OBJECTIVE: To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes. METHODS: We performed a nationwide, multicenter, open-label, randomized controlled trial, the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and preterm prelabor rupture of membranes at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm). Participants were allocated to transabdominal amnioinfusion or no intervention in a one-to-one ratio by a web-based system. If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation. The primary outcome was perinatal mortality. We needed 56 women to show a reduction in perinatal mortality from 70% to 35% (β error 0.20, two-sided α error 0.05). RESULTS: Between June 15, 2012, and January 13, 2016, we randomized 28 women to amnioinfusion and 28 to no intervention. One woman was enrolled before the trial registration date (June 19, 2012). Perinatal mortality rates were 18 of 28 (64%) in the amnioinfusion group vs 21 of 28 (75%) in the no intervention group (relative risk 0.86, 95% CI 0.60–1.22, P=.39). CONCLUSION: In women with second-trimester preterm prelabor rupture of membranes and oligohydramnios, we found no reduction in perinatal mortality after amnioinfusion. CLINICAL TRIAL REGISTRATION: NTR Dutch Trial Register, NTR3492.

Background The COVID-19 pandemic led to regional or nationwide lockdowns as part of risk mitigation measurements in many countries worldwide. Recent studies suggest an unexpected and unprecedented decrease in preterm births during the initial COVID-19 lockdowns in the first half of 2020. The objective of the current study was to assess the effects of the two months of the initial national COVID-19 lockdown period on the incidence of very and extremely preterm birth in the Netherlands, stratified by either spontaneous or iatrogenic onset of delivery, in both singleton and multiple pregnancies. Methods Retrospective cohort study using data from all 10 perinatal centers in the Netherlands on very and extremely preterm births during the initial COVID-19 lockdown from March 15 to May 15, 2020. Incidences of very and extremely preterm birth were calculated using an estimate of the total number of births in the Netherlands in this period. As reference, we used data from the corresponding calendar period in 2015–2018 from the national perinatal registry (Perined). We differentiated between spontaneous versus iatrogenic onset of delivery and between singleton versus multiple pregnancies. Results The incidence of total preterm birth < 32 weeks in singleton pregnancies was 6.1‰ in the study period in 2020 versus 6.5‰ in the corresponding period in 2015–2018. The decrease in preterm births in singletons was solely due to a significant decrease in iatrogenic preterm births, both < 32 weeks (OR 0.71; 95%CI 0.53 to 0.95) and < 28 weeks (OR 0.53; 95%CI 0.29 to 0.97). For multiple pregnancies, an increase in preterm births < 28 weeks was observed (OR 2.43; 95%CI 1.35 to 4.39). Conclusion This study shows a decrease in iatrogenic preterm births during the initial COVID-19-related lockdown in the Netherlands in singletons. Future studies should focus on the mechanism of action of lockdown measures and reduction of preterm birth and the effects of perinatal outcome.

Objective: Perinatal mortality after previable prelabor rupture of membranes (previable PROM) might be underestimated as most studies exclude patients with poor prognosis, or solely include patients in tertiary-care centers. We aimed to report perinatal, neonatal and long-term outcomes in a consecutive series of women with pregnancies complicated by previable PROM. Study design: We conducted a prospective cohort study including women with singleton pregnancies and previable PROM 23 +6 weeks gestational age (GA) from one tertiary hospital and eight affiliated secondary hospitals in the region of Amsterdam, the Netherlands (June 2012 until January 2016, PPROMEXIL-III cohort). Exclusion criteria were signs of active labor before onset of PROM or fetal structural anomalies visible at ultrasound. We assessed perinatal mortality. Furthermore, outcomes were maternal, perinatal, neonatal and long-term child characteristics. Results: We included 98 pregnancies with previable PROM. Twelve women (12.2%) opted for termination of pregnancy, resulting in 86 pregnancies included in further analyses. Median GA at PROM was 20 +2 weeks (interquartile range (IQR) 17 +6 -22 +0 ). Median GA at delivery was 22 +6 weeks (IQR 20 +1 -26 +4 ). Delivery within 1 week occurred in 38.4% of women and 60.4% delivered before 24 weeks GA (viability). Perinatal mortality occurred in 73.3% of pregnancies. 23/33 (69.7%) live-born neonates survived to discharge, representing 26.7% of total. None of the children died after discharge. Developmental data at two and/or five years of age was available for 13/23 children (i.e. all children born before 32 weeks of gestation), with 69.2% of children reporting a normal neurodevelopment. However, more than half of children reported respiratory problems. Conclusion:In women with previable PROM perinatal mortality was 73.3%, with a normal neurodevelopment in 69.2% of surviving children with follow-up data. Due to broad inclusion criteria, this cohort represents a population more generalizable to daily practice as compared to previous studies.

Objective To assess the effect of transabdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester prelabour rupture of the membranes (PROM between 16 +0/7-24 +0/7 weeks) and oligohydramnios. Population Follow up of infants of women who participated in the randomised controlled trial: PPROMEXIL-III (NTR3492). Methods Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires. Main outcome measures Neurodevelopmental outcomes were measured. Mild delay was defined as −1 standard deviation (SD), severe delay as −2 SD. Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems. Results In the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60-1.22). Follow-up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy longterm survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53-11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long-term survivor. Conclusions In this small sample of women suffering secondtrimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay.

Over-activation of the receptor, causing excessive influx of Ca ++ can lead to excitotoxicity. The NMDA-Rs encompass three main subtypes (1, 2 and 3) with different modes of action. Magnesium sulphate (Mg) neuroprotective effect in preterm births is mediated in part via blocking of NMDA-Rs. We sought to determine the expression of preterm fetal brain NMDA-R subtypes and the response to inflammation and MG treatment. STUDY DESIGN: Pregnant rats at 16 and 18 days of gestation (48 rats; n¼6 per group) received injections of LPS (500 ug/kg i.p.) or saline at time 0. Dams were randomized to treatment with s.c. saline or Mg (270 mg/kg loading followed by 27 mg/kg q20 min) for 2 hours prior to and following LPS/saline injections. Rats were sacrificed 4 hours following LPS/ saline injection. Fetal brains were harvested and NMDA1-R, NMDA2-R and NMDA3-R protein levels and expression determined by western blot. RESULTS: Saline group: At e16 fetal brain NMDA-R subtypes 1, 2 and 3 protein levels were similar (0.11+0.01, 0.11+0.01, 0.10+ 0.01 u, corresponding to 34%, 34%, 32% respectively). At e18 all NMDA-R subtypes were comparable to their e16 levels (32%, 30%, 38%, respectively). Inflammation group: Following maternal inflammation at e16 and e18 all NMDA-Rs subtypes protein levels increased by approximately twofold. Mg treatment to LPS dams significantly reduced all NMDA-R subtypes to levels similar to control at both e16 and e18. Interestingly, Mg administration to Controls group at e16 significantly decreased (p<0.05) NMDA1-R and NMDA2-R by 10-20%, with no effect on NMDA3-R. At e18, Mg administration to Controls had no effect on NMDA1-R and NMDA2-R, but significantly (p<0.05) decreased NMDA3-R protein levels by 30%. CONCLUSION: Mg neuroprotective effect in preterm birth may be mediated via modulation of the expression of NMDA-Rs thus decreasing Ca ++ induced excitotoxicity. However, Mg treatment may have NMDA-R subtype effects dependent upon gestational age that might interfere with the normal development of the synaptic plasticity.