAL HEIGHT: WHETHER

ACTING OR NOT :

INVESTIGATIONS:

HB% :

URINE :

ALBUMIN

SUGAR

BLOOD SUGAR :

HIV :

BLOOD GROUPING:

S.FERRITIN:

ULTRA SOUND -

Ist TRIMESTER IInd TRIMESTER

FOLLOW UP:

GESTATIONAL AGE AT DELIVERY :

PPROM:

CONSENT FORM

I Mrs____________________________ hereby volunteer to participate

in the study ‘DIAGNOSTIC PERFORMANCE AND

DISCRIMINATIVE VALUE OF SERUM FERRITIN IN PRETERM

LABOUR AND PPROM’. I am fully explained about the nature of study

by the doctor,knowing which I fully give my consent to participate in this

study.

Date :

Place :

SIGNATURE OF PATIENT/GUARDIAN

S.NO NAME AGE OP.NO PARITY GEST AGE S.E. STATUS HB IN GRAMS S.FERRITIN PPROM +/ - G.AGE AT DELIVERY PREV. PRETERM

1 PARKAVI 22 14230 PRIMI 20W3D V 10.1 25.22 - 38w -

2 VANITHA 19 13245 G2A1 21W4D IV 10.2 30.33 + 32w3d -

3 SHEELA 23 14325 G2A1 21w V 11 45 + 30w3d -

4 ROSYLYN 24 13456 G2P1L1 22W V 11.3 32.1 + 29w5d +

5 RANI 20 12356 PRIMI 22W3D V 11.9 28 - 38w5d -

6 JENNIFER 23 14567 G3P1L1A1 21W3D V 11.4 14 - 39w +

7 VIMALARANI 25 14568 PRIMI 21W6D IV 10.5 20 - 40w5d -

8 PRIYA 29 14568 G3A2 22W3D IV 10.6 33 + 36w2d -

9 RASATHI 27 13457 G2A1 23W4D V 10 54.44 + 28w6d -

10 VICTORIA 23 12569 PRIMI 22W5D IV 10.3 43.21 + 29w5d -

11 MARIYAMMAL 26 13458 G2P1L1 21W4D IV 10.3 21.3 + 39w -

12 PONNU 27 12569 G3P1L1A1 21W6D IV 11.5 19.4 - 38w6d -

13 DEEPA 24 12670 G4P2L2A1 23W5D V 11.5 18 - 39w4d -

14 GEETHA 23 13456 PRIMI 22W4D V 12 20 - 38w -

15 VENNILA 23 13480 G2A1 21W V 13.4 17 - 37w1d -

16 CHRISTY 25 12560 G3P1L1A1 23W V 12 19.22 - 36w4d +

17 ROOPA 22 12547 G2P1L1 22W1D IV 13.4 28 - 39w4d -

18 PRAVEENA 21 16423 PRIMI 22W4D IV 11.4 23.11 + 38w3d -

19 MAHADEVI 21 16547 PRIMI 22W5D V 11.3 14.23 - 40w4d -

20 POORNIMA 20 17653 PRIMI 23W5D V 10.5 12.5 - 40w5d -

21 VASANTI 30 13780 G2P1L1 23W1D IV 10 24.5 + 39w -

22 ABIRAMI 32 19874 G3A2 23W1D IV 10.4 62 + 30w1d -

23 DIVYA 25 13670 G3P1L1A1 22W5D IV 12.1 20.15 - 40w1d -

24 GOWRI 26 14256 G3P1L1A1 22W6D V 13 22.3 + 38w5d -

25 HELEN 22 17345 G2P1L1 23W5D IV 12.4 23.2 + 37w4d -

26 SARASWATHY 23 12789 PRIMI 21w V 12.7 21.4 - 37w2d -

27 SELENA 26 17690 G2A1 20W6D V 13 34.66 + 35w2d +

28 BACKIYAM 28 12670 G2P1L1 21W4D IV 13.3 41.0132 + 34w4d +

29 MAHARANI 30 14588 G2A1 21W6D IV 12.6 31 - 36w5d -

30 BANU 32 13355 PRIMI 22W3D IV 11.8 12 - 38w6d -

31 PRIYADHARSINI 21 16788 PRIMI 22W1D V 12.4 22.4 - 39w -

32 POONGODI 20 13420 G3P1L1A1 22W4D V 13 22 - 37w1d -

33 INDUMATHY 25 14269 G2P1L1 23W5D V 12.6 29 - 38w3d -

34 JANAKI 26 15675 G2A1 23W6D IV 11.5 39.44 - 34w5d -

35 KRUPA 26 13425 PRIMI 23W4D IV 11 18 - 33w6d -

36 MALARKODI 27 16546 G3P1L1A1 23W5D V 12.6 28 - 36w1d -

37 NITHYA 28 17753 G2P1L1 23W1D IV 12.9 33.4 + 38w3d -

38 PAVITRADEVI 23 18853 G2A1 22W1D IV 11.3 59.6 + 32w1d +

39 VANARANI 25 17852 G3A2 20W6D IV 11.3 22 - 36w4d -

40 SHRUTHI 28 19542 G4A3 21W4D IV 11.4 23 - 38w -

41 SHALINI 29 16341 PRIMI 23W4D V 11.7 16 - 39w4d -

42 PONMANI 24 23456 PRIMI 22W5D IV 12.1 45.7 + 31w3d -

43 ABIRAMI 25 12356 G2P1L1 21W4D V 12 44.2 + 33w5d -

44 VALARMATHY 27 166789 G2P1L1 20W3D V 13.1 21 - 39w3d -

45 DIVYAPRIYA 29 23478 G2P1L0 21w3D V 11.1 19 - 40w4d +

46 MAHALAKSHMI 33 1257 G2A1 21w V 10.9 56 + 30w1d -

47 MAILATHAL 32 4568 G3P1L1A1 21W5D IV 10.8 21 - 40w2d -

48 SHANTHI 30 23451 G4P3L3 23W6D III 12 29 - 40w4d -

49 RAJI 24 13452 G4P2L1A1 23W5D IV 11.3 21.4 - 39w -

50 PRIYA 26 16678 G3P1L1A1 23W4D IV 11.4 16.1 - 30w2d +

51 NATASHA 28 13675 G2P1L1 22W4D III 12.8 18.9 - 39w1d -

52 DHARANI 29 13444 PRIMI 22W5D IV 13 10.4 - 39w -

53 REKHA 28 17890 PRIMI 21W V 12.9 25.8 - 39w5d -

54 CHRISTY 21 27896 G3A2 21W4D IV 11.9 69.8 + 27w3d -

S.NO NAME AGE OP.NO PARITY GEST AGE S.E. STATUS HB IN GRAMS S.FERRITIN PPROM +/ - G.AGE AT DELIVERY PREV. PRETERM

55 NILOFER 21 22345 G2P1L1 22W4D V 11 45.7 + 31w1d -

56 TAJNISHA 37 26789 G3P2L1 23W5D V 11.7 33 - 40w -

57 THAVAMANI 18 12347 G3P1L1A1 23W6D IV 10.7 31.8 - 40w3d -

58 MANI 17 23568 PRIMI 21w5D III 12 17.1 - 39w6d -

59 MEKALAI 24 34589 G2A1 22W4D IV 13.1 12.9 - 38w3d -

60 POOJA 26 43521 G2A1 21W4D IV 13.1 17.9 - 32w -

61 VASUKI 28 26345 PRIMI 21W3D IV 12.7 66 + 31w5d -

62 KRITHIKA 29 27432 G2P1L1 21W4D IV 12.1 52.1 + 33w +

63 PREETHI 30 14456 G2P1L1 20W2D IV 11.1 55.9 - 33w1d +

64 KEERTHI 23 13245 G3P1L1A1 22w6D V 11.2 29 - 40w1d -

65 SORNA 25 12323 G2P1L1 21W5D V 11.3 21.08 - 39w5d +

66 REVATHY 27 14353 G2A1 23W6D V 12.4 22.41 - 35w -

67 KEERTHANA 29 16234 PRIMI 21w3D IV 12.5 41.77 + 34w2d -

68 SWAPNA 21 16234 PRIMI 22W2D III 11.5 21.9 - 39w1d -

69 SPOORNA 19 17754 G2P1L1 22W3D III 13.5 23.4 - 38w -

70 MUTHULAKSMI 19 15678 G3P1L1A1 21W3D IV 13.2 21 - 37w5d -

71 HARINI 20 11332 G2P1L1 20W3D III 12.4 20.9 - 38w4d -

72 GOWRI 21 16678 G2A1 20W5D IV 13.1 12.6 - 39w3d -

73 LALITHA 23 15568 G2A1 22W5D IV 14.1 13 - 41w -

74 JAYANTHI 25 18890 G2P1L1 22W1D IV 13.2 18.6 - 40w1d -

75 MYTHILI 27 14467 G3P1L1A1 23W4D V 10.9 17.6 - 40w2d -

76 BOOMIKA 29 13247 G2P1L1 22W5D V 11.2 19.7 - 38w +

77 YAMINI 22 21420 PRIMI 23W4D V 11.1 55 + 33w -

78 MINI 26 22145 PRIMI 23W6D V 11.7 60.3 - 29w5d -

79 MEENA 24 22679 G3A2 21w5D V 11.8 49.09 + 31w6d -

80 PARKAVI 22 23456 G3P1L1A1 22W6D IV 12.4 49.9 + 32w1d -

81 ROOPA 28 22367 G2P1L1 21w IV 12.5 57.3 + 30w2d +

82 JOSHNA 20 15678 PRIMI 21W IV 13.1 39.8 - 36w5d -

83 NISHANTHI 19 11459 PRIMI 23W III 12.1 31.9 - 38w -

84 SHANTHI 19 10908 G2P1L1 22W1D III 12.3 28.79 - 37w5d -

85 APARNA 23 10678 G3P1L1A1 22W4D IV 11.4 21.32 - 39w3d -

86 SADHANA 24 15679 G2P1L1 22W5D III 11.6 20.67 - 40w4d -

87 DHARSHINI 25 15076 G3P1L1A1 23W5D V 11.8 19.32 - 39w1d -

88 RUTHRA 27 14539 PRIMI 21w5D V 10.8 21 - 38w4d -

89 CATHY 28 12378 G2P1L1 23W6D IV 12.1 30.1 - 37w5d -

90 BINU 28 15678 G4P2L2A1 21W3D IV 11.4 10.98 - 38w -

91 BEENA 29 19654 G5P3L2A1 21w2D IV 11.7 72.2 + 29w -

92 HEENA 26 15328 PRIMI 21W2D V 10.7 38.9 + 33w -

93 ASIFA 25 19865 G2P1L1 23W4D IV 12.4 49.8 + 34w2d -

94 SHADIYA 32 19543 G3P1L1A1 23W3D IV 12.9 20.7 - 37w4d -

95 SEETHA 31 12256 G2P1L1 22W V 12.1 17.7 - 39w -

96 TAMILSELVI 35 34562 PRIMI 21W3D V 11.4 10.3 - 40w4d -

97 PREETHA 25 27835 G4P2L1A1 21W1D IV 12.4 17.3 - 40w3d +

98 VANITHAMANI 38 28645 G3P1L1A1 21W IV 13.1 10.8 - 38w -

99 NIKITHA 33 22789 G2P1L1 20W5D IV 12.6 10.3 - 39w3d -

100 THAMARAI 32 43990 PRIMI 20W4D V 11.5 11.9 - 38w4d -