Preterm premature rupture of membranes (PROM) complicates approximately 1–5% of pregnancies.1 Previable preterm PROM (before 24 weeks of gestation) occurs in 3.7 out of every 1,000 births.2 Neonatal survival is poor in most previable preterm PROM case series, but there is great variation among reports with survival rates ranging from 12% to 92%.3,43,4 Persistent oligohydramnios is associated with lower survival. In addition, patients with previable preterm PROM show a higher incidence of neonatal morbidity than preterm neonates born at the same gestational age without preterm PROM.3,5,63,5,63,5,6 We compared the postnatal outcome of neonates born to women managed expectantly after previable preterm PROM with and without persistent oligohydramnios and evaluated factors associated with postnatal survival and developmental delay in a contemporary cohort.
MATERIALS AND METHODS
We performed a retrospective cohort study that spanned January 2002 to September 2014. We identified 148 cases of previable preterm PROM (14 1/7–24 0/7 weeks of gestation) at two tertiary care Korean hospitals (Fig. 1). The study cohort was divided into two groups: those with persistent oligohydramnios, defined as the maximum vertical pocket of amniotic fluid less than 2 cm or as an amniotic fluid index less than 5 cm (n=58), and those with normal amniotic fluid volume (n=34) (Fig. 1). The institutional review boards of Seoul National University Hospital Clinical Research Institute and Ulsan University Hospital approved this study: institutional review board No. H-1501-056-640, Ulsan University Hospital 2015-01-001.
All of the children who were discharged from the hospital had follow-up visits at the same institution. Both singleton and multiple gestations were included. We analyzed only the offspring affected by preterm PROM in multiple gestations. We reviewed the clinical records of the mothers and children for information concerning maternal demographics, clinical presentation, laboratory examinations, ultrasound assessments, and child outcome.
To evaluate the child's short-term outcome, we investigated small for gestational age, neonatal sepsis, intracranial hemorrhage, periventricular leukomalacia, seizure, retinopathy of prematurity, patent ductus arteriosus, pulmonary hypertension, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and foot deformities as well as the child's survival. In addition, we investigated the long-term outcomes in cases of cerebral palsy, developmental delay, and chronic lung disease. Developmental delay of children was evaluated using the Korean-Ages and Stages Questionnaire or by telephone interview. Because the Korean-Ages and Stages Questionnaire is useful only for young children (4–60 months of age), older children (preschool or elementary school age) were instead interviewed by telephone regarding their learning ability. We considered development to be normal in respondents who reported no difficulties in fulfilling their normal academic obligations; those who attended special schools for mentally retarded children were categorized as cases of developmental delay.
Gestational age was determined based on the patient's last menstrual period and an ultrasonographic evaluation. Each patient underwent a sterile speculum examination to confirm preterm PROM. The diagnosis of ruptured membranes was established by observing gross pooling of fluid in the vagina. A Nitrazine paper test of the fluid was performed to assist in the diagnosis.
We performed ultrasound examinations to assess fetal well-being, to measure amniotic fluid volume, and to screen for fetal anomalies. Counseling related to perinatal outcome was provided. If there were no symptoms or signs that met Gibbs' criteria for clinical chorioamnionitis, expectant management was permitted. Gibbs' criteria consist of a temperature of at least 37.8°C and two or more of the following: maternal tachycardia, fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid, and maternal leukocytosis.7
Patients who wanted expectant (conservative) management were admitted to the hospital at the time of preterm PROM diagnosis. All of the admitted patients were promptly treated with broad-spectrum antibiotics. We used third-generation cephalosporin, clarithromycin, and metronidazole as broad-spectrum antibiotics for patients with preterm PROM. Use of these three antibiotics has been a routine regimen for treating patients with preterm PROM since September 2003 at our institution. The antibiotics were continued until there was no evidence of amniotic fluid leakage (no gross pooling of fluid in the vagina and negative Nitrazine paper test) and no evidence of maternal or fetal signs and symptoms of infection. Maternal blood count, maternal body temperature monitoring, fetal heart rate surveillance, and ultrasound scans were serially checked for fetal well-being, and amniotic fluid volume was determined at least twice weekly during the hospital stay.
We also used a single course of steroids (dexamethasone or betamethasone) when delivery was considered imminent after 24 weeks of gestation. Moreover, intravenous tocolytics (magnesium sulfate or ritodrine) were used if regular uterine contractions occurred. Expectant management was continued unless there was clinical or laboratory evidence of an intraamniotic infection, abnormal fetal heart rate pattern, or regular and painful uterine contractions, which were not controlled by tocolytics. The indications for cesarean delivery included previous uterine surgery, suspected fetal jeopardy, fetal malpresentation, placental abruption, and umbilical cord prolapse. We did not consider gestational age to be an indication for cesarean delivery.
Statistical analysis was performed using SPSS 19.0. We analyzed discrete data using the χ2 or Fisher's exact test and continuous variables using Student's t test and Mann-Whitney U test, as appropriate. We also performed multivariable analyses, controlling for confounding variables. A P value <.05 was considered statistically significant.
Ninety-two women gave birth to live neonates, and all of them were transferred to the neonatal intensive care unit after delivery (Table 1). Survival rate at discharge was significantly different between those with and without oligohydramnios—44 of 58 (75.9%) compared with 34 of 34 (100.0%; P=.001; Table 2). In univariate analyses, significant differences were observed in the rates of pulmonary hypertension, respiratory distress syndrome, bronchopulmonary dysplasia, and developmental delay. However, we found that only developmental delay was significantly different after performing multiple regression analysis (adjusted odds ratio [OR] 70.3, 95% confidence interval [CI] 2.9–1,719.9, P=.009) between participants with persistent oligohydramnios and participants with normal amniotic fluid volume.
Developmental delay was evaluated in 74 children. Eighteen participants could not be evaluated as a result of the age of the children or loss of the participant to follow-up. We assessed 46 children using the Korean-Ages and Stages Questionnaire and 28 children by telephone interview or chart review about their preschool or elementary school learning abilities. Three children with cerebral palsy were included as developmental delay cases. The median corrected age at the time of evaluation was 4.0 years (range 4 months to 12 years). Developmental delay was observed in 12 of 40 (30.0%) (8/30 [26.7%] with Korean-Ages and Stages Questionnaire and 4/10 [40.0%] with telephone interview) in participants with persistent oligohydramnios compared with 1 of 34 (2.9%) (1/16 [6.3%] with Korean-Ages and Stages Questionnaire and 0/18 with telephone interview) in participants with normal amniotic fluid volume.
We compared the clinical characteristics of survivors and nonsurvivors in the oligohydramnios group to evaluate factors affecting their survival rate (Table 3). Gestational age at PROM (22.2 compared with 20.3 weeks) and at delivery (28.5 compared with 25.7 weeks of gestation), birth weight (1,110 g compared with 881 g), and incidence of low Apgar scores (less than 7) at 5 minutes (56.8% compared with 100.0%) were significantly different. A multiple regression analysis, performed to control for confounders, revealed that gestational age at delivery (adjusted OR 0.3, 95% CI 0.1–0.7, P=.008) and breech presentation (adjusted OR 90.8, 95% CI 2.2–3,778.1, P=.018) were significant factors affecting survival of children with persistent oligohydramnios.
There were no differences in survival rates at discharge among very early (gestational age at preterm PROM occurred at 14–18 weeks), early (18–22 weeks of gestation), and late preterm PROM participants (22–24 weeks of gestation), although there was an insufficient number of patients with preterm PROM cases 14 and 18 weeks of gestation for meaningful analysis. There was a statistically significant difference in developmental delay between the early and late participants with preterm PROM (Table 4).
Our results show the postnatal survival rate was lower and developmental delay more frequent in patients with persistent oligohydramnios after preterm PROM before 24 weeks of gestation than in participants with normal amniotic fluid volume. However, the overall survival rate was higher than in previous studies.
Several previous previability studies have been conducted. However, most of them did not report the duration of oligohydramnios before delivery. They have demonstrated variability in the proportion of participants with normal amniotic fluid volume after preterm PROM. Hunter et al3 reported a normal amniotic fluid volume rate of 14–24%; in a study by Margato et al,5 20 of 31 participants (64.5%) were characterized by normal amniotic fluid volume. The reason for such wide variation is not clear.
Hadi et al8 investigated 178 pregnancies with PROM at 20–25 weeks of gestation. The perinatal survival rate was lower in the group with than without oligohydramnios (2.1% compared with 69.2%). However, they identified only 13 cases of preterm PROM accompanied by “persistent” oligohydramnios. Brumbaugh et al9 reported a 90% neonatal survival rate in 58 participants with persistent oligohydramnios after previable PROM; because their study showed only the lowest and last maximum vertical pocket, it did not reflect changes in amniotic fluid volume during the entire latency period.
Several studies indicate that gestational age at preterm PROM and latency from preterm PROM to delivery are factors that influence survival.2,5,6,10,112,5,6,10,112,5,6,10,112,5,6,10,112,5,6,10,11 However, because these studies were performed without determining amniotic fluid volume, these predictors cannot be applied to participants with persistent oligohydramnios. We found that gestational at delivery and breech presentation were predictors of survival in participants with persistent oligohydramnios. We speculate that the breech presentation might result in diminished transfer of amniotic fluid to the fetal lung. Interestingly, the incidence of chronic lung disease did not differ significantly in relationship to amniotic fluid volume in our study, although participants with persistent oligohydramnios may have a particular risk for pulmonary hypoplasia.2,5,122,5,122,5,12 These results suggest that a relatively small amniotic fluid volume is required to mature the fetal lungs.
Our study had several limitations. First, we did not include all patients with preterm PROM before 24 weeks of gestation, because we only analyzed data from patients with deliveries after 24 weeks of gestation or greater. Second, we could not evaluate developmental delays using an identical method for all patients as a result of the wide age range of the children at the time of examination. A further limitation was our use of a retrospective cohort study design.
In conclusion, the postnatal survival rate after expectant management of cases of previable preterm PROM with persistent oligohydramnios was lower than that in cases with normal amniotic fluid volume. Developmental delay occurred more frequently in cases of oligohydramnios. However, postnatal outcomes were improved compared with previous studies. We found that early gestational age at delivery and breech presentation were important predictors of poor outcome.
1. Mackeen AD, Seibel-Seamon J, Grimes-Dennis J, Baxter JK, Berghella V. Tocolytics for preterm premature rupture of membranes. The Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007062. DOI: 10.1002/14651858.CD007062.pub2.
2. Waters TP, Mercer BM, The management of preterm premature rupture of the membranes near the limit of fetal viability. Am J Obstet Gynecol 2009;201:230–40.
3. Margato MF, Martins GL, Passini Junior R, Nomura ML. Previable preterm rupture of membranes: gestational and neonatal outcomes. Arch Gynecol Obstet 2012;285:1529–34.
4. Verma U, Goharkhay N, Beydoun S, Conservative management of preterm premature rupture of membranes between 18 and 23 weeks of gestation—maternal and neonatal outcome. Eur J Obstet Gynecol Reprod Biol 2006;128:119–24.
5. Hunter TJ, Byrnes MJ, Nathan E, Gill A, Pennell CE. Factors influencing survival in pre-viable preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2012;25:1755–61.
6. Pristauz G, Bader AA, Schwantzer G, Kutschera J, Lang U. Assessment of risk factors for survival of neonates born after second-trimester PPROM. Early Hum Dev 2009;85:177–80.
7. Gibbs RS, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991;164:1317–26.
8. Hadi HA, Hodson CA, Strickland D. Premature rupture of the membranes between 20 and 25 weeks' gestation: role of amniotic fluid volume in perinatal outcome. Am J Obstet Gynecol 1994;170:1139–44.
9. Brumbaugh JE, Colaizy TT, Nuangchamnong N, O'Brien EA, Fleener DK, Rijhsinghani A, et al.. Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation. Obstet Gynecol 2014;124:992–8.
10. Falk SJ, Campbell LJ, Lee-Parritz A, Cohen AP, Ecker J, Wilkins-Haug L, et al.. Expectant management in spontaneous preterm premature rupture of membranes between 14 and 24 weeks' gestation. J Perinatol 2004;24:611–6.
11. Winn HN, Chen M, Amon E, Leet TL, Shumway JB, Mostello D. Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes—a critical analysis. Am J Obstet Gynecol 2000;182:1638–44.
© 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
12. Van Teeffelen AS, van der Ham DP, Oei SG, Porath MM, Willekes C, Mol BW. The accuracy of clinical parameters in the prediction of perinatal pulmonary hypoplasia secondary to midtrimester prelabour rupture of fetal membranes: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2010;148:3–12.