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.

Depression, anxiety, and post-traumatic stress disorder symptoms after hyperemesis gravidarum: a prospective cohort study.

OBJECTIVE: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity. MATERIAL AND METHODS: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester. RESULTS: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively. CONCLUSION: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

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.

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.

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood.

This study aimed to investigate the association between hyperemesis gravidarum (HG) severity and early enteral tube feeding on cardiometabolic markers in offspring cord blood. We included women admitted for HG, who participated in the MOTHER randomised controlled trial (RCT) and observational cohort. The MOTHER RCT showed that early enteral tube feeding in addition to standard care did not affect symptoms/birth outcomes. Among RCT and cohort participants, we assessed how HG severity affected lipid, c-peptide, glucose and free thyroxine cord blood levels. HG severity measures were severity of vomiting at inclusion and 3 weeks after inclusion, pregnancy weight gain and 24-h energy intake at inclusion, readmissions and duration of hospital admissions. Cord blood measures were also compared between RCT participants allocated to enteral tube feeding and those receiving standard care. Between 2013-2016, 215 women were included: 115 RCT and 100 cohort participants. Eighty-one cord blood samples were available. Univariable not multivariable regression analysis showed that lower maternal weight gain was associated with higher cord blood glucose levels (ß: -0·08, 95% CI -0·16, -0·00). Lower maternal weight gain was associated with higher Apo-B cord blood levels in multivariable regression analysis (ß: -0·01, 95% CI -0·02, -0·01). No associations were found between other HG severity measures or allocation to enteral tube feeding and cord blood cardiometabolic markers. In conclusion, while lower maternal weight gain was associated with higher Apo-B cord blood levels, no other HG severity measures were linked with cord blood cardiometabolic markers, nor were these markers affected by enteral tube feeding.

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study.

INTRODUCTION: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies. MATERIAL AND METHODS: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies. RESULTS: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03). CONCLUSIONS: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.

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.

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.

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.

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.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

INTRODUCTION: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section. MATERIAL AND METHODS: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders. RESULTS: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001)). CONCLUSIONS: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section.

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.

Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial.

BACKGROUND: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. METHODS/DESIGN: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. DISCUSSION: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. TRIAL REGISTRATION: Trial registration number: NTR 4414 . Date of registration January 29th 2014.

Early enteral tube feeding in optimizing treatment of hyperemesis gravidarum: the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial.

Background: Hyperemesis gravidarum (HG) leads to dehydration, poor nutritional intake, and weight loss. HG has been associated with adverse pregnancy outcomes such as low birth weight. Information about the potential effectiveness of treatments for HG is limited.Objective: We hypothesized that in women with HG, early enteral tube feeding in addition to standard care improves birth weight.Design: We performed a multicenter, open-label randomized controlled trial [Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER)] in 19 hospitals in the Netherlands. A total of 116 women hospitalized for HG between 5 and 20 wk of gestation were randomly allocated to enteral tube feeding for ≥7 d in addition to standard care with intravenous rehydration and antiemetic treatment or to standard care alone. Women were encouraged to continue tube feeding at home. On the basis of our power calculation, a sample size of 120 women was anticipated. Analyses were performed according to the intention-to-treat principle.Results: Between October 2014 and March 2016 we randomly allocated 59 women to enteral tube feeding and 57 women to standard care. The mean ± SD birth weight was 3160 ± 770 g in the enteral tube feeding group compared with 3200 ± 680 g in the standard care group (mean difference: -40 g, 95% CI: -230, 310 g). Secondary outcomes, including maternal weight gain, duration of hospital stay, readmission rate, nausea and vomiting symptoms, decrease in quality of life, psychological distress, prematurity, and small-for-gestational-age, also were comparable. Of the women allocated to enteral tube feeding, 28 (47%) were treated according to protocol. Enteral tube feeding was discontinued within 7 d of placement in the remaining women, primarily because of its adverse effects (34%).Conclusions: In women with HG, early enteral tube feeding does not improve birth weight or secondary outcomes. Many women discontinued tube feeding because of discomfort, suggesting that it is poorly tolerated as an early routine treatment of HG. This trial was registered at www.trialregister.nl as NTR4197.

Atosiban versus fenoterol as a uterine relaxant for external cephalic version: randomised controlled trial.

OBJECTIVE:  To compare the effectiveness of the oxytocin receptor antagonist atosiban with the beta mimetic fenoterol as uterine relaxants in women undergoing external cephalic version (ECV) for breech presentation. DESIGN:  Multicentre, open label, randomised controlled trial. SETTING:  Eight hospitals in the Netherlands, August 2009 to May 2014. PARTICIPANTS:  830 women with a singleton fetus in breech presentation and a gestational age of more than 34 weeks were randomly allocated in a 1:1 ratio to either 6.75 mg atosiban (n=416) or 40 µg fenoterol (n=414) intravenously for uterine relaxation before ECV. MAIN OUTCOME MEASURES:  The primary outcome measures were a fetus in cephalic position 30 minutes after the procedure and cephalic presentation at delivery. Secondary outcome measures were mode of delivery, incidence of fetal and maternal complications, and drug related adverse events. All analyses were done on an intention-to-treat basis. RESULTS:  Cephalic position 30 minutes after ECV occurred significantly less in the atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95% confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n=139) of the atosiban group and 40% (n=166) of the fenoterol group (0.86, 0.72 to 1.03), and caesarean delivery was performed in 60% (n=240) of women in the atosiban group and 55% (n=218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were found in neonatal outcomes or drug related adverse events. CONCLUSIONS:  In women undergoing ECV for breech presentation, uterine relaxation with fenoterol increases the rate of cephalic presentation 30 minutes after the procedure. No statistically significant difference was found for cephalic presentation at delivery. TRIAL REGISTRATION:  Dutch Trial Register, NTR 1877.

Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders - genetic counseling and pregnancy outcome in 57 cases.

BACKGROUND: Whole genome array testing not only provides an increased diagnostic yield of pathogenic causative findings, but it may also reveal so called susceptibility loci (SL) for neurodevelopmental disorders. The goal of this study was to evaluate the pregnancy outcomes in SL cases and to establish a protocol for pregnancy management, follow-up and additional investigations. METHODS: Fifty seven cases were evaluated: 34 with and 23 without ultrasound anomalies at referral. Each pregnant couple received pretest counseling and extensive posttest genetic counseling. RESULTS: After diagnosis of SL, parental testing and an additional ultrasound examination were offered. The severity of the ultrasound anomalies and not the diagnosis of SL was the most important factor contributing to the decision on pregnancy continuation. In the majority of cases with milder or no ultrasound anomalies, the pregnancy was continued and a normal outcome after birth was observed. CONCLUSIONS: The diagnosis of a SL did not seem to be a reason for termination of pregnancy. Most patients were able to cope with the uncertainty and were interested in both prenatal and postnatal actionability of SL. Long-term follow-up is crucial to assess the actual risks for neurodevelopmental disorders, especially in families with unremarkable history. © 2016 John Wiley & Sons, Ltd.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.