Neonatal outcomes following previable prelabour rupture of membranes before 23 weeks of gestation - A retrospective cohort study

Abbreviations

CLD

Chronic lung disease

1 Introduction

Previable preterm rupture of membranes (PPROM) (<24 weeks of gestation) complicates < 1% of pregnancies with a reported incidence of 3.7/1000 pregnancies [1, 2]. Previable PPROM is associated with significant maternal and neonatal morbidity [3, 4]. Preterm birth is usual, with 40–50% delivered within the 1st week and approximately 70–80% delivered after two–five weeks [5–7]. Latency period, gestational age (GA) at PPROM, and severity and persistence of oligohydramnios are the critical factors influencing survival to discharge in this condition [2, 8–10]. Van der Marel and colleagues [11] compared pregnancy and neonatal outcomes in all women with previable PPROM before 20 weeks of gestation (PPROM < 20) and after 20 weeks of pregnancy (PPROM > 20). They reported maternal complications in 50% of the PPROM < 20 group, including intrauterine infection, retained placenta, placental abruption, or sepsis. Neonates born following PPROM < 20 weeks had a higher mortality (46.9% vs. 22.7%, p = 0.008), significantly higher rates of persistent pulmonary hypertension of newborn (PPHN) (64.7%, p = 0.001), and joint contractures (58.8%, p < 0.001) [10]. Lee et al. [12] compared amniotic fluid volume and postnatal outcome after previable PPROM and reported a lower postnatal survival rate and increased developmental delays in participants with persistent oligohydramnios. However, most surviving neonates born after previable PPROM and with oligohydramnios survived to discharge (75.9%) and were developmentally normal. Dotters-Katz [13] studied 174 women with previable PPROM (14.0–22.9 weeks of gestation) and concluded that one in seven women experienced significant morbidity. Hunter and colleagues [8] from our institution published a consecutive case series of previable PPROM (16–24 weeks) from January 2001 to December 2006. They focussed on survival to discharge and concluded that it was significantly lower with PPROM at 16–20 weeks compared with 20–24 weeks (17% vs 39%; p = 0.042). They also generated a predictive model to provide valuable data to assist with antenatal counselling.

Data from the neonatal perspective of short and long-term outcomes of pregnancies that are complicated by previable PPROM remain limited [14]. Given the variability in findings derived from data across tertiary centres and small sample sizes, contemporary and single-centre outcome data are a valuable contribution to guide antenatal counselling from the neonatal outcome perspective. In this audit, preterm infants born after previable PPROM were grouped as follows: Group 1 PPROM≤20 and Group 2 PPROM between 20–22 + ⁶ weeks gestation (PPROM > 20). Short and long-term neonatal outcomes were compared.

2 Methods

Eighty-two admissions [28 infants with PPROM < 20 weeks GA (Group 1), and 54 infants with PPROM 20–22 + ⁶ weeks GA (Group 2)] to NICU were identified with PPROM < 23 weeks between January 2006 to December 2016. There were 17 deaths prior to one year of age of which seven (41%) died within one week, four (23%) died between the first week and six weeks of age, and six (35%) died in early infancy (6 weeks-12 months). Bayley-III outcomes were available in 9 of 18 (50%) surviving infants in Group 1 and 27 of 47 (57%) survivors in Group 2.

Maternal clinical characteristics differed between Group 1 and 2 in terms of duration of PPROM or latency period: median 69 days vs median 29 days (P < 0.001), and incidence of oligohydramnios (defined as AFI < 5 cm or maximum vertical pocket of < 2 cm): 46.4% vs 14.8% (P = 0.002) in the two groups respectively (Table 1). Incidence of anhydramnios in Group 1 was 25% versus group 2 which was 5.5 % (p = 0.016). Details of mode of delivery and fetal presentation are specified in Table 1. There was no difference in the incidence of clinical chorioamnionitis (39.3% vs. 46.3%; p = 0.554). Antenatal magnesium sulphate for neuroprotection was introduced in routine obstetric practice at our institute in 2013 and there was no difference in use of magnesium sulphate between the two groups (7.1% vs. 7.4%; p = 1). Neonatal demographic and clinical characteristics were similar with respect to GA at birth, birthweight and gender. Group 1 was more likely to have Apgar scores < 7 at 5 minutes: 67.9% vs 44.4% (p = 0.044), increased incidence of pulmonary hypoplasia: 46.4% vs 9.3% (p < 0.001), joint contractures: 10.7% vs 0% (p = 0.037), and higher mortality: 35.7% vs 13.0% (p = 0.016) (Table 2). Further analysis of neonatal outcomes with sufficient numbers showed that after adjustment for GA at birth, Group 1 was more likely to have Apgar scores < 7 at 5 minutes (aOR 3.9, 95% CI 1.3–11.6, p = 0.012), pulmonary hypoplasia (aOR 8.5, 95% CI 2.6–28.1, p < 0.001), and mortality (aOR 7.0, 95% CI 1.8–26.3, p = 0.004).

Short term outcomes such as PPHN (46.4 vs 42.6%), CLD (46.4 vs 57.4%), PDA (50 vs 59.3%), sepsis (37 vs 50%), duration of ventilatory support (median 96 vs 178 hrs), and length of hospital stay (median: 124 vs 160 days) did not differ between the groups univariately or after adjustment for GA age at birth. Other short-term outcomes such as joint contractures, NEC≥stage 2 (0% vs. 7.4%), IVH > grade 2 (41.7% vs 28%), ROP≥stage 2 (10.7% vs 27.8%), and incidence of pulmonary hemorrhage (14.3% vs 9.3%) had insufficient sample sizes to run an adjusted analysis.

Of the 36 children who underwent Bayley-III assessment at 24 months corrected age, 2/9 (22.3%) in Group 1 and 7/27 (25.9%) in Group 2 had neurodevelopmental delay and all cases were mild (composite score range 70–85) (Table 3). Two children in Group 2 had delay across all three areas and the remainder had delay in one area only. None had cerebral palsy (CP).

Our study indicates that previable PPROM < 20 weeks was associated with significantly higher morbidity and mortality as compared to those with PPROM between 20 and 22 + ⁶ weeks. Neurodevelopmental outcomes of survivors across both groups at 24 months corrected age were not significantly different between the two groups, although generalisation of this finding is hindered by the small sample size.

The latency period between membrane rupture and delivery is a critical factor in determining the outcomes in PPROM before or at the limit of viability. Median PPROM days were significantly greater in Group 1 than in Group 2 (69 days vs. 29 days, p < 0.001). Dagklis et al. [16] investigated the association of epidemiological and pregnancy-related factors with latency period in cases with PPROM. 303/319 cases of PPROM between 24 + 0–36 + 6 were eligible for inclusion. Median latency period was 5.2 days and exceeded 48 hrs in 65% cases (197/303). They concluded that higher GA at admission (p < 0.001), twin pregnancy (P = 0.02), and chorioamnionitis (p = 0.048) was associated with short latency interval. Our study however, differed from that of Dagklis, predominantly due to the difference in the gestational range studied, with our population focussing on extremely preterm PROM and this would likely explain the differences in outcomes. Phupong et al. [17] in their retrospective study showed that prophylactic antibiotics and tocolysis were major factors associated with latency period≥2 days, where prophylactic antibiotics were associated with latency≥7 days. In our study, there was no difference in prophylactic antibiotics and/or tocolysis. However, our findings were comparable to a previous study by Van der Marel et al. [11] which showed a latency period of 35 days versus 12 days in the groups. Kiver and colleagues [18] reported a median latency period of 38 days (1–126 days) in their cohort of 73 mothers with 93 fetuses hospitalized with PPROM at 15–24 weeks gestation and managed expectantly. They reported an intact survival rate of 45.5%. Also, to survive to achieve admission in a neonatal intensive care unit a fetus in a pregnancy with PPROM < 20 weeks gestation must remain in utero longer than one in which the pregnancy is complicated by PPROM at later gestations. This study assesses a select cohort, those pregnancies with previable PPROM in which the pregnancy continued to a gestation in which the fetus was liveborn and suitable to be admitted to a neonatal intensive care unit.

The incidence of oligohydramnios (defined as AFI < 5 cm or maximum vertical pocket of < 2 cm) was also significantly higher in Group 1 than for Group 2 (46.4% vs 14.8% p = 0.002). However, this was lower than previously published data which showed an average incidence of nearly 70% [11]. The mean GA at birth was higher in Group 1 (27.4 weeks) compared with Group 2 (25.1 weeks), although this difference was not statistically significant (p = 0.09). Our study showed an inverse relationship between the latency period and GA age at rupture with earlier rupture in gestations having longer latencies which also explains the higher GA age at birth [18].

The overall mortality was higher among babies in Group 1 compared to Group 2 (35.7% vs. 13%; p = 0.016); the leading cause of death being hypoxic respiratory failure. This finding is consistent with previous literature which has reported higher mortality. Mia Kibel et al. [11] reported 51% mortality, with Esteves and colleagues reporting mortality rates of 54% [10, 20]. Survival rates in both groups from our cohort (64.3% & 87% respectively) were higher compared to prior reports of 55.6% and 76% across the two groups in Van der Marel et al. study. Esteves et al. [20] noted an average survival of 68.2%. Lorthe et al. recorded 51.7% survivors at discharge (14.1%, 39.5%, 66.8% and 75.8%) with preterm premature rupture of membranes at 22, 23, 24 and 25 weeks respectively in their large prospective study [21]. The higher survival rate in our cohort could be due to advances in contemporary perinatal and neonatal care at our institute although previously Hunter et al. [8] have reported lower survival rates (17% in PPROM < 20 weeks and 39% in PPROM 20–23 weeks) in a similar cohort from our institution. We recognise the differences in outcome are based on the denominator used. The denominator in Hunter et al. included fetal deaths in utero, intrapartum stillbirths, and labour ward deaths, whereas, our study denominator represents fetuses who were live born and survived to be admitted to the neonatal intensive care unit. This explains the differences in survival rates between the studies.

The incidence of pulmonary hypoplasia was significantly greater in Group 1 (46.4%) relative to Group 2 (9.3%; p < 0.001). Fetal lung development during mid-trimester coincided with the critical canalicular stage [22]. PPROM and subsequently oligohydramnios contributed to suboptimal fetal lung development. The main physical force experienced by the lungs during development is mechanical stretch induced by breathing movements and lung fluid in the airspaces. Oligohydramnios reduces the intrathoracic cavity size, thus disrupting fetal lung growth leading to pulmonary hypoplasia. Interestingly, the rates of PPHN and CLD were not significantly different in the two groups in our cohort. This is in contrast to a previous study published by Van der Marel et al. [11] where 64.7 % and 44.4% of infants with PPROM < 20 weeks had PPHN and CLD respectively. Pulmonary hypoplasia is likely irreversible with structural and functional changes in the lung parenchyma. PPHN and CLD on the other hand are multifactorial. The lower incidence of PPHN and CLD across both groups could possibly be explained by all deliveries being inborn, high antenatal steroid use in these GAs (>98%), lower LOS, and standardized ventilation and nutritional strategies with no difference in the use of postnatal steroids for CLD (17.9% vs. 18.4%; p = 0.941).

The risk of developing joint contractures was significantly higher among infants born in group 1 (10.7% vs 0% : p = 0.037) although numbers in each group were a limiting factor. A significant amount of limb growth occurs in the second and third trimesters. Asymmetric intrauterine pressure and restriction in fetal movement associated with PROM before viability may lead to limb deformities [23]. Van der Marel et al. [11] report an incidence of 58.8 % of limb deformities in infants born after PPROM < 20 weeks group. Other important clinical outcomes such as NEC≥stage 2 (7.4%), IVH≥grade 3 (28%), ROP≥stage 2 (28%), and length of hospital stay (124–160 days) were similar to previous published literature [11].

There were no cases of CP in our cohort. Mild neurodevelopmental delay (composite score < 85 : 22.3% vs. 25.9%) was observed in the PPROM < 20 weeks and PPROM between 20–22 + ⁶ weeks groups respectively. Farooqi and colleagues [24] studied 53 consecutive singleton pregnancies with PPROM at 14–28 weeks gestation. Survival without major impairment was observed in 75% (ROM 14–19 weeks) and 80% (ROM 20–25 weeks) respectively. Manuck et al. [25] published data from secondary analysis of a multi-centre-controlled trial of magnesium sulphate for CP prevention. They defined early PPROM as < 25 weeks. Of the 275 infants in this early PPROM group, 4.4% had moderate-severe CP, 29.5% had a Bayley-II mental development index (MDI) <70 and 31% had a physical development index (PDI) <70. Lee and colleagues [26] compared short- and long-term postnatal outcomes after expectant management of pregnancies complicated by previable PPROM (at GA: 14 + 1–24 + 0 weeks) with and without persistent oligohydramnios. They reported 75.9% survival at discharge and developmental delay at a median age of four years (adjusted Odds Ratio: 70.3, 95% CI: 2.9–1,719.9; p = 0.009) in those with persistent oligohydramnios. Accordino and colleagues [27] reported a significant association between lower GA at PPROM, longer latent period, lower GA at delivery, presence of funisitis, and CP. They concluded that neurologic damage was initiated at the moment of rupture of membranes in cases of PPROM. Lorthe et al. reported perinatal and two-year outcomes from the EPIPAGE-2 study [21], where 379/1435 women had a diagnosis of PPROM (22–25 weeks gestation) with 14.1% and 39.5% survivors at discharge with PPROM at 22 and 23 weeks respectively. They concluded that survival without CP at two years was low with PPROM at 22 and 23 weeks.

Strengths and limitations of our study need to be acknowledged. Our study represents comprehensive data from the sole tertiary referral centre for the entire state of Western Australia over a ten-year period (2006–2016), with a high rate of antenatal steroids (>98%), contemporary perinatal and neonatal care, with reasonable follow up rates at 24 months in our neonatal follow up program. However, our study was limited by its retrospective design, small sample size, and data representative only of those periviable infants admitted to the intensive care unit. Our mortality data did not include infants whose families chose ‘no resuscitation’, pregnancies that were medically terminated, or still births.

5 Conclusions

Previable PPROM < 23 weeks is associated with significantly higher morbidity and mortality in our small retrospective study with no significant differences in early childhood neurodevelopmental outcomes among survivors. Larger prospective studies with substantial sample size and longer term neurodevelopmental follow up data are needed to confirm these findings. This crucial information is important for optimizing antenatal and perinatal care.

“Disclosure Statements* Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

There is no funding source.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

The study was approved by the institutional review board of King Edward Memorial Hospital for Women (project ID #13285).