Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

The association between depressive symptoms during pregnancy and post-delivery fear of childbirth; a prospective study.

BACKGROUND: Fear of childbirth is an important reason for a caesarean section on request. OBJECTIVE: To assess the association between depressive symptoms during pregnancy and post-delivery fear of childbirth (PFOC). METHODS: We prospectively studied pregnant women from two hospitals in the Netherlands. Women completed the Edinburgh Depression Scale (EPDS), the Wijma Delivery Experience Questionnaire (W-DEQ B) and questions concerning risk factors. Depressive symptoms were assessed at baseline and six weeks post-delivery. PFOC was assessed six weeks post-delivery. Baseline characteristics and pregnancy outcomes were compared between women with and without a depression at baseline. The association between depression and PFOC was assessed with multivariable logistic regression analysis. RESULTS: 245 women participated in this study. At baseline 11% suffered from depressive symptoms. There were no differences in pregnancy outcomes. Women with depressive symptoms more often suffered from depressive symptoms six weeks post-delivery (adjusted OR 4.9, 95% CI 1.4-17). PFOC six weeks post-delivery was present in 11%. Women with depression were at increased risk of PFOC six weeks post-delivery (adjusted OR 9.2, 95% CI 2.6-32). CONCLUSION: This study shows that women with depression at baseline are at increased risk for depression and PFOC six weeks post-delivery.

Placental studies elucidate discrepancies between NIPT showing a structural chromosome aberration and a differently abnormal fetal karyotype.

OBJECTIVE: Placental cytogenetic studies may reveal the origin of discordant noninvasive prenatal testing (NIPT). We performed placental studies to elucidate discordances between NIPT showing a structural chromosome aberration and the fetus having a different chromosome aberration in three cases. METHOD: Diagnostic testing with genomic SNP microarray was performed in three cases with NIPT showing a duplication on 4q (case 1), a terminal deletion of 13q (case 2), and a terminal deletion of 15q (case 3). Placental studies involved SNP array analysis of cytotrophoblast and mesenchymal core of chorionic villi of four placental quadrants. Clinical follow-up was performed as well. RESULTS: Amniotic fluid revealed a different structural chromosome aberration than predicted by NIPT: a terminal 2q deletion (case 1), a segmental uniparental isodisomy of 13q (case 2), and a terminal duplication of 15q and of 13q (case 3). Placental studies revealed the aberration detected with NIPT in the cytotrophoblast, whereas the fetal karyotype was confirmed in the placental mesenchymal core. CONCLUSION: Our study shows that targeted cytogenetic investigations for confirmation of NIPT showing a microscopically visible structural chromosome aberration should be avoided, since another aberration, even a submicroscopic one or one involving another chromosome, may be present in the fetus.

Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

OBJECTIVE: Non-invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed. METHOD: NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected. RESULTS: In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre-eclampsia, low birth weight, preterm delivery, and/or congenital malformations. CONCLUSION: The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases.

The effectiveness of mediolateral episiotomy in preventing obstetric anal sphincter injuries during operative vaginal delivery: a ten-year analysis of a national registry.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injuries (OASIS) are associated with an increased risk of faecal incontinence after vaginal delivery. The aim of this retrospective population-based cohort study was to assess whether mediolateral episiotomy is associated with a reduction in the rate of OASIS during operative vaginal delivery. METHODS: We used data from the Dutch Perinatal Registry (Perined) that includes records of almost all births between 2000 and 2010 in The Netherlands. In a cohort of 170,969 primiparous and multiparous women whose delivery was recorded, we estimated the association between mediolateral episiotomy and OASIS following both vacuum and forceps deliveries using univariate and multivariate logistic regression analysis. RESULTS: The incidences of OASIS following vacuum delivery in 130,157 primiparous women were 2.5% and 14% in those with and without a mediolateral episiotomy, respectively (adjusted OR 0.14, 95% CI 0.13-0.15), and in 29,183 multiparous women were 2.0% and 7.5%, respectively (adjusted OR 0.23, 95% CI 0.21-0.27). The incidences of OASIS following forceps delivery in 9,855 primiparous women were 3.4% and 26.7% in those with and without a mediolateral episiotomy, respectively (adjusted OR 0.09, 95% CI 0.07-0.11), and in 1,774 multiparous women were 2.6% and 14.2%, respectively (adjusted OR 0.13, 95% CI 0.08-0.22). CONCLUSIONS: The use of a mediolateral episiotomy during both vacuum delivery and forceps delivery is associated with a fivefold to tenfold reduction in the rate of OASIS in primiparous and multiparous women.

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial.

BACKGROUND: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING: ZonMw.

Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis.

OBJECTIVE: We performed an individual participant data (IPD) metaanalysis to calculate the recurrence risk of hypertensive disorders of pregnancy (HDP) and recurrence of individual hypertensive syndromes. STUDY DESIGN: We performed an electronic literature search for cohort studies that reported on women experiencing HDP and who had a subsequent pregnancy. The principal investigators were contacted and informed of our study; we requested their original study data. The data were merged to form one combined database. The results will be presented as percentages with 95% confidence interval (CI) and odds ratios with 95% CI. RESULTS: Of 94 eligible cohort studies, we obtained IPD of 22 studies, including a total of 99,415 women. Pooled data of 64 studies that used published data (IPD where available) showed a recurrence rate of 18.1% (n=152,213; 95% CI, 17.9-18.3%). In the 22 studies that are included in our IPD, the recurrence rate of a HDP was 20.7% (95% CI, 20.4-20.9%). Recurrence manifested as preeclampsia in 13.8% of the studies (95% CI,13.6-14.1%), gestational hypertension in 8.6% of the studies (95% CI, 8.4-8.8%) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome in 0.2% of the studies (95% CI, 0.16-0.25%). The delivery of a small-for-gestational-age child accompanied the recurrent HDP in 3.4% of the studies (95% CI, 3.2-3.6%). Concomitant HELLP syndrome or delivery of a small-for-gestational-age child increased the risk of recurrence of HDP. Recurrence increased with decreasing gestational age at delivery in the index pregnancy. If the HDP recurred, in general it was milder, regarding maximum diastolic blood pressure, proteinuria, the use of oral antihypertensive and anticonvulsive medication, the delivery of a small-for-gestational-age child, premature delivery, and perinatal death. Normotensive women experienced chronic hypertension after pregnancy more often after experiencing recurrence (odds ratio, 3.7; 95% CI, 2.3-6.1). CONCLUSION: Among women that experience hypertension in pregnancy, the recurrence rate in a next pregnancy is relatively low, and the course of disease is milder for most women with recurrent disease. These reassuring data should be used for shared decision-making in women who consider a new pregnancy after a pregnancy that was complicated by hypertension.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Oxytocin receptor antagonists for inhibiting preterm labour.

BACKGROUND: Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists (ORA), such as atosiban, have been specially developed for the treatment of preterm labour. ORA have been proposed as effective tocolytic agents for women in preterm labour to prolong pregnancy with fewer side effects than other tocolytic agents. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of tocolysis with ORA for women with preterm labour compared with placebo or any other tocolytic agent. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013). SELECTION CRITERIA: We included all randomised controlled trials (published and unpublished) of ORA for tocolysis of labour between 20 and 36 completed weeks' gestation. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated methodological quality and extracted trial data. When required, we sought additional data from trial authors. Results are presented as risk ratio (RR) for categorical and mean difference (MD) for continuous data with the 95% confidence intervals (CI). Where appropriate, the number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated. MAIN RESULTS: This review update includes eight additional studies (790 women), giving a total of 14 studies involving 2485 women.Four studies (854 women) compared ORA (three used atosiban and one barusiban) with placebo. Three studies were considered at low risk of bias in general (blinded allocation to treatment and intervention), the fourth study did not adequately blind the intervention. No difference was shown in birth less than 48 hours after trial entry (average RR 1.05, 95% CI 0.15 to 7.43; random-effects, (two studies, 152 women), perinatal mortality (RR 2.25, 95% CI 0.79 to 6.38; two studies, 729 infants), or major neonatal morbidity. ORA (atosiban) resulted in a small reduction in birthweight (MD -138.86 g, 95% CI -250.53 to -27.18; two studies with 676 infants). In one study, atosiban resulted in an increase in extremely preterm birth (before 28 weeks' gestation) (RR 3.11, 95% CI 1.02 to 9.51; NNTH 31, 95% CI 8 to 3188) and infant deaths (up to 12 months) (RR 6.13, 95% CI 1.38 to 27.13; NNTH 28, 95% CI 6 to 377). However, this finding may be confounded due to randomisation of more women with pregnancy less than 26 weeks' gestation to atosiban. ORA also resulted in an increase in maternal adverse drug reactions requiring cessation of treatment in comparison with placebo (RR 4.02, 95% CI 2.05 to 7.85; NNTH 12, 95% CI 5 to 33). No differences were shown in preterm birth less than 37 weeks' gestation or any other adverse neonatal outcomes. No differences were evident by type of ORA, although data were limited.Eight studies (1402 women) compared ORA (atosiban only) with betamimetics; four were considered of low risk of bias (blinded allocation to treatment and to intervention). No statistically significant difference was shown in birth less than 48 hours after trial entry (RR 0.89, 95% CI 0.66 to 1.22; eight studies with 1389 women), very preterm birth (RR 1.70, 95% CI 0.89 to 3.23; one study with 145 women), extremely preterm birth (RR 0.84, 95% CI 0.37 to 1.92; one study with 244 women) or perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; three studies with 816 infants). One study (80 women), of unclear methodological quality, showed an increase in the interval between trial entry and birth (MD 22.90 days, 95% CI 18.03 to 27.77). No difference was shown in any reported measures of major neonatal morbidity (although numbers were small). ORA (atosiban) resulted in less maternal adverse effects requiring cessation of treatment (RR 0.05, 95% CI 0.02 to 0.11; NNTB 6, 95% CI 6 to 6; five studies with 1161 women).Two studies including (225 women) compared ORA (atosiban) with calcium channel blockers (CCB) (nifedipine only). The studies were considered as having high risk of bias as neither study blinded the intervention and in one study it was not known if allocation was blinded. No difference was shown in birth less than 48 hours after trial entry (average RR 1.09, 95% CI 0.44 to 2.73, random-effects; two studies, 225 women) and extremely preterm birth (RR 2.14, 95% CI 0.20 to 23.11; one study, 145 women). No data were available for the outcome of perinatal mortality. One small trial (145 women), which did not employ blinding of the intervention, showed an increase in the number of preterm births (before 37 weeks' gestation) (RR 1.56, 95% CI 1.13 to 2.14; NNTH 5, 95% CI 3 to 19), a lower gestational age at birth (MD -1.20 weeks, 95% CI -2.15 to -0.25) and an increase in admission to neonatal intensive care unit (RR 1.70, 95% CI 1.17 to 2.47; NNTH 5, 95% CI 3 to 20). ORA (atosiban) resulted in less maternal adverse effects (RR 0.38, 95% CI 0.21 to 0.68; NNTB 6, 95% CI 5 to 12; two studies, 225 women) but not maternal adverse effects requiring cessation of treatment (RR 0.36, 95% CI 0.01 to 8.62; one study, 145 women). No longer-term outcome data were included. AUTHORS' CONCLUSIONS: This review did not demonstrate superiority of ORA (largely atosiban) as a tocolytic agent compared with placebo, betamimetics or CCB (largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths and more births before completion of 28 weeks of gestation in one placebo-controlled study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well-designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side-effect profile than betamimetics) are needed. Consideration of further placebo-controlled studies seems warranted. Future studies of tocolytic agents should measure all important short- and long-term outcomes for women and infants, and costs.

Calcium channel blockers for inhibiting preterm labour and birth.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in low- and middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 November 2013). SELECTION CRITERIA: All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different. MAIN RESULTS: This update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias.Two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.Comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (MD -5.40 days,95% CI -10.84 to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI -8.17 to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.No differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower-dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity. AUTHORS' CONCLUSIONS: Calcium channel blockers (mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longer-term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs.

Outcomes after internal versus external tocodynamometry for monitoring labor.

BACKGROUND: It has been hypothesized that internal tocodynamometry, as compared with external monitoring, may provide a more accurate assessment of contractions and thus improve the ability to adjust the dose of oxytocin effectively, resulting in fewer operative deliveries and less fetal distress. However, few data are available to test this hypothesis. METHODS: We performed a randomized, controlled trial in six hospitals in The Netherlands to compare internal tocodynamometry with external monitoring of uterine activity in women for whom induced or augmented labor was required. The primary outcome was the rate of operative deliveries, including both cesarean sections and instrumented vaginal deliveries. Secondary outcomes included the use of antibiotics during labor, time from randomization to delivery, and adverse neonatal outcomes (defined as any of the following: an Apgar score at 5 minutes of less than 7, umbilical-artery pH of less than 7.05, and neonatal hospital stay of longer than 48 hours). RESULTS: We randomly assigned 1456 women to either internal tocodynamometry (734) or external monitoring (722). The operative-delivery rate was 31.3% in the internal-tocodynamometry group and 29.6% in the external-monitoring group (relative risk with internal monitoring, 1.1; 95% confidence interval [CI], 0.91 to 1.2). Secondary outcomes did not differ significantly between the two groups. The rate of adverse neonatal outcomes was 14.3% with internal monitoring and 15.0% with external monitoring (relative risk, 0.95; 95% CI, 0.74 to 1.2). No serious adverse events associated with use of the intrauterine pressure catheter were reported. CONCLUSIONS: Internal tocodynamometry during induced or augmented labor, as compared with external monitoring, did not significantly reduce the rate of operative deliveries or of adverse neonatal outcomes. (Current Controlled Trials number, ISRCTN13667534; Netherlands Trial number, NTR285.)

Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.

BACKGROUND: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour.

BACKGROUND: In some women, an episode of preterm labour settles and does not result in immediate preterm birth. Subsequent treatment with tocolytic agents such as oxytocin receptor antagonists may then have the potential to prevent the recurrence of preterm labour, prolonging gestation, and preventing the adverse consequences of prematurity for the infant. OBJECTIVES: To assess the effects of maintenance therapy with oxytocin antagonists administered by any route after an episode of preterm labour in order to delay or prevent preterm birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2013), sought ongoing and unpublished trials by contacting experts in the field and searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised controlled trials comparing oxytocin antagonists with any alternative tocolytic agent, placebo or no treatment, used for maintenance therapy after an episode of preterm labour. DATA COLLECTION AND ANALYSIS: We used the standard methods of The Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group. Two review authors independently undertook evaluation of methodological quality and extracted trial data. MAIN RESULTS: This review includes one trial of 513 women. When compared with placebo, atosiban did not reduce preterm birth before 37 weeks (risk ratio (RR) 0.89; 95% confidence intervals (CI) 0.71 to 1.12), 32 weeks (RR 0.85; 95% CI 0.47 to 1.55), or 28 weeks (RR 0.75; 95% CI 0.28 to 2.01). No difference was shown in neonatal morbidity, or perinatal mortality. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of oxytocin receptor antagonists to inhibit preterm birth after a period of threatened or actual preterm labour. Any future trials using oxytocin antagonists or other drugs as maintenance therapy for preventing preterm birth should examine a variety of important infant outcome measures, including reduction of neonatal morbidity and mortality, and long-term infant follow-up. Future research should also focus on the pathophysiological pathways that precede preterm labour.

Internal versus external tocodynamometry during induced or augmented labour.

BACKGROUND: Uterine contractions can be registered by external tocodynamometry (ET) or, after rupture of the membranes, by internal tocodynamometry (IT). Monitoring of the frequency of contractions is important especially when intravenous oxytocin is used as excessive uterine activity (hyperstimulation or tachysystole) can cause fetal distress. During induction of labour as well as during augmentation with intravenous oxytocin, some clinicians choose to monitor frequency and strength of contractions with IT rather than with ET as an intrauterine pressure catheter measures intrauterine activity more accurately than an extra-abdominal tocodynamometry device. However, insertion of an intrauterine catheter has higher costs and also potential risks for mother and child. OBJECTIVES: To assess the effectiveness of IT compared with using ET when intravenous oxytocin is used for induction or augmentation of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2013) and PubMed (1966 to 6 April 2013). SELECTION CRITERIA: We included all published randomised controlled trials with data from women in whom IT was compared with ET in induced or augmented labour with oxytocin. We excluded trials that employed quasi-randomised methods of treatment allocation. We found no unpublished or ongoing studies on this subject. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. MAIN RESULTS: Three studies involving a total of 1945 women were included. Overall, risk of bias across the three trials was mixed. No serious complications were reported in the trials and no neonatal or maternal deaths occurred. The neonatal outcome was not statistically different between groups: Apgar score less than seven at five minutes (RR 1.78, 95% CI 0.83 to 3.83; three studies, n = 1945); umbilical artery pH less than 7.15 (RR 1.31, 95% CI 0.95 to 1.79; one study, n = 1456); umbilical artery pH less than 7.16 (RR 1.23, 95% CI 0.39 to 3.92; one study, n = 239); admission to the neonatal intensive care unit (RR 0.34, 95% CI 0.07 to 1.67; two studies, n = 489); and more than 48 hours hospitalisation (RR 0.92, 95% CI 0.71 to 1.20; one study, n = 1456). The pooled risk for instrumental delivery (including caesarean section, ventouse and forceps extraction) was not statistically significantly different (RR 1.05, 95% CI 0.91 to 1.21; three studies, n = 1945). Hyperstimulation was reported in two studies (n = 489), but there was no statistically significant difference between groups (RR 1.21, 95% CI 0.78 to 1.88). AUTHORS' CONCLUSIONS: This review found no differences between the two types of monitoring (internal or external tocodynamometry) for any of the maternal or neonatal outcomes. Given that this review is based on three studies (N = 1945 women) of moderate quality, there is insufficient evidence to recommend the use of one form of tocodynamometry over another for women where intravenous oxytocin was administered for induction or augmentation of labour.

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Detection of postpartum uterine activity with electrohysterography.

OBJECTIVE: Uterine contractions are essential for childbirth, but also for expulsion of the placenta and for limiting postpartum blood loss. Postpartum hemorrhage is associated with almost 25% of the maternal deaths worldwide and the leading cause of maternal death in most low-income countries. Little is known about the physiology of the uterus postpartum, particularly due to the lack of an accurate measurement tool. The primary objective of this pilot study is to explore the potential of using electrohysterography to detect postpartum uterine contractions. If postpartum uterine activity can be objectified, this could contribute to understanding the physiology of the uterus and improve diagnosis and treatment of postpartum hemorrhage. STUDY DESIGN: In this observational study we included women aiming for a vaginal birth in two large maternity clinics in the Netherlands, Amphia Hospital Breda (group A, N2018-0161) and Máxima Medical Center Veldhoven (group B, N17.149). An electrode patch was placed on the maternal abdomen to record real-time electrical uterine activity until one hour postpartum continuously. In group A, the placement of the patch was lower than in group B. For analysis, tracings were divided into five different phases (1: dilatation until start pushing, 2: from start pushing until childbirth, 3: from childbirth until placental expulsion, 4: first hour after placental expulsion and 5: after one hour postpartum). Readability, signal quality and contraction frequency per hour were assessed. Additionally, patient satisfaction was evaluated through a survey. RESULTS: In total 91 pregnant women were included of whom 45 in group A and 46 women in group B. Complete registrations were obtained throughout the five labor phases with very little artefacts or signal loss. The readability of the tracings decreased after childbirth. A significantly better readability was found in tracings where the patch placement was lower on the abdomen for phases 4 and 5. Contraction frequency was highest during phase 2 and decreased towards phase 5. Women rated the satisfaction with electrohysterography as high and mostly did not notice the patch. CONCLUSION: It is possible to detect uterine activity postpartum with electrohysterography. Further investigation is recommended to improve diagnosis and treatment of postpartum hemorrhage.

Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial.

BACKGROUND: Induction of labour is a common obstetric procedure. Both mechanical (eg, Foley catheters) and pharmacological methods (eg, prostaglandins) are used for induction of labour in women with an unfavourable cervix. We aimed to compare the effectiveness and safety of induction of labour with a Foley catheter with induction with vaginal prostaglandin E2 gel. METHODS: We did an open-label, randomised controlled trial in 12 hospitals in the Netherlands between Feb 10, 2009, and May 17, 2010. We enrolled women with a term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix, an indication for induction of labour, and no prior caesarean section. Participants were randomly allocated by an online randomisation system to induction of labour with a 30 mL Foley catheter or vaginal prostaglandin E2 gel (1:1 ratio). Because of the nature of the intervention this study was not blinded. The primary outcome was caesarean section rate. Secondary outcomes were maternal and neonatal morbidity and time from intervention to birth. All analyses were done on an intention-to-treat basis. We also did a meta-analysis that included our trial. The trial was registered with the Dutch trial registry, number NTR 1646. FINDINGS: 824 women were allocated to induction of labour with a Foley catheter (n=412) or vaginal prostaglandin E2 gel (n=412). Caesarean section rates were much the same between the two groups (23%vs 20%, risk ratio [RR] 1·13, 95% CI 0·87-1·47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture. INTERPRETATION: In women with an unfavourable cervix at term, induction of labour with a Foley catheter is similar to induction of labour with prostaglandin E2 gel, with fewer maternal and neonatal side-effects. FUNDING: None.

Neonatal outcome following elective cesarean section of twin pregnancies beyond 35 weeks of gestation.

OBJECTIVE: We sought to assess neonatal morbidity and mortality of elective cesarean section (CS) of uncomplicated twin pregnancies per week of gestation >35(+0). STUDY DESIGN: We performed a retrospective cohort study in our nationwide database including all elective CS of twin pregnancies. Two main composite outcome measures were defined, ie, severe adverse neonatal outcome and mild neonatal morbidity. RESULTS: We report on 2228 neonates. More than 17% were born <37(+0) weeks of gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for severe adverse neonatal outcome at 35(+0-6), 36(+0-6), and 37(+0-6) weeks were, OR, 9.4; 95% CI, 3.2-27.6; OR, 1.7; 95% CI, 0.5-5.3; and OR, 0.7; 95% CI, 0.2-2.0, respectively; and for mild neonatal morbidity, OR, 4.7; 95% CI, 2.6-8.7; OR, 4.9; 95% CI, 3.1-7.9; and 1.4; 95% CI, 0.9-2.1, respectively, compared to neonates born ≥38(+0) weeks of gestation. CONCLUSION: In uncomplicated twin pregnancies elective CS can best be performed between 37(+0) and 39(+6) weeks of gestation.

Internal versus external tocodynamometry during induced or augmented labour.

BACKGROUND: Uterine contractions can be registered by external tocodynamometry (ET) or, after rupture of the membranes, by internal tocodynamometry (IT). Monitoring of the frequency of contractions is important especially when intravenous oxytocin is used as excessive uterine activity (hyperstimulation or tachysystole) can cause fetal distress. During induction of labour as well as during augmentation with intravenous oxytocin, some clinicians choose to monitor frequency and strength of contractions with IT rather than with ET as an intrauterine pressure catheter measures intrauterine activity more accurately than an extra-abdominal tocodynamometry device. However, insertion of an intrauterine catheter has higher costs and also potential risks for mother and child. OBJECTIVES: To assess the effectiveness of IT compared with using ET when intravenous oxytocin is used for induction or augmentation of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 April 2012) and PubMed (1966 to 7 March 2012). SELECTION CRITERIA: We included all published randomised controlled trials with data from women in whom IT was compared with ET in induced or augmented labour with oxytocin. We excluded trials that employed quasi-randomised methods of treatment allocation. We found no unpublished or ongoing studies on this subject. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. MAIN RESULTS: Three studies involving a total of 1945 women were included. Overall, risk of bias across the three trials was mixed. No serious complications were reported in the trials and no neonatal or maternal deaths occurred. The neonatal outcome was not statistically different between groups: Apgar score less than seven at five minutes (RR 1.78, 95% CI 0.83 to 3.83; three studies, n = 1945); umbilical artery pH less than 7.15 (RR 1.31, 95% CI 0.95 to 1.79; one study, n = 1456); umbilical artery pH less than 7.16 (RR 1.23, 95% CI 0.39 to 3.92; one study, n = 239); admission to the neonatal intensive care unit (RR 0.34, 95% CI 0.07 to 1.67; two studies, n = 489); and more than 48 hours hospitalisation (RR 0.92, 95% CI 0.71 to 1.20; one study, n = 1456). The pooled risk for instrumental delivery (including caesarean section, ventouse and forceps extraction) was not statistically significantly different (RR 1.05, 95% CI 0.91 to 1.21; three studies, n = 1945). Hyperstimulation was reported in two studies (n = 489), but there was no statistically significant difference between groups (RR 1.21, 95% CI 0.78 to 1.88). AUTHORS' CONCLUSIONS: This review found no differences between the two types of monitoring (internal or external tocodynamometry) for any of the maternal or neonatal outcomes. Given that this review is based on three studies (N = 1945 women) of moderate quality, there is insufficient evidence to recommend the use of one form of tocodynamometry over another for women where intravenous oxytocin was administered for induction or augmentation of labour.

Remifentanil patient controlled analgesia versus epidural analgesia in labour. A multicentre randomized controlled trial.

BACKGROUND: Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments. METHODS/DESIGN: The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared. DISCUSSION: This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR2551, http://www.trialregister.nl.