Child outcomes after amnioinfusion compared with no intervention in women with second-trimester rupture of membranes: a long-term follow-up study of the PROMEXIL-III trial

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 long-term 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 second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay.Tweetable abstract Healthy long-term survival was comparable for children born after second-trimester PROM and treatment with amnioinfusion or no intervention.Research into fetal development and medicin

How to monitor pregnancies complicated by fetal growth restriction and delivery below 32 weeks: a post-hoc sensitivity analysis of the TRUFFLE-study.

OBJECTIVES: In the recent TRUFFLE study it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks, monitoring of the ductus venosus (DV) combined with computerised cardiotocography (cCTG) as a trigger for delivery, increased the chance of infant survival without neurological impairment. However, concerns in interpretation were raised as DV monitoring appeared associated with a non-significant increase in fetal death, and part of the infants were delivered after 32 weeks, after which the study protocol was no longer applied. This secondary sensitivity analysis focuses on women who delivered before 32 completed weeks, and analyses fetal death cases in detail. METHODS: We analysed the monitoring data of 317 women who delivered before 32 weeks, excluding women with absent infant outcome data or inevitable perinatal death. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis. RESULTS: The primary outcome (two year survival without neurological impairment) occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however the difference was not statistically significant (p = 0.21). Nevertheless, in surviving infants 93% was free of neurological impairment in the DV groups versus 85% in the CTG-STV group (p = 0.049). All fetal deaths (n = 7) occurred in women allocated to DV monitoring, which explains this difference. Assessment of the monitoring parameters that were obtained shortly before fetal death in these 7 cases showed an abnormal CTG in only one. Multivariable regression analysis of factors at study entry demonstrated that higher gestational age, larger estimated fetal weight 50th percentile ratio and lower U/C ratio were significantly associated with the (normal) primary outcome. Allocation to the DV groups had a smaller effect, but remained in the model (p < 0.1). Assessment of the last monitoring data before delivery showed that in the CTG-STV group abnormal fetal arterial Doppler was significantly associated with adverse outcome. In contrast, in the DV groups an abnormal DV was the only fetal monitoring parameter that was associated with adverse infant outcome, while fetal arterial Doppler, STV below CTG-group cut-off or recurrent fetal heart rate decelerations were not. CONCLUSIONS: In accordance with the results of the overall TRUFFLE study of the monitoring-intervention management of very early severe FGR we found that the difference in the proportion of infants surviving without neuroimpairment (the primary endpoint) was non-significant when comparing timing of delivery with or without changes in the DV waveform. However, the uneven distribution of fetal deaths towards the DV groups was likely by chance, and among surviving children neurological outcomes were better. Before 32 weeks, delaying delivery until abnormalities in DVPI or STV and/or recurrent decelerations occur, as defined by the study protocol, is therefore probably safe and possibly benefits long-term outcome

Longitudinal study of computerised cardiotocography in early fetal growth restriction.

OBJECTIVES: To explore if in early fetal growth restriction (FGR) the longitudinal pattern of short-term fetal heart rate (FHR) variation (STV) can be used for identifying imminent fetal distress and if abnormalities of FHR registration associate with two-year infant outcome. METHODS: The original TRUFFLE study assessed if in early FGR the use of ductus venosus Doppler pulsatility index (DVPI), in combination with a safety-net of very low STV and / or recurrent decelerations, could improve two-year infant survival without neurological impairment in comparison to computerised cardiotocography (cCTG) with STV calculation only. For this secondary analysis we selected women, who delivered before 32 weeks, and who had consecutive STV data for more than 3 days before delivery, and known infant two-year outcome data. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values except the last one were calculated. Life table analysis and Cox regression analysis were used to calculate the day by day risk for a low STV or very low STV and / or FHR decelerations (DVPI group safety-net) and to assess which parameters were associated to this risk. Furthermore, it was assessed if STV pattern, lowest STV value or recurrent FHR decelerations were associated with two-year infant outcome. RESULTS: One hundred and fourty-nine women matched the inclusion criteria. Using the individual STV regression lines prediction of a last STV below the cCTG-group cut-off had a sensitivity of 0.42 and specificity of 0.91. For each day after inclusion the median risk for a low STV(cCTG criteria) was 4% (Interquartile range (IQR) 2% to 7%) and for a very low STV and / or recurrent decelerations (DVPI safety-net criteria) 5% (IQR 4 to 7%). Measures of STV pattern, fetal Doppler (arterial or venous), birthweight MoM or gestational age did not improve daily risk prediction usefully. There was no association of STV regression coefficients, a last low STV or /and recurrent decelerations with short or long term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DVPI monitoring with a safety-net delivery indication of very low STV and / or recurrent decelerations could increase infant survival without neurological impairment at two years. This post-hoc analysis demonstrates that in early FGR the day by day risk of an abnormal cCTG as defined by the DVPI protocol safety-net criteria is 5%, and that prediction of this is not possible. This supports the rationale for cCTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DVPI is in the normal range

Maternal and Paternal Perception of Child Vulnerability and Behaviour Problems in Very Preterm Born Children

Preterm born children have more behaviour problems than term born children. Perinatal risks, current child functioning, sociodemographic characteristics, parental psychological distress and parental perceptions of child vulnerability (PCV) have been shown to be risk factors for behaviour problems. However, the role of maternal and paternal PCV is unclear, as these have not been investigated as a risk factor for behaviour problems, with all other risk factors taken into account. Aim of this study is to investigate whether maternal and paternal PCV are independent risk factors for behaviour problems in very preterm (VP) and term born children. The present study is a single centre prospective cohort study. Preterm children (n = 104), born at <30 weeks' gestation and/or birth weight <1000 g, and term children (n = 95) were assessed at age 5. Results showed that risk factors for parent-rated behaviour problems were low/middle parental education, VP birth, parental stress and, in VP children, maternal PCV. Risk factors for teacher-rated behaviour problems were low/middle parental education, foreign parental country of birth, intrauterine growth restriction and objective child vulnerabilities. It can be concluded that maternal PCV is a risk factor for parent-rated behaviour problems in VP children. When VP children are presented with behavioural problems, clinicians ought to be aware of the possibility that parents might still perceive their child as vulnerable. The neonatal history of the child, the way parents experienced that period, their perceptions of the child and possible consequences of these perceptions could be subjects for conversation during visits at follow-up clinics

Visual sensory and perceptive functioning in 5-year-old very preterm/very-low-birthweight children

Aim: To examine visual sensory and perceptive functions, study their interrelations, and explore associations between visual dysfunctions and intelligence in very preterm/very-low-birthweight (VP/VLBW) children. Method: One-hundred and sixteen VP/VLBW children (57 males, 59 females; mean gestational age 30.1wks, SD 2.3; mean corrected age 5y 6mo, SD 1mo) and 73 term-born children (40 males, 33 females; mean gestational age 39.9wks, SD 1.3; mean age 5y 6mo, SD 3mo) completed visual sensory (acuity, visual field, contrast-, color-, and stereovision), perceptive (visual coherence, and Developmental Test of Visual Perception non-motor scale), and intelligence assessments. Results: Compared with term-born children, VP/VLBW children had reduced acuity (d=0.70, p<0.001), inferior visual field (d=0.67, p<0.001), and stereovision (v=0.19, p=0.008). VP/VBLW children showed weaker static coherence (d=0.49, p=0.001) and Position in Space (d=0.41, p=0.006) performance, independent of visual sensory deficits, and showed lower Verbal IQ (VIQ) and Performance IQ (PIQ; p<0.001). Visual perceptive functioning accounted for 13% of variance in VIQ, and for 35% of variance in PIQ. Interpretation: Visual sensory and perceptive dysfunctions are present in VP/VLBW children and occur largely independently of each other. Visual perceptive dysfunctions are moderately associated with PIQ, and weakly with VIQ. © 2014 Mac Keith Press

Catch-up growth in children born growth restricted to mothers with hypertensive disorders of pregnancy

Background: In preterm hypertensive disorders of pregnancy, fetal growth restriction (FGR) occurs frequently. The timing and severity of FGR impacts childhood growth and is associated with metabolic changes later in life. Aim: To examine growth and the impact of FGR in early childhood. Design: Prospective cohort study. Participants: Children (n=135) born to mothers who were admitted before 34 weeks' gestational age with a severe hypertensive disorder of pregnancy. Outcome measures: Height, weight, body mass index (BMI), head circumference (HC), SD scores (SDS) at 3 months, and 1 and 4.5 years of age, and complete catch-up growth (height SDS-target height SDS >-1.6). Results: Growth scores were lower compared to Dutch growth curves, except for BMI at 3 months and girls' HC at all ages. Mean height SDS increased over time from -1.4 to -0.5 at 4.5 years, with 94% having complete catch-up growth. Mean BMI SDS decreased from -0.2 at 3 months to -1.0 at 1 year, and was -0.8 at age 4.5. Mean HC SDS was stable over time and -0.3 at 4.5 years. The customised birth weight ratio, as a measure of the degree of FGR, was related to all growth SDS at 4.5 years, while gestational age at birth was not. Conclusions: Although the majority of children born growth restricted had catch-up growth of height within the normal range at 4.5 years of age, they were smaller, but especially lighter compared to Dutch growth charts. The degree of FGR was associated with all growth outcomes

Maternal, perinatal and childhood outcomes of the PPROMEXIL-III cohort: Pregnancies complicated by previable prelabor rupture of membranes

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.Noor E. Simons, Annemijn A. de Ruigh, Larissa I. van der Windt, Brenda M. Kazemier, Aleid G. van Wassenaer-Leemhuis, Augustinus S. van Teeffelen, Elisabeth van Leeuwen, Ben Willem Mol, Janneke van ’t Hooft, Eva Pajkr

Progesterone for preterm birth prevention in women with short cervical length: outcomes in children at 2 years

Objective: To evaluate, in children born to women with a short cervix, and otherwise low-risk , the long-term outcomes after antenatal vaginal progesterone versus placebo (follow-up of the Triple P trial). Methods: The Triple P trial randomized low risk women (n=80) with a short cervix at screening (≤30mm), to progesterone (n=41) or placebo (n=39). At 2'years corrected age children were invited for a neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development-third edition (BSID-III) and a neurological and physical examination by a blinded assessor. Parents filled out the Ages and Stages Questionnaire, the Child Behaviour Checklist (CBCL) and a general health questionnaire. The main outcome of interest was the mean BSID-III cognitive and motor score. Additionally, a composite score of abnormal developmental outcome included BSID-III '1 surgery or >'1 hospital admittance) or mortality. Our sample size, dictated by the original sample of the Triple P trial, gave us 80% power to detect a mean difference (MD) of 15 points (1SD) between groups for the BSID-III tests. Results: Of the 80 children born to the randomised women, 1 child in the progesterone group and 2 children in the placebo group died in the neonatal period. Follow-up data were obtained from 59/77 children (77%) and BSID-III outcomes in 57 children (n=28 progesterone vs n=29 placebo) born at a median gestational age (GA) of 38+6'weeks (IQR 37+3; 40+1'weeks) with a median birthweight of 3240 grams (IQR 2785; 3620grams), Mean BSID-III cognitive developmental scores were 101.6 and 105.0 , mean difference (MD) [95% Confidence Interval (CI)] -3.4 [ 95% -9.3 to 2.6], p=0.29 ) while mean motor scores were 102.4 and 107.3 , MD -4.9 [95% CI -11.2 to 1.4], p='0.13) for progesterone and placebo, respectively. No differences in physical outcomes (including genital and neurological examination) were seen between groups. Conclusion: In this sample of children born to low risk women with a short cervix at screening no relevant differences in neurodevelopmental, behavioural, health care related and physical outcomes were found in the offspring between those exposed to vaginal progesterone or placebo.C.J.J. Cuijpers, J. Van’t Hooft, C. Schneeberger, J.H. Van Der Lee, N.E. Simons, M.A. Van Os, J. Van Der Ven, C.J.M. De Groot, B.W.J. Mol, and A.G. Van Wassenaer-Leemhui

The Ages and Stages Questionnaire and Neurodevelopmental Impairment in Two-Year-Old Preterm-Born Children

OBJECTIVE: To test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two. METHODS: We studied the test results of 224 children, born at <32 postmenstrual weeks, who had scores on ASQ3 and Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII) and neurological examination at 22-26 months' corrected age. We defined NDI as a score of <70 on the cognitive--or motor composite scale of BSIDIII, or impairment on neurological examination or audiovisual screening. We compared NDI with abnormal ASQ3 scores, i.e., < -2SDs on any domain, and with ASQ3 total scores. To correct for possible overestimation of BSIDIII, we also analyzed the adjusted BSIDIII thresholds for NDI, i.e., scores <80 and <85. RESULTS: We found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (<70). Twelve children had NDI at BSIDIII thresholds at <80, and 15 had <85. None of the 163 (73%) children who passed ASQ3 had NDI. The sensitivity of ASQ3 to detect NDI was excellent (100%), its specificity was acceptable (76%), and its negative predictive value (NPV) was 100%. Sensitivity and NPV remained high with the adjusted BSIDIII thresholds. CONCLUSION: The Ages and Stages Questionnaire is a simple, valid and cost-effective screening tool to help identify and exclude NDI in very preterm-born children at the corrected age of two years