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Background: Early risk stratification can facilitate timely interventions for adverse pregnancy outcomes, including preeclampsia (PE), small-for-gestational-age neonates (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM)., Objectives: To perform a systematic review and meta-analysis of first-trimester prediction models for adverse pregnancy outcomes., Search Strategy: The PubMed database was searched until 6 June 2024., Selection Criteria: First-trimester prediction models based on maternal characteristics were included. Articles reporting on prediction models that comprised biochemical or ultrasound markers were excluded., Data Collection and Analysis: Two authors identified articles, extracted data and assessed risk of bias and applicability using PROBAST., Main Results: A total of 77 articles were included, comprising 30 developed models for PE, 15 for SGA, 11 for sPTB and 35 for GDM. Discriminatory performance in terms of median area under the curve (AUC) of these models was 0.75 [IQR 0.69-0.78] for PE models, 0.62 [0.60-0.71] for SGA models of nulliparous women, 0.74 [0.72-0.74] for SGA models of multiparous women, 0.65 [0.61-0.67] for sPTB models of nulliparous women, 0.71 [0.68-0.74] for sPTB models of multiparous women and 0.71 [0.67-0.76] for GDM models. Internal validation was performed in 40/91 (43.9%) of the models. Model calibration was reported in 21/91 (23.1%) models. External validation was performed a total of 96 times in 45/91 (49.5%) of the models. High risk of bias was observed in 94.5% of the developed models and in 58.3% of the external validations., Conclusions: Multiple first-trimester prediction models are available, but almost all suffer from high risk of bias, and internal and external validations were often not performed. Hence, methodological quality improvement and assessment of the clinical utility are needed., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To assess the added value of fetal fraction of cell-free DNA in the maternal circulation in the prediction of adverse pregnancy outcomes., Design: Retrospective cohort study., Setting: Nationwide implementation study on non-invasive prenatal testing (NIPT; TRIDENT-2 study)., Population: Pregnant women in the Netherlands opting for NIPT between June 2018 and June 2019., Methods: Two logistic regression prediction models were constructed for each adverse pregnancy outcome. The first model (base model) included prognostic clinical parameters that were selected from existing first-trimester prediction models for adverse pregnancy outcomes. The second model (fetal fraction model) included fetal fraction as a predictor on top of the prognostic clinical parameters included in the base model. The added prognostic value of fetal fraction was assessed by comparing the base and fetal fraction models in terms of goodness of fit and predictive performance., Main Outcome Measures: Likelihood ratio test (LRT), area under the curve (AUC) and Integrated Discrimination Improvement (IDI) index., Results: The study cohort consisted of 56 110 pregnancies. The incidence of adverse pregnancy outcomes was 5.7% for hypertensive disorders of pregnancy (HDP; n = 3207), 10.2% for birthweight < p10 (n = 5726), 3.2% for birthweight < p2.3 (n = 1796), 3.4% for spontaneous preterm birth (sPTB; n = 1891), 3.4% for diabetes (n = 1902) and 1.3% for congenital anomalies (n = 741). Adding fetal fraction to the base model improved model fit for HDP, birthweight < p10, birthweight < p2.3, all sPTB, and diabetes, but not for congenital anomalies (LRT p < 0.05). For HDP, the AUC improved from 0.67 to 0.68 by adding fetal fraction to the base model (p = 0.14) with an IDI of 0.0018 (p < 0.0001). For birthweight < p10, the AUC improved from 0.65 to 0.66 (p < 0.0001) with an IDI of 0.0023 (p < 0.0001). For birthweight < p2.3, the AUC improved from 0.67 to 0.69 (p < 0.0001) with an IDI of 0.0011 (p < 0.0001). For all sPTB, the AUC was similar for both models (AUC 0.63, p = 0.021) with an IDI of 0.00028 (p = 0.0023). For diabetes, the AUC was similar (AUC 0.72, p = 0.35) with an IDI of 0.00055 (p = 0.00015)., Conclusions: Fetal fraction has statistically significant but limited prognostic value in the prediction of adverse pregnancy outcomes in addition to known prognostic clinical parameters., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To explore the perspectives of pregnant women on broadening the scope of noninvasive prenatal testing (NIPT) from screening for foetal aneuploidies to prediction of adverse pregnancy outcomes., Methods: Four online focus groups (n = 23 participants) and 14 individual semi-structured interviews were conducted. Participants included pregnant women with and without a history of adverse pregnancy outcomes., Results: Both women at low and high risk of adverse pregnancy outcomes had a positive attitude towards using NIPT to predict adverse pregnancy outcomes. Perceived benefits included the possibility to potentially improve maternal and foetal outcomes by taking risk-reducing measures and/or intensified monitoring during pregnancy and the ability to mentally prepare for the potential adverse outcome. Perceived concerns included anxiety and stress caused by a high-risk test result, a false sense of control over pregnancy, and potential false reassurance. Additionally, women reasoned that broadening the scope of NIPT could increase the complexity of prenatal screening and raised concerns on the combined screening aims in one test (prediction of adverse pregnancy outcomes to improve foetal and maternal health vs. screening for foetal aneuploidies to increase reproductive autonomy). On a societal level, considerations on the risk of medicalising pregnancy and overall pressure to opt for NIPT were mentioned., Conclusion: In general, pregnant women have a positive attitude towards broadening the scope of NIPT to the prediction of pregnancy outcomes, although some concerns are acknowledged., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation., Objective: This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as <10th percentile, corresponding to a fetal fraction <2.5%., Results: The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89-2.78]), small for gestational age neonates <10th percentile (adjusted odds ratio, 1.37 [1.28-1.45]) and <2.3rd percentile (adjusted odds ratio, 2.63 [1.96-3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01-1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00-1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96-1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96-1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was <10th percentile., Conclusion: In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Some studies have suggested that introducing a second-trimester anomaly scan (SAS) leads to increased rates of termination of pregnancy (TOP) in fetuses with orofacial clefts (OFCs). The aim of this study was to evaluate the impact of a nationwide introduction of SAS on the prevalence of live births with OFCs in the Netherlands., Design: Retrospective cohort study., Setting: Tertiary setting., Population: Included in the study were all patients diagnosed with OFCs as recorded in the "Dutch Association for Cleft Palate Anomalies" database between 1997 and 2019., Interventions: Patients were divided into three categories: cleft lip with or without alveolus (CL/A), cleft lip, alveolus and palate (CLAP) and cleft palate (CP) based on anatomical landmarks at the first consultation., Main Outcome Measures: Prevalence rates of OFCs before and after the nationwide introduction of the SAS on January 1, 2007 were compared., Result: Overall, 1899 patients were diagnosed with CL/A, 2586 with CLAP and 2927 with CP. The prevalence of clefts before and after introduction of the SAS did not differ ( P = 0.85). The prevalence of CL/A decreased ( P = 0.04), and that of CLAP decreased ( P = 0.01) and that of CP increased ( P = 0.02)., Conclusions: This study demonstrates a significant decrease in the prevalence of CL/A and CLAP after introduction of the SAS. However, due to an increase in CP, the prevalence of all patients born with OFCs has not changed in the Netherlands between 1997 and 2019., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The screening performance of non-invasive prenatal testing (NIPT) in vanishing twin (VT) pregnancies is relatively unknown. To close this knowledge gap, we conducted a systematic review of the available literature. Studies describing the test performance of NIPT for trisomy 21, 18, 13, sex chromosomes and additional findings in pregnancies with a VT were retrieved from a literature search with a publication date until October 4, 2022. The methodological quality of the studies was assessed with the quality assessment tool for diagnostic accuracy studies-2 (QUADAS-2). The screen positive rate of the pooled data and the pooled positive predictive value (PPV) were calculated using a random effects model. Seven studies, with cohort sizes ranging from 5 to 767, were included. The screen positive rate of the pooled data for trisomy 21 was 35/1592 (2.2%), with a PPV of 20% (confirmation in 7/35 cases [95% CI 9.8%-36%]). For trisomy 18, the screen positive rate was 13/1592 (0.91%) and the pooled PPV 25% [95% CI 1.3%-90%]. The screen positive rate for trisomy 13 was 7/1592 (0.44%) and confirmed in 0/7 cases (pooled PPV 0% [95% CI 0%-100%]). The screen positive rate for additional findings was 23/767 (2.9%), of which none could be confirmed. No discordant negative results were reported. There is insufficient data to fully evaluate NIPT performance in pregnancies with a VT. However, existing studies suggest that NIPT can successfully detect common autosomal aneuploidies in pregnancies affected by a VT but with a higher false positive rate. Further studies are needed to determine the optimal timing of NIPT in VT pregnancies., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings., Competing Interests: Declaration of interests E.A.S. was one of the applicants of the ZonMW grant and is a member of the GenQA advisory board (unpaid) and the associate editor of Extracellular Vesicles and Circulating Nucleic Acids. D.V.O. is a member of the project group NIPT additional findings and Project group NIPT Laboratories of the National Institute for Public Health & Environment (RIVM) – Center for Population Screening (CvB). L.H. was one of the applicants of the ZonMW grant. M.N.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). C.J.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). M.J.P. is a member of the Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid). M.V.E.M. is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT Laboratories, all of the RIVM-CvB (unpaid). Part of the ZonMW grant was paid to his institution for TRIDENT-2 bio-informatic research. R.-J.H.G. was one of the applicants of the ZonMW grant, and he is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This study assesses the results of a mandatory blended learning-program for counselors (e.g. midwives, sonographers, obstetricians) guiding national implementation of the Non-Invasive Prenatal Test (NIPT). We assessed counselors' 1) knowledge about prenatal aneuploidy screening, 2) factors associated with their knowledge (e.g. counselors' characteristics, attitudes towards NIPT), and 3) counselors' attitudes regarding the blended learning. A cross-sectional online pretest-posttest implementation survey was sent to all 2,813 Dutch prenatal counselors. Multivariate linear regression analyses were performed to identify associations between counselors' knowledge and e.g. their professional backgrounds, work experience and attitudes towards NIPT. At T0 and T1 1,635 and 913 counselors completed the survey, respectively. Overall results show an increased mean number of correct answered knowledge questions; 23/35 (66%) items at T0 and 28/37 (76%) items at T1. Knowledge gaps on highly specific topics remained. Work experience and secondary care work-setting were positively associated with a higher level of knowledge. Most counselors (74%) showed positive attitudes towards the blended learning program. The mandatory blended learning, along with learning by experience through implementation of NIPT, has facilitated an increase in counselors' knowledge and was well received. New implementations in healthcare may benefit from requiring blended learning for healthcare providers, especially if tailored to professionals' learning goals., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To assess the association between low fetal fraction (FF) in prenatal cell-free DNA (cfDNA) testing and adverse pregnancy outcomes., Methods: We conducted a retrospective cohort study of participants of the TRIDENT-2 study (Dutch nationwide government-supported study offering cfDNA screening for fetal aneuploidies) who received a failed test result due to low FF (<4%) between April 2017 until February 2018. Outcome measures included pregnancy-induced hypertension (PIH), pre-eclampsia (PE), small for gestational age neonates (SGA), spontaneous preterm birth (sPTB), gestational diabetes mellitus (GDM), chromosomal aberrations, and congenital structural anomalies., Results: Test failure due to low FF occurred in 295 women (1.12% of tests performed). Information regarding pregnancy outcomes was available for 96.3% of these women. The incidence of PIH, PE, SGA, sPTB, and GDM was 11.2%, 4.1%, 7.3%, 5.1%, and 14.8%, respectively. The prevalence of chromosomal aberrations and congenital structural anomalies was 1.4% and 4.1%, respectively. Incidences of PIH, PE ≥ 34 weeks of gestation, GDM, and prevalence of aneuploidy and congenital structural anomalies were higher in women with low FF compared to the general Dutch obstetric population., Conclusion: Low FF is associated with adverse pregnancy outcomes. The value of FF in the prediction of these outcomes needs to be further established., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: Low fetal fraction (LFF) in prenatal cell-free DNA (cfDNA) testing is an important cause of test failure and no-call results. LFF might reflect early abnormal placentation and therefore be associated with adverse pregnancy outcome. Here, we review the available literature on the relationship between LFF in cfDNA testing and adverse pregnancy outcome., Method: A systematic literature search was conducted in MEDLINE and EMBASE up to November 1, 2020., Results: Five studies met the criteria for inclusion; all were retrospective observational cohort studies. The cohort sizes ranged from 370 to 6375 pregnancies, with all tests performed in the first trimester or early second trimester. A 4% cutoff for LFF was used in two studies, two studies used the 5th and 25th percentiles, respectively, and one study used a variety of cutoff values for LFF. LFF in prenatal cfDNA testing was observed to be associated with hypertensive disease of pregnancy, small for gestational age neonates, and preterm birth. Conflicting results were found regarding the association between LFF and gestational diabetes mellitus., Conclusions: LFF in cfDNA testing is associated with adverse pregnancy outcome,specifically pregnancy-related hypertensive disorders, preterm birth, and impaired fetal growth related to placental dysfunction. Since the available evidence is limited, a large prospective cohort study on the relationship between fetal fraction and pregnancy outcomes is needed., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Clear inter-individual differences exist in the response to C. trachomatis (CT) infections and reproductive tract complications in women. Host genetic variation like single nucleotide polymorphisms (SNPs) have been associated with differences in response to CT infection, and SNPs might be used as a genetic component in a tubal-pathology predicting algorithm. Our aim was to confirm the role of four genes by investigating proven associated SNPs in the susceptibility and severity of a CT infection. A total of 1201 women from five cohorts were genotyped and analyzed for TLR2 + 2477 G > A, NOD1 + 32656 T -> GG, CXCR5 + 10950 T > C, and IL10 - 1082 A > G. Results confirmed that NOD1 + 32656 T ->GG was associated with an increased risk of a symptomatic CT infection (OR: 1.9, 95%CI: 1.1-3.4, p = 0.02), but we did not observe an association with late complications. IL10 - 1082 A > G appeared to increase the risk of late complications (i.e., ectopic pregnancy/tubal factor infertility) following a CT infection (OR = 2.8, 95%CI: 1.1-7.1, p = 0.02). Other associations were not found. Confirmatory studies are important, and large cohorts are warranted to further investigate SNPs' role in the susceptibility and severity of a CT infection.

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management., Material and Methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27 +5 and 33 +5  weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat., Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P = .14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes., Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To develop a prediction model of postnatal renal function in fetuses with lower urinary tract obstruction (LUTO) based on fetal ultrasound parameters and amniotic fluid volume., Methods: Retrospective nationwide cohort study of fetuses with postnatally confirmed LUTO and known eGFR. Fetuses treated with fetal interventions such as vesico-amniotic shunting or cystoscopy were excluded. Logistic regression analysis was used to identify prognostic ultrasound variables with respect to renal outcome following multiple imputation of missing data. On the basis of these fetal renal parameters and amniotic fluid volume, a model was developed to predict postnatal renal function in fetuses with LUTO. The main study outcome was an eGFR less than 60 mL/min * 1.73 m 2 based on the creatinine nadir during the first year following diagnosis. Model performance was evaluated by receiver operator characteristic (ROC) curve analysis, calibration plots, and bootstrapping., Results: Hundred one fetuses with a confirmed diagnosis of LUTO were included, eGFR less than 60 was observed in 40 (39.6%) of them. Variables predicting an eGFR less than 60 mL/min * 1.73m 2 included the following sonographic parameters: hyperechogenicity of the renal cortex and abnormal amniotic fluid volume. The model showed fair discrimination, with an area under the ROC curve of 0.70 (95% confidence interval, 0.59-0.81, 0.66 after bootstrapping) and was overall well-calibrated., Conclusion: This study shows that a prediction model incorporating ultrasound parameters such as cortical appearance and abnormal amniotic fluid volume can fairly discriminate an eGFR above or below 60 mL/min * 1.73m 2 . This clinical information can be used in identifying fetuses eligible for prenatal interventions and improve counseling of parents., (© 2019 John Wiley & Sons, Ltd.)

Objectives: The objective of this study was to assess if there is evidence of publication bias in prognostic accuracy studies of middle cerebral artery (MCA) or cerebroplacental ratio (CPR) for adverse perinatal outcome., Study Design and Setting: We queried PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov and searched abstract books of five perinatal conferences (1989-2017). We included prognostic accuracy studies on MCA and/or CPR. Highest reported accuracy estimates, sample size, study design, and conclusion positivity were extracted and compared., Results: We included 127 full-text articles and 51 conference abstracts, 29 of which had not been reported as full-text article. In conference abstracts not reported in full, median negative predictive value was significantly lower compared to full-text articles (0.79 [interquartile range 0.67-0.97] vs. 0.95 [0.89-0.99]; P < 0.001). No significant difference was identified for positive predictive value (0.62 vs. 0.59; P = 0.827), sensitivity (0.67 vs. 0.71; P = 0.159), and specificity (0.86 vs. 0.86; P = 0.632). Study design differed significantly as well (P = 0.030), with fewer prospective studies in conference abstracts not reported in full compared to full-text articles (28% vs. 54%). We found no significant differences in sample size or conclusion positivity., Conclusion: Possibly, a publication bias in previously published meta-analyses of MCA and CPR has led to overly generous estimates of prognostic performance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To develop a nationwide, evidence-based framework to support prenatal counseling in extreme prematurity, focusing on organization, decision-making, content, and style aspects., Methods: A nationwide multicenter RAND-modified Delphi method study was performed between November 2016 and December 2017 in the Netherlands. Firstly, recommendations were extracted from literature and previous studies. Secondly, an expert panel ( n = 21) with experienced parents, obstetricians, and neonatologists rated the recommendations on importance for inclusion in the framework. Thirdly, ratings were discussed in a consensus meeting. The final set of recommendations was approved and transformed into a framework., Results: A total of 101 recommendations on organization, decision-making, content, and style were included in the framework, including tools to support personalization. The most important recommendations regarding organization were to have both parents involved in the counseling with both the neonatologist and obstetrician. The shared decision-making model was recommended for deciding between active support and comfort care. Main recommendations regarding content of conversation were explanation of treatment options, information on survival, risk of permanent consequences, impossibility to predict an individual course, possibility for multiple future decision moments, and a discussion on parental values and standards. It was considered important to avoid jargon, check understanding, and provide a summary. The expert panel, patient organization, and national professional associations (gynecology and pediatrics) approved the framework., Conclusions: A nationwide, evidence-based framework for prenatal counseling in extreme prematurity was developed. It contains recommendations and tools for personalization in the domains of organization, decision-making, content, and style of prenatal counseling., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objective: To explore experiences among pregnant women diagnosed with a small-for-gestational age (SGA) fetus, and monitored by frequent ultrasounds., Methods: We performed a qualitative study at the outpatient clinic of the Gynecology and Obstetrics department of a large academic hospital in Amsterdam. Semi-structured interviews were conducted with fifteen women, diagnosed with an SGA fetus during their pregnancy and having had at least two monitoring ultrasounds since. Themes were identified following analysis of the interview transcripts., Results: Most women experienced the frequent ultrasounds as a source of support providing comfort and a feeling of safety. It was considered necessary, in the best interest of the baby, which outweighed the discomfort caused by having to come to the hospital frequently. Women described anxiety building up prior to each ultrasound, but feeling reassured and relieved afterwards. During the ultrasound a continuous explanation was preferred, which provided confirmation and a feeling of security. Women identified the uncertainty of SGA's cause and prognosis as one of the biggest challenges to cope with, for which they used different strategies. Many women expressed a need for more detailed information and counselling, including non-medical aspects of pregnancy and delivery as well. Lastly, many women reported that seeing different doctors negatively influenced the perceived quality of care., Conclusions: In general, women in this study were satisfied with the ultrasounds for their small-for-gestational age pregnancies. However, women expressed a need for additional information to help cope with a feeling of uncertainty regarding cause and prognosis. Their medical team should preferably provide this in a consistent and continuous manner., Competing Interests: The authors have declared that no competing interests exist.

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

Objective: To investigate the best criteria for discriminating fetuses with isolated posterior urethral valves from those theoretically not eligible for fetal treatment because of complex megacystis, high chance of spontaneous resolution, and urethral atresia., Methods: A retrospective national study was conducted in fetuses with megacystis detected before 17 weeks' gestation (early megacystis)., Results: In total, 142 cases with fetal megacystis were included in the study: 52 with lower urinary tract obstruction, 29 with normal micturition at birth, and 61 with miscellaneous syndromal associations, chromosomal and multiple structural abnormalities (complex megacystis). Only a nuchal translucency > 95th centile, and not a longitudinal bladder diameter ≤15 mm (p = 0.24), significantly increased the risk of complex megacystis (p < 0.01). Cases with a high chance of spontaneous resolution were identified by using the cut-off of 12 mm, as demonstrated in a previous study, and the finding of an associated umbilical cord cyst carried a high-risk of urethral atresia (odds ratio: 15; p = 0.026), an unfavorable condition for antenatal treatment. An algorithm encompassing these three criteria demonstrated good accuracy in selecting fetuses theoretically eligible for fetal treatment (specificity 73%; sensitivity 92%)., Conclusions: Cases theoretically eligible for early fetal therapy are those with normal nuchal translucency, a longitudinal bladder diameter > 12 mm, and without ultrasound evidence of umbilical cord cysts., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Objective: To assess agreement of Doppler ultrasound measurements of the two umbilical arteries in small-for gestational age (SGA) fetuses, and to compare discriminative ability between the two arteries for adverse perinatal outcome., Study Design: We analysed a prospective cohort of singleton SGA pregnancies, in which the pulsatility index (PI) of both umbilical arteries was standardly measured by Doppler ultrasound in the free-floating umbilical cord. The outcome of interest was a composite adverse outcome, defined as perinatal death, Apgar score <7 at 5 min, cesarean section for fetal distress, and neonatal intensive care unit admission., Results: A total of 531 measurements were performed in 124 patients. Mean absolute difference between PI measured in the two umbilical arteries was 0.14 (95% CI: 0.12 to 0.15), showing good agreement with an ICC of 0.830 (95% CI: 0.801 to 0.854). Perinatal outcomes were available for 101 patients, of which 48 patients (48%) had a composite adverse perinatal outcome. We found no significant differences between AUCs for prediction of an adverse outcome based on lowest, highest and mean PI values in the two umbilical arteries (AUCs = 0.75, 0.74, 0.75 with p = 0.91). As a comparison, the AUC of a PI value obtained in a single, randomly selected umbilical artery was 0.74., Conclusion: The two umbilical arteries show good agreement in terms of their PI values in the free-floating umbilical cord, and do not differ in terms of their discriminative ability for adverse perinatal outcome in SGA fetuses. We found no evidence of an added value of standard Doppler measurement of both umbilical arteries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective  We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods  We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results  Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion  The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To evaluate the clinical impact of nationwide implementation of genome-wide non-invasive prenatal testing (NIPT) in pregnancies at increased risk for fetal trisomies 21, 18 and 13 (TRIDENT study)., Method: Women with elevated risk based on first trimester combined testing (FCT ≥ 1:200) or medical history, not advanced maternal age alone, were offered NIPT as contingent screening test, performed by Dutch University Medical laboratories. We analyzed uptake, test performance, redraw/failure rate, turn-around time and pregnancy outcome., Results: Between 1 April and 1 September 2014, 1413/23 232 (6%) women received a high-risk FCT result. Of these, 1211 (85.7%) chose NIPT. One hundred seventy-nine women had NIPT based on medical history. In total, 1386/1390 (99.7%) women received a result, 6 (0.4%) after redraw. Mean turn-around time was 14 days. Follow-up was available in 1376 (99.0%) pregnancies. NIPT correctly predicted 37/38 (97.4%) trisomies 21, 18 or 13 (29/30, 4/4 and 4/4 respectively); 5/1376 (0.4%) cases proved to be false positives: trisomies 21 (n = 2), 18 (n = 1) and 13 (n = 2). Estimated reduction in invasive testing was 62%., Conclusion: Introduction of NIPT in the Dutch National healthcare-funded Prenatal Screening Program resulted in high uptake and a vast reduction of invasive testing. Our study supports offering NIPT to pregnant women at increased risk for fetal trisomy. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd., (© 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.)

Objective: The objective of this study is to evaluate the relation among fetal gender, ethnicity, and preterm labor (PTL) and preterm delivery (PTD)., Methods: A secondary analysis was performed of a prospective cohort study including women with symptoms of PTL between 24 and 34 weeks. The proportion of women carrying a male or female fetus at the onset of PTL was calculated. Gestational age at delivery and risk of PTD of both fetal genders was compared and interaction of fetal gender and maternal ethnicity on the risk of PTD was evaluated., Results: Of the 594 included women, 327 (55%) carried a male fetus. Median gestational age at delivery in women pregnant with a male fetus was 37 5/7 (IQR 34 4/7-39 1/7) weeks compared with 38 1/7 (IQR 36 0/7-39 5/7) weeks in women pregnant with a female fetus (p = 0.032). The risk of PTD did not differ significantly. In Caucasians, we did find an increased risk of PTD before 37 weeks in women pregnant with a male fetus (OR 1.9 (95% CI 1.2-3.0))., Conclusions: The majority of women with PTL are pregnant with a male fetus and these women deliver slightly earlier. Race seems to affect this disparity.

Introduction: As the prenatal detection rates of congenital heart defects (CHDs) increase, obstetricians are more frequently faced with pregnancies complicated by a fetal CHD. Congenital anomalies in general are associated with preterm birth and fetal demise. The aim of this study was to gain insight into the prevalence of preterm birth and fetal demise in singleton pregnancies with fetuses with isolated CHDs., Material and Methods: A geographical cohort study was performed in a large region in the Netherlands. Fetuses and infants from singleton pregnancies diagnosed with severe isolated CHD, born between 1 January 2002 and 1 January 2012, were included. All cases in the CHD cohort were assessed for preterm birth or fetal demise. The proportions of preterm birth and fetal demise were compared with those in a control group and odds ratios were calculated., Results: The proportion of preterm births in the CHD cohort (n = 1013) was 9.1% (95% CI 7.3-10.9) compared with 5.6% (95% CI 5.4-5.8) in the control group, with an odds ratio of 1.7 (95% CI 1.4-2.1). The preterm birth started spontaneously in 49.5% and 38.4% were induced. In 15 cases fetal demise occurred (1.5%; 95% CI 0.8-2.2), compared with 0.7% (95% CI 0.6-0.8) in the control group, odds ratio 2.0 (95% CI 1.2-3.4)., Conclusions: Higher rates of preterm birth and fetal demise occur in fetuses with isolated CHD compared with the general population. Prenatal specialists should be vigilant for signs of heart failure, premature closure of the foramen ovale or fetal distress in fetuses with isolated CHDs., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To compare the accuracy of the Actim Partus test and fetal fibronectin (fFN) test in the prediction of spontaneous preterm delivery within seven days in symptomatic women undergoing cervical length measurement., Study Design: We performed a post-hoc analysis on frozen samples of a nationwide cohort study in all 10 perinatal centres in the Netherlands. We selected samples from women with signs of preterm labour between 24 and 34 weeks of gestational age and a cervical length below 30mm. Delivery within seven days after initial assessment was the primary endpoint. We calculated sensitivity, specificity, and positive and negative predictive values for the combination of both the Actim Partus test and fFN test with cervical length. A test was considered positive in case of a cervical length between 15 and 30mm with a positive Actim Partus or fFN test, and a cervical length below 15mm regardless the test result., Results: In total, samples of 350 women were tested, of whom 69 (20%) delivered within seven days. Eighty-four women had a positive Actim Partus test and 162 women a positive fFN test, of whom 54 (64%) and 63 (39%) delivered within seven days, respectively. Ninety-seven women had a cervical length below 15mm, of whom 50 (52%) delivered within seven days. Sensitivity, specificity, positive and negative predictive values of combining cervical length with the Actim Partus test or the fFN test were 91%, 75%, 47% and 97%, and 96%, 58%, 36% and 98%, respectively., Conclusion: According to this post-hoc study, in combination with cervical length, the Actim Partus test could be used as an alternative for the fFN test to identify women who will not deliver within seven days after presentation. Further evidence should be collected in a prospective comparative study., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy., Study Design: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized., Trial Registry: NTR 3363., Results: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79)., Conclusion: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Preterm birth is a major cause of neonatal mortality and morbidity. As preventive strategies are largely ineffective, threatened preterm labor is a frequent problem that affects approximately 10 % of pregnancies. In recent years, risk assessment in these women has incorporated cervical length measurement and fetal fibronectin testing, and this has improved the capacity to identify women at increased risk for delivery within 14 days. Despite these improvements, risk for preterm birth continues to be increased in women who did not deliver after an episode of threatened preterm labor, as indicated by a preterm birth rate between 30 to 60 % in this group of women. Currently no effective treatment is available. Studies on maintenance tocolysis and progesterone have shown ambiguous results. The pessary has not been evaluated in women with threatened preterm labor, however studies in asymptomatic women with a short cervix show reduced rates of preterm birth rates as well as perinatal complications. The APOSTEL VI trial aims to assess the effectiveness of a cervical pessary in women who did not deliver within 48 h after an episode of threatened preterm labor., Methods/design: This is a nationwide multicenter open-label randomized clinical trial. Women with a singleton or twin gestation with intact membranes, who were admitted for threatened preterm labor, at a gestational age between 24 and 34 weeks, a cervical length between 15 and 30 mm and a positive fibronectin test or a cervical length below 15 mm, who did not deliver after 48 h will be eligible for inclusion. Women will be allocated to a pessary or no intervention (usual care). Primary outcome is preterm delivery < 37 weeks. Secondary outcomes are amongst others a composite of perinatal morbidity and mortality. Sample size is based on an expected 50 % reduction of preterm birth before 37 weeks (two-sided test, α 0.05 and β 0.2). Two hundred women with a singleton pregnancy need to be randomized. Analysis will be done by intention to treat., Discussion: The APOSTEL VI trial will provide evidence whether a pessary is effective in preventing preterm birth in women who did not deliver 48 h after admission for threatened preterm labor and who remain at high risk for preterm birth., Trial Registration: Trial is registered at the Dutch Trial Register: http://www.trialregister.nl , NTR4210, date of registration: October 16th 2013.

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)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: In asymptomatic women with a multiple pregnancy and short cervix prophylactic use of a cervical pessary might reduce preterm birth. We assessed the possible treatment effects of pessary use in pregnancy duration and for poor perinatal outcome., Study Design: This cohort study was performed between December 2012 and September 2014 in 44 hospitals in the Netherlands. Women with multiple pregnancy had a cervical length measurement between 16 and 22 weeks of gestation. When cervical length was below 38 mm, women were offered a cervical pessary. The course of pregnancy, including perinatal outcome in these women was compared to the outcome of women from the placebo group of the AMPHIA trial (ISRCTN40512715) (historical cohort). Propensity-score matching with replacement was used to create comparable baseline characteristics between both populations., Results: We studied 63 women in the pessary group and 56 women as controls. Propensity-score matching generated 57 women in the intervention group matched to 57 women (31 unique) in the control group. Gestational age at delivery was comparable between both groups (HR 0.96, 95%-CI 0.46-1.46) as well as their delivery rates before 28, 32 and 37 weeks, RR 0.68 (95%-CI 0.21-2.18), RR 0.54 (95%-CI 0.21-1.41), and RR 1.22 (95%-CI 0.47-3.15), respectively. There was no difference in composite perinatal outcome (RR 1.36, 95%-CI 0.53-3.51) and perinatal mortality (RR 0.89, 95%-CI 0.24-3.38) either., Conclusion: In this cohort study with propensity score analysis, pessary use did not prevent preterm birth in asymptomatic women with a multiple pregnancy and short cervix., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients., Methods/design: The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle., Discussion: With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome., Trial Registration Number: NTR4197 . Date of registration: October 2(nd) 2013.

Objective: We recently reported that induction of labour does not improve short term neonatal outcome in women with late preterm premature rupture of membranes (PPROM) as compared to expectant management (PPROMEXIL trial). In this study the neurodevelopmental and behavioural outcome of the children from this trial at 2 years of age was studied., Study Design: We studied outcome of offspring of women randomised in the PPROMEXIL study. These women had >24h of ruptured membranes and were between 34 and 37 weeks of pregnancy when they were randomised to induction of labour (IoL) or expectant management (EM). Two years after delivery, the parents received the ages and stages questionnaire (ASQ), the child behaviour checklist (CBCL) and a general questionnaire., Results: Follow-up data were obtained from 234 children (121 after IoL, 113 after EM, response rate 59% (44% of the original 532 randomised women)). In the IoL group 16 children (14%) had an abnormal score in ≥1 domains of the ASQ, versus 27 (26%) in the EM group (difference in percentage -11.4 (95% CI -21.9 to -0.98; p=0.033)). For the CBCL, an abnormal score was found in 13% (n=15) in the IoL group and in 15% (n=16) in the EM group (difference in percentage -2.13 (95% CI -11.2 to 6.94; p=0.645))., Conclusion: Although a policy of induction of labour in women with late PPROM does not improve short term neonatal outcome, it might be associated with a decrease in neurodevelopmental difficulties at the age of two years as compared to expectant management. Expectant management did not lead to a difference in behavioural problems., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the impact of cervical length (CL) measurement and fetal fibronectin testing (fFN) on the clinicians' decision to prescribe antenatal corticosteroids (ACS) to women with symptoms of preterm labor., Study Design: This is a secondary analysis of a prospective cohort study including women with symptoms of preterm labor and intact membranes between 24 and 34 weeks' gestation. We compared the proportion prescribed and completed ACS courses, preterm delivery within seven days and median intervals from ACS to delivery in four groups: group 1 CL<10 mm, group 2 CL 10-30 mm and positive fFN, group 3 CL 10-30 mm and negative fFN, group 4 CL>30 mm., Results: ACS were prescribed to 63/65 (97%) women in group 1, 176/192 (91%) in group 2, 111/172 women (65%) in group 3 and 55/242 (23%) in group 4. In group 1, 42 (65%) women delivered within seven days, compared to 34 (18%) in group 2, 6 (3%) in group 3 and 3 (1%) in group 4. Median intervals between ACS and delivery were 6 days (IQR 3-61 days), 44 days (IQR 17-69 days), 53 days (IQR 37-77 days) and 66 days (IQR 43-78 days) in group 1, 2, 3 and 4 respectively., Conclusion: ACS were prescribed frequently to women with a CL of 10-30 mm and a negative fFN test or a CL>30 mm. There is room for improvement in the prescription of ACS in these low risk women., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess whether patient characteristics add to the fetal fibronectin test and cervical length measurement in the prediction of preterm delivery in symptomatic women., Study Design: A nationwide prospective cohort study was conducted in all ten perinatal centres in the Netherlands. Women with symptoms of preterm labour between 24 and 34 weeks gestation with intact membranes were invited. In all women qualitative fibronectin testing (0.050 μg/mL cut-off) and cervical length measurement were performed. Only singleton pregnancies were included in this analysis. Logistic regression was used to construct two multivariable models to predict spontaneously delivery within 7 days: a model including cervical length and fetal fibronectin as predictors, and an extended model including all potential predictors. The models were internally validated using bootstrapping techniques. Predictive performances were assessed as the area under the receiver operator characteristic curve (AUC) and calibration plots. We compared the models' capability to identify women with a low risk to deliver within 7 days. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk., Results: Seventy-three of 600 included women (12%) had delivered spontaneously within 7 days. The extended model included maternal age, parity, previous preterm delivery, vaginal bleeding, C-reactive protein, cervical length, dilatation and fibronectin status. Both models had high discriminative performances (AUC of 0.92 (95% CI 0.88-0.95) and 0.95 (95% CI 0.92-0.97) respectively). Compared to the model with fibronectin and cervical length, our extended model reclassified 38 women (6%) from low risk to high risk and 21 women (4%) from high risk to low risk. Preterm delivery within 7 days occurred once in both the reclassification groups., Conclusion: In women with symptoms of preterm labour before 34 weeks gestation, a model that integrates maternal characteristics, clinical signs and laboratory tests, did not predict delivery within 7 days better than a model with only fibronectin and cervical length., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To stratify the risk of spontaneous preterm delivery using cervical length (CL) and fetal fibronectin (fFN) in women with threatened preterm labor who remained pregnant after 7 days., Design: Prospective observational study., Setting: Nationwide cohort of women with threatened preterm labor from the Netherlands., Population: Women with threatened preterm labor between 24 and 34 weeks with a valid CL and fFN measurement and remaining pregnant 7 days after admission., Methods: Kaplan-Meier and Cox proportional hazards models were used to estimate cumulative percentages and hazard ratios (HR) for spontaneous delivery., Main Outcome Measures: Spontaneous delivery between 7 and 14 days after initial presentation and spontaneous preterm delivery before 34 weeks., Results: The risk of delivery between 7 and 14 days was significantly increased for women with a CL < 15 mm or a CL ≥15 to <30 mm and a positive fFN, compared with women with a CL ≥30 mm: HR 22.3 [95% confidence interval (CI) 2.6-191] and 14 (95% CI 1.8-118), respectively. For spontaneous preterm delivery before 34 weeks the risk was increased for women with a CL < 15 mm [HR 6.3 (95% CI 2.6-15)] or with a CL ≥15 to <30 mm with either positive fFN [HR 3.6 (95% CI 1.5-8.7)] or negative fFN [HR 3.0 (95% CI 1.2-7.1)] compared with women with a CL ≥ 30 mm., Conclusions: In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test., Study Design: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women., Results: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women., Conclusion: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor., Methods: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk., Results: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk., Conclusion: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days., Level of Evidence: II.

Background: Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome., Methods/design: Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial., Intervention: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, β-error 0.2 and α-error 0.05)., Discussion: This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure., Trial Registration: NTR3492 Dutch Trial Register (http://www.trialregister.nl).

Background: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects., Methods/design: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, β 0.2 at alpha 0.05)., Discussion: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour., Clinical Trial Registration: NTR2947, date of registration: June 20th 2011.

Background: Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection (STI) worldwide. A strong link between C. trachomatis serogroup/serovar and serological response has been suggested in a previous preliminary study. The aim of the current study was to confirm and strengthen those findings about serological IgG responses in relation to C. trachomatis serogroups and serovars., Methods: The study population (n = 718) consisted of two patient groups with similar characteristics of Dutch STI clinic visitors. We performed genotyping of serovars and used titre based and quantitative commercially available ELISA kits (medac Diagnostika) to determine specific serum IgG levels. Optical density (OD) values generated by both tests were used to calculate the IgG titres (cut-off 1:50). Analyses were conducted stratified by gender., Results: We observed very significant differences when comparing the median IgG titres of three serogroups, B, C and I: in women for B vs. C: p < 0.0001 (median titres B 200 vs. C <50); B vs. I: p < 0.0001 (200 vs. 50), and in men for B vs. C: p = 0.0006 (150 vs. <50); B vs. I: p = 0.0001 (150 vs. <50); C vs. I was not significant for both sexes. Serovars D and E of serogroup B had the highest median IgG titres compared to the other serovars in both men and women: 200 and 200 vs. ≤ 100 for women and 100 and 200 vs. ≤ 75 for men, respectively., Conclusions: This study shows that B group serovars induce higher serological responses compared to the C and I group serovars in vivo in both men and women.

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.