Prevotella timonensis bacteria associated with vaginal dysbiosis enhance HIV-1 susceptibility of vaginal CD4+ T cells.

Dysbiosis of the vaginal microbiome poses a serious risk for sexual HIV-1 transmission. Prevotella spp. are abundant during vaginal dysbiosis and associated with enhanced HIV-1 susceptibility; however, underlying mechanisms remain unclear. Here, we investigated the direct effect of vaginal bacteria on HIV-1 susceptibility of vaginal CD4+ T cells. Notably, pre-exposure to Prevotella timonensis enhanced HIV-1 uptake by vaginal T cells, leading to increased viral fusion and enhanced virus production. Pre-exposure to antiretroviral inhibitors abolished Prevotella timonensis-enhanced infection. Hence, our study shows that the vaginal microbiome directly affects mucosal CD4+ T cell susceptibility, emphasising importance of vaginal dysbiosis diagnosis and treatment.

"Hypertension in Pregnancy Intervention Trial At Term" and "Disproportionate Intrauterine Growth Intervention Trial At Term" Studies.

In 2003, in the context of a national research funding program in which obstetric research was prioritized, several perinatal centers took the initiative to jointly submit a number of applications to the subsidy programs of Effectiveness Research and Prevention of ZonMw. This has led to the funding of the Obstetric Consortium with several projects, including the "Hypertension in Pregnancy Intervention Trial At Term" and the "Disproportionate Intrauterine Growth Intervention Trial At Term" studies. The studies showed that induction of labor for hypertension and growth restriction at term was the appropriate management. Subsequent implementation improved maternal and perinatal outcomes.

Does induction of labor at 41 weeks (early, mid or late) improve birth outcomes in low-risk pregnancy? A nationwide propensity score-matched study.

INTRODUCTION: This study aimed to assess whether induction of labor at 41 weeks of gestation improved perinatal outcomes in a low-risk pregnancy compared with expectant management. MATERIAL AND METHODS: Registry-based national cohort study in The Netherlands. The study population comprised 239 971 low-risk singleton pregnancies from 2010 to 2019, with birth occurring from 41+0 to 42+0 weeks. We used propensity score matching to compare induction of labor in three 2-day groups to expectant management, and further conducted separate analyses by parity. The main outcome measures were stillbirth, perinatal mortality, 5-min Apgar <4 and <7, neonatal intensive care unit (NICU) admissions ≥24 h, and emergency cesarean section rate. RESULTS: Compared with expectant management, induction of labor at 41+0 to 41+1 weeks resulted in reduced stillbirths (adjusted odds ratio [aOR] 0.15, 95% confidence interval [CI] 0.05-0.51) in both nulliparous and multiparous women. Induction of labor increased 5-min Apgar score <7 (aOR 1.30, 95% CI 1.09-1.55) and NICU admissions ≥24 h (aOR 2.12, 95% CI 1.53-2.92), particularly in nulliparous women, and increased the cesarean section rate (aOR 1.42, 95% CI 1.34-1.51). At 41+2-41+3 weeks, induction of labor reduced perinatal mortality (aOR 0.13, 95% CI 0.04-0.43) in both nulliparous and multiparous women. The rate of 5-min Apgar score <7 was increased (aOR 1.26, 95% CI 1.06-1.50), reaching significance in multiparous women. The cesarean section rate increased (aOR 1.57, 95% CI 1.48-1.67) in both nulliparous and multiparous women. Induction of labor at 41+4 to 41+5 weeks reduced stillbirths (aOR 0.30, 95% CI 0.10-0.93). Induction of labor increased rates of 5-min Apgar score <4 (aOR 1.61, 95% CI 1.01-2.56) and NICU admissions ≥24 h (aOR 1.52, 95% CI 1.08-2.13) in nulliparous women. Cesarean section rate was increased (aOR 1.47, 95% CI 1.38-1.57) in nulliparous and multiparous women. CONCLUSIONS: At 41+2 to 41+3 weeks, induction of labor reduced perinatal mortality, and in all 2-day groups at 41 weeks, it reduced stillbirths, compared with expectant management. Low 5-min Apgar score (<7 and <4) and NICU admissions ≥24 h occurred more often with induction of labor, especially in nulliparous women. Induction of labor in all 2-day groups coincided with elevated cesarean section rates in nulliparous and multiparous women. These findings pertaining to the choice of induction of labor vs expectant management should be discussed when counseling women at 41 weeks of gestation.

Offspring school performance at age 12 after induction of labor vs non-intervention at term: A linked cohort study.

INTRODUCTION: The incidence of induction of labor, for both medical reasons and as an elective procedure, has been rising and a further increase in induction of labor following the ARRIVE trial may be expected. The effects of induction of labor at term on childhood neurodevelopment, however, are not well studied. We aimed to study the influence of elective induction of labor for each week of gestation separately from 37 to 42 weeks on offspring school performance at 12 years of age after uncomplicated pregnancies. MATERIAL AND METHODS: We performed a population-based study among 226 684 liveborn children from uncomplicated singleton pregnancies, born from 37+0 to 42+0 weeks of gestation in cephalic presentation in 2003-2008 (no hypertensive disorders, diabetes or birthweight ≤p5) in the Netherlands. Children with congenital anomalies, of non-white mothers and born after planned cesarean section were excluded. Birth records were linked with national data on school achievement. We compared, using a fetus-at-risk approach and per week of gestation, school performance score and secondary school level at age 12 in those born after induction of labor to those born after non-intervention, ie spontaneous onset of labor in the same week plus all those born at later gestations. Education scores were standardized to a mean of 0 and a standard deviation of 1 and adjusted in the regression analyses. RESULTS: For each gestational age up to 41 weeks, induction of labor was associated with decreased school performance scores compared with non-intervention (at 37 weeks -0.05 SD, 95% confidence interval [CI] -0.10 to -0.01 SD; adjusted for confounding factors). After induction of labor, fewer children reached higher secondary school level (at 38 weeks 48% vs 54%; adjusted odds ratio [aOR] 0.88, 95% CI 0.82-0.94). CONCLUSIONS: In women with uncomplicated pregnancies at term, consistently, at every week of gestation from 37 to 41 weeks, induction of labor is associated with lower offspring school performance at age 12 and lower secondary school level compared with non-intervention, although residual confounding may remain. These long-term effects of induction of labor should be incorporated in counseling and decision making.

Risk factors for spontaneous preterm birth among healthy nulliparous pregnant women in the Netherlands, a prospective cohort study.

Introduction: Spontaneous preterm birth (sPTB) is a major contributor to neonatal morbidity and mortality worldwide. The pathophysiology of sPTB is poorly understood, in particular among nulliparous women without apparent medical or obstetric risk factors. Therefore, we aimed to identify risk factors for sPTB in healthy nulliparous women. Material and Methods: We performed a prospective cohort study. Recruitment took place from February 2014 to December 2016 in 16 community midwifery centers in the Netherlands. Eligibility criteria were: ≥18 years, no previous pregnancy >16 weeks of gestation, healthy singleton pregnancy, and antenatal booking <24 weeks of gestation. At study inclusion, participants completed a questionnaire, including details on lifestyle, work, and medical history. Cervical length was measured by vaginal ultrasound at the second-trimester anomaly scan. Detailed information concerning pregnancy and birth was collected via antenatal charts. We calculated the adjusted odds ratio (aOR) and 95% confidence intervals (CI) for various risk factors with correction for socioeconomic status (SES) using logistic regression and Firth's correction. Results: We included 363 women of whom pregnancy outcomes were available in 349 (96.1%) participants. The cervical length measurement was available for 225 (62.0%) participants. sPTB occurred in 26 women (7.5%). SES was associated with sPTB (OR: 3.7, 95%  CI: 1.6-8.5) in univariate analysis. First or second trimester vaginal bleeding (aOR: 3.6, 95% CI: 1.4-9.0) and urinary tract infection during pregnancy (aOR: 4.9, 95% CI: 1.7-13.9) were associated with sPTB in multivariate analysis. Conclusions: This prospective cohort confirms established risk factors for sPTB in nulliparous women deemed at low risk of sPTB.

Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. METHODS: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or ß2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 µg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39. RESULTS: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure. INTERPRETATION: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. FUNDING: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

TBX2, a Novel Regulator of Labour.

Background and Objectives: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods: RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results: Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions: We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.

Ethnic differences in the impact of male fetal gender on the risk of spontaneous preterm birth.

OBJECTIVE: To study the impact of fetal gender on the risk of spontaneous preterm birth in various ethnicities. STUDY DESIGN: National cohort study in which all singleton live births from 25+0 weeks onwards without congenital anomalies were included of African, Asian, and Mediterranean women (1999-2010). Our primary outcome measure was preterm birth before 37 weeks. Per ethnic group, male and female neonates were compared. RESULT: In each ethnic group, male fetuses were at increased risk of preterm birth (adjusted odds ratio (aOR) 1.63 for African, aOR 1.71 for Asian, and aOR 1.84 for Mediterranean males). The population-attributable risk of male gender on spontaneous preterm birth is lower in African women (3.9%) than in Asian (10.3%) and Mediterranean women (9.0%). CONCLUSION: Male fetal gender is associated with spontaneous preterm birth in African, Asian, and Mediterranean women, but the total impact of ethnicity on spontaneous preterm birth rate is different.

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: A prospective cohort study.

INTRODUCTION: Little is known about the pathophysiology of hyperemesis gravidarum (HG). Proposed underlying causes are multifactorial and thyroid function is hypothesized to be causally involved. In this study, we aimed to assess the utility of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) as a marker and predictor for the severity and clinical course of HG. MATERIAL AND METHODS: We conducted a prospective cohort study including women admitted for HG between 5 and 20 weeks of gestation in 19 hospitals in the Netherlands. Women with a medical history of thyroid disease were excluded. TSH and FT4 were measured at study entry. To adjust for gestational age, we calculated TSH multiples of the median (MoM). We assessed HG severity at study entry as severity of nausea and vomiting (by the Pregnancy Unique Quantification of Emesis and nausea score), weight change compared with prepregnancy weight, and quality of life. We assessed the clinical course of HG as severity of nausea and vomiting and quality of life 1 week after inclusion, duration of hospital admissions, and readmissions. We performed multivariable regression analysis with absolute TSH, TSH MoMs, and FT4. RESULTS: Between 2013 and 2016, 215 women participated in the cohort. TSH, TSH MoM, and FT4 were available for, respectively, 150, 126, and 106 of these women. Multivariable linear regression analysis showed that lower TSH MoM was significantly associated with increased weight loss or lower weight gain at study entry (ΔKg; ß = 2.00, 95% CI 0.47-3.53), whereas absolute TSH and FT4 were not. Lower TSH, not lower TSH MoM or FT4, was significantly associated with lower nausea and vomiting scores 1 week after inclusion (ß = 1.74, 95% CI 0.36-3.11). TSH and FT4 showed no association with any of the other markers of the severity or clinical course of HG. Twenty-one out of 215 (9.8%) women had gestational transient thyrotoxicosis. Women with gestational transient thyrotoxicosis had a lower quality of life 1 week after inclusion than women with no gestational transient thyrotoxicosis (p = 0.03). CONCLUSIONS: Our findings show an inconsistent role for TSH, TSH MoM, or FT4 at time of admission and provide little guidance on the severity and clinical course of HG.

Severe postpartum hemorrhage increases risk of posttraumatic stress disorder: a prospective cohort study.

PURPOSE: To evaluate whether severe postpartum hemorrhage (PPH) is a risk factor for posttraumatic stress disorder (PTSD). Severe PPH can be experienced as a traumatic event. PTSD leads to negative mental health effects. Knowing risk factors for PTSD during childbirth offers opportunities for early interventions, which may prevent the development of PTSD. MATERIALS AND METHODS: In this prospective study, we compared two groups of participants; women with ≥2000 mL of blood loss (severe PPH, patients) and women with ≤500 mL of blood loss (controls). Participants were screened for PTSD using the PCL-5 four to six weeks after delivery. Positive screening was followed by the CAPS-5 to diagnose PTSD. RESULTS: We included 187 PPH patients and 121 controls. Median PCL-5 scores were higher for PPH patients (5.0) than controls (4.0, p = 0.005). Thirteen PPH patients (7.0%) and two controls (1.7%) scored ≥32 on the PCL-5, indicative of probable PTSD (OR 4.45, 95% CI 0.99-20.06, p = 0.035). Significant more PPH patients than controls met criteria for a clinical diagnosis of PTSD on the CAPS-5 (n = 10, 5.6% vs n = 0, 0.0%; p = 0.007). CONCLUSIONS: There is a significant and clinically relevant increased risk for developing PTSD after severe PPH. Gynecologists and midwives are advised to screen for PTSD at postpartum follow-up visits to prevent long-term negative mental health effects. CLINICAL TRIAL REGISTRATION: NL50273.100.14.

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials.

BACKGROUND: The risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject. METHODS AND FINDINGS: We searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available. From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] -57/10,000 [95% CI -106/10,000 to -8/10,000], I2 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267). Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD -31/10,000, [95% CI -56/10,000 to -5/10,000], I2 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD -97/10,000 [95% CI -169/10,000 to -26/10,000], I2 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results. Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD -127/10,000, [95% CI -204/10,000 to -50/10,000], I2 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI -29/10,000 to 84/10,000], I2 55%). A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited. CONCLUSIONS: In this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks. Study Registration: PROSPERO CRD42020163174.

Decreasing trend in preterm birth and perinatal mortality, do disparities also decline?

BACKGROUND: In the Netherlands, several initiatives started after the publication of the PERISTAT findings that showed the perinatal mortality risk was higher than in other European countries. The objective of this study is 1) to report recent trends in perinatal mortality and in intermediate risk groups (preterm birth, congenital anomalies and small for gestational age (SGA)), 2) describing perinatal mortality risk among children born preterm, with congenital anomalies or SGA, and born in maternal high risk groups (parity, age, ethnicity and socio-economic status (SES)). METHODS: A nationwide cohort study in the Netherlands among 996,423 singleton births in 2010-2015 with a gestational age between 24.0 and 42.6 weeks. Trend tests, univariate and multivariable logistic regression analyses were used. We did separate analyses for gestational age subgroups and line of care. RESULTS: The perinatal mortality rate was 5.0 per 1000 and it decreased significantly from 5.6 in 2010 to 4.6 per 1000 in 2015. Preterm birth significantly declined (6.1% in 2010 to 5.6% in 2015). Analysis by gestational age groups showed that the largest decline in perinatal mortality of 32% was seen at 24-27 weeks of gestation where the risk declined from 497 to 339 per 1000. At term, the decline was 23% from 2.2 to 1.7 per 1000. The smallest decline was 3% between 32 and 36 weeks. In children with preterm birth, congenital anomalies or SGA, the perinatal mortality risk significantly declined. Main risk factors for perinatal mortality were African ethnicity (adjusted odds ratio (aOR) 2.1 95%CI [1.9-2.4]), maternal age ≥ 40 years (aOR1.9 95%CI [1.7-2.2]) and parity 2+ (aOR 1.4 95%CI [1.3-1.5]). Among the (post)term born neonates, there was no significant decline in perinatal mortality in women with low age, low or high SES, non-Western ethnicity and among women who started or delivered under primary care. CONCLUSIONS: There is a decline in preterm birth and in perinatal mortality between 2010 and 2015. The decline in perinatal mortality is both in stillbirths and in neonatal mortality, most prominently among 24-27 weeks and among (post)term births. A possible future target could be deliveries among 32-36 weeks, women with high maternal age or non-Western ethnicity.

Intrapartum epidural analgesia and low Apgar score among singleton infants born at term: A propensity score matched study.

INTRODUCTION: The associations of epidural analgesia and low Apgar score found in the Swedish Registry might be a result of confounding by indication. The objective of this study was to assess the possible effect of intrapartum epidural analgesia on low Apgar score and neonatal intensive care unit (NICU) admission in term born singletons with propensity score matching. MATERIAL AND METHODS: This was a propensity score matched study (n = 257 872) conducted in a national cohort of 715 449 term live born singletons without congenital anomalies in the Netherlands. Mothers with prelabor cesarean section were excluded. Main outcome measures were 5-minute Apgar score <7, 5-minute Apgar score <4 and admission to a NICU for at least 24 hours. First, an analysis of the underlying risk factors for low Apgar score <7 was performed. Multivariable analyses were applied to assess the effect of the main risk factor, intrapartum epidural analgesia, on low Apgar score to adjust the results for confounding factors. Second, a propensity score matched analysis on the main risk factors for epidural analgesia was applied. By propensity score matching the (confounding) characteristics of the women who received epidural analgesia with the characteristics of the control women without epidural analgesia, the effect of possible confounding by indication is minimized. RESULTS: Intrapartum epidural analgesia was performed in 128 936 women (18%). Apgar score <7 was present in 1.0%, Apgar score <4 in .2% and NICU admission in .4% of the deliveries. The strongest risk factor for Apgar score <7 was epidural analgesia (adjusted odds ratio [aOR] 1.9, 95% confidence interval [CI] 1.8-2.0). The propensity score matched adjusted analysis of women with epidural analgesia showed significant adverse neonatal outcomes: aOR 1.8 (95% CI 1.7-1.9) for AS <7, aOR 1.6 (95% CI 1.4-1.9) for AS <4 and aOR 1.7 (95% CI 1.6-1.9) for NICU admission. The results of epidural analgesia on AS <7 were also significantly increased for spontaneous start of labor (aOR 2.0, 95% CI 1.8-2.1) and for spontaneous delivery. CONCLUSIONS: Intrapartum epidural analgesia at term is strongly associated with low Apgar score and more NICU admissions, especially in spontaneous deliveries. This association needs further research and awareness.

Determinants of disease course and severity in hyperemesis gravidarum.

OBJECTIVE: We aimed to identify determinants that predict hyperemesis gravidarum (HG) disease course and severity. STUDY DESIGN: For this study, we combined data of the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial (RCT) and its associated observational cohort with non-randomised patients. Between October 2013 and March 2016, in 19 hospitals in the Netherlands, women hospitalised for HG were approached for study participation. In total, 215 pregnant women provided consent for participation. We excluded women enrolled during a readmission (n = 24). Determinants were defined as patient characteristics and clinical features, available to clinicians at first hospital admission. Patient characteristics included i.e. age, ethnicity, socio-economic status, history of mental health disease and HG and gravidity. Clinical features included weight loss compared to pre-pregnancy weight and symptom severity measured with Pregnancy Unique Quantification of Emesis (PUQE-24) questionnaire and the Nausea and Vomiting in Pregnancy specific Quality of Life questionnaire (NVPQoL). Outcome measures were measures of HG disease severity present at 1 week after hospital admission, including weight change, PUQE-24 and NVPQoL scores. Total days of admission hospital admission and readmission were also considered outcome measures. RESULTS: We found that high PUQE-24 and NVPQoL scores at hospital admission were associated with those 1 week after hospital admission (difference (ß) 0.36, 95 %CI 0.16 to 0.57 and 0.70,95 %CI 0.45-1.1). PUQE-24 and NVPQoL scores were not associated with other outcome measures. None of the patient characteristics were associated with any of the outcome measures. CONCLUSION: Our findings suggest that the PUQE-24 and NVPQoL questionnaires can identify women that maintain high symptom scores a week after admission, but that patient characteristics cannot be used as determinants of HG disease course and severity.

Posttraumatic stress disorder in partners following severe postpartum haemorrhage: A prospective cohort study.

BACKGROUND: Partners of women are increasingly present during childbirth and may be exposed to a traumatic experience. Since parents' mental health issues (i.e. posttraumatic stress disorder) have been shown to increase the risk of problems in the child's development, it is important to identify these risk factors. Partners often describe severe postpartum haemorrhage as traumatic. AIM: Whether witnessing severe postpartum haemorrhage is a risk factor for developing posttraumatic stress disorder in partners. METHODS: In this prospective cohort study, we compared partners of women with severe postpartum haemorrhage (≥2000 mL) and partners of women with ≤500 mL of blood loss (controls). Four weeks after birth partners were screened for posttraumatic stress disorder symptoms with a self-report questionnaire. Scores ≥11 were followed by a gold standard clinical interview to diagnose posttraumatic stress disorder. FINDINGS: We included 123 severe postpartum haemorrhage partners and 62 control partners. Partners of women with severe postpartum haemorrhage reported higher scores than control partners (median 3.0 (0.0-7.0) vs 2.0 (0.0-4.0), p = 0.04) on symptoms of posttraumatic stress, but no significant difference in probable posttraumatic stress disorder diagnosis according to the self-report questionnaire was found. According to the clinical interview no partners were diagnosed with posttraumatic stress disorder. Severe postpartum haemorrhage was experienced as traumatic by the partners who felt excluded. CONCLUSION: None of the partners developed posttraumatic stress disorder, revealing the resilience of young fathers. Because some partners reported severe postpartum haemorrhage as traumatic, we recommend sufficient information and support is provided during childbirth.

Intrapartum and neonatal mortality in low-risk term women in midwife-led care and obstetrician-led care at the onset of labor: A national matched cohort study.

INTRODUCTION: Midwife-led models of care have been the subject of debate for many years. We conducted a study to compare intrapartum and neonatal mortality rates in midwife-led (primary) vs obstetrician-led (secondary) care at the onset of labor in low-risk term women. MATERIAL AND METHODS: We performed an unmatched and a propensity score matched cohort study using data from the national perinatal audit registry (PAN) and from the national perinatal registry (PERINED) of the Netherlands. We included women with singleton pregnancies (without congenital anomalies or antepartum fetal death) who gave birth at term between 2010 and 2012. We excluded the following major risk factors: non-vertex position of the fetus, previous cesarean birth, hypertension, diabetes mellitus, prolonged rupture of membranes (≥24 hours), vaginal bleeding in the second half of pregnancy, nonspontaneous start of labor and post-term pregnancy (≥42 weeks). The primary outcome was intrapartum or neonatal mortality up to 28 days after birth. Secondary outcome measures were mode of delivery and a 5-minute Apgar score <7. RESULTS: We included 259 211 women. There were 100/206 642 (0.48‰) intrapartum and neonatal deaths in the midwife group and 23/52 569 (0.44‰) in the obstetrician group (odds ratio [OR] 1.11, 95% CI 0.70-1.74). Propensity score matched analysis showed mortality rates of 0.49‰ (26/52 569) among women in midwife-led care and 0.44‰ (23/52 569) for women in obstetrician-led care (OR 1.13, 95% CI 0.65-1.98). In the midwife group there were significantly lower rates of vaginal instrumental deliveries (8.4% vs 13.0%; matched OR 0.65, 95% CI 0.62-0.67) and intrapartum cesarean sections (2.6% vs 8.2%; matched OR 0.32, 95% CI 0.30-0.34), and fewer neonates with low Apgar scores (<7 after 5 minutes) (0.69% vs 1.11%; matched OR 0.61, 95% CI 0.53-0.69). CONCLUSIONS: Among low-risk term women, there were comparable intrapartum and neonatal mortality rates for women starting labor in midwife-led vs obstetrician-led care, with lower intervention rates and fewer low Apgar scores in the midwife group.

CONDISOX- continued versus discontinued oxytocin stimulation of induced labour in a double-blind randomised controlled trial.

BACKGROUND: Oxytocin is an effective drug for induction of labour, but is associated with serious adverse effects of which uterine tachysystole, fetal distress and the need of immediate delivery are the most common. Discontinuation of oxytocin once the active phase of labour is established could reduce the adverse effects. The objective is to investigate how the caesarean section rate is affected when oxytocin stimulation is discontinued in the active phase of labour compared to labours where oxytocin is continued. METHODS: CONDISOX is a double-blind multicentre randomised controlled trial conducted at Danish and Dutch Departments of Obstetrics and Gynaecology. The first participant was recruited on April 8 2016. Based on a clinically relevant relative reduction in caesarean section rate of 7%, an alpha of 0.05, a beta of 80%, we aim for 1200 participating women (600 in each arm). The CONDISOX trial includes women at a gestational age of 37-42 complete weeks of pregnancy, who have uterine activity stimulated with oxytocin infusion for the induction of labour. Women are randomised when the active phase of labour becomes established, to study medication containing either oxytocin (continuous group) or placebo (discontinued group) infusion. Women are stratified by birth site, indication for oxytocin stimulation (induction of labour, prelabour rupture of membranes) and parity (nulliparous, parous +/- previous caesarean section). We will compare the primary outcome, caesarean section rate, in the two groups using a chi-square test with a p-value of 0.05. If superiority is not demonstrated, we have a pre-defined post hoc non-inferiority boundary (margin, delta) at 1.09. Secondary outcomes include duration of the active phase of labour, incidence of uterine tachysystole, postpartum haemorrhage, admission to the neonatal intensive care unit, Apgar score, umbilical arterial blood pH, and birth experience. DISCUSSION: The high frequency of oxytocin use and the potential risks of both maternal and fetal adverse effects of oxytocin emphasise the need to determine the optimal oxytocin regime for induction of labour. TRIAL REGISTRATION: NCT02553226 (registered September 17, 2015). Eudra-CT number: 2015-002942-30.

Postnatal Catch-Up Growth After Suspected Fetal Growth Restriction at Term.

Objective: The aim of this study was to study growth patterns of children born after suspected fetal growth restriction (FGR) at term and to compare the effect of induction of labor (IoL) and expectant management (EM), also in relation to neurodevelopmental and behavioral outcome at age 2. Methods: We performed a 2 years' follow-up of growth of children included in the Disproportionate Intrauterine Growth Restriction Trial at Term (DIGITAT) study, a Randomized Controlled Trial (RCT) comparing IoL with EM in pregnancies with suspected FGR at term. We collected data on child growth until the age of 2 years. Standard deviation scores (SDSs) for height and weight were calculated at different ages. We assessed the effects of IoL compared with EM and the effects of a birth weight below or above the 3rd or 10th centile on catch-up growth. Target height SDSs were calculated using the height of both parents. Results: We found a significant increase in SDS in the first 2 years. Children born after EM showed more catch-up growth in the first month [height: mean difference -0.7 (95% CI: 0.2; 1.3)] and weight [mean difference -0.5 (95% CI: 0.3; 0.7)]. Children born with a birth weight below the 3rd and 10th centiles showed more catch-up growth after 1 year [mean difference -0.8 SDS (95% CI: -1.1; -0.5)] and after 2 years [mean difference -0.7 SDS (95% CI: -1.2; -0.2)] as compared to children with a birth weight above the 3rd and 10th centiles. SDS at birth had the strongest effect on adverse neurodevelopmental outcome at 2 years of age. Conclusion: After FGR at term, postnatal catch-up growth is generally present and associated with the degree of FGR. Obstetric management in FGR influences postnatal growth. Longer-term follow-up is therefore needed and should be directed at growth and physical health. Clinical Trial Registration: www.ClinicalTrials.gov, identifier SRCTN10363217.

Predicting seizures in pregnant women with epilepsy: Development and external validation of a prognostic model.

BACKGROUND: Seizures are the main cause of maternal death in women with epilepsy, but there are no tools for predicting seizures in pregnancy. We set out to develop and validate a prognostic model, using information collected during the antenatal booking visit, to predict seizure risk at any time in pregnancy and until 6 weeks postpartum in women with epilepsy on antiepileptic drugs. METHODS AND FINDINGS: We used datasets of a prospective cohort study (EMPiRE) of 527 pregnant women with epilepsy on medication recruited from 50 hospitals in the UK (4 November 2011-17 August 2014). The model development cohort comprised 399 women whose antiepileptic drug doses were adjusted based on clinical features only; the validation cohort comprised 128 women whose drug dose adjustments were informed by serum drug levels. The outcome was epileptic (non-eclamptic) seizure captured using diary records. We fitted the model using LASSO (least absolute shrinkage and selection operator) regression, and reported the performance using C-statistic (scale 0-1, values > 0.5 show discrimination) and calibration slope (scale 0-1, values near 1 show accuracy) with 95% confidence intervals (CIs). We determined the net benefit (a weighted sum of true positive and false positive classifications) of using the model, with various probability thresholds, to aid clinicians in making individualised decisions regarding, for example, referral to tertiary care, frequency and intensity of monitoring, and changes in antiepileptic medication. Seizures occurred in 183 women (46%, 183/399) in the model development cohort and in 57 women (45%, 57/128) in the validation cohort. The model included age at first seizure, baseline seizure classification, history of mental health disorder or learning difficulty, occurrence of tonic-clonic and non-tonic-clonic seizures in the 3 months before pregnancy, previous admission to hospital for seizures during pregnancy, and baseline dose of lamotrigine and levetiracetam. The C-statistic was 0.79 (95% CI 0.75, 0.84). On external validation, the model showed good performance (C-statistic 0.76, 95% CI 0.66, 0.85; calibration slope 0.93, 95% CI 0.44, 1.41) but with imprecise estimates. The EMPiRE model showed the highest net proportional benefit for predicted probability thresholds between 12% and 99%. Limitations of this study include the varied gestational ages of women at recruitment, retrospective patient recall of seizure history, potential variations in seizure classification, the small number of events in the validation cohort, and the clinical utility restricted to decision-making thresholds above 12%. The model findings may not be generalisable to low- and middle-income countries, or when information on all predictors is not available. CONCLUSIONS: The EMPiRE model showed good performance in predicting the risk of seizures in pregnant women with epilepsy who are prescribed antiepileptic drugs. Integration of the tool within the antenatal booking visit, deployed as a simple nomogram, can help to optimise care in women with epilepsy.

Timing induction of labour at 41 or 42 weeks? A closer look at time frames of comparison: A review.

BACKGROUND: Postterm pregnancy is associated with increased perinatal risk. The WHO defines postterm pregnancy as a pregnancy at or beyond 42 weeks + 0 days, though currently labour is induced at 41 weeks in many settings. Guidelines on timing of labour induction are frequently based on the Cochrane systematic review 'Induction of labour for improving birth outcomes for women at or beyond term' in which is concluded that a policy of induction of labour is associated with fewer adverse perinatal outcome and fewer Caesarean sections. However, the included trials differed regarding the timing of induction, ranging from 39 to beyond 42 weeks while the upper limit of expectant management exceeded a gestational age of 42 weeks in most studies. OBJECTIVE: to evaluate perinatal mortality, meconium aspiration syndrome and Caesarean section rate of trials comparing a policy of elective induction of labour and expectant management according to timeframes of comparison with a focus on studies within the 41-42 weeks' timeframe. DESIGN: Review. METHODS: The systematic review of Cochrane was used as a starting point for assessing relevant trials and a search was performed for additional recent trials. We evaluated incidence and causes of perinatal mortality, incidence of meconium aspiration syndrome and Caesarean section according to three time frames of comparison. We pooled estimates and heterogeneity was tested. The quality of the included trials was assessed using the Quality Assessment Tool for Quantative Studies (EPHPP). FINDINGS: In total 22 trials were included which had all different timeframes of comparison. Only one trial compared induction of labour at 41 weeks + 0-2 days with induction at 42 weeks + 0 days, three other trials compared induction of labour at 41 weeks + 0-6 days with induction at 42 weeks + 0-6 days. In 18 trials the comparison was outside the 41-42 weeks' timeframe: in six trials induction was planned ≤ 40 weeks and in another 12 trials expectant management was beyond 43 weeks. The incidence of potentially gestational age associated perinatal mortality between 41 and 42 weeks was 0/2.444 [0%] (induction) versus 4/2.452 [0.16%] (expectant management), NNT 613; 95%CI 613 - infinite. Two trials in the timeframe of comparison 41-42 weeks were available for evaluation of meconium aspiration syndrome (6/554 (induction) versus 14/554 (expectant management), RR 0.44; 95%CI 0.17-1.16). Three trials in the timeframe 41-42 weeks could be evaluated for Caesarean section, with different inclusion criteria regarding Bishop score. There was no significant difference in the Caesarean section rate 93/629 (induction) versus 106/629 (expectant management), RR 0.88; 95%CI 0.68-1.13. CONCLUSION: Evidence is lacking for the recommendation to induce labour at 41 weeks instead of 42 weeks for the improvement of perinatal outcome. More studies comparing both timeframes with an adequate sample size are needed to establish the optimal timing of induction of labour in late-term pregnancies.