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

Objective While large fetal copy number aberrations can generally be detected through sequencing of DNA in maternal blood, the reliability of tests depends on the fraction of DNA that originates from the fetus. Existing methods to determine this fetal fraction require additional work or are limited to male fetuses. We aimed to create a sex‐independent approach without additional work. Methods DNA fragments used for noninvasive prenatal testing are cut only by natural processes; thus, influences on cutting by the packaging of DNA in nucleosomes will be preserved in sequencing. As cuts are expected to be made preferentially in linker regions, the shorter fetal fragments should be enriched for reads starting in nucleosome covered positions. Results We generated genome‐wide nucleosome profiles based on single end sequencing of cell‐free DNA. We found a difference between DNA digestion of fetal cell‐free DNA and maternal cell‐free DNA and used this to calculate the fraction of fetal DNA in maternal plasma for both male and female fetuses. Conclusion Our method facilitates cost‐effective noninvasive prenatal testing, as the fetal DNA fraction can be estimated without the need for expensive paired‐end sequencing or additional tests. The methodology is implemented as a tool, which we called SANEFALCON (Single reAds Nucleosome‐basEd FetAL fraCtiON). It is available for academic and non‐profit purposes under Creative Commons Attribution‐NonCommercial‐ShareAlike 4.0 International Public License. github.com/rstraver/sanefalcon. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd., What's Already Known About This Topic? Fetal DNA is found in small and varying amounts in maternal blood, enough to detect fetal aberrations such as Down syndrome through next generation sequencing methods.Fetal DNA is generally shorter, and this is believed to be influenced by nucleosomes. What Does This Study Add? We obtained nucleosome positions from cell‐free DNA over a combination of low‐coverage samples.Our method shows how fetal fragments are influenced by nucleosomes compared with maternal fragments.We deduced the fetal fraction using the distribution of reads starting around nucleosome positions, independent of the fetal sex.

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

Background: Vasa praevia (VP) is a rare phenomenon that is assumed to increase the risk of severe complications, including fetal death. Critical data on its incidence are lacking, so there is no rational basis for prenatal screening. Objectives: To review the literature on the incidence and risk indicators for VP. Search strategy: We searched OVID MEDLINE, OVID EMBASE, the Cochrane Library and PubMed for case-control and cohort studies on incidence and risk indicators for VP. Selection criteria: Two reviewers selected studies and scored their methodological quality. Data collection and analysis: We calculated the mean incidence of VP. We constructed 2 × 2 tables cross-classifying potential risk indicators against the incidence of VP to calculate common odds ratios and 95% confidence intervals, using the Mantel-Haenszel method. Main results: We included 13 studies (two prospective cohort studies, ten retrospective cohort studies and one case-control study) reporting on 569 410 patients with 325 cases of VP. Based on ten included cohort studies providing information on the incidence, the mean incidence of VP was 0.60 per 1000 pregnancies. We identified five different risk indicators and markers for VP: second-trimester placenta praevia, conception by assisted reproductive technologies, a bilobed or succenturiate placenta, umbilical cord insertion in the lower third part of the uterus at first-trimester ultrasound and velamentous cord insertion. Almost 83% of the cases of VP had one or more risk indicators. Authors' conclusions: In view of the low incidence, screening for VP in an unselected population is not advised. Targeted screening of women with one or more risk indicators as a part of routine mid-gestation scanning should be considered. Tweetable abstract: Vasa praevia is more common in placenta praevia, conception by ART, velamentous cord insertion and bilobed placenta. Tweetable abstract: Vasa praevia is more common in placenta praevia, conception by ART, velamentous cord insertion and bilobed placenta.

Item does not contain fulltext 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: 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. CONCLUSIONS: In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery.

Objective Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? Design Secondary outcomes of the FRUIT-RCT. Setting Multicentre, international. Population The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. Methods After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22–24, 28–30 and 34–36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22–24 weeks) was examined using a chi-square test. Main outcome measures Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. Results No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. Conclusion The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. Tweetable abstract LMWH does not influence fetal growth or uterine or umbilical flow velocities.

Information about the recurrence of spontaneous preterm birth in subsequent twin/singleton pregnancies is scattered. To quantify the risk of recurrence of spontaneous preterm birth in different subtypes of subsequent pregnancies. An electronic literature search in OVID MEDLINE and EMBASE, complemented by PubMed, to find recent studies. Studies comparing the risk of spontaneous preterm birth after a previous preterm and previous term pregnancy. The absolute risk of recurrence with a 95% confidence interval and the absolute risk of preterm birth after a term delivery were calculated. Data from studies were pooled using the Mantel-Haenszel method. We detected 13 relevant studies. The risk of recurrence of preterm birth was significantly increased in all preterm pregnancy subtypes, compared with their term counterparts. Women pregnant with twins after a previous preterm singleton had the highest absolute risk of recurrence (57.0%, 95% CI 51.9-61.9%), and after a previous term singleton their absolute risk was 25% (95% CI 24.3-26.5%). Women pregnant with a singleton after a previous preterm twin pregnancy have an absolute recurrence risk of 10% (95% CI 8.2-12.3%), whereas a singleton pregnancy after delivering a previous twin up to term yields a low absolute risk of only 1.3% (95% CI 0.8-2.2). Women pregnant with a singleton after a previous preterm singleton have an absolute recurrence risk of 20% (95% CI 19.9-20.6). The risk of recurrence of preterm birth is influenced by the singleton/twin order in both pregnancies, and varies between 10% for a singleton after previous preterm twins to 57% for twins after a previous preterm singleton

1. The present study examined the relationship between centrally measured stroke volume variation (SVV) and peripherally derived pulse pressure variation (PPV) in the setting of increased total arterial compliance (CA rt ). 2. Ten male Wistar rats were anaesthetized, paralysed and mechanically ventilated before being randomized to receive intrapulmonary lipopolysaccharide (LPS) or no LPS. Pulse pressure (PP) was derived from the left carotid artery, whereas stroke volume (SV) was measured directly in the left ventricle. Values of SVV and PPV were calculated over three breaths. Balloon inflation of a catheter positioned in the inferior vena cava was used, for a maximum of 30 s, to decrease preload while the SVV and PPV measurements were repeated. Values of CA rt were calculated as SV/PP. 3. Intrapulmonary LPS increased CA rt and SV. Values of SVV and PPV increased in both LPS-treated and untreated rats during balloon inflation. There was a correlation between SVV and PPV in untreated rats before (r = 0.55; P = 0.005) and during (r = 0.69; P < 0.001) occlusion of the vena cava. There was no such correlation in LPS-treated rats either before (r = -0.08; P = 0.70) or during (r = 0.36; P = 0.08) vena cava occlusion. 4. In conclusion, under normovolaemic and hypovolaemic conditions, PPV does not reflect SVV during an increase in CA rt following LPS-induced pneumonia in mechanically ventilated rats. Our data caution against their interchangeability in human sepsis.

Please cite this paper as: Tajik P, van der Tuuk K, Koopmans C, Groen H, van Pampus M, van der Berg P, van der Post J, van Loon A, de Groot C, Kwee A, Huisjes A, van Beek E, Papatsonis D, Bloemenkamp K, van Unnik G, Porath M, Rijnders R, Stigter R, de Boer K, Scheepers H, Zwinderman A, Bossuyt P, Mol B. Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial. BJOG 2012;119:11231130. Objective To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. Design A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). Setting Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. Population A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. Methods Data were analysed using logistic regression modelling. Main outcome measures The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. Results The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. Conclusion Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. Trial registration The trial has been registered in the clinical trial register as ISRCTN08132825.

Unexplained subfertility is a diagnosis by exclusion in the diagnostic work-up of known causes of subfertility such as anovulation, tubal occlusion, endometriosis, cervical hostility, and abnormal sperm counts. The basic fertility work-up consists of history-taking, physical examination, ovulation detection, evaluation of tubal patency, a postcoital test, and a sperm analysis. In case of unexplained subfertility a prognosis of a natural conception can be calculated by female age, presence of previous pregnancies, duration of the subfertility, sperm motility, and referral status. The formula for the prognosis can be determined by means of calculators publicly available on the Internet. Treatment is empirical and depends on the prognosis of a natural pregnancy of the couple. The treatment modalities vary from an expectant management to six or more cycles of intrauterine insemination with mild hormonal ovarian stimulation and three or more cycles of in-vitro fertilization.

Background Long-term impairment of pulmonary function in trachea-esophageal fistula (TEF) patients is, at least in part, commonly ascribed to gastro-esophageal reflux disease (GERD). The objective of this study was to examine the independent effects of the underlying condition and GERD on cardiopulmonary function. Methods Cardiopulmonary function of TEF patients, who had (severe) GERD (s-GERD) requiring antireflux surgery (TEF + GERD, n = 11) and TEF patients who did not have s-GERD (group TEF–GERD, n = 20) were compared with control patients who had isolated s-GERD requiring antireflux surgery (group GERD, n = 13). All patients performed spirometry, lung volume measurements, measurement of diffusion capacity and maximal cardiopulmonary exercise testing (CPET). Results Mean age of the participants was 13.8 ± 2.7 (group TEF + GERD). 13.2 ± 2.9 (group TEF–GERD), and 14.7 ± 1.5 years (group GERD). FVC and TLC were significantly lower in patients with TEF (with and without s-GERD) when compared to patients with isolated s-GERD. Most pulmonary function parameters were similarly affected in both TEF groups, but FEV1 was lower in the TEF + GERD group than in the TEF–GERD group. Cardiopulmonary exercise parameters were similar in all groups. Conclusions TEF patients had restrictive lung function impairment when compared to patients with isolated s-GERD. This difference may be due to several causes, including thoracotomy. FEV1 was lower in TEF + GERD when compared to TEF–GERD indicating that GERD may affect large airway function in TEF patients. Other differences between TEF patients with and without s-GERD were not significant, suggesting only a minor role for GERD. Pediatr Pulmonol. 2011; 46:348–355. © 2010 Wiley-Liss, Inc.

Purpose To assess the value of magnetic resonance (MR) diffusion-weighted imaging (DWI) in the evaluation of deep infiltrating endometriosis (DIE). Materials and Methods In a prospective single-center study, DWI was added to the standard MRI protocol in 56 consecutive patients with known or suspected endometriosis. Endometriotic lesions as well as (functional) ovarian cysts were analyzed for location, size, and signal intensity on T1, T2, and DWI. Apparent diffusion coefficient (ADC) values were calculated using b-values of 50, 400, 800, and 1200 s/mm2. Statistical analysis included the Spearman correlation coefficient, Mann–Whitney U, and Kruskal–Wallis tests. Results A total of 112 lesions (62 endometrial cysts and 48 DIE) were detected, 60 of which were large enough to analyze. Mean ADC values of endometrial cysts and functional ovarian cysts were 1.11 × 10−3/mm2/s and 2.14 × 10−3/mm2/s, respectively. Mean ADC values of DIE retrocervical, infiltrating the colon, and bladder were 0.70 × 10−3/mm2/s, 0.79 × 10−3/mm2/s, and 0.76 × 10−3/mm2/s, respectively. ADC values of DIE did not show a significant difference between varying pelvic locations (P = 0.63). Conclusion Results of our study suggest that ADC values of DIE are consistently low, without significant difference between pelvic locations. J. Magn. Reson. Imaging 2010;31:1117–1123. © 2010 Wiley-Liss, Inc.

Objective. The purpose of this study was to examine the longitudinal relationship between Doppler flow velocity waveforms of the spiral artery (SA) and uterine artery (UA) in pregnant women. Methods. Ninety-seven primigravidas with uncomplicated singleton pregnancies were analyzed. Spiral artery and combined UA velocity waveforms were assessed by transabdominal color Doppler sonography at gestational ages of 11 through 13, 14 through 17, and 18 through 24 weeks; each measurement was performed twice. The pulsatility index (PI) was calculated for the left and right UA, and the results were averaged as a combined UA. In addition, the presence of UA bilateral notching was reported. BlandAltman plots and generalized estimating equations were used to assess intraobserver variability and the longitudinal relationship between SA and UA blood velocities. Results. A total of 284 UA and 263 SA Doppler flow measurements were analyzed. Intraobserver variability rates for the SA and UA were 0.54 and 0.90, respectively. Results showed a continuous decrease of the mean PI in the SA and UA with increasing gestational age. Uterine artery bilateral notching was reported in 35%, 9%, and 3% of the cases at gestational ages of 11 through 13, 14 through 17, and 18 through 24 weeks. Generalized estimating equation analysis showed a significant correlation (r = 0.41) between the SA and UA (P < .0001). Conclusions. Uterine artery Doppler measurements in early pregnancy seem to accurately reflect peripheral resistance of SAs. Furthermore, trophoblastic invasion seems a continuous process in the first half of pregnancy, in which early UA bilateral notching is a physiologic event. Key words: Doppler sonography; placenta; spiral artery; uterine artery.

This review focuses on the heart and vascular system in patients with Down syndrome. A clear knowledge on the wide spectrum of various abnormalities associated with this syndrome is essential for skillful management of cardiac problems in patients with Down syndrome. Epidemiology of congenital heart defects, cardiovascular aspects and thyroid-related cardiac impairment in patients with Down syndrome will be discussed.

Background In the Netherlands, prenatal screening for trisomy 21 in the first trimester of pregnancy for singletons is conducted through a combined test based on maternal age, nuchal translucency measurement and maternal serum free β-hCG and PAPP-A. In our clinic risk calculations in twins are currently based on the NT of both fetuses instead of the combined test. In this study we looked at differences in early first-trimester free β-hCG and PAPP-A between mono- and dichorionic twins. Methods A total of 202 twin pregnant women participated in the study and agreed to donate first-trimester serum for research. Results The data of 200 twins with normal outcome were used for setting up reference values for free β-hCG and PAPP-A. Trisomy 21 was identified in the two remaining pregnancies. The overall median weight-corrected MoM was 1.99 for free β-hCG, and 2.14 for PAPP-A in all twins. Monochorionic twins have a significantly lower free β-hCG weight-corrected MoM (1.53 vs 2.11; Mann-Whitney U, p = 0.002) and a significantly lower PAPP-A weight-corrected MoM (1.59 vs 2.40; Mann-Whitney U, p = 0.003) compared to dichorionic. Conclusion This study strengthened the need to make a distinction between mono- and dichorionic twins for the risk calculation in Down syndrome screening as biochemical markers are significantly lower in monochorionic than in dichorionic twins.

Background: We hypothesized that acarbose would delay conversion from impaired glucose tolerance (IGT) to type 2 diabetes by alleviating postprandial hyperglycaemia. Our study's main objective was to investigate the effect of acarbose in IGT-persons on their 2-h plasma glucose level and beta-cell function. Subjects and Methods: The study included a random sample of 45-70-year-old residents of Hoorn, Netherlands, with mean fasting plasma glucose

Objectives Saline contrast sonohysterography (SCSH) is a diagnostic test for the examination of intracavitary abnormalities. The objective of this study was to calculate interobserver and intraobserver agreement for the interpretation of video recordings of SCSH procedures according to different levels of experience. Methods SCSH examinations were carried out by an operator experienced at performing SCSH and were recorded on video. To assess interobserver and intraobserver agreement, video material was scored by observers allocated to different groups according to their level of experience. Observers who had performed 25 or more SCSH procedures were defined as experienced (Group A), those who had carried out 1–24 as less experienced (Group B), and those with no experience of performing SCSH as inexperienced (Group C). All observers were blinded to the case histories of the patients. Results There was a significant difference in kappa values for interobserver agreement between the most experienced group and the less experienced observers. Group A, with the highest level of experience, had a mean kappa value of 0.62 (95% CI, 0.56–0.67), compared with 0.38 (95% CI, 0.33–0.43) in Group B and 0.47 (95% CI, 0.43–0.52) in Group C. The interobserver agreement in Group A was significantly higher than that in Groups B and C (P < 0.001 and P = 0.023, respectively), and Group C performed better than Group B (P = 0.024). Intraobserver agreement (n = 7) was good, with a mean kappa value of 0.66 (Group A, 0.63; Group C, 0.71). Conclusions Interobserver agreement in interpretation of video recordings of SCSH by inexperienced sonographers is poor, whereas the intraobserver agreement is good. We consider the poor interobserver agreement to be due to non-uniform diagnostic criteria. Uniform diagnostic criteria for SCSH should be incorporated into the training of residents and other physicians performing these examinations. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Objective To evaluate the predictive value of serial uterine artery Doppler ultrasound for embryo implantation in in-vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) cycles. Methods This was a prospective observational study at the VU University Medical Center, Amsterdam. Patients with an indication for IVF or IVF-ICSI according to departmental protocol underwent controlled ovarian hyperstimulation followed by IVF or IVF-ICSI and embryo transfer and had serial Doppler ultrasound performed during this treatment cycle. Patient and cycle characteristics, number of conceptions and ongoing pregnancies and pulsatility index (PI) of both uterine arteries on different cycle days were assessed and results were compared between patients who conceived and those who did not. Results Of the 102 patients enrolled into the study, 83 underwent embryo transfer. Of these, 41 became pregnant and 42 did not (Group 1). Of the 41 pregnancies, 30 were ongoing (Group 2) and 11 miscarried (Group 3). Between Groups 1, 2 and 3, linear regression revealed no significant difference between any of the variables examined except in the quality of transferred embryos. There was no significant difference in the mean PI of the left and right uterine arteries on any day of the cycle, or in the change in PI during the cycle. Receiver–operating characteristics curves derived to determine the performance of PI to predict pregnancy outcome supported our findings that the uterine artery PI is not a suitable marker for identifying patients with implantation failure. Multivariate analysis showed no relationship between pregnancy and PI between groups, but it did show a relationship between pregnancy and some patient and cycle characteristics. Conclusion In an unselected group of patients undergoing IVF or IVF-ICSI and embryo transfer, serial Doppler ultrasound examination of the uterine artery does not discriminate between cycles resulting in ongoing pregnany, miscarriage and no pregnancy. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.