Effect of Terbutaline on Latency Period in PPROM

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Original Article

Gynecol Obstet Invest 2012;73:130134DOI: 10.1159/000331661

Effect of Terbutaline on LatencyPeriod in Preterm Premature Ruptureof Membranes

Lalita Kulmala Vorapong Phupong

Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok , Thailand

There were no differences in maternal morbidity and mortal-ity. However, neonatal infectious morbidity was higher in theterbutaline group. Copyright 2012 S. Karger AG, Basel

Introduction

Premature or prelabor rupture of the membranes isdefined as rupture of membranes before labor onset [1] .Preterm premature rupture of the membranes (PPROM)is defined as premature rupture of the membranes thatoccurs before 37 weeks gestation. This is a commonproblem, which usually results in preterm delivery andcauses complications in the mother as well as neonate [1] .These complications are more common in PPROM of lessthan 34 weeks gestation [2]. Prolongation of the latencyperiod is believed to reduce neonatal complications.However, physicians should consider the risk of infec-tions and whether it outweighs the benefits of prolongingpregnancy [3] .

The management of PPROM is expectant. Accordingto the American College of Obstetricians and Gynecolo-gists Clinical Management Guidelines, prophylactic an-tibiotics are recommended in the management of PPROMto prolong pregnancy, reduce infectious and gestational

Key Words Tocolysis Terbutaline Preterm Premature rupture ofmembranes

Abstract Aims: To assess whether terbutaline is able to prolong thelatency period in women with preterm premature rupture ofmembranes (PPROM) and compare maternal and neonatalmorbidity and mortality in the terbutaline and nontocolysisgroups. Methods: This study retrospectively analyzed datafrom women with singleton pregnancies (gestational agesbetween 28 and 34 weeks) suffering from PPROM from Janu-ary 1998 to December 2009. Results: A total of 163 cases ofPPROM were analyzed; there were 61 cases (37.4%) in the ter-butaline group and 102 cases (62.6%) in the nontocolysisgroup. The median latency period was comparable in thetwo groups (78 vs. 75 h, p = 0.44). The percentage of patientswho did not deliver within 48 h was significantly higher inthe terbutaline group compared with the nontocolysisgroup (78.7 vs. 62.7%, p = 0.03). There were no differences inmaternal morbidity and mortality, and neonatal mortalitybetween the two groups. Interestingly, neonatal infectiousmorbidity was significantly higher in the terbutaline groupwhen compared with the nontocolysis group. Conclusions: Terbutaline cannot prolong the latency period in PPROM.

Received: January 5, 2011Accepted: July 18, 2011Published online: February 3, 2012

Vorapong Phupong, MDDepartment of Obstetrics and GynecologyFaculty of Medicine, Chula longkorn University

Rama IV Road, Pathumwan, Bangkok 10330 (Thailand)Tel. +66 2 256 4241, E-Mail vorapong.p @ chula.ac.th

2012 S. Karger AG, Basel03787346/12/07320130$38.00/0

Accessible online at:www.karger.com/goi


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Terbutaline in PPROM Gynecol Obstet Invest 2012;73:130134 131

age (GA)-dependent neonatal morbidity. Corticosteroidsshould be administered in PPROM to reduce the risks ofneonatal prematurity-related complications [3] .

The utility of tocolysis after PPROM remains contro- versial. Prophylactic tocolysis after PPROM is associat-ed with a brief pregnancy prolongation. But neonatalbenefits are unclear. Therapeutic tocolysis might pro-long pregnancy but does not improve neonatal outcome[4].

Even though terbutaline is one of the most common-ly used tocolytic drugs, its role in PPROM is still un-known. Therefore, we retrospectively compared the ef-fects of terbutaline on the latency period, maternal andneonatal morbidity and mortality in patients withPPROM.

Patients and Methods

This study was approved by the Research Ethics Committee ofthe Faculty of Medicine, Chulalongkorn University. Medical re-cords of pregnant women with GAs between 28 and 34 completeweeks with PPROM admitted to the Department of Obstetricsand Gynecology, Faculty of Medicine, Chulalongkorn University,Bangkok, Thailand, between January 1998 and December 2009were reviewed. Singleton pregnancies with cervical dilatation lessthan 4 cm at admission were reviewed. Only women who receivedprophylactic antibiotics to prolong the latency period and had asingle course of antenatal corticosteroids to induce fetal lung ma-

turity were included. Intravenous ampicillin and oral macrolide(roxithromycin or azithromycin) for 2 days, followed by oralamoxicillin and oral macrolide (roxithromycin or azithromycin)for 5 days were used as prophylactic antibiotics. Pregnant womenwere divided into two groups: a terbutaline group and a nonto-colysis group. The terbutaline group was composed of womenwho received intravenous terbutaline for 48 h upon admission

and later switched to oral terbutaline when the uterine contrac-tion stopped. The dosage of intravenous terbutaline was 10 g/min and the dosage of oral terbutaline was 2.5 mg every 6 h. Thewomen in the nontocolysis group did not receive any tocolysis.The decision to use tocolysis was made based on the preference ofthe attending obstetr icians, irrespect ive of clinical presence or ab-sence of uterine contraction. We excluded cases that had fetalanomalies or any conditions that would require the pregnancy tobe terminated upon admission, such as chorioamnionitis or fetaldistress. Diagnosis of PPROM was based on a combination ofclinical history, gross leakage of amniotic f luid, the Ferning test,the Nile blue test and oligohydramnios by an ultrasonogram. Thelatency period was defined as the time interval between the rup-ture of membranes and delivery.

Data on maternal age, gravidity, parity, total number of ante-natal care visits, GA at admission, uterine contraction, cervicaldilatation by speculum inspection, latency period, GA at delivery,mode of delivery, maternal and neonatal outcomes, and durationof hospitalization were extracted from the patients medical re-cords.

Statistical AnalysisStatistical analysis was performed with SPSS software package

version 12.0 (SPSS Inc, Chicago, Ill., USA). Continuous variableswere compared by Students t test and the Mann-Whitney U testwhile the 2 test or Fishers exact test was applied when appropri-ate to compare categorical variables. A p value ! 0.05 was consid-ered statistically significant.

Results

A total of 163 cases of PPROM were analyzed. Therewere 61 cases (37.4%) in the terbutaline group and 102cases (62.6%) in the nontocolysis group.

Demographic characteristics are shown in table 1 .There were no statistical differences between the terbuta-line and nontocolysis groups for gravidity, parity, totalnumber of antenatal care visits, GA at admission, uterinecontractions and cervical dilatation. But mean maternalage was significant higher in the terbutaline group thannontocolysis group. Group B streptococcus infection wasfound in 2 (3.3%) and 4 (3.9%) cases in the terbutaline andnontocolysis group, respectively (p = 1.00).

Latency periods, GA at delivery and mode of deliveryare shown in table 2 . GA at delivery and mode of deliverywere not different in the two groups. There was 1 casedelivered by vacuum extraction in the terbutaline group.

Table 1. Demographic characteristics

Characteristics Terbutalinegroup(n = 61)

Nontocolysisgroup(n = 102)

p value

Age, years 29.18 6.1 26.68 6.1 0.01

Gravidity PrimigravidaMultigravida

23 (37.7)38 (62.3)

46 (45.1)56 (54.9) 0.36

Parity 01

43 (70.5)18 (29.5)

66 (64.7)36 (35.3) 0.45

Total number of antenatal care visits 5.7 8 2.1 5.18 2.5 0.10

GA at admission, weeks 31.18 2.0 31.58 1.6 0.15Uterine contraction 35 (57.4) 42 (41.2) 0.05Cervical dilatation

01 cm23 cm

49 (80.3)12 (19.7)

89 (87.3)13 (12.7)

0.23

Data are presented as means 8 SDs or n (%).


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There were 3 and 2 cases in the nontocolysis group deliv-ered by vacuum extraction and by assisted breech deliv-ery, respectively. The median latency periods were com-parable in the two groups. However, the percentage ofpatients in the terbutaline group who did not deliverwithin 48 h was significantly higher compared with thenontocolysis group (78.7 vs. 62.7%, p = 0.03). But the per-centage of patients who did not deliver within 7 days wassimilar in the two groups.

Maternal morbidity is shown in table 3 . Maternal in-fectious morbidity, such as chorioamnionitis, postpar-tum metritis and surgical wound infection, was not sig-nificantly different in the two groups. Similarly, therewere no differences between the two groups for the dura-tion of maternal hospitalization.

Neonatal outcomes are shown in table 4 . There wereno significant differences between the terbutaline andnontocolysis groups for birth weight, Apgar scores, dura-tion of neonatal hospitalization, neonatal intensive careunit stay and ventilation assistance. Rates of respiratorydistress syndrome, intraventricular hemorrhage, necro-tizing enterocolitis and neonatal mortality were not sig-nificantly different between the two groups. But neonatalinfectious morbidity, including sepsis, pneumonia, men-ingitis and omphalitis, was significantly higher in the ter-butaline group (40.9 vs. 22.5%, p = 0.01).

The organisms that caused infection in mothers andneonates were group B streptococcus (2 cases), Klebsiella pneumoniae (1), Enterobacter faecalis (1) and Pseudomo-nas aeruginosa (1) in the terbutaline group and group Bstreptococcus (4 cases), E. faecalis (1) and Escherichia coli (4) in the nontocolysis group. There was no growth of or-ganisms in the remaining cases of maternal and neonatalinfections.

Table 2. Latency periods, GA at delivery and mode of delivery

Terbutalinegroup(n = 61)


p value

Latency periods, h 78 (50, 169) 75 (25, 173) 0.44

>2 days 48 (78.7) 64 (62.7) 0.03>7 days 15 (24.6) 27 (26.5) 0.79GA at delivery, weeks 32.08 2.1 32.48 2.0 0.27Mode of delivery 0.21

Vaginal delivery Cesarean section

37 (60.7)24 (39.3)

76 (74.5)26 (25.5)

Indication for cesarean section (n = 24) (n = 26) 0.32OligohydramniosUnfavorable cervixPlacental previaPrevious cesarean sectionFetal distressAbruptio placentaeAbnormal presentation

6700218

8615114

Data are presented as means 8 SDs, medians (interquartileranges) or n (%).

Table 3. Maternal morbidity

Terbutalinegroup(n = 61)


p value

Infectious morbidity

ChorioamnionitisMetritisWound infection

9 (14.8)

900

20 (19.6)

1901

0.57

Days of hospitalization 7 (5, 13) 8 (5, 12) 0.66

Data are presented as medians (interquartile ranges) or n (%).

Table 4. Neonatal outcomes

Characteristics Terbutalinegroup(n = 61)


p value

SexMaleFemale

43 (70.5)18 (29.5)

69 (67.6)33 (32.4) 0.71

Birth weight, g 1,849.78 489.4 1,947.48 444.6 0.19Apgar scores

At 1 min


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Discussion

The utility of tocolysis after PPROM remains contro- versial. This retrospective study evaluated the effect ofterbutaline on the latency period in patients with PPROM.The result showed that there were no significant differ-ences in the latency period between the two groups. Thisfinding supports other reports that tocolysis does notprolong the latency period [59] .

In the present study, prophylactic antibiotics andantenatal corticosteroids were used to manage PPROMin both groups. Terbutaline was used for tocolysis in themanagement of PPROM. Our results were similar tothose of another prospective study conducted by How etal. [6] which showed no differences in the latency period,no improvement in maternal and neonatal outcomes be-tween the tocolysis and nontocolysis groups. This studyalso used prophylactic antibiotics and antenatal cortico-steroids in both groups. Unlike our study, How et al. [6]used intravenous magnesium sulfate for tocolysis.

On the other hand, a retrospective study by Jazayeri etal. [7] using magnesium sulfate as tocolysis with prophy-lactic antibiotics and antenatal corticosteroids showed ashorter latency period in the tocolysis group without anyimprovement in maternal and neonatal outcomes. Theystated that higher intra-amniotic magnesium levels mightlead to enhanced bacterial growth and to subclinical cho-rioamnionitis and initiation of labor.

Two other prospective studies that evaluated tocolyticagents, without the use of prophylactic antibiotics andantenatal corticosteroids, showed a prolonged latency pe-riod in the tocolysis group [10, 11] without any improve-ment in maternal and neonatal outcomes. In contrast,Matsuda et al. [12] and Fortunato et al. [13] administeredprophylactic antibiotics only in the tocolysis group. Thelatency period was prolonged in the tocolysis group. Itwas suspected that the combination of antibiotics and to-colysis prolonged the latency period.

In the present study, maternal age in the terbutalinegroup was higher than in the nontocolysis group. How-ever, maternal age was not associated with latency periodin previous studies [14, 15]. GA at the time of PPROM wasinversely associated with duration of latency in bothstudies [14, 15]. Moreover, nulliparity was associated witha lower latency period in the Test et al. study [15] .

We did not find any differences between the terbuta-line group and nontocolysis group in maternal morbidity.This is similar to other previously mentioned studies [68]. The use of prophylactic antibiotics may have prevent-ed maternal morbidity in both groups.

In the present study, we also did not detect any differ-ences in neonatal mortality between the two groups.However, we noticed that in the terbutaline group, neo-natal infectious morbidity, such as sepsis, pneumonia,meningitis and omphalitis, were significantly highercompared with the nontocolysis group. Since PPROM isassociated with subclinical intrauterine infection, it ispossible that uterine contraction could be a marker forovert infection. Thus, tocolysis may be able to prolongpregnancy but at the same time increase the risk of expos-ing the fetus to intrauterine infections [4] . Our findingscorroborate the results obtained from Matsuda et al. [12] .

The percentage of patients in the terbutaline groupwho did not deliver within 48 h was significantly highercompared with the nontocolysis group (78.7 vs. 62.7%,p = 0.03). This result is supported by other previouslymentioned studies [7, 10, 12] . Interestingly, there were nodifferences between the two groups in the percentage ofpatients who did not deliver within 7 days. Therefore, ter-butaline may have a short-term benefit of 48 h in patientswith PPROM. This duration of time is just enough forsteroids to promote fetal lung maturity.

Recently, the United States Food and Drug Adminis-tration warned the public that terbutaline should not beused in pregnant women for prevention or prolongedtreatment (beyond 4872 h) of preterm labor in either thehospital or outpatient setting because of the potential forserious maternal heart problems and death [16] .

The strength of this study was the use of terbutalinewith prophylactic antibiotics and antenatal corticoste-roids for the management of PPROM. But due to the na-ture and limitation of a retrospective study, bias may havebeen introduced. Hence, a randomized controlled trial ofterbutaline for the management of PPROM is still war-ranted.

In conclusion, terbutaline cannot prolong the latencyperiod in patients with PPROM nor improve maternalmorbidity. However, it should be noted that neonatal in-fectious morbidity was higher in the terbutaline group.Because terbutaline has a short-term benefit, it can beused for 48 h in patients with PPROM so that the steroidscan promote fetal lung maturity. Physicians should con-sider the risk of neonatal infectious morbidity and deter-mine whether it outweighs the benefit before administer-ing terbutaline in patients with PPROM.


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Effect of Terbutaline on Latency Period in PPROM

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