Ultrasound markers for prediction of complex gastroschisis and adverse outcome: longitudinal prospective nationwide cohort study.

OBJECTIVES: To identify antenatal ultrasound markers that can differentiate between simple and complex gastroschisis and assess their predictive value. METHODS: This was a prospective nationwide study of pregnancies with isolated fetal gastroschisis that underwent serial longitudinal ultrasound examination at regular specified intervals between 20 and 37 weeks' gestation. The primary outcome was simple or complex (i.e. involving bowel atresia, volvulus, perforation or necrosis) gastroschisis at birth. Fetal biometry (abdominal circumference and estimated fetal weight), the occurrence of polyhydramnios, intra- and extra-abdominal bowel diameters and the pulsatility index (PI) of the superior mesenteric artery (SMA) were assessed. Linear mixed modeling was used to compare the individual trajectories of cases with simple and those with complex gastroschisis, and logistic regression analysis was used to estimate the strength of association between the ultrasound parameters and outcome. RESULTS: Of 104 pregnancies with isolated fetal gastroschisis included, four ended in intrauterine death. Eighty-one (81%) liveborn infants with simple and 19 (19%) with complex gastroschisis were included in the analysis. We found no relationship between fetal biometric variables and complex gastroschisis. The SMA-PI was significantly lower in fetuses with gastroschisis than in healthy controls, but did not differentiate between simple and complex gastroschisis. Both intra- and extra-abdominal bowel diameters were larger in cases with complex, compared to those with simple, gastroschisis (P < 0.001 and P < 0.005, respectively). The presence of intra-abdominal bowel diameter ≥ 97.7th percentile on at least three occasions, not necessarily on successive examinations, was associated with an increased risk of the fetus having complex gastroschisis (relative risk, 1.56 (95% CI, 1.02-2.10); P = 0.006; positive predictive value, 50.0%; negative predictive value, 81.4%). CONCLUSIONS: This large prospective longitudinal study found that intra-abdominal bowel dilatation when present repeatedly during fetal development can differentiate between simple and complex gastroschisis; however, the positive predictive value is low, and therefore the clinical usefulness of this marker is limited. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fluorinated steroids do not improve outcome of isolated atrioventricular block.

INTRODUCTION: Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands. METHODS: All fetuses identified with isolated congenital AVB-II° or AVB-III° in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed. RESULTS: Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%). CONCLUSION: No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB.

Outcome of Multifetal Pregnancy Reduction in Women with a Dichorionic Triamniotic Triplet Pregnancy to a Singleton Pregnancy: A Retrospective Nationwide Cohort Study.

OBJECTIVE: To study the pregnancy outcomes of women with a dichorionic triamniotic triplet pregnancy that was reduced to a singleton pregnancy and to review the literature. METHODS: We performed a nationwide retrospective cohort study. We compared time to delivery and perinatal mortality in dichorionic triplet pregnancies reduced to singletons with ongoing dichorionic triplet pregnancies and primary singleton pregnancies. Additionally, we reviewed the literature on the subject. RESULTS: We studied 46 women with a reduced dichorionic triplet pregnancy and 42 women with an ongoing dichorionic triplet pregnancy. Median gestational age at delivery was 38.7 vs. 32.8 weeks, respectively (p < 0.001). Delivery <24 weeks occurred in 9 (19.6%) women with a reduced triplet pregnancy and 4 (9.5%) with an ongoing triplet pregnancy (p = 0.19). Perinatal survival rates between the reduced group and the ongoing triplet group were not significantly different. CONCLUSION: Multifetal pregnancy reduction in women with a dichorionic triplet pregnancy to a singleton pregnancy prolongs median gestational age at birth. No statistically significant association was found with miscarriage and perinatal survival rates.

Unexplained False Negative Results in Noninvasive Prenatal Testing: Two Cases Involving Trisomies 13 and 18.

Noninvasive prenatal testing (NIPT) validation studies show high sensitivity and specificity for detection of trisomies 13, 18, and 21. False negative cases have rarely been reported. We describe a false negative case of trisomy 13 and another of trisomy 18 in which NIPT was commercially marketed directly to the clinician. Both cases came to our attention because a fetal anatomy scan at 20 weeks of gestation revealed multiple anomalies. Karyotyping of cultured amniocytes showed nonmosaic trisomies 13 and 18, respectively. Cytogenetic investigation of cytotrophoblast cells from multiple placental biopsies showed a low proportion of nontrisomic cells in each case, but this was considered too small for explaining the false negative NIPT result. The discordant results also could not be explained by early gestational age, elevated maternal weight, a vanishing twin, or suboptimal storage or transport of samples. The root cause of the discrepancies could, therefore, not be identified. The couples involved experienced difficulties in accepting the unexpected and late-adverse outcome of their pregnancy. We recommend that all parties involved in caring for couples who choose NIPT should collaborate to clarify false negative results in order to unravel possible biological causes and to improve the process of patient care from initial counseling to communication of the result.

Pregnancy outcome after fetal reduction in women with a dichorionic twin pregnancy.

STUDY QUESTION: What are the pregnancy outcomes for women with a twin pregnancy that is reduced to a singleton pregnancy? SUMMARY ANSWER: Fetal reduction of a twin pregnancy significantly improves gestational age at birth and neonatal birthweight, however at an increased risk of pregnancy loss and preterm delivery. WHAT IS KNOWN ALREADY: Women with a multiple pregnancy are at increased risk for preterm delivery. Fetal reduction can be considered in these women. STUDY DESIGN, SIZE, AND DURATION: Retrospective cohort study of 118 women with a twin pregnancy reduced to a singleton pregnancy between 2000 and 2010. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We compared the outcome of pregnancy in consecutive women with a dichorionic twin pregnancy that was reduced to a singleton pregnancy to that of women with a dichorionic twin pregnancy that was managed expectantly and women with a primary singleton pregnancy. Reductions were performed between 10-23(6/7) weeks' gestation by intracardiac or intrathoracic injection of potassium chloride, mostly for congenital anomalies. We compared median gestational age, pregnancy loss <24 weeks, preterm delivery <32 weeks, neonatal birthweight and perinatal deaths. MAIN RESULTS AND THE ROLE OF CHANCE: We studied 118 women with a twin pregnancy that was reduced to a singleton, 818 women with an ongoing dichorionic twin pregnancy and 611 women with a primary singleton pregnancy. Loss of the entire pregnancy <24 weeks and preterm delivery occurred significantly more in the reduction group compared with the ongoing twin group (11.9 versus 3.1% <24 weeks, P< 0.001 and 18.6 versus 11.5% <32 weeks, respectively, P < 0.001). In the reduction group, the percentage of women without any surviving child was significantly higher compared with the ongoing twin and primary singleton group (14.4, 3.4 and 0.7%, respectively, P < 0.001). Median gestational age was 38.9 weeks (interquartile range (IQR) 34.7-40.3) for reduced pregnancies, 37.1 weeks (IQR 35.3-38.1) for ongoing twin pregnancies and 40.1 (IQR 39.1-40.9) for primary singletons (P < 0.001 for all comparisons). LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study were its retrospective character, and the fact that indications for reduction were heterogeneous. WIDER IMPLICATIONS OF THE FINDINGS: In women with a dichorionic twin pregnancy fetal reduction increases median gestational age only at considerable risk of complete early pregnancy loss. STUDY FUNDING/COMPETING INTERESTS: The study was not funded. None of the authors has conflicts of interest.

Detection of fetal chromosomal anomalies: does nuchal translucency measurement have added value in the era of non-invasive prenatal testing?

OBJECTIVES: The objective of this study is to determine what percentage of fetal chromosomal anomalies remains undetected when first trimester combined testing is replaced by non-invasive prenatal testing for trisomies 13, 18, and 21. We focused on the added clinical value of nuchal translucency (NT) measurement. METHODS: Data on fetal karyotype, ultrasound findings, and pregnancy outcome of all pregnancies with an NT measurement ≥3.5 mm were retrospectively collected from a cohort of 25,057 singleton pregnancies in which first trimester combined testing was performed. RESULTS: Two hundred twenty-five fetuses (0.9 %) had an NT ≥3.5 mm. In 24 of these pregnancies, a chromosomal anomaly other than trisomy 13, 18, or 21 was detected. Eleven resulted in fetal demise, and ten showed fetal ultrasound anomalies. In three fetuses with normal ultrasound findings, a chromosomal anomaly was detected, of which one was a triple X. CONCLUSIONS: In three out of 25,057 pregnancies (0.01%), non-invasive prenatal testing and fetal ultrasound would have missed a chromosomal anomaly that would have been identified by NT measurement. © 2015 John Wiley & Sons, Ltd.

The accuracy of prenatal ultrasound in determining the type of orofacial cleft.

OBJECTIVE: The aim of this study was to assess the accuracy of prenatal transabdominal ultrasound in determining the oral cleft type. METHODS: A retrospective cohort study was performed on all consecutive cases of orofacial cleft diagnosed by prenatal ultrasound examination in the Wilhelmina Children's Hospital, a tertiary referral hospital, between January 2002 and December 2012. Prenatal findings were compared with postnatal diagnoses. RESULTS: A total of 134 patients were included. The mean gestational age at ultrasound examination was 24 weeks + 5 days. Prenatal diagnosis was in accordance with postnatal findings in 76.9% of the cases (103/134) with regard to the cleft type. Underestimation of the cleft occurred in 19.4% (26/134), whereas in 3.7% (5/134), the extent was overestimated. In distinguishing bilateral from unilateral clefts, no errors were made. CONCLUSION: Prenatal ultrasound is accurate in assessing the types of orofacial clefts in a large majority of the cases and is completely accurate in distinguishing between unilateral and bilateral clefts. This study indicates that it is a reliable technique to assess the cleft type, which is important for counseling future parents. Although, the clinician should be aware of the fact that a cleft palate is easily missed, and subsequently, underestimation of cleft extend is frequent.

Facial profile markers in second- and third-trimester fetuses with trisomy 18.

OBJECTIVES: To evaluate nasal bone length (NBL), maxilla-nasion-mandible (MNM) angle, fetal profile (FP) line, prenasal thickness (PT), prenasal thickness to nasal bone length (PT:NBL) ratio and prefrontal space ratio (PFSR) as markers of trisomy 18 in the second and third trimesters of pregnancy. METHODS: The NBL, MNM angle, FP line, PT, PT:NBL ratio and PFSR were measured retrospectively from stored two-dimensional images or three-dimensional volumes of trisomy-18 fetuses, and were compared with our previously reported normal ranges for euploid fetuses. Additional ultrasound findings were noted at initial routine second-trimester scan and at subsequent advanced ultrasound examination performed after referral for karyotyping. RESULTS: A total of 43 trisomy-18 fetuses were included in the analysis. At initial examination, median gestational age was 21 + 2 weeks. NBL and PT were correlated with gestational age (P < 0.001), but the other markers were not. Mean NBL, MNM angle, PT, PT:NBL ratio and PFSR were 3.76 mm, 16.67°, 4.25 mm, 1.39 and 0.87, respectively. The FP line was zero (normal) in 53.7% of cases and negative (abnormal) in 46.3%. All markers were significantly associated with trisomy 18, with the PT:NBL ratio yielding the highest detection rate (88.4%) followed by NBL (83.7%), MNM angle (56.4%), FP line (46.3%), PT (27.9%) and the PFSR (20.5%) (for a 5% false-positive rate for the continuous variables). Various combinations of the four best markers (NBL, FP line, MNM angle and PT:NBL ratio) yielded detection rates of between 72% and 95%. Structural anomalies were not detected in 22% of fetuses at the initial scan and in 2% at the advanced scan. CONCLUSIONS: The PT:NBL ratio and NBL are robust second- and third-trimester markers for trisomy 18. A negative FP line has a 0% false-positive rate and the potential to differentiate between trisomy 18 and Down syndrome, as in the latter the FP line is often positive. No major anomaly was observed at the initial scan in about a quarter of trisomy-18 fetuses, underlining the role of second-trimester facial marker evaluation.

Fetal heart disease: severity, associated anomalies and parental decision.

OBJECTIVE: This study describes the association between the complexity of congenital cardiac and extracardiac malformations, and the parental decision of pregnancy continuation or termination. METHODS: Congenital heart defects (CHD) was diagnosed by ultrasound in 251 fetuses before the 24th week (23 + 6 weeks) of gestation during the four year period from 2007 to 2010. All fetuses from the Utrecht region were referred to our center due to a strict referral pattern. The complexity and severity of the cardiac and possible extracardiac malformations were retrospectively categorized by a pediatric cardiologist and a perinatologist who were blinded to the pregnancy outcome. The groups with and without termination of pregnancy were compared using a univariate analysis and multivariate logistic regression. RESULTS: In 119 (47%) of the 251 fetuses, parents opted for termination of pregnancy. In 103 of these cases (87%) there was a high complex or lethal cardiac, or a major or lethal extracardiac malformation. Of the 132 continued pregnancies, 42 fetuses (32%) had a high complex or lethal cardiac, or a major or lethal extracardiac malformation. There were significantly more terminations of pregnancy in case of a high or lethal complex cardiac or extracardiac anomaly (71 vs. 15%, p <0.001). CONCLUSION: Parents opted for termination of pregnancy significantly more often in cases with high complex cardiac and extracardiac malformations. It was rare for parents to opt for pregnancy termination in the absence of a severe cardiac or extracardiac malformation.

Sotalol as first-line treatment for fetal tachycardia and neonatal follow-up.

OBJECTIVES: In fetal tachycardia, pharmacological therapy with digoxin, flecainide and sotalol has been reported to be effective. In a recent retrospective multicenter study, sotalol was considered to be less effective than the other drugs in treatment of fetal supraventricular tachycardia (SVT). The aim of this study was to re-evaluate the efficacy and safety of maternally administered sotalol in the treatment of fetal tachycardia. METHODS: This was a retrospective review of the records of 30 consecutive fetuses with tachycardia documented on M-mode echocardiography between January 2004 and December 2010 at Wilhelmina Children's Hospital, a tertiary referral university hospital. Patients were subdivided into those diagnosed with supraventricular tachycardia and those with atrial flutter (AF) and presence of hydrops was noted. Other variables investigated included QTc interval measured on maternal electrocardiogram before and after initiation of antiarrhythmic therapy, fetal heart rhythm and heart rate pre- and postnatally, oral maternal drug therapy used, time to conversion to sinus rhythm (SR), percentage of fetuses converted following transplacental treatment, maternal adverse effects, presence or absence of tachycardia as noted on postnatal ECG, postnatal therapy or prophylaxis and neonatal outcome. Findings are discussed with reference to the literature. RESULTS: A total of 28 patients (18 with SVT, 10 with AF) were treated with sotalol as first-line therapy. Fetal hydrops was present in six patients (five with SVT, one with AF). All hydropic patients converted antenatally to SR (67% with sotalol as a single-drug therapy, 33% after addition of flecainide). Of the non-hydropic patients, 91% converted to SR (90% with sotalol only, 10% after addition of flecainide or digoxin). In 9% (with AF) rate control was achieved. There was no mortality. No serious drug-related adverse events were observed. Postnatally, rhythm disturbances were detected in 10 patients, two of whom still had AF. In eight, SVT was observed within 3 weeks postnatally, and in five of these within 72 hours. CONCLUSIONS: Sotalol can be recommended as the drug of first choice for treatment of fetal AF and has been shown to be an effective and safe first-line treatment option for SVT, at least in the absence of hydrops. Postnatal maintenance therapy after successful prenatal therapy is not necessarily indicated, as the risk of recurrence is low beyond 72 hours of age.

Isolated abdominal wall defect with complete liver herniation without a covering or remnant membrane: an ominous sign: case report and review of literature.

Complete liver herniation in abdominal wall defects without a membrane is rare and its prognosis is not well documented. We present a case diagnosed at 12 weeks of gestation. At 27 weeks, a C-section was performed for fetal distress. The infant proved impossible to ventilate and died. In literature, 16 similar cases are described of whom 14 died in the neonatal period and two in infancy. This suggests that herniation of the complete liver in isolated abdominal wall defects without a remnant membrane is lethal and counselling should be provided accordingly.

Maxilla-nasion-mandible angle: a new method to assess profile anomalies in pregnancy.

OBJECTIVES: To collect normative data and test the feasibility and reproducibility of measurement of the maxilla-nasion-mandible (MNM) angle between 16 and 36 weeks' gestation and its diagnostic ability in a group of pathological cases. METHODS: The MNM angle is defined as the angle between the intersection of the maxilla-nasion and mandible-nasion lines in the exact mid-sagittal plane. After assessing reproducibility, the MNM angle was measured in 3D volumes in 241 fetuses cross-sectionally and in 11 fetuses longitudinally. The MNM angle was then tested in 18 pathological cases with facial malformations or syndromes with specific facial features. RESULTS: The MNM angle could be measured in 92.3% of normal fetuses. Intra- and interobserver intraclass correlation coefficient (ICC) variability was 0.92 and 0.81, respectively. The difference between paired measurements performed by one or two observers was less than 2.5° and 3.6°, respectively in 95% of the cases. The mean MNM angle was 13.5° and did not change significantly during pregnancy (r = - 0.08, P = 0.25). The MNM angle was above the 95(th) centile in all cases of retrognathia and maxillary alveolar ridge interruption. The MNM angle was below the 5(th) centile in Apert syndrome, thanatophoric dysplasia and in two of the three Down syndrome cases. CONCLUSIONS: The feasibility and reproducibility of measurement of the MNM angle is good. The MNM angle can be used to evaluate the convexity of the fetal profile by enabling an objective assessment of the anteroposterior relationship of the jaws and it may therefore be of help in the diagnosis of retrognathia, maxillary alveolar ridge interruption and flat profile.

The role of lipoprotein (a) in pregnancies complicated by pre-eclampsia.

Endothelial cell dysfunction is a key feature of the pathogenesis of pre-eclampsia. The cause of the endothelial cell injury is probably multifactorial, but poor placenta perfusion plays a major role. In pre-eclampsia, characteristic pathological lesions in the placenta are fibrin deposits, acute atherosis and thrombosis. The similarity between the lesions of pre-eclampsia and atherosclerosis has led to speculations of a common pathophysiological pathway. An abnormal lipid profile is known to be strongly associated with atherosclerotic cardiovascular disease and has a direct effect on endothelial function. Abnormal lipid metabolism seems important in the pathogenesis of pre-eclampsia too. An elevated plasma lipoprotein (a) concentration is a known risk factor for atherosclerotic cardiovascular disease. In this paper, we discuss three hypotheses about the mechanisms by which lipoprotein (a) may be associated with pre-eclampsia: 1. Lp(a), as an acute-phase reactant, transporting cholesterol to sites of endothelial damage for reparation, temporarily increases during pregnancy and increases more during a pregnancy complicated by mild to moderate pre-eclampsia as compared to an uncomplicated pregnancy, in response to a greater extend of endothelial injury in pre-eclampsia. After delivery, pre-eclampsia subsides and Lp(a) concentrations return to baseline levels. 2. In cases of severe pre-eclampsia, there is even more extensive endothelial damage and consequently a higher consumption of Lp(a) in reparation of this vascular damage. These women will have lower concentrations of Lp(a). 3. High baseline concentrations of Lp(a), which are genetically determined, may induce or contribute to the development of pre-eclampsia by promoting endothelial dysfunction. In this line of reasoning one would expect to find higher concentrations of Lp(a) in women at risk for developing pre-eclampsia in a future pregnancy or with a history of pre-eclampsia. As discussed above, these women are also at increased risk for future cardiovascular disease as compared to women with a history of normal pregnancy. The pathophysiologic changes associated with cardiovascular disease may also be responsible for the increased incidence of pre-eclampsia in these women.

Increased high molecular weight fibrinogen in pre-eclampsia.

INTRODUCTION: The major coagulation protein fibrinogen (Fg) is a heterogeneous protein with three main fractions: high molecular weight fibrinogen (HMW-Fg), low molecular weight fibrinogen (LMW-Fg) and low molecular weight' fibrinogen. The clottability of high molecular weight fibrinogen is highest as compared to the other fractions. Pre-eclampsia is associated with a state of hypercoagulability, and with an increase of fibrinogen concentration. The aim of the present study was to examine if the increased total fibrinogen plasma concentration in patients with pre-eclampsia is associated with a change in distribution of the main fibrinogen fractions. MATERIAL AND METHODS: Plasma was collected from 14 patients with pre-eclampsia and from 14 healthy pregnant matched controls. Total fibrinogen concentrations were determined according to Clauss. The percentage high molecular weight fibrinogen was assessed by SDS-electrophoresis and densitometry after isolation of fibrinogen by precipitation. The study groups were compared by the Mann-Whitney U-test. RESULTS: The median (range) total fibrinogen concentration in the pre-eclampsia group was 5.04 (3.25-6.51) g/l and in the control group 4.19 (3.61-5.38) g/l (p<0.05). The median (range) percentage high molecular weight fibrinogen was 76.5 (69.6-84.0)% and 73.0 (69.0-78.9)% in the pre-eclampsia and control group, respectively (p<0.05). CONCLUSIONS: In pre-eclampsia, the concentration of total fibrinogen is increased and the percentage high molecular weight fibrinogen is also slightly higher than in normal pregnancy. These results may be a reflection of the exaggerated inflammatory response, and subsequent endothelial activation, which are currently believed to be the key pathophysiological mechanisms in pre-eclampsia.

Changes of plasma lipoprotein(a) during and after normal pregnancy in Caucasians.

OBJECTIVE: Elevated plasma concentrations of lipoprotein(a) are associated with an increased risk for development of atherosclerosis. High lipoprotein(a) concentrations may also be associated with pregnancy-induced hypertension and pre-eclampsia, but reference data on the course of lipoprotein(a) during uneventful pregnancies are limited and questionable. METHODS: We studied plasma lipoprotein(a) concentrations in 19 healthy nulliparous Caucasian women during and after uncomplicated pregnancy. Blood was sampled every 4 weeks during pregnancy from 9 weeks onwards, during labor and at 2-4 weeks and 3-5 months after delivery. An apolipoprotein(a) (apo(a)) isoform-independent enzyme-linked immunosorbent assay (ELISA) was used to measure lipoprotein(a). Multilevel analysis was used to describe the data. RESULTS: Lipoprotein(a) increased until 35 weeks, subsequently decreased slightly until delivery, and fell to values below early pregnancy concentrations thereafter. The curve is defined by the formula lipoprotein(a) (mg/l) = exp [4.789 + (0.05215 x GA) + (-0.0007371 x GA2)] where GA = gestational age in weeks. CONCLUSIONS: We constructed a curve for plasma lipoprotein(a) which may serve as the standard reference for changes in pregnancy. Its formula is helpful in predicting changes of gestational age-dependent changes of lipoprotein(a) in normal pregnancy.