Neonatal outcomes following previable prelabour rupture of membranes before 23 weeks of gestation

Abstract

OBJECTIVE:

To compare outcomes of hospitalized preterm infants following previable prelabour rupture of membranes (PPROM) at≤23 weeks of gestation.

METHODS:

Retrospective cohort study of preterm infants admitted for intensive care, between January 2006 and December 2016 following PPROM, was conducted. Short term clinical outcomes included severity of respiratory morbidity, length of hospital stay and mortality. Neurodevelopment in survivors was assessed using Bayley’s Scales of Infant Development (3rd edition) at 24 months corrected age.

RESULTS:

A total of 82 preterm infants were admitted following PPROM at < 23 weeks and were grouped as: Group 1 (n = 28) with PPROM < 20 weeks and Group 2 (n = 54) with PPROM between 20–22 + ⁶ weeks. Median latency following PPROM was significantly longer in Group 1 infants [69(Interquartile range (IQR): 43–74; Range (R): 25–100 vs. 29(IQR: 10–53; R: 2–72) days, p < 0.001]. Median gestation at delivery was 27.4 weeks (Group 1) vs. 25.1 weeks (Group 2). Group 1 had a significantly higher incidence of oligohydramnios [13(46.4%) vs. 8(14.8%), p = 0.002], lower Apgar scores (<7) at 5 minutes [19(67.9%) vs. 24(44.4%), p = 0.044], increased pulmonary hypoplasia [13(46.4%) vs. 5(9.3%), p < 0.001], joint contractures [3(10.7%) vs. 0, p = 0.037] and mortality [10(35.7%) vs. 7(13.0%), p = 0.016]. Neurodevelopmental outcomes at 24 months corrected age were comparable in the 36 surviving infants (9/18 vs. 27/547).

CONCLUSION:

Morbidity and mortality is high in infants born after previable PPROM; specifically, in those with PPROM < 20 weeks although early childhood neurodevelopmental outcomes were comparable. Larger prospective studies focussing on long term neonatal outcomes are needed to confirm these findings.

Keywords

PPROM previable extreme prematurity preterm morbidity mortality

Abbreviations

CLD

Chronic lung disease

Cerebral palsy

HMD

Hyaline membrane disease

IVH

Intraventricular haemorrhage

LOS

Late onset sepsis

NEC

Necrotizing enterocolitis

NICU

Neonatal intensive care unit

PDA

Patent ductus arteriosus

PPHN

Persistent pulmonary hypertension of newborn

PPROM

Preterm premature rupture of membranes

ROP

Retinopathy of prematurity.

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

2.1 Study design, setting and ethics approval

This single-centre retrospective audit study was approved by the institutional review board of King Edward Memorial Hospital for Women (project ID #13285), the sole tertiary perinatal centre in Western Australia (current population of 2.589 million).

2.2 Participants

Maternal and neonatal health records of all preterm infants with a pregnancy history of previable PPROM before 23 weeks of gestation and admitted to the neonatal intensive care unit between January 2006 and December 2016 were comprised in the study population.

2.3 Subgroups

Outcomes of neonates with PPROM before 20 weeks of gestation (Group 1) were compared to neonates with PPROM at 20–22 + ⁶ weeks of gestation (Group 2).

2.4 Data extraction

Neonatal outcome data to discharge or death as well as long-term developmental data were extracted from the health service’s institutional clinical coding databases: Neobase and neonatal follow up system database.

2.5 Outcomes

Our neonatal intensive care unit follows a standard clinical guideline with reference to use of high frequency ventilation, use of inotropes and surfactant, optimal use of inhaled nitric oxide and judicious use of postnatal steroids in extremely preterm infants. Short-term primary outcomes included: (1) respiratory: incidence of hyaline membrane disease (HMD), chronic lung disease (CLD), need for postnatal steroids, pulmonary hypoplasia, pneumothorax, duration of ventilator support, need for high frequency ventilation and pulmonary haemorrhage, (2) cardiovascular: patent ductus arteriosus (PDA), persistent pulmonary hypertension of newborn (PPHN, (3) gastrointestinal: ≥stage 2 necrotizing enterocolitis (NEC), (4) neurological: significant intraventricular haemorrhage (IVH) i.e. ≥grade 3, periventricular leukomalacia (5) miscellaneous: culture proven late onset sepsis (LOS), retinopathy of prematurity (ROP), joint contractures, length of hospital stay and overall mortality (Detailed definitions of different outcomes are provided in Appendix 1). Secondary long-term neurodevelopmental outcomes for survivors at 24 months corrected age were also compared using the Bayley Scales of Infant and Toddler Development, 3rd Edition [15].

2.6 Developmental measurement

The Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) [15] is undertaken in the neonatal follow-up program at King Edward Memorial Hospital to review the development of infants at 24 months corrected age. This is offered to all infants born less than 29 weeks gestation and/or with a birthweight less than 1250 g. This state-wide program has follow-up rates of approximately 80% and 60% at 24 months for children residing in metropolitan and rural areas, respectively. Bayley-III assessments were performed by clinical psychologists and administered under standardised conditions. The cognitive, language and motor scales were submitted for analysis. The test norms for the Bayley-III fit a normal curve, with a mean of 100 and standard deviation of 15. The cognitive, receptive and expressive communication, gross and fine motor subscales produce age-standardized scores with a mean of 10 and standard deviation of 3. Developmental delay was defined as follows: (a) mild: standard scores between > 1–2 SD below mean (i.e. composite score < 85), (b) moderate-severe: standard scores > 2–3 SD below mean (i.e. composite score < 70). Infants who couldn’t complete assessments due to severe impairment were assigned a composite score of 40 (4SD below mean and below any achievable score).

2.7 Statistical analysis

Table 1
Maternal and neonatal demographic characteristics

Group 1 Group 2 p value

N = 28 N = 54

Maternal

PPROM days/latency period 69 (43–74;25–100) 29 (10–53;2–72) <0.001

APH maternal 16 57.1% 25 46.3% 0.352

Oligohydramnios 12 42.9% 7 13.0% 0.002

Anhydramnios 7 25% 3 5.6% 0.016

Chorioamnionitis (clinical) 11 39.3% 25 46.3% 0.544

AN steroids 28 100.0% 53 98.1% 1.000

GBS 5 17.9% 7 13.0% 0.533

MgSO4 2 7.1% 4 7.4% 1.000

Mode of delivery: SVD 6 21.4% 28 51.9% 0.028

CS 18 64.3% 21 38.9%

Assisted delivery 4 14.3% 5 9.3%

Presentation: Vertex 11 39.3% 33 61.1% 0.029

Breech 15 53.6% 21 38.9%

Oblique/transverse 2 7.1% – –

Neonatal

GA at birth 27.4 (24.9–29.2;23.3–30.9) 25.1 (23.8–29.3;22.7–31.7) 0.090

Birthweight 915 (743–1304;425–1615) 745 (580–1265;440–1972) 0.155

Male 15 53.6% 33 61.1% 0.511

IUGR 4 14.3% 4 7.4% 0.435

Apgar <7 at 1 min 22 78.6% 50 92.6% 0.083

Apgar <7 at 5 mins 19 67.9% 24 44.4% 0.044

	Group 1	Group 2	p value
Maternal
PPROM days/latency period	69	(43–74;25–100)	29	(10–53;2–72)	<0.001
APH maternal	16	57.1%	25	46.3%	0.352
Oligohydramnios	12	42.9%	7	13.0%	0.002
Anhydramnios	7	25%	3	5.6%	0.016
Chorioamnionitis (clinical)	11	39.3%	25	46.3%	0.544
AN steroids	28	100.0%	53	98.1%	1.000
GBS	5	17.9%	7	13.0%	0.533
MgSO4	2	7.1%	4	7.4%	1.000
Mode of delivery: SVD	6	21.4%	28	51.9%	0.028
CS	18	64.3%	21	38.9%
Assisted delivery	4	14.3%	5	9.3%
Presentation: Vertex	11	39.3%	33	61.1%	0.029
Breech	15	53.6%	21	38.9%
Oblique/transverse	2	7.1%	–	–
Neonatal
GA at birth	27.4	(24.9–29.2;23.3–30.9)	25.1	(23.8–29.3;22.7–31.7)	0.090
Birthweight	915	(743–1304;425–1615)	745	(580–1265;440–1972)	0.155
Male	15	53.6%	33	61.1%	0.511
IUGR	4	14.3%	4	7.4%	0.435
Apgar <7 at 1 min	22	78.6%	50	92.6%	0.083
Apgar <7 at 5 mins	19	67.9%	24	44.4%	0.044

Data represent median, interquartile range, range or number and percentage. Abbreviations: AN: antenatal; APH: antepartum haemorrhage; CS: caesarean section; GA: gestational age; GBS: Group B Streptococcus; IUGR: intrauterine growth restriction; MgSO4: magnesium sulphate; PPROM: previable prelabour rupture of membranes; SVD: spontaneous vaginal delivery.

Continuous data were summarised with medians, interquartile ranges (IQR) and ranges (R) and categorical data were summarised as frequency distributions. Comparisons of continuous normal data were made using the Mann-Whitney test and categorical comparisons were made using the Chi-square test or Fisher exact test. Duration of ventilation, nursery stay, and overall hospital stay were made using Kaplan-Meier survival estimates with deaths censored in the analysis and compared between groups using the log-rank test. Neonatal outcomes with sufficient numbers, including Apgar < 7 at 5 minutes, pulmonary hypoplasia, CLD, PDA, PPHN, ventilation duration, hospital length of stay, and mortality, were further analysed by multiple logistic regression for binary outcomes or Cox proportional hazards regression for time to event data with an adjustment for GA at birth. IBM SPSS 20.0 statistical software (IBM Corp, Armonk, NY) was used for statistical analysis and p-values <0.05 were considered statistically significant.

3 Results

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).

Table 2
Short term outcomes

Group 1 Group 2 p value

N = 28 N = 54

HMD 26 92.9% 54 100.0% 0.114

CLD 13 46.4% 31 57.4% 0.344

PDA requiring treatment 14 50.0% 32 59.3% 0.423

PPHN 13 46.4% 23 42.6% 0.740

NEC – 4 7.4% 0.294

Culture proven sepsis 10 37.0% 27 50.0% 0.270

IVH≥grade 3 5 41.7% 7 28.0% 0.468

PVL 0% 0% –

ROP≥stage 2 3 10.7% 15 27.8% 0.077

Ventilation duration (hrs)# 96 (19–533) 178 (66–858) 0.599

HFOV 18 64.3% 23 42.6% 0.062

HFJV 3 10.7% 6 11.1% 1.000

Nitric oxide 15 53.6% 22 40.7% 0.268

Pulmonary hypoplasia 13 46.4% 5 9.3% <0.001

Joint contractures 3 10.7% – 0.037

Pulmonary haemorrhage 4 14.3% 5 9.3% 0.483

Air leak 9 32.1% 17 31.5% 0.951

PN Dexamethasone 5 17.9% 10 18.5% 0.941

Nursery length of stay (d) # 62 (46–115) 86 (47–124) 0.494

Total hospital length of stay (d) # 124 (60–227) 160 (92–225) 0.666

Mortality 10 35.7% 7 13.0% 0.016

	Group 1	Group 2	p value
HMD	26	92.9%	54	100.0%	0.114
CLD	13	46.4%	31	57.4%	0.344
PDA requiring treatment	14	50.0%	32	59.3%	0.423
PPHN	13	46.4%	23	42.6%	0.740
NEC		–	4	7.4%	0.294
Culture proven sepsis	10	37.0%	27	50.0%	0.270
IVH≥grade 3	5	41.7%	7	28.0%	0.468
PVL		0%		0%	–
ROP≥stage 2	3	10.7%	15	27.8%	0.077
Ventilation duration (hrs)#	96	(19–533)	178	(66–858)	0.599
HFOV	18	64.3%	23	42.6%	0.062
HFJV	3	10.7%	6	11.1%	1.000
Nitric oxide	15	53.6%	22	40.7%	0.268
Pulmonary hypoplasia	13	46.4%	5	9.3%	<0.001
Joint contractures	3	10.7%		–	0.037
Pulmonary haemorrhage	4	14.3%	5	9.3%	0.483
Air leak	9	32.1%	17	31.5%	0.951
PN Dexamethasone	5	17.9%	10	18.5%	0.941
Nursery length of stay (d) #	62	(46–115)	86	(47–124)	0.494
Total hospital length of stay (d) #	124	(60–227)	160	(92–225)	0.666
Mortality	10	35.7%	7	13.0%	0.016

Data represent number and percentage, unless otherwise specified. #Data represent median and interquartile range Kaplan-Meier survival estimates. Abbreviations: CLD: chronic lung disease; HFJV: high frequency jet ventilation; HFOV: high frequency oscillatory ventilation; HMD: hyaline membrane disease; IVH: intraventricular haemorrhage; NEC: necrotizing enterocolitis; PDA: patent ductus arteriosus; PN: postnatal; PPHN: persistent pulmonary hypertension; PPROM: previable prelabour rupture of membranes; PVL: periventricular leukomalacia; ROP: retinopathy of prematurity.

Table 3

Neurodevelopmental outcomes at 2 years of age (n = 36)

	Group 1		Group 2		p value
	N = 9		N = 27
GA at birth (wks)	26	(24–29)	25	(22–29)	0.086
Birthweight (g)	880	(650–1615)	740	(430–1460)	0.117
Male	4	44.4%	19	70.4%	0.235
Corrected age at assessment (months)	23.4	(22.9–27.6)	23.9	(20.5–26.1)	0.136
Scaled scores
Cognitive	10	(8–11)	10	(3–13)	0.753
Receptive	9.5	(6–13)	9	(3–13)	0.428
Expressive	8	(7–12)	8	(2–13)	0.631
Fine motor	11	(8–14)	10	(4–16)	0.838
Gross motor	9	(1–12)	9	(2–10)	0.878

Data summaries represent median, range or number and percentage, as appropriate. Abbreviations: GA: gestational age.

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).

4 Discussion

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).

Footnotes

Appendix 1: Definitions

Gestational age is defined as completed weeks of gestation as determined according to the best obstetrical estimate that was based on the last menstrual period or prenatal ultrasonogram or a combination of both.

Oligohydramnios is typically defined as a maximum vertical pocket < .2 cm or an amniotic fluid index < 5 cm on ultrasound.

Anhydramnios is defined as a deepest pocket of amniotic fluid of less than 1 cm.

Chorioamnionitis was defined as acute inflammation of the membranes and chorion of the placenta which can be clinical [presence of typical clinical findings of fever, uterine fundal tenderness, maternal tachycardia (>100/min), fetal tachycardia (>160/min), and purulent or foul amniotic fluid] or histopathologic (microscopic evidence of infection or inflammation on examination of the placenta or chorioamnionic specimens).

Prolonged Rupture of membranes (ROM) is an obvious gush of clear amniotic fluid from vagina or if fluid available, by differentiation with urine or vaginal secretions, for more than 24 hours before birth.

Preterm premature rupture of membranes (PPROM) is defined as spontaneous rupture of the membranes before the onset of labour prior to 37 weeks gestation. It is diagnosed by using Al –Sense Panty Liners and further confirmed by an ultrasound examination to detect oligohydramnios.

Respiratory distress syndrome (RDS) is defined as clinical evidence of respiratory distress along with radiographic findings of bilateral air bronchograms, and/or ground glass, or reticulogranular pattern.

Pulmonary hypoplasia was a clinical diagnosis based on the presence of hypoxic respiratory failure with the need for mechanical ventilation at high pressures and plain chest radiography showing reduced aeration and small lung fields.

Chronic lung disease (CLD) is defined as a continued need for any form of respiratory support (supplemental oxygen and/or assisted ventilation) at 36 weeks post menstrual age (PMA) (post menstrual age is calculated by adding the baby’s age in weeks to the gestational age at birth in weeks).

Persistent pulmonary hypertension of newborn (PPHN) is defined as oxygen requirements of > 60% to maintain an oxygen saturation (SpO2) of > 90% causing hypoxic respiratory failure (HRF). Echocardiographic evidence of right-to-left or bidirectional shunting of blood at the foramen ovale and/or the ductus arteriosus is documented, as well as high pulmonary arterial/right ventricular systolic pressure estimated by doppler velocity measurement of tricuspid regurgitation jet.

Patent ductus arteriosus (PDA) requiring treatment. All infants < 28 weeks of gestation get an echocardiogram done in the first 24 hours of life. Normal cardiac anatomy should be confirmed. Those with a ductus arteriosus > 1.5 mm and/or evidence of ductal steal with reverse flow in diastole in the major blood vessels including descending aorta are targeted for treatment.

Intraventricular haemorrhage (IVH) includes germinal matrix haemorrhage, intraventricular haemorrhage, or periventricular hemorrhage confirmed by a head ultrasound performed by a sonographer and reported by a radiologist using a neonatal probe. The severity is defined according to the Papile and Burstein classification [28].

Necrotizing enterocolitis (NEC) is an inflammatory condition of the gut characterised by gastrointestinal and systemic signs and symptoms including feed intolerance, abdominal distension and tenderness, occult or gross blood and mucus per rectum, lethargy, temperature instability, apnea, and poor peripheral perfusion along with radiologic evidence documented by a radiograph of the abdomen. The severity is described according to the Bell’s staging [].

Retinopathy of prematurity (ROP) is a disorder of the eye, which results in the abnormal development of retinal blood vessels in the preterm neonate established by capturing retinal images by a team of nurses using Retcam device and then viewed by a pediatric ophthalmologist. The severity is described according to the International classification for ROP (ICROP) [29, 30].

Early onset sepsis (EOS) is defined as the presence of at least one episode of systemic sepsis where the initial symptoms occurred within the first 48 hours after birth.

Late onset sepsis (LOS) is the presence of at least one episode of systemic sepsis with the initial symptoms occurring among babies aged 48 hours or more.

Neonatal neurodevelopmental follow up is done for babies born < 32 weeks or < 1500 grams. The developmental assessment (Griffiths Test) [31] is carried out at 12 months of corrected age. Babies born < 29 weeks or < 1250 grams get an additional Bayley III assessment at 24 months of corrected age. This data for our cohort of babies was obtained by using neonatal follow-up database.

Cerebral palsy (CP) is characterised by abnormal muscle tone and impaired motor function and control. The movement ability of infants with CP is graded by the Gross Motor Function Classification System (GMFCS) [32, 33], from level 1 for minimal impairment to level 5 for severe impairment.

Developmental delay is graded as mild, moderate or severe, whereby severe delay is greater than 3 standard deviations (SD), moderate delay as between 2 and 3 SD, and mild delay as between 1 and 2 SD below the mean on either of the cognitive or language scales.

Acknowledgments

Mr. Damber Shrestha, neonatal database manager, Neonatal directorate, King Edward Memorial Hospital.

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

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

Abbreviations

1 Introduction

2 Methods

2.1 Study design, setting and ethics approval

2.2 Participants

2.3 Subgroups

2.4 Data extraction

2.5 Outcomes

2.6 Developmental measurement

2.7 Statistical analysis

5 Conclusions

“Disclosure Statements* Conflict of Interest

Funding

Ethical approval

Footnotes

Appendix 1: Definitions

Acknowledgments

References