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OBJECTIVE: We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an expectant management. STUDY DESIGN: Parents of 2-year-old children included in the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) answered the Ages and Stages Questionnaire (ASQ) and Child Behavior Checklist (CBCL). RESULTS: We approached 582 (89.5%) of 650 parents. The response rate was 50%. Of these children, 27% had an abnormal score on the ASQ and 13% on the CBCL. Results of the ASQ and the CBCL for the 2 policies were comparable. Low birthweight, positive Morbidity Assessment Index score, and admission to intermediate care increased the risk of an abnormal outcome of the ASQ. This effect was not seen for the CBCL. CONCLUSION: In women with intrauterine growth restriction at term, neither a policy of induction of labor nor expectant management affect developmental and behavioral outcome when compared to expectant management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) compared induction of labor and expectant management in suspected intrauterine growth restriction (IUGR) at term. In this subanalysis, we report neonatal morbidity between the policies based on the Morbidity Assessment Index for Newborns (MAIN). STUDY DESIGN: We used data from the DIGITAT. For each neonate, we calculated the MAIN score, a validated outcome scale. RESULTS: There were no differences in mean MAIN scores or in MAIN morbidity categories. We found that neonatal admissions are lower after 38 weeks' gestational age compared with 36 and 37 weeks in both groups. CONCLUSION: The incidence of neonatal morbidity in IUGR at term is comparable and relatively mild either after induction or after an expectant policy. However, neonatal admissions are lower after 38 weeks of pregnancy, so if induction to preempt possible stillbirth is considered, it is reasonable to delay until 38 weeks, provided watchful monitoring. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the incidence and risk factors for neurodevelopmental impairment (NDI) in children with hemolytic disease of the fetus/newborn treated with intrauterine transfusion (IUT). STUDY DESIGN: Neurodevelopmental outcome in children at least 2 years of age was assessed using standardized tests, including the Bayley Scales of Infant Development, the Wechsler Preschool and Primary Scale of Intelligence, and the Wechsler Intelligence Scale for Children, according to the children's age. Primary outcome was the incidence of neurodevelopmental impairment defined as at least one of the following: cerebral palsy, severe developmental delay, bilateral deafness, and/or blindness. RESULTS: A total of 291 children were evaluated at a median age of 8.2 years (range, 2-17 years). Cerebral palsy was detected in 6 (2.1%) children, severe developmental delay in 9 (3.1%) children, and bilateral deafness in 3 (1.0%) children. The overall incidence of neurodevelopmental impairment was 4.8% (14/291). In a multivariate regression analysis including only preoperative risk factors, severe hydrops was independently associated with neurodevelopmental impairment (odds ratio, 11.2; 95% confidence interval, 1.7-92.7). CONCLUSION: Incidence of neurodevelopmental impairment in children treated with intrauterine transfusion for fetal alloimmune anemia is low (4.8%). Prevention of fetal hydrops, the strongest preoperative predictor for impaired neurodevelopment, by timely detection, referral and treatment may improve long-term outcome. [ABSTRACT FROM AUTHOR]

Background: In the past 30 years karyotyping was the gold standard for prenatal diagnosis of chromosomal aberrations in the fetus. Traditional karyotyping (TKT) has a high accuracy and reliability. However, it is labor intensive, the results take 14-21 days, the costs are high and unwanted findings such as abnormalities with unknown clinical relevance are not uncommon. These disadvantages challenged the practice of karyotyping. Multiplex ligation-dependent probe amplification (MLPA) is a new molecular genetic technique in prenatal diagnosis. Previous preclinical evidence suggests equivalence of MLPA and traditional karyotyping (TKT) regarding test performance.Methods/design: The proposed study is a multicentre diagnostic substitute study among pregnant women, who choose to have amniocentesis for the indication advanced maternal age and/or increased risk following prenatal screening test. In all subjects, both MLPA and karyotyping will be performed on the amniotic fluid sample. The primary outcome is diagnostic accuracy. Secondary outcomes will be maternal quality of life, women's preferences and costs. Analysis will be intention to treat and per protocol analysis. Quality of life analysis will be carried out within the study population. The study aims to include 4500 women.Discussion: The study results are expected to help decide whether MLPA can replace traditional karyotyping for 'low-risk' pregnancies in terms of diagnostic accuracy, quality of life and women's preferences. This will be the first clinical study to report on all relevant aspects of the potential replacement.Trial Registration: The protocol is registered in the clinical trial register number ISRCTN47252164. [ABSTRACT FROM AUTHOR]

Purpose: In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection., Materials and Methods: This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area's inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status., Results: Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group ( p <0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group ( p >0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis ( p <0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process., Conclusion: The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Introduction: Recurrent pregnancy loss (RPL) is defined as the loss of two or more conceptions before 24 weeks gestation. Despite extensive diagnostic workup, in only 25%-40% an underlying cause is identified. Several factors may increase the risk for miscarriage, but the chance of a successful pregnancy is still high. Prognostic counselling plays a significant role in supportive care. The main limitation in current prediction models is the lack of a sufficiently large cohort, adjustment for relevant risk factors, and separation between cumulative live birth rate and the success chance in the next conception. In this project, we aim to make an individualised prognosis for the future chance of pregnancy success, which could lead to improved well-being and the ability managing reproductive choices., Methods and Analysis: In this multicentre study, we will include both a prospective and a retrospective cohort of at least 931 and 1000 couples with RPL, respectively. Couples who have visited one of the three participating university hospitals in the Netherlands for intake are eligible for the study participation, with a follow-up duration of 5 years. General medical and obstetric history and reports of pregnancies after the initial consultation will be collected. Multiple imputation will be performed to cope for missing data. A Cox proportional hazards model for time to pregnancy will be developed to estimate the cumulative chance of a live birth within 3 years after intake. To dynamically estimate the chance of an ongoing pregnancy, given the outcome of earlier pregnancies after intake, a logistic regression model will be developed., Ethics and Dissemination: The Medical Ethical Research Committee of the Leiden University Medical Center approved this study protocol (N22.025). There are no risks or burden associated with this study. Participant written informed consent is required for both cohorts. Findings will be published in peer-reviewed journals and presentations at international conferences., Trial Registration Number: NCT05167812., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development., Methods: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme., Results: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses., Conclusion: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objectives: Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software., Methods: We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses., Results: A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases., Conclusion: The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance., (© 2020 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to analyze the annual detection rate (DR) of transposition of the great arteries (TGA) and tetrology of Fallot (ToF), after the introduction of the three-vessel view as a mandatory plane in 2012., Methods: All registered TGA and ToF cases were retrospectively extracted from our registry between 2007 and 2016. We compared the DR in a 10-year period, before 2011, with the DR of TGA and ToF after 2012., Results: In the period before 2012, 23 of the 52 TGA cases were prenatally detected (44.2%), compared with 42 of the 51 cases (82.4%) after 2012. For ToF, the DRs increased from 28 of 64 cases (43.8%) to 42 of 62 cases (67.7%) in the aforementioned periods. The increase in DRs for both defects was statistically significant (P ≤ 0.001 and P ≤ 0.05)., Conclusions: In this nationally organized prenatal screening program with a quality monitoring system and a uniform protocol, DRs of 82.4% for TGA and 67.7% for ToF were reached after the introduction of the three-vessel view as a mandatory item. The three-vessel view significantly contributes to the detection of these conotruncal anomalies., (© 2018 John Wiley & Sons, Ltd.)

Background: CenteringPregnancy (CP) is a multifaceted group based care-model integrated in routine prenatal care, combining health assessment, education, and support. CP has shown some positive results on perinatal outcomes. However, the effects are less obvious when limited to the results of randomized controlled trials: as there are few trials and there is a variation in reported outcomes. Furthermore, former research was mostly conducted in the United States of America and in specific (often high risk) populations. Our study aims to evaluate the effects of CP in the Netherlands in a general population of pregnant women (low and high risk). Furthermore we aim to explore the mechanisms leading to the eventual effects by measuring potential mediating factors., Design: We will perform a stepped wedge cluster randomized controlled trial, in a Western region in the Netherlands. Inclusion criteria are <24 weeks of gestation and able to communicate in Dutch (with assistance). Women in the control period will receive individual care, women in the intervention period (starting at the randomized time-point) will be offered the choice between individual care or CP. Primary outcomes are maternal and neonatal morbidity, retrieved from a national routine database. Secondary outcomes are health behavior, psychosocial outcomes, satisfaction, health care utilization and process outcomes, collected through self-administered questionnaires, group-evaluations and individual interviews. We will conduct intention-to-treat analyses. Also a per protocol analysis will be performed comparing the three subgroups: control group, CP-participants and non-CP-participants, using multilevel techniques to account for clustering effects., Discussion: This study contributes to the evidence regarding the effect of CP and gives a first indication of the effect and implementation of CP in both low and high-risk pregnancies in a high-income Western society other than the USA. Also, measuring factors that are hypothesized to mediate the effect of CP will enable to explain the mechanisms that lead to effects on maternal and neonatal outcomes., Trial Registration: Dutch Trial Register, NTR4178 , registered September 17 th 2013.

Objectives: Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters., Methods: Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth., Results: Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18))., Conclusions: Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

HLA-C is the only polymorphic classical HLA I antigen expressed on trophoblast cells. It is known that higher incidence of C4d deposition on trophoblast cells is present in women with recurrent miscarriage. C4d is a footprint of antibody-mediated classical complement activation. Therefore, this study hypothesize that antibodies against HLA-C may play a role in the occurrence of unexplained consecutive recurrent miscarriage. Present case control study compared the incidence of HLA-C specific antibodies in 95 women with at least three consecutive miscarriages and 105 women with uneventful pregnancy. In the first trimester of the next pregnancy, presence and specificity of HLA antibodies were determined and their complement fixing ability. The incidence of HLA antibodies was compared with uni- and multivariate logistic regression models adjusting for possible confounders. Although in general a higher incidence of HLA antibodies was found in women with recurrent miscarriage 31.6% vs. in control subjects 9.5% (adjusted OR 4.3, 95% CI 2.0-9.5), the contribution of antibodies against HLA-C was significantly higher in women with recurrent miscarriage (9.5%) compared to women with uneventful pregnancy (1%) (adjusted OR 11.0, 95% CI 1.3-89.0). In contrast to the control group, HLA-C antibodies in the recurrent miscarriage group were more often able to bind complement. The higher incidence of antibodies specific for HLA-C in women with recurrent miscarriage suggests that HLA-C antibodies may be involved in the aetiology of unexplained consecutive recurrent miscarriage., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Congenital heart defects (CHDs) are associated with neurodevelopmental (ND) delay. This study aims to assess evidence for impaired prenatal brain development, in fetuses with CHD. A systematical search was performed, and 34 studies evaluating the fetal brain [magnetic resonance imaging (MRI) or ultrasound] in isolated CHD were included (1990-2015). Data regarding cerebral abnormalities, head circumference growth and middle cerebral artery flow were extracted. Prenatal MRI was studied in ten articles (445 fetuses), resulting in a pooled prevalence of 18% (95%CI -6%; 42%) for combined structural and acquired cerebral abnormalities. Prenatal head circumference was studied in 13 articles (753 fetuses), resulting in a pooled z-score of -0.51 (95%CI -0.84; -0.18). Doppler was studied in 21 articles (1412 fetuses), resulting in a lower middle cerebral artery pulsatility index (z-score -0.70 95%CI -0.99; -0.41) in left-sided CHD only. We conclude that prenatal MRI and ultrasound demonstrate brain abnormalities, delay in head growth and brainsparing in subgroups of CHD. However, large MRI studies are scarce, and ultrasound data are biased towards severe and left-sided CHD. Long-term follow-up studies correlating prenatal findings with postnatal ND outcome are limited, and data are lacking to support counseling families regarding ND outcome based on prenatal findings suggestive of altered brain development. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Problem: The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM)., Method of Study: A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated., Results: We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05-1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15-2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20-1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45-0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31-0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11-1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10-1.25) were both associated with the occurrence of RM., Conclusion: Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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 determine women's satisfaction with pain relief using patient controlled analgesia with remifentanil compared with epidural analgesia during labour., Design: Multicentre randomised controlled equivalence trial., Setting: 15 hospitals in the Netherlands., Participants: Women with an intermediate to high obstetric risk with an intention to deliver vaginally. To exclude a clinically relevant difference in satisfaction with pain relief of more than 10%, we needed to include 1136 women. Because of missing values for satisfaction this number was increased to 1400 before any analysis. We used multiple imputation to correct for missing data., Intervention: Before the onset of active labour consenting women were randomised to a pain relief strategy with patient controlled remifentanil or epidural analgesia if they requested pain relief during labour., Main Outcome Measures: Primary outcome was satisfaction with pain relief, measured hourly on a visual analogue scale and expressed as area under the curve (AUC), thus providing a time weighted measure of total satisfaction with pain relief. A higher AUC represents higher satisfaction with pain relief. Secondary outcomes were pain intensity scores, mode of delivery, and maternal and neonatal outcomes. Analysis was done by intention to treat. The study was defined as an equivalence study for the primary outcome., Results: 1414 women were randomised, of whom 709 were allocated to patient controlled remifentanil and 705 to epidural analgesia. Baseline characteristics were comparable. Pain relief was ultimately used in 65% (447/687) in the remifentanil group and 52% (347/671) in the epidural analgesia group (relative risk 1.32, 95% confidence interval 1.18 to 1.48). Cross over occurred in 7% (45/687) and 8% (51/671) of women, respectively. Of women primarily treated with remifentanil, 13% (53/402) converted to epidural analgesia, while in women primarily treated with epidural analgesia 1% (3/296) converted to remifentanil. The area under the curve for total satisfaction with pain relief was 30.9 in the remifentanil group versus 33.7 in the epidural analgesia group (mean difference -2.8, 95% confidence interval -6.9 to 1.3). For who actually received pain relief the area under the curve for satisfaction with pain relief after the start of pain relief was 25.6 in the remifentanil group versus 36.1 in the epidural analgesia group (mean difference -10.4, -13.9 to -7.0). The rate of caesarean section was 15% in both groups. Oxygen saturation was significantly lower (SpO2 <92%) in women who used remifentanil (relative risk 1.5, 1.4 to 1.7). Maternal and neonatal outcomes were comparable between both groups., Conclusion: In women in labour, patient controlled analgesia with remifentanil is not equivalent to epidural analgesia with respect to scores on satisfaction with pain relief. Satisfaction with pain relief was significantly higher in women who were allocated to and received epidural analgesia., Trial Registration: Netherlands Trial Register NTR2551., (© Freeman et al 2015.)

Background: Recent meta-analyses recommend delayed cord clamping (DCC) after uncomplicated births as well as preterm births, but there is no clear definition of timing and uniform national guidelines are lacking., Objective: We aimed to investigate if guidelines for the timing of cord clamping (CC) are followed and what the national practice entails., Methods: A postal questionnaire concerning CC after uncomplicated vaginal, Caesarean term and preterm deliveries was sent to all midwifery practices (n = 526) and obstetrical departments (n = 94) in the Netherlands., Results: The response rate was 81% (500/620). CC protocols were present in 16 and 38% of midwifery and obstetric practices, respectively. Early cord clamping (ECC) was recommended in 54%, DCC in 33%, 6% indicated a specific time point and 7% did not specify. In current practice, DCC was applied after uncomplicated vaginal term deliveries in 90% and ECC in 6%, and no timing was specified in 4%. Midwives used DCC more often than obstetricians (97 vs. 75%). Cessation of cord pulsations was often (54%) used as a time point, 40% used a fixed time point, 2% waited for placental expulsion and 4% did not specify. ECC was preferred in obstetric practices after Caesarean deliveries (in 81%). In preterm births, ECC was practised by 36%, DCC by 54 and 10% did not specify., Conclusion: In the Netherlands, although often not protocolized, DCC is widely used after uncomplicated vaginal term and preterm deliveries, but not after Caesareans. Cessation of cord pulsation is often used as the time point for CC., (© 2014 S. Karger AG, Basel.)

Prenatal screening pathways, as nowadays offered in most Western countries consist of similar tests. First, a risk-assessment test for major aneuploides is offered to pregnant women. In case of an increased risk, invasive diagnostic tests, entailing a miscarriage risk, are offered. For decades, only conventional karyotyping was used for final diagnosis. Moreover, several foetal ultrasound scans are offered to detect major congenital anomalies, but the same scans also provide relevant information for optimal support of the pregnancy and the delivery. Recent developments in prenatal screening include the application of microarrays that allow for identifying a much broader range of abnomalities than karyotyping, and non-invasive prenatal testing (NIPT) that enables reducing the number of invasive tests for aneuploidies considerably. In the future, broad NIPT may become possible and affordable. This article will briefly address the ethical issues raised by these technological developments. First, a safe NIPT may lead to routinisation and as such challenge the central issue of informed consent and the aim of prenatal screening: to offer opportunity for autonomous reproductive choice. Widening the scope of prenatal screening also raises the question to what extent 'reproductive autonomy' is meant to expand. Finally, if the same test is used for two different aims, namely detection of foetal anomalies and pregnancy-related problems, non-directive counselling can no longer be taken as a standard. Our broad outline of the ethical issues is meant as an introduction into the more detailed ethical discussions about prenatal screening in the other articles of this special issue., (© 2014 John Wiley & Sons Ltd.)

Background: During neonatal transition, ductus arteriosus (DA) flow changes from right-to-left to left-to-right and contributes considerably to the increase in pulmonary blood flow. Large transpulmonary pressures generated by crying at birth can influence the DA shunt., Objective: This study aimed to assess differences in DA shunt during quiet breathing and crying directly after birth., Methods: In healthy term infants born by caesarean section, echocardiography was performed at 2, 5 and 10 min after birth. The velocity time integral of DA flow, DA flow ratio (right-to-left/left-to-right flow) and left ventricular output were assessed using echocardiography. Shunting was compared within each patient during crying and quiet breathing, and between time points., Results: A total of 23 infants were studied. The velocity time integral of left-to-right shunting was significantly larger during the inspiratory phase of crying than during quiet breathing [12.8 (9.2-17.4) vs. 5.9 (3.9-7.7) cm at 2 min, p < 0.0001; 14.3 (11.5-22.3) vs. 6.7 (4.1-11.1) cm at 5 min, p < 0.0001, and 18.6 (14.8-22.5) vs. 6.7 (4.4-10.7) cm at 10 min, p < 0.0001, after birth]. The increase in left-to-right shunting during crying was independent from the cardiac cycle as the QRS start of shunt interval time was 138 (82) ms during crying and 156 (35) ms during quiet breathing (n.s.). The DA flow ratio was lower in infants who cried at 0-1 time points versus those who cried at 2-3 time points (n.s.) out of the 3 time points measured. Left ventricular output was higher in infants who cried at 2-3 time points versus 0-1 time points (n.s.)., Conclusion: Crying at birth significantly influences the DA shunt during transition., (© 2014 S. Karger AG, Basel.)

In its successful annual cycle of controversies and debates, the International Society of Prenatal Diagnosis and Therapy once again addressed non-invasive prenatal testing (NIPT) by following up on the 2013 controversy, 'Should non-invasive DNA testing be the standard screening test for Down syndrome in all pregnant women'? with the proposition, 'NIPT for chromosomel abnormalities should be offered to women with low a priori risk'., (© 2014 John Wiley & Sons, Ltd.)

Objective: To assess ductus arteriosus (DA) blood flow directly after birth in healthy term infants after elective caesarean section., Design: In healthy term newborns, echocardiography was performed at 2, 5 and 10 min after birth to monitor cardiac output and DA blood flow. Heart rate (HR) was assessed using ECG., Setting: The delivery rooms of the Leiden University Medical Center., Patients: 24 healthy term infants born after a caesarean section were included in this study., Results: Mean (SD) HR did not change (158 (18) beats per minute (bpm), 5 min (159 (23) bpm) and 10 min (156 (19) bpm). DA diameter decreased from 5.2 (1.3) mm at 2 min to 4.6 (1.3) mm at 5 min (p=0.01) to (3.9 (1.2) mm) (p=0.01) at 10 min. Right-to-left DA shunting was unaltered (median (IQR) 95 (64-154) mL/kg/min to 90 (56-168) mL/kg/min and 80 (64-120) mL/kg/min, respectively (ns)), whereas left-to-right shunting significantly increased between 2 and 5 min (41 (31-70) mL/kg/min vs 67 (37-102) mL/kg/min (p=0.01)) and increased significantly between 2 and 10 min (93 (67-125)) mL/kg/min (p<0.001). Right-to-left/left-to-right shunting ratio decreased significantly from 2.1 (1.4-3.1) at 2 min to 1.4 (1.0-1.8) at 5 min (p<0.0001) and to 0.9 (0.6-1.1) at 10 min (p<0.0001)., Conclusions: DA shunting changes swiftly from predominantly right-to-left shunting to predominantly left-to-right shunting at 10 min after birth, reflecting differential changes in pulmonary and systemic vascular resistance., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Cardiac output depends on stroke volume and heart rate (HR). Only HR is used to monitor hemodynamic transition., Methods: In 24 term newborns born via cesarean section, HR and preductal blood pressure (BP) were measured. Also, using echocardiography, left ventricular dimensions and (Doppler derived) left ventricular output (LVO) were examined at 2, 5, and 10 min after birth., Results: Mean (SD) HR and BP did not change with time (mean HR: 157 (21) bpm at 2 min, 154 (17) bpm at 5 min, and 155 (14) bpm at 10 min; mean BP: 51.2 (15.4) mm Hg at 2 min, 50.5 (11.7) mm Hg at 5 min, and 49.6 (9.5) mm Hg at 10 min). Left ventricular end-diastolic diameter increased from 2 to 5 min (14.3 (1.3) vs. 16.3 (1.7) mm; P < 0.001) and stabilized at 10 min (16.7 (1.4) mm). LVO increased between 2 and 5 min (151 (47) vs. 203 (55) ml/kg/min; P < 0.001) and stabilized at 10 min (201 (45) ml/kg/min). LVO increase was associated with rise in left ventricular stroke volume (r = 0.94; P < 0.001), not with rise in HR (r = 0.37; P value not significant)., Conclusion: Left ventricular dimensions and LVO significantly increased the first 5 min after birth and stabilized at 10 min, whereas BP remained stable. LVO and left ventricular dimension increase are presumably due to increasing left ventricular preload resulting from pulmonary blood flow and ductal shunting increase.

Genomic microarray analysis is increasingly being applied as a prenatal diagnostic tool. Microarrays enable searching the genome at a higher resolution and with higher sensitivity than conventional karyotyping for identifying clinically significant chromosomal abnormalities. As yet, no clear guidelines exist on whether microarrays should be applied prenatally for all indications or only in selected cases such as ultrasound abnormalities, whether a targeted or genome-wide array should be used, and what these should include exactly. In this paper, we present some ethical considerations on the prenatal use of microarrays. There is a strong consensus, at least in Western countries, that the aim of prenatal screening for foetal abnormalities should be understood as facilitating autonomous reproductive choice for prospective parents. The tests offered should be valid and useful to reach that purpose. Against this background, we address several ethical issues raised by the prenatal application of microarrays. First, we argue that the general distinction between a targeted and a genome-wide microarray needs to be scrutinised. Then we examine whether microarrays are 'suitable tests' to serve either a screening or a diagnostic purpose. Given the wide range of findings possibly generated by microarrays, the question arises whether microarrays actually promote or interfere with autonomous reproductive decision-making. Moreover, if variants of unknown clinical significance are identified, this adds to the burden and complexity of reproductive decision-making. We suggest a qualified use of microarrays in the prenatal context.

Objective: The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT trial) showed that in women with suspected intrauterine growth restriction (IUGR) at term, there were no substantial outcome differences between induction of labour and expectant monitoring. The objective of the present analysis is to evaluate whether maternal or fetal markers could identify IUGR fetuses who would benefit from early labour induction., Study Design: The DIGITAT trial was a multicenter, parallel and open-label randomised controlled trial in women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected IUGR (n=650). Women had been randomly allocated to either labour induction or expectant monitoring. The primary outcome was a composite measure of adverse neonatal outcome, defined as neonatal death before hospital discharge, Apgar score <7, umbilical artery pH <7.05, or admission to neonatal intensive care. Using logistic regression modelling, we investigated associations between outcome and 17 markers, maternal characteristics and fetal sonographic and Doppler velocimetry measurements, all collected at study entry., Results: 17 (5.3%) infants in the induction group had an adverse neonatal outcome compared to 20 (6.1%) in the expectant monitoring group. The only potentially informative marker for inducing labour was maternal pre-pregnancy body mass index (BMI). Otherwise, we observed at best weak associations between a benefit from labour induction and maternal age, ethnicity, smoking, parity, pregnancy-induced hypertension or preeclampsia, Bishop score and gestational age, or fetal sonographic markers (gender, estimated fetal weight, body measurements, oligohydramnios, or umbilical artery pulsatility index and end diastolic flow)., Conclusion: In late preterm and term pregnancies complicated by suspected intrauterine growth restriction, most of the known prognostic markers seem unlikely to be helpful in identifying women who could benefit from labour induction, except for maternal pre-pregnancy BMI., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pregnancies complicated by intrauterine growth restriction (IUGR) are at increased risk for neonatal morbidity and mortality. The Dutch nationwide disproportionate intrauterine growth intervention trial at term (DIGITAT trial) showed that induction of labour and expectant monitoring were comparable with respect to composite adverse neonatal outcome and operative delivery. In this study we compare the costs of both strategies., Study Design: A cost analysis was performed alongside the DIGITAT trial, which was a randomized controlled trial in which 650 women with a singleton pregnancy with suspected IUGR beyond 36 weeks of pregnancy were allocated to induction or expectant management. Resource utilization was documented by specific items in the case report forms. Unit costs for clinical resources were calculated from the financial reports of participating hospitals. For primary care costs Dutch standardized prices were used. All costs are presented in Euros converted to the year 2009., Results: Antepartum expectant monitoring generated more costs, mainly due to longer antepartum maternal stays in hospital. During delivery and the postpartum stage, induction generated more direct medical costs, due to longer stay in the labour room and longer duration of neonatal high care/medium care admissions. From a health care perspective, both strategies generated comparable costs: on average €7106 per patient for the induction group (N=321) and €6995 for the expectant management group (N=329) with a cost difference of €111 (95%CI: €-1296 to 1641)., Conclusion: Induction of labour and expectant monitoring in IUGR at term have comparable outcomes immediately after birth in terms of obstetrical outcomes, maternal quality of life and costs. Costs are lower, however, in the expectant monitoring group before 38 weeks of gestation and costs are lower in the induction of labour group after 38 weeks of gestation. So if induction of labour is considered to pre-empt possible stillbirth in suspected IUGR, it is reasonable to delay until 38 weeks, with watchful monitoring., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The increasing number of prenatal diagnostic tests in prenatal screening strategies, raises the question what tests to offer and why. This qualitative study investigated the views and preferences of professionals and potential users regarding four diagnostic test options for women at increased risk for common aneuploidies. Seven focus group sessions were conducted in The Netherlands between October 2009 and June 2010, with various categories of participants (n = 55): professionals engaged in prenatal testing and potential users of this testing (meaning pregnant women and parents of young children). Participants were invited to mention all pros and cons and their preferences regarding four hypothetical diagnostic test options, presented on vignettes: a standard offer of rapid aneuploidy detection, karyotyping or array comparative genomic hybridization, representing a narrow, traditional and broad test, respectively, and the option of individualised choice. Then, a semi-structured group interview was conducted. The data were analysed by the constant comparative method. Participants identified similar test-specific pros and cons but showed different preferences. Users' opinion on what test to offer as a general policy differed from what they would choose themselves. All participants agreed that in theory, users should be enabled to make an informed choice about what test to apply, but they disagreed about the feasibility of this ideal. Standard narrow testing was favoured for its limiting effects on emotional and organisational burdens; individualised choice was preferred for assuring women's decisive influence. The varying opinions reflect different views on what autonomy in the prenatal screening context means, suggest that a single standard test offer is inadequate and that differentiation will be needed.

Monochorionic (MC) twin pregnancies are at increased risk of several complications including acute or chronic twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). Both TTTS and TAPS result from inter-twin fetofetal transfusion through the placental vascular anastomoses. In addition, MC twin pregnancies are at increased risk of having a velamentous cord insertion, which has been linked with poor perinatal outcome due to risk of rupture of the velamentous vessels. In sporadic cases, these vascular connections may have a positive effect instead of a deleterious effect. We present a case of acute fetal distress in a MC twin pregnancy caused by acute hemorrhage following rupture of velamentous vessels. An emergency cesarean section delivery was performed at 29+2 weeks' gestation. One infant was severely anemic at birth and required immediate treatment with volume expansion and blood transfusion. Acute fetal blood loss through the ruptured vessels led to an acute fetofetal transfusion from the co-twin through the placental vascular anastomoses. Delayed intervention could have resulted in severe hypovolemic shock and acute anemia in both fetuses. Instead, in the current case, placental vascular anastomoses had a transient protective role and allowed transfusion of blood from one co-twin into the circulation of the anemic twin., (Copyright © 2013 S. Karger AG, Basel.)

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.

Objective: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome., Design: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial., Setting: Nine Dutch hospitals., Population: Pregnant women with a term singleton fetus in cephalic position., Methods: Data were obtained from a randomized trial that compared monitoring by STAN® (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines., Main Outcome Measures: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy., Results: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented., Conclusions: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To predict instrumental vaginal delivery or caesarean section for suspected fetal distress or failure to progress., Design: Secondary analysis of a randomised trial., Setting: Three academic and six non-academic teaching hospitals in the Netherlands., Population: 5667 labouring women with a singleton term pregnancy in cephalic presentation., Methods: We developed multinomial prediction models to assess the risk of operative delivery using both antepartum (model 1) and antepartum plus intrapartum characteristics (model 2). The models were validated by bootstrapping techniques and adjusted for overfitting. Predictive performance was assessed by calibration and discrimination (area under the receiver operating characteristic), and easy-to-use nomograms were developed., Main Outcome Measures: Incidence of instrumental vaginal delivery or caesarean section for fetal distress or failure to progress with respect to a spontaneous vaginal delivery (reference)., Results:   375 (6.6%) and 212 (3.6%) women had an instrumental vaginal delivery or caesarean section due to fetal distress, and 433 (7.6%) and 571 (10.1%) due to failure to progress, respectively. Predictors were age, parity, previous caesarean section, diabetes, gestational age, gender, estimated birthweight (model 1) and induction of labour, oxytocin augmentation, intrapartum fever, prolonged rupture of membranes, meconium stained amniotic fluid, epidural anaesthesia, and use of ST-analysis (model 2). Both models showed excellent calibration and the receiver operating characteristics areas were 0.70-0.78 and 0.73-0.81, respectively., Conclusion:   In Dutch women with a singleton term pregnancy in cephalic presentation, antepartum and intrapartum characteristics can assist in the prediction of the need for an instrumental vaginal delivery or caesarean section for fetal distress or failure to progress., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Background: Noninvasive fetal aneuploidy detection by use of free DNA from maternal plasma has recently been shown to be achievable by whole genome shotgun sequencing. The high-throughput next-generation sequencing platforms previously tested use a PCR step during sample preparation, which results in amplification bias in GC-rich areas of the human genome. To eliminate this bias, and thereby experimental noise, we have used single molecule sequencing as an alternative method., Methods: For noninvasive trisomy 21 detection, we performed single molecule sequencing on the Helicos platform using free DNA isolated from maternal plasma from 9 weeks of gestation onwards. Relative sequence tag density ratios were calculated and results were directly compared to the previously described Illumina GAII platform., Results: Sequence data generated without an amplification step show no GC bias. Therefore, with the use of single molecule sequencing all trisomy 21 fetuses could be distinguished more clearly from euploid fetuses., Conclusions: This study shows for the first time that single molecule sequencing is an attractive and easy to use alternative for reliable noninvasive fetal aneuploidy detection in diagnostics. With this approach, previously described experimental noise associated with PCR amplification, such as GC bias, can be overcome.

We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth., (Copyright © 2012 by Thieme Medical Publishers, Inc.)

Purpose: To assess the cost-effectiveness of Multiplex Ligation-dependent Probe Amplification (MLPA, P095 kit) compared to karyotyping., Methods: A cost-minimization analysis alongside a nationwide prospective clinical study of 4,585 women undergoing amniocentesis on behalf of their age (≥36 years), an increased risk following first trimester prenatal screening or parental anxiety., Results: Diagnostic accuracy of MLPA (P095 kit) was comparable to karyotyping (1.0 95% CI 0.999-1.0). Health-related quality of life did not differ between the strategies (summary physical health: mean difference 0.31, p = 0.82; summary mental health: mean difference 1.91, p = 0.22). Short-term costs were lower for MLPA: mean difference 315.68 (bootstrap 95% CI 315.63-315.74; -44.4%). The long-term costs were slightly higher for MLPA: mean difference 76.42 (bootstrap 95% CI 71.32-81.52; +8.6%). Total costs were on average 240.13 (bootstrap 95% CI 235.02-245.23; -14.9%) lower in favor of MLPA. Cost differences were sensitive to proportion of terminated pregnancies, sample throughput, individual choice and performance of tests in one laboratory, but not to failure rate or the exclusion of polluted samples., Conclusion: From an economic perspective, MLPA is the preferred prenatal diagnostic strategy in women who undergo amniocentesis on behalf of their age, following prenatal screening or parental anxiety.

No consensus exists whether women at increased risk for trisomy 21, 13, and 18 should be offered stand-alone rapid aneuploidy detection (RAD) or karyotyping. In this paper, the ethical implications of a fast, relatively cheap and targeted RAD are examined. The advantages of RAD seem less robust than its proponents suggest. Fast test results only give a short-term psychological benefit. The cost advantage of RAD is apparent, but must be weighed against consequences like missed abnormalities, which are evaluated differently by professionals and pregnant women. Since pre-test information about RAD will have to include telling women about karyotyping as a possible alternative, the advantage of RAD in terms of the quantity of information that needs to be given may also be smaller than suggested. We conclude that none of the supposed arguments in favour of RAD is decisive in itself. Whether the case for RAD may still be regarded as convincing when taking these arguments together seems to depend on one's implicit view of what prenatal screening is about. Are we basically dealing with a test for trisomy 21 and a few conditions more? Or are there good grounds for also testing for the wider range of abnormalities that karyotyping can detect? As professionals and pregnant women may have different views about this, we suggest that the best approach is to offer women a choice between RAD and karyotyping. This approach is most in line with the general aim of prenatal screening: providing opportunities for autonomous reproductive choice.

The presence of placental vascular anastomoses is a conditio sine qua non for the development of twin-to-twin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS)(1,2). Injection studies of twin placentas have shown that such anastomoses are almost invariably present in monochorionic twins and extremely rare in dichorionic twins(1). Three types of anastomoses have been documented: from artery to artery, from vein to vein and from artery to vein. Arterio-venous (AV) anastomoses are unidirectional and are referred to as "deep" anastomoses since they proceed through a shared placental cotyledon, whereas arterio-arterial (AA) and veno-venous (VV) anastomoses are bi-directional and are referred to as "superficial" since they lie on the chorionic plate. Both TTTS and TAPS are caused by net imbalance of blood flow between the twins due to AV anastomoses. Blood from one twin (the donor) is pumped through an artery into the shared placental cotyledon and then drained through a vein into the circulation of the other twin (the recipient). Unless blood is pumped back from the recipient to the donor through oppositely directed deep AV anastomoses or through superficial anastomoses, an imbalance of blood volumes occurs, gradually leading to the development of TTTS or TAPS. The presence of an AA anastomosis has been shown to protect against the development of TTTS and TAPS by compensating for the circulatory imbalance caused by the uni-directional AV anastomoses(1,2). Injection of monochorionic placentas soon after birth is a useful mean to understand the etiology of various (hematological) complications in monochorionic twins and is a required test to reach the diagnosis of TAPS(2). In addition, injection of TTTS placentas treated with fetoscopic laser surgery allows identification of possible residual anastomoses(3-5). This additional information is of paramount importance for all perinatologists involved in the management and care of monochorionic twins with TTTS or TAPS. Several placental injection techniques are currently being used. We provide a simple protocol to accurately evaluate the presence of (residual) vascular anastomoses using colored dye injection.

Objective: To assess the cost-effectiveness of addition of ST analysis of the fetal electrocardiogram (ECG; STAN) to cardiotocography (CTG) for fetal surveillance during labor compared with CTG only., Design: Cost-effectiveness analysis based on a randomized clinical trial on ST analysis of the fetal ECG., Setting: Obstetric departments of three academic and six general hospitals in The Netherlands. Population. Laboring women with a singleton high-risk pregnancy, a fetus in cephalic presentation, a gestational age >36 weeks and an indication for internal electronic fetal monitoring., Methods: A trial-based cost-effectiveness analysis was performed from a health-care provider perspective., Main Outcome Measures: Primary health outcome was the incidence of metabolic acidosis measured in the umbilical artery. Direct medical costs were estimated from start of labor to childbirth. Cost-effectiveness was expressed as costs to prevent one case of metabolic acidosis., Results: The incidence of metabolic acidosis was 0.7% in the ST-analysis group and 1.0% in the CTG-only group (relative risk 0.70; 95% confidence interval 0.38-1.28). Per delivery, the mean costs per patient of CTG plus ST analysis (n= 2 827) were €1,345 vs. €1,316 for CTG only (n= 2 840), with a mean difference of €29 (95% confidence interval -€9 to €77) until childbirth. The incremental costs of ST analysis to prevent one case of metabolic acidosis were €9 667., Conclusions: The additional costs of monitoring by ST analysis of the fetal ECG are very limited when compared with monitoring by CTG only and very low compared with the total costs of delivery., (© 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Small for gestational age (SGA) is associated with increased neonatal morbidity and mortality. At present, evidence on whether these pregnancies should be managed expectantly or by induction is lacking. To get insight in current policy we analysed data of the National Dutch Perinatal Registry (PRN)., Methods: We used data of all nulliparae between 2000 and 2005 with a singleton in cephalic presentation beyond 36+0 weeks, with a birth weight below the 10th percentile. We analysed two groups of pregnancies: (I) with isolated SGA and (II) with both SGA and hypertensive disorders. Onset of labour was related to route of delivery and neonatal outcome., Results: Induction was associated with a higher risk of emergency caesarean section (CS), without improvement in neonatal outcome. For women with isolated SGA the relative risk of emergency CS after induction was 2.3 (95% Confidence Interval [CI] 2.1 to 2.5) and for women with both SGA and hypertensive disorders the relative risk was 2.7 (95% CI 2.3 to 3.1)., Conclusion: Induction in pregnancies complicated by SGA at term is associated with a higher risk of instrumental deliveries without improvement of neonatal outcome. Prospective studies are needed to determine the best strategy in suspected IUGR at term.

Objective: To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term., Design: Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT))., Setting: Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008., Participants: Pregnant women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected intrauterine growth restriction., Interventions: Induction of labour or expectant monitoring., Main Outcome Measures: The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means., Results: 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference -9.9 days, 95% CI -11.3 to -8.6) and weighed 130 g less (mean difference -130 g, 95% CI -188 g to -71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference -0.8%, 95% CI -4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI -5.0% to 5.6%)., Conclusions: In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth., Trial Registration: International Standard Randomised Controlled Trial number ISRCTN10363217.

Objective: To determine expert consensus on which chromosomal abnormalities should and should not be detected in prenatal diagnosis, and for which abnormalities disagreement remains after structured discussion., Methods: An expert panel of 24 prenatal experts (8 clinical cytogeneticists, 8 clinical geneticists and 8 obstetricians) rated 15 chromosomal abnormalities sampled from a nationwide study on rapid aneuploidy detection (RAD). In two individual anonymous rating rounds and one group meeting, the participants rated PRO or AGAINST detection and stated their main argument. The 15 chromosomal abnormalities were described in detail by a stylized vignette containing an obstetrical history, the indication for prenatal diagnosis and the range of possible outcomes of the chromosomal abnormality. Consensus was defined to be present if at least 80% of the experts agreed., Results: Consensus was reached in 12 out of 15 cases. In ten cases, there was agreement PRO detection and in two cases experts agreed AGAINST detection. At the end of the third round, dissensus remained on three abnormalities., Conclusion: Experts largely agreed on detecting chromosomal abnormalities with severe consequences and AGAINST detection in case of irrelevant clinical consequences. For chromosomal abnormalities with mild or uncertain outcomes, dissensus remained. None of the currently available tests corresponds to these demands.

During pregnancy, maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Recently, CD4(+)CD25(bright) regulatory T cells have been shown to be concentrated in decidual tissue, where they are able to suppress fetus-specific and nonspecific immune responses. Decidual CD8(+) T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal-maternal interface, but data on the characteristics of these cells are limited. In this study we examined the decidual and peripheral CD8(+) T cell pool for CD45RA, CCR7, CD28, and CD27 expression, using nine-color flow cytometry. Our data demonstrate that decidual CD8(+) T cells mainly consist of differentiated CD45RA(-)CCR7(-) effector-memory (EM) cells, whereas unprimed CD45RA(+)CCR7(+) naive cells are almost absent. Compared with peripheral blood EM CD8(+) T cells, the decidual EM CD8(+) T cells display a significantly reduced expression of perforin and granzyme B, which was confirmed by immunohistochemistry of decidual tissue sections. Interestingly, quantitative PCR analysis demonstrates an increased perforin and granzyme B mRNA content in decidual EM CD8(+) T cells in comparison with peripheral blood EM CD8(+) T cells. The presence of high levels of perforin and granzyme B mRNA in decidual EM T cells suggests that decidual CD8(+) T cells pursue alternative means of EM cell differentiation that may include a blockade of perforin and granzyme B mRNA translation into functional perforin and granzyme B proteins. Regulation of decidual CD8(+) T cell differentiation may play a crucial role in maternal immune tolerance to the allogeneic fetus.