Nationwide confidential enquiries into maternal deaths because of obstetric hemorrhage in the Netherlands between 2006 and 2019.

INTRODUCTION: Obstetric hemorrhage-related deaths are rare in high income countries. Yet, with increasing incidences of obstetric hemorrhage in these countries, it is of utmost importance to learn lessons from each obstetric hemorrhage-related death to improve maternity care. Our objective was to calculate the obstetric hemorrhage-related maternal mortality ratio (MMR), assess causes of obstetric hemorrhage-related deaths, and identify lessons learned. MATERIAL AND METHODS: Nationwide mixed-methods prospective case-series with confidential enquiries into maternal deaths due to obstetric hemorrhage in the Netherlands from January 1, 2006 to December 31, 2019. RESULTS: The obstetric hemorrhage-related MMR in the Netherlands in 2006-2019 was 0.7 per 100 000 livebirths and was not statistically significantly different compared with the previous MMR of 1.0 per 100 000 livebirths in 1993-2005 (odds ratio 0.70, 95% confidence interval 0.38-1.30). Leading underlying cause of hemorrhage was retained placenta. Early recognition of persistent bleeding, prompt involvement of a senior clinician and timely management tailored to the cause of hemorrhage with attention to coagulopathy were prominent lessons learned. Also, timely recourse to surgical interventions, including hysterectomy, in case other management options fail to stop bleeding came up as an important lesson in several obstetric hemorrhage-related deaths. CONCLUSIONS: The obstetric hemorrhage-related MMR in the Netherlands in 2006-2019 has not substantially changed compared to the MMR of the previous enquiry in 1993-2005. Although obstetric hemorrhage is commonly encountered by maternity care professionals, it is important to remain vigilant for possible adverse maternal outcomes and act upon an ongoing bleeding following birth in a more timely and adequate manner. Our confidential enquiries still led to important lessons learned with clinical advice to professionals as how to improve maternity care and avoid maternal deaths. Drawing lessons from maternal deaths should remain a qualitative and moral imperative.

Women of reproductive age in a tertiary intensive care unit: indications, outcome and the impact of pregnancy-a retrospective cohort study.

BACKGROUND: To evaluate the indications for admission and mortality rates of women of reproductive age admitted to a tertiary Intensive Care Unit (ICU) and to compare the outcomes of obstetric and non-obstetric admissions. METHODS: A retrospective cohort study was performed, including all women aged 17-41 years admitted to a level 3 ICU in the Netherlands, between January 1, 2000 and January 1, 2016. Primary outcome was indication for admission and mortality. Mortality, length of stay (LOS), need for mechanical ventilation and APACHE II score were compared between obstetric and non-obstetric admissions. The obstetric group was further analyzed for maternal and perinatal outcomes. RESULTS: 3461 women (median age 32 years) were included, with an overall mortality rate of 13.3%. The obstetric group consisted of 265 women (7.7%). The non-obstetric group (n = 3196) was admitted most often for cardiovascular disease (19.6%), followed by oncologic disease (15%). Mortality was the highest in women with oncologic disease (23.9%). The obstetric group had lower mortality compared to the non-obstetric group (4.9% vs. 14%, p < 0.001), despite higher APACHE II score (14 vs. 11, p < 0.001) and a higher ventilation rate (47.9% vs. 39%, p = 0.004). Major surgical or endovascular interventions, besides caesarean section, were performed in 46% of the obstetric group. Perinatal death occurred in 17.2% and of the surviving infants, 63.2% were born preterm and 45.1% required Neonatal Intensive Care Unit admission. CONCLUSIONS: Cardiovascular disease is the most important indication for admission and oncologic disease is associated with highest mortality in women of reproductive age. Obstetric patients constitute a small percentage of all ICU admissions in a tertiary ICU center. They have lower mortality rates than non-obstetric young female patients, despite a more severe initial presentation. Nevertheless lasting maternal morbidity and perinatal mortality and morbidity is frequent.

Prenatal influence of congenital heart defects on trajectories of cortical folding of the fetal brain using three-dimensional ultrasound.

OBJECTIVE: The objective of the study is to investigate the prenatal influence of congenital heart defects (CHD) on trajectories of fetal cortical folding using three-dimensional ultrasound (3D US). METHOD: We included 20 CHD fetuses and 193 controls for studying the fetal brain at 22, 26 and 32 weeks' gestational age (GA). The Sylvian, insula and parieto-occipital fissure (POF) depths were measured using 3D US, and reliability was evaluated. Doppler indices of the umbilical artery and middle cerebral artery were measured to calculate the cerebro-placental ratio. Associations between CHD and cortical folding were estimated using linear mixed models. RESULTS: Brain fissure measurements were successful in over 80% of 3D US scans, except for the POF at 32 weeks' GA (65%). All measurements showed a good reliability (intraclass correlation coefficients > 0.84). Growth trajectories of the left insula depth (ß = -2.753, 95% CI = -5.375; -0.130, p = 0.040) and right POF (ß = -3.762, 95% CI = -7.178; -0.346, p = 0.031) were decreased in CHD compared with controls, whereas growth rates were increased (ß = 0.014, 95% CI = 0.001; 0.027, p = 0.036 and ß = 0.024, 95% CI = 0.007; 0.041, p = 0.006). In contrast to controls, we found no associations between cerebro-placental ratio and cortical folding in CHD. CONCLUSION: Fetal cortical folding can be evaluated reliably by measuring brain fissure depths. Trajectories of cortical folding between 22 and 32 weeks' GA seem to be influenced by CHD. © 2017 John Wiley & Sons, Ltd.

Which Factors Contribute to False-Positive, False-Negative, and Invalid Results in Fetal Fibronectin Testing in Women with Symptoms of Preterm Labor?

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.

Risk stratification with cervical length and fetal fibronectin in women with threatened preterm labor before 34 weeks and not delivering within 7 days.

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.

Effects of antiplatelet therapy on menstrual blood loss in reproductive-aged women: a systematic review.

Background: The effects of antiplatelet therapy on menstrual bleeding have not been well characterized. Objectives: To systematically review the effects of antiplatelet therapy on menstrual bleeding. Methods: A literature search was performed for studies of reproductive-aged women who received antiplatelet therapy. Characteristics of menstrual bleeding both before and after initiation of antiplatelet therapy and from comparison groups were collected. Two reviewers independently assessed the risk of bias in individual studies. Results: Thirteen studies with a total of 611 women who received antiplatelet therapy were included. Types of antiplatelet drugs used were aspirin (n = 8), aspirin and/or clopidogrel (n = 2), prasugrel (n = 1), and not specified (n = 2). Risk of bias was assessed at moderate (n = 1), serious (n = 8), critical (n = 2), and no information (n = 2). Three studies reported changes in menstrual blood loss volume. One of these showed no increase during antiplatelet therapy; the other 2 studies suggested that aspirin may increase menstrual blood loss volume. In 3 studies that assessed the duration of menstrual bleeding, up to 13% of women reported an increased duration of menstruation. In 5 studies that reported the intensity of menstrual flow, 13% to 38% of women experienced an increase in the intensity of flow. Five studies reported the prevalence of heavy menstrual bleeding in women who received antiplatelet therapy, with estimates ranging from 7% to 38%. Conclusion: There is lack of high-quality data on the effects of antiplatelet therapy on menstrual bleeding. Aspirin may increase menstrual blood loss, at least in a minority of women, whereas the effects of P2Y12 inhibitors are unknown.

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Maternal, fetal, neonatal and breastmilk flecainide concentration during maternal therapy and lactation: a case report.

BACKGROUND: Mothers requiring the antiarrhythmic agent flecainide are often advised not to breastfeed, because of the lack of data concercing neonatal effects and flecainide plasma concentrations following maternal exposure as well as via lactation. This is the first report on combined maternal, fetal, neonatal and breastmilk flecainide concentrations in a breastfed infant of a mother requiring flecainide treatment. CASE PRESENTATION: A 35-year old Gravida 2 Para 1, known with ventricular arrhythmia, was referred to our tertiary center at 35 + 4 weeks of gestation. Because of an increase of ventricular ectopy, oral metoprolol 11.9 milligrams once daily was switched to oral flecainide 87.3 milligrams twice daily. Weekly collected maternal flecainide plasma trough concentrations fell within the therapeutic range of 0.2 to 1.0 mg/L and no further clinically significant arrhythmias occurred during the study period. A healthy son was born at 39 weeks of gestation and had a normal electrocardiogram. The fetal to maternal flecainide ratio was 0.72 and at three different timepoints, the flecainide concentration was higher in breastmilk than in maternal plasma. The relative infant dose received via breastmilk compared to maternal dose was 5.6%. Neonatal plasma concentrations were not detectable, despite the flecainide passage into breastmilk. All electrocardiograms to assess the neonatal antiarrhytmic effect were normal. CONCLUSIONS: Our results assume that flecainide can be prescribed safely to lactating mothers. Quantification of drug concentrations in neonatal blood in addition to measurements in maternal and fetal blood, and breastmilk, are helpful to evaluate the effects and safety of maternal medication use during pregnancy and lactation.

Pregnancy outcomes in women with a mitral valve prosthesis: A systematic review and meta-analysis.

Objectives: To evaluate the ongoing debate concerning the choice of valve prosthesis for women requiring mitral valve replacement (MVR) and who wish to conceive. Bioprostheses are associated with risk of early structural valve deterioration. Mechanical prostheses require lifelong anticoagulation and carry maternal and fetal risks. Also, the optimal anticoagulation regimen during pregnancy after MVR remains unclear. Methods: A systematic review and meta-analysis was conducted of studies reporting on pregnancy after MVR. Valve- and anticoagulation-related maternal and fetal risks during pregnancy and 30 days' postpartum were analyzed. Results: Fifteen studies reporting 722 pregnancies were included. In total, 87.2% of pregnant women had a mechanical prosthesis and 12.5% a bioprosthesis. Maternal mortality risk was 1.33% (95% confidence interval [CI], 0.69-2.56), any hemorrhage risk 6.90% (95% CI, 3.70-12.88). Valve thrombosis risk was 4.71% (95% CI, 3.06-7.26) in patients with mechanical prostheses. 3.23% (95% CI, 1.34-7.75) of the patients with bioprostheses experienced early structural valve deterioration. Of these, the mortality was 40%. Pregnancy loss risk was 29.29% (95% CI, 19.74-43.47) with mechanical prostheses versus 13.50% (95% CI, 4.31-42.30) for bioprostheses. Switching to heparin during the first trimester demonstrated a bleeding risk of 7.78% (95% CI, 3.71-16.31) versus 4.08% (95% CI, 1.17-14.28) for women on oral anticoagulants throughout pregnancy and a valve thrombosis risk of 6.99% (95% CI, 2.08-23.51) versus 2.89% (95% CI, 1.40-5.94). Administration of anticoagulant dosages greater than 5 mg resulted in a risk of fetal adverse events of 74.24% (95% CI, 56.11-98.23) versus 8.85% (95% CI, 2.70-28.99) in ≤5 mg. Conclusions: A bioprosthesis seems the best option for women of childbearing age who are interested in future pregnancy after MVR. If mechanical valve replacement is preferred, the favorable anticoagulation regimen is continuous low-dose oral anticoagulants. Shared decision-making remains priority when choosing a prosthetic valve for young women.

Gravid uterine torsion after prone positioning in SARS-CoV2 (COVID-19)-related acute respiratory distress syndrome.

A multiparous pregnant patient was admitted to the intensive care unit in her third trimester of pregnancy for prone positioning mechanical ventilation after developing SARS-CoV2 (COVID-19)-related acute respiratory distress syndrome. Repositioning in left lateral tilt was followed by uterine contractions and cardiotocography alterations. Preterm caesarean section was performed based on persistent foetal tachycardia and suspected foetal distress, followed by a per-operative diagnosis of uterine levotorsion. This case report is the first to explore a potential causal link between prolonged prone positioning in late pregnancy and postural gravid uterine torsion and highlights the need for appropriate foetal monitoring during prone positioning mechanical ventilation support.

Patient-reported preconceptional characteristics in the prediction of recurrent preeclampsia.

OBJECTIVE: To develop a prediction model for recurrent preeclampsia using patient-reported preconceptional characteristics, which can be used for risk stratification of subsequent pregnancies. STUDY DESIGN: Retrospective cohort study using data from The Preeclampsia Registry™ of 1028 women with a history of preeclampsia and at least one subsequent pregnancy. MAIN OUTCOME MEASURES: Candidate predictors were included in a multivariable logistic regression analysis and a backward selection procedure was used to select the final predictors. Internal validation took place by internally validating the model in 500 simulated samples (bootstrapping), which provided a shrinkage factor to create the final model. This final model was evaluated for performance by a calibration plot and the area under the receiver operating curve (AUC). Missing data was handled by multiple imputation. RESULTS: Recurrent preeclampsia occurred in 467 (45.4%) women. Predictors in the final model were: a history of migraine, first degree relative with cardiovascular disease, first degree relative with placenta-related pregnancy complication, gestational age at delivery of index pregnancy, birthweight of the previous child, history of placental abruption, multiparity, chronic hypertension, interval between index and subsequent pregnancy, paternal non-white ethnicity and maternal age. AUC of the model was 0.63 (95% CI 0.59-0.66). In a subset of women who used aspirin prior or during their subsequent pregnancy, performance of the model was similar (AUC 0.60; 95% CI 0.50-0.71). CONCLUSIONS: In this study we developed a prediction model for recurrent preeclampsia with moderate performance after internal validation. Early risk stratification of subsequent pregnancies that allows for customization of antenatal care and personalized prevention strategies, is not yet possible.

Cardiometabolic Profiles in Women with a History of Hypertensive and Normotensive Fetal Growth Restriction.

Background: The majority of evidence on associations between pregnancy complications and future maternal disease focuses on hypertensive (Ht) complications. We hypothesize that impaired cardiometabolic health after pregnancies complicated by severe fetal growth restriction (FGR) is independent of the co-occurrence of hypertension. Materials and Methods: In a prospective cohort of women with a pregnancy complicated by early FGR (delivery <34 weeks gestation), with or without concomitant hypertension, cardiometabolic risk factors were assessed after delivery. A population-based reference cohort was used for comparison, and analyses were adjusted for age, current body mass index (BMI), smoking habits, and hormonal contraceptive use. Results: Median time from delivery to assessment was 4 months in both the Ht (N = 115) and normotensive (Nt) (N = 42) FGR groups. Compared with the reference group (N = 380), in both FGR groups lipid profile and glucose homeostasis at assessment were unfavorable. Women with Ht-FGR had the least favorable cardiometabolic profile, with higher prevalence ratios (PRs) for diastolic blood pressure >85 mmHg (PR 4.0, 95% confidence interval [CI] 2.1-6.7), fasting glucose levels >5.6 mmol/L (PR 2.9, 95% CI 1.4-5.6), and total cholesterol levels >6.21 mmol/L (PR 4.5, 95% CI 1.9-8.8), compared with the reference group. Women with Nt-FGR more often had a BMI >30 kg/m2 (PR 2.5, 95% CI 1.2-4.7) and high-density lipoprotein-cholesterol levels <1.29 mmol/L (PR 2.4, 95% CI 1.4-3.5), compared with the reference group. Conclusions: Women with a history of FGR showed unfavorable short-term cardiometabolic profiles in comparison with a reference group, independent of the co-occurrence of hypertension. Therefore, women with a history of FGR may benefit from cardiovascular risk factor assessment and subsequent risk reduction strategies.

Low prevalence of anti-SSA (anti-Ro) and anti-SSB (anti-La) autoantibodies in female patients with rheumatoid arthritis with a wish to conceive.

OBJECTIVES: Guidelines advise to test for anti-Sjögren's-syndrome-related antigen A (anti-SSA) and anti-Sjögren's-syndrome-related antigen B (anti-SSB) antibodies in all patients with rheumatoid arthritis (RA) who wish to conceive. Our objective was to determine the prevalence and titres of anti-SSA and anti-SSB autoantibodies in patients with RA with a wish to conceive or pregnant. METHODS: Patients were derived from two large cohorts on RA and pregnancy (PARA cohort and PreCARA cohort). In addition, to determine the clinical relevance of searching for anti-SSA and anti-SSB in patients with RA, we studied the prevalence of the maternal diagnosis of RA in the French national registry of neonatal lupus syndrome (NLS) and congenital heart block (CHB). RESULTS: 26 out of 647 patients with RA had detectable anti-SSA and/or anti-SSB. Anti-SSA was detected in 25 out of 647 patients (3.9%) (Ro-52, n=17; Ro-60, n=19), anti-SSB in 7 out of 647 (1.1%). Thirteen women had a titre of >240 units/mL of anti-SSA antibodies. The prevalence of anti-SSA and/or anti-SSB was higher in rheumatoid factor (RF)-positive patients compared with RF-negative patients (5.1% vs 1.6%, p=0.04). No cases of CHB and/or NLS in the offspring were observed. In the French national register, the prevalence of RA in mothers with SSA related CHB was 1.5%. CONCLUSION: Anti-SSA and anti-SSB have a low prevalence in patients with RA who wish to conceive. Especially for RF-negative patients, the current advise to test for anti-SSA and anti-SSB should be reconsidered.

The physiological effect of early pregnancy on a woman's response to a submaximal cardiopulmonary exercise test.

Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (<13 weeks gestation) and 20 healthy, non-pregnant women, we performed a CPET with stationary cycling during a RAMP protocol until 70% of the estimated maximum heart rate (HR) of each participant. Hemodynamic and respiratory parameters were non-invasively monitored by impedance cardiography (PhysioFlow® ) and a breath-by-breath analyzer (OxyconTM ). To compare both groups, we used linear regression analysis, adjusted for age. We observed a similar response of stroke volume, cardiac output (CO) and HR to stationary cycling in pregnant and non-pregnant women, but a slightly lower 1-min recovery rate of CO (-3.9 [-5.5;-2.3] vs. -6.6 [-8.2;-5.1] L min-1  min-1 ; p = .058) and HR (-38 [-47; -28] vs. -53 [-62; -44] bpm/min; p = .065) in pregnant women. We also observed a larger increase in ventilation before the ventilatory threshold (+6.2 [5.4; 7.0] vs. +3.2 [2.4; 3.9] L min-1  min-1 ; p < .001), lower PET CO2 values at the ventilatory threshold (33 [31; 34] vs. 36 [34; 38] mmHg; p = .042) and a larger increase of breathing frequency after the ventilatory threshold (+4.6 [2.8; 6.4] vs. +0.6 [-1.1; 2.3] breaths min-1  min-1 ; p = .015) in pregnant women. In conclusion, we observed a slower hemodynamic recovery and an increased ventilatory response to exercise in early pregnancy.

Influence of pregnancy on long-term durability of allografts in right ventricular outflow tract.

BACKGROUND: There is very limited published evidence about the influence of pregnancy on allograft durability in right ventricular outflow tract position. We present the first study using mixed and joint modeling. METHODS: This retrospective study compared clinical and valve related outcomes of all consecutive female hospital survivors in their fertile life phase (18-50 years) based on pregnancy. Serial echocardiographic measurements of pulmonary gradient and regurgitation were analyzed for their association with valve replacement using joint models for longitudinal and time-to-event data. Occurrence of first pregnancy was included as a time-dependent intermediate event in both the longitudinal and survival analyses of the joint model to assess its impact on the hemodynamic and clinical outcome. RESULTS: In total, 196 consecutive women in their fertile life-phase with an allograft were included. Complete information of 176 (90%) allografts in 165 women was available, including 1395 echocardiograms. Of these women, 51 (30.9%) women had 84 completed pregnancies at an average age of 29.1 ± 3.9 (SD) years; 8.1 ± 6.1 years since allograft implantation. Tetralogy of Fallot was the most common diagnosis in both groups. After a mean follow-up of 15.2 years (range 0.1-30), 7 (13.7%) parous women underwent valve replacement versus 20 (17.5%) nulliparous women. During this follow-up, the mean allograft gradient in parous (24.2 mm Hg) and nulliparous (21.0 mm Hg) women was comparable (P = .225). A 1-mm Hg increase in pulmonary gradient increased the instantaneous risk of pulmonary valve replacement (PVR) by a ratio of 1.051 (P < .001), regardless of pregnancy. Similarly, development of moderate or severe regurgitation increased the risk of PVR (P = .038), regardless of pregnancy. Pregnancy was not associated with a change in the allograft gradient (P = .258), regurgitation grade (P = .774), or hazard of PVR (P = .796) during follow-up. CONCLUSIONS: Pregnancy is not associated with impaired allograft durability in women with good cardiac health.

Study protocol for a prospective cohort study to investigate Hemodynamic Adaptation to Pregnancy and Placenta-related Outcome: the HAPPO study.

INTRODUCTION: The importance of cardiovascular health in relation to pregnancy outcome is increasingly acknowledged. Women who develop certain pregnancy complications, in particular preeclampsia, are at higher risk for future cardiovascular disease. Independent of its outcome, pregnancy requires a substantial adaptive response of the maternal cardiovascular system. In the Hemodynamic Adaptation to Pregnancy and Placenta-related Outcome (HAPPO) study, we aim to examine longitudinal maternal haemodynamic adaptation to pregnancy from the preconception period onwards. We hypothesise that women who will develop adverse pregnancy outcomes have impaired cardiovascular health before conception, leading to haemodynamic maladaptation to pregnancy and diminished uteroplacental vascular development. METHODS AND ANALYSIS: In this prospective cohort study embedded in the Rotterdam periconception cohort, 200 women with a history of placenta-related pregnancy complications (high-risk group) and 100 women with an uncomplicated obstetric history (low-risk group) will be included. At five moments (preconception, first, second and third trimester and postdelivery), women will undergo an extensive examination of the macrocirculatory and microcirculatory system and uteroplacental vascular development. The main outcome measures are differences in maternal haemodynamic adaptation to pregnancy between women with and without placenta-related pregnancy complications. In a multivariate linear mixed model, the relationship between maternal haemodynamic adaptive parameters, (utero)placental vascularisation indices and clinical outcomes (occurrence of pregnancy complications, embryonic and fetal growth trajectories, miscarriage rate, gestational age at delivery, birth weight) will be studied. Subgroup analysis will be performed to study baseline and trajectory differences between high-risk and low-risk women, independent of subsequent pregnancy outcome. ETHICS AND DISSEMINATION: This study protocol was approved by the Medical Ethics Committee of the Erasmus MC, Rotterdam, the Netherlands (MEC 2018-150). Results will be disseminated to the medical community by publications in peer-reviewed journals and presentations at scientific congresses. Also, patient associations will be informed and the public will be informed by dissemination through (social) media. TRIAL REGISTRATION NUMBER: NL7394 (www.trialregister.nl).

Internal Podalic Version and Breech Extraction: Enhancing Realistic Sensations in a Simulation Model.

BACKGROUND: Experience with internal podalic version and breech extraction is diminishing, especially in the younger generation of obstetricians. Simulation training is essential to teach and maintain these skills. INSTRUMENT: We present a mannequin-based simulation method that enhances realistic sensations during training. EXPERIENCE: By positioning the fetal mannequin into a thin plastic bag filled with water, the impression of palpating, grabbing, and pulling the fetal feet through the plastic bag is similar to reaching feet through intact membranes. The unique approach of this realistic simulation model makes the experience fun and memorable, which contributes to the didactic value and success of the model. CONCLUSION: The simulation model we present mimics the situation and sensation obstetricians experience while performing internal podalic version and breech extraction.

Outcomes of Pregnancy After Right Ventricular Outflow Tract Reconstruction With an Allograft Conduit.

BACKGROUND: There is no published evidence on pregnancy after right ventricular outflow tract (RVOT) reconstruction with an allograft. OBJECTIVES: The aim of this study was to describe pregnancy outcomes in women with allografts in the RVOT position. METHODS: A retrospective cohort study of consecutive female patients who received allografts in the RVOT position was conducted. All patients between 18 and 50 years of age were screened for cardiac, obstetric, and fetal outcomes of completed (≥20 weeks' gestation) pregnancies. RESULTS: In total, 196 women met the inclusion criteria, of whom 56 had 89 completed pregnancies. Information could be retrieved in 84 cases (94.4%). Mean maternal age was 29.6 ± 4.3 years, with 80 patients (95.2%) in New York Heart Association functional class I or II. The most common diagnosis was tetralogy of Fallot. All women survived pregnancy. There were 2 cases (2.4%) of heart failure (arrhythmic and diastolic dysfunction), 1 case (1.2%) of infection (chorioamnionitis), and 3 cases (3.6%) of pre-eclampsia. No other cardiac or obstetric events were reported. All children were born alive at a median gestational age of 38.4 weeks (interquartile range: 36.9 to 39.6 weeks), with a median birthweight of 2,930 g (interquartile range: 2,535 to 3,385 g). Seventeen (20.2%) were small for gestational age, and 20 (23.8%) were premature. Neonatal death was reported in 2 children (2.5%). Preconception pulmonary regurgitation was associated with an increased probability of pre-term labor (odds ratio: 2.610; 95% confidence interval: 1.318 to 5.172). Compared with the general Dutch population, pre-term delivery (25.0% vs. 7.4%, p < 0.001) and children small for gestational age (20.2% vs. 10.0%, p = 0.002) were more common. CONCLUSIONS: Women in good cardiac health after RVOT reconstruction with allografts can safely experience pregnancy and labor. The higher incidence of pre-term delivery and children small for gestational age warrants special attention.

Interstitial 6q21q23 duplication - variant of variable phenotype and incomplete penetrance or benign duplication?

BACKGROUND: Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known. CASES PRESENTATION: We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members. CONCLUSIONS: Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.

The impact of fetal gender and ethnicity on the risk of spontaneous preterm delivery in women with symptoms of preterm labor.

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.