At-risk Fetuses Research Articles

Two‐ and three‐dimensional prenatal sonographic diagnosis of alagille syndrome

We describe a case of Alagille syndrome diagnosed by second-trimester ultrasound. Features included the characteristic prominent chin, single umbilical artery, and hemivertebrae. Three-dimensional imaging demonstrated classic butterfly vertebrae, which were not otherwise appreciable. Alagille syndrome may be detected by second-trimester ultrasound in the at-risk fetus.

Shattered Schemata and Fragmented Identities

While pregnant women’s views about antenatal screening have been widely researched, those of expectant fathers remain underexplored. Interviews were thus conducted with 12 men and 6 women, either during pregnancy or soon after birth. Findings suggested that the men started to construct a schema of their child and a paternal identity even before she/he was born. One of the paternal responsibilities men encountered was to participate in screening. However, men’s ideas, beliefs, and feelings about being a father and about the future child were challenged by the receipt of screening results. Their child-schema became splintered into a wanted, imagined child and the at-risk fetus. Moreover, their paternal identity became fragmented into genetic and social components. Screening thereby caused some disruption in men’s experience of impending fatherhood and of pregnancy, eliciting ambivalence and confusion. Further research is now required to explore the issues raised in the study.

Antenatal management and outcomes of gastroschisis in the UK

The birth prevalence of gastroschisis is increasing worldwide, yet little evidence exists concerning the optimal monitoring strategies after diagnosis. The aim of this study was to describe the U.K. prevalence, antenatal management and outcomes of affected pregnancies. Cases were identified throughout the U.K. between October 2006 and September 2007, using three different sources. The overall birth prevalence of gastroschisis was 4.2 cases per 10, 000 total births (95% CI 3.6-4.8). Infants were variably monitored with growth scans (90%), umbilical artery Doppler ultrasound (85%), cardiotocography (65%) and biophysical profile (27%). Bowel measurements were undertaken for only 113 infants (52%). Eighty-nine women (43%) were induced and 63 (31%) laboured spontaneously. Eleven women (5%) had an elective caesarean delivery where the sole indication was fetal gastroschisis. The variability in management and paucity of evidence on antenatal monitoring approaches suggests there may be a place for randomised trials of fetal surveillance strategies in order to develop the evidence to improve outcomes for the at-risk fetus with gastroschisis. This study suggests that case ascertainment by regional congenital anomaly registers is high; extension of the coverage of these registers to the entire cohort of U.K. births would facilitate ongoing surveillance and research.

Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits

Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus has been described as safe and effective in several reports. A review of data from animal experimentation and human trials indicates that first-trimester dexamethasone decreases birthweight; affects renal, pancreatic beta cell, and brain development; increases anxiety; and predisposes to adult hypertension and hyperglycemia. In human studies, first-trimester dexamethasone is associated with orofacial clefts, decreased birthweight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of congenital adrenal hyperplasia with dexamethasone should only be done in prospective clinical research settings with institutional review board approval, and therefore is not appropriate for routine community practice.

The risk of intrauterine fetal death in the small-for-gestational-age fetus

We sought to evaluate the risk of intrauterine fetal death (IUFD) in small-for-gestational-age (SGA) fetuses. We analyzed a retrospective cohort of all births in the United States in 2005, as recorded in a national database. We calculated the risk of IUFD within 3 sets of SGA threshold categories as well as within non-SGA pregnancies using the number of at-risk fetuses as the denominator. The risk of IUFD increased with gestational age and was inversely proportional to percentile of birthweight for gestational age. The risk for IUFD in those <3rd percentile was as high as 58.0 IUFDs per 10,000 at-risk fetuses, 43.9 for <5th percentile, and 26.3 for <10th percentile compared to 5.1 for non-SGA gestations. There is an increase in the risk of IUFD in SGA fetuses compared to non-SGA fetuses at all gestational ages with the greatest risk demonstrated in the lowest percentile cohort evaluated.

Review of neonatal alloimmune thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT), with an incidence of one in 1000 live births, is the most common cause of severe thrombocytopenia and intra-cerebral haemorrhage in term neonates. NAIT results from trans-placental passage of maternal antibodies against a paternally derived fetal platelet alloantigen. Clinical presentation varies from unexpected thrombocytopenia on a blood film in a well newborn to intracranial haemorrhage (ICH). In contrast to haemolytic disease of the newborn, NAIT can present in a first pregnancy, and subsequent pregnancies are usually more severely affected. The role of antenatal screening for maternal alloantibodies instead of fetal blood sampling to identify at-risk fetuses remains uncertain, but there is a trend towards less invasive maternally directed treatment for at-risk pregnancies. Neonatal management is aimed at preventing or limiting thrombocytopenic bleeding with transfusion of antigen-matched platelets.

Customising fetal weight by ethnicity may ignore confounding with socio-economic status in a UK population

IntroductionCustomised antenatal growth charts (CAGCs) adjust expectations of estimated fetal weight (EFW) based on the assumed effects of maternal characteristics on potential birthweight (Gardosi et al 1992). Previous studies have...

Determination of human platelet antigen typing by molecular methods: Importance in diagnosis and early treatment of neonatal alloimmune thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia and intracranial hemorrhage in the perinatal period. While the gold standard for making a diagnosis of NAIT is detection of a human platelet antigen (HPA)-specific antibody in maternal serum, together with identifying an incompatibility between the parents for the cognate HPA antigen, platelet genotyping is the gold standard method for HPA typing. Platelet genotyping is critical in screening at-risk fetuses for the presence ofthe HPA corresponding to the maternal antibody. In addition, platelet genotyping may play a role in population screening to identify women at risk for sensitization, and thus, fetuses at risk for NAIT. The most commonly used methods of platelet genotyping are sequence-specific primer-polymerase chain reaction (PCR-SSP), restriction fragment length polymorphism-PCR (PCR-RFLP), and TaqMan real-time PCR. PCR-SSP and PCR-RFLP are relatively inexpensive and technically simple methods, but they are not easily automated and require expertise for reliable interpretation of results. Newer methods that allow for multiplexing, automation, and easily interpretable results, such as bead arrays, are currently in development and available for research purposes.

580: A race-stratified analysis of the risk of intrauterine fetal demise within small for gestational age deliveries

580 A race-stratified analysis of the risk of intrauterine fetal demise within small for gestational age deliveries Jonathan M. Snowden, Yvonne W. Cheng, Amy E. Doss, Rachel Pilliod, Aaron B. Caughey Oregon Health and Science University, Department of Obstetrics & Gynecology, Portland, OR, University of California, San Francisco, Obstetrics & Gynecology, San Francisco, CA, Oregon Health & Science University, Department of Obstetrics and Gynecology, Portland, OR, Oregon Health and Science University, Department of Obstetrics and Gynecology, Portland, OR OBJECTIVE: To assess the risk of intrauterine fetal demise (IUFD) in the general population and within strata of race/ethnicity, using multiple percentile cutoffs to define small for gestational age (SGA). STUDY DESIGN: This study analyzed the retrospective cohort of all singleton births in the US in 2005, as recorded in the National Center for Health Statistics natality database. Using the entire population of 2005 births without congenital anomalies as the reference, we generated three sets of SGA thresholds based on percentiles of birthweight for gestational age: the 10th percentile (as SGA is commonly defined), the 5th percentile, and the 3rd percentile. We then calculated the risk of IUFD within each of the SGA categories for each term week of gestational age (37 41), using the number of at-risk SGA fetuses as the denominator. This pool of at-risk fetuses was calculated by summing the number of SGA births in the index week and in all subsequent weeks. RESULTS: Unsurprisingly, the risk of IUFD increased with lower percentile thresholds of SGA; for the 3rd birthweight percentile, risks reached 40 60 IUFDs per 10,000 at-risk fetuses in most racial groups. Risks increased with each passing week of gestation, owing to the diminishing pool of at-risk SGA fetuses at each subsequent week. Births to black women exhibited elevated risk at many gestational ages, but the most striking racial difference was the exceptionally low IUFD risk among SGA Asian births. The risk among Asians rarely exceeded 1/1,000 at-risk fetuses, and was in many cases less than half of the risk in other racial groups at the same week of gestation, though small cell sizes for Asian births resulted in large variability around these estimates. CONCLUSION: These findings call attention to racial differences in risk associated with SGA. In Asians in particular, SGA appears to be less pathological and less predictive of IUFD. Future research should examine different outcomes and attempt to identify the range of healthy gestational-age-specific birthweights applying to the Asian population. 581 Antibody responses to pandemic and seasonal influenza A H1N1 strains during the 2009-2010 influenza season: are the responses during pregnancy similar? Barbra M. Fisher, Janice Scott, Ronald S. Gibbs, Anne Lynch, Virginia D. Winn, Adriana Weinberg University of Colorado School of Medicine, Obstetrics and Gynecology, Aurora, CO, University of Colorado School of Medicine, Department of Obstetrics and Gynecology, Aurora, CO, University of Colorado School of Medicine, Departments of Pediatrics, Medicine, and Pathology, Aurora, CO OBJECTIVE: The 2009-2010 seasonal influenza vaccination contained vaccine against an A/Brisbane/29-2007 (H1N1)-like virus (seasonal H1N1). During that season, pandemic influenza A H1N1 emerged and it was recommended that pregnant women be administered a monovalent vaccination against this strain. We sought to compare the antibody responses to the pandemic H1N1 and seasonal H1N1 influenza vaccines. STUDY DESIGN: During the 2009-2010 influenza season, we enrolled a cohort of pregnant women (n 40) who received pandemic H1N1 influenza, seasonal H1N1 influenza, both, or neither vaccine. Maternal and umbilical cord venous blood samples were collected at delivery. Hemagglutination inhibition assays (HAI) for pandemic and seasonal H1N1 were performed for each matched maternal/cord blood pair. Data were analyzed using correlation and linear regression analyses. RESULTS: Fourteen participants were vaccinated against pandemic H1N1 influenza during pregnancy and 28 women were vaccinated against seasonal H1N1 influenza. We found that (1) 6/14 (43%) women vaccinated against pandemic influenza and 17/28 (61%) women vaccinated against seasonal influenza had protective antibody titers ( 1:40) at delivery, (2) the geometric mean titer for the pandemic strain was similar to that for the seasonal strain (38 vs 54), (3) there was a similar linear relationship between maternal antibody titers at delivery and cord antibody titers for both pandemic and seasonal influenza vaccines, (4) eleven women were vaccinated against both H1N1 strains; of the 5 women who did not have an antibody titer 1:40 against the seasonal vaccine, 4 did not have a titer 1:40 for the pandemic vaccination. CONCLUSION: Both pandemic and seasonal H1N1 vaccinations produce similar antibody responses during pregnancy and confer passive immunity to the neonate. Further study of influenza vaccination during pregnancy should advance our understanding of immune responses in pregnancy and aid in the development of novel vaccines. PosterSessionIV Epidemiology, Infectious Disease, Intrapartum Fetal Assessment, Operative Obstetrics, Obstetric Quality & Safety, Public Health-Global Health www.AJOG.org

Assessing antepartum fetal health

Most pregnancies lead to the delivery of a healthy baby, irrespective of risk factors. Some pregnancies, however, are complicated by differing pathologies that can lead to increased risk of perinatal morbidity and mortality. Fetal surveillance should be instituted, attempting to identify at-risk fetuses and reduce their chances of complications. Traditionally obstetricians have classified pregnancies into ‘low-risk’ or ‘high-risk’ and applied surveillance tools to the latter group. However, the majority of stillbirths occur in low-risk women. In this article we will evaluate the evidence behind the current tools used to assess antepartum fetal health in both high- and low-risk groups, and their ability to detect an at-risk fetus or improve outcome. This article does not address fetal surveillance during labour.

DNA‐based prenatal diagnosis of plectin‐deficient epidermolysis bullosa simplex associated with pyloric atresia

Mutations in the plectin gene (PLEC) generally lead to epidermolysis bullosa simplex (EBS) associated with muscular dystrophy. It has been recently demonstrated that PLEC mutations can also cause a different clinical subtype, EBS associated with pyloric atresia (EBS-PA), which shows early lethality. Prenatal diagnosis (PND) of EBS-PA using mutation screening of PLEC has not been described. This study aimed to perform DNA-based PND for an EBS-PA family. The EBS-PA proband was compound-heterozygous for a paternal c.1350G>A splice-site mutation and a maternal p.Q305X nonsense mutation. Genomic DNA was obtained from amniocytes taken from an at-risk fetus of the proband's family. Direct sequencing and restriction enzyme digestion of polymerase chain reaction products from the genomic DNA were performed. Mutational analysis showed that the fetus harbored both pathogenic mutations, suggesting that the fetus was a compound-heterozygote and therefore affected with EBS-PA. The skin sample obtained by autopsy from the abortus confirmed the absence of plectin expression at the dermal-epidermal junction. This is the first successful DNA-based PND for an EBA-PA family.

Prenatal diagnosis of methylmalonic aciduria by measuring methylmalonic acid in dried amniotic fluid on filter paper using gas chromatography-mass spectrometry

Methylmalonic aciduria is a common inherited metabolic disorder. Methylmalonic acid (MMA), a key indicator of methylmalonic aciduria, increases in the amniotic fluid of affected fetuses. For prenatal diagnosis, the MMA in amniotic fluid can be measured by stable-isotope dilution gas chromatography-mass spectrometry. Here, we quantified the MMA in cell-free amniotic fluid samples that had been dried on filter paper and transported at ambient temperatures, and compared the results with data obtained from the original amniotic fluid. Our results indicated that the filter paper method was reproducible and accurate enough to be applied to clinical analysis. We also used the filter paper method to screen at-risk fetuses and obtained a clear diagnosis in each case. We conclude that our method enables the prenatal diagnosis of methylmalonic aciduria using practical procedures and a simplified method for transporting the samples.

The customised growth potential: an international research tool to study the epidemiology of fetal growth

Customised centiles based on individual fetal growth potential enhance our ability to differentiate between physiological and pathological smallness. A series of studies in different maternity populations has found striking similarities in the way fetal growth varies with maternal and pregnancy related characteristics, and has established the clear advantages of this method over generic, population-based birthweight or fetal weight standards. The method opens up many new avenues for the retrospective study of risk factors and fetal growth. The findings quantify the strength of association between fetal growth restriction and perinatal outcome, and therefore also highlight the clinical imperative to improve antenatal detection of the at-risk fetus. Applied prospectively as customised charts, the concept improves the detection of fetal growth restriction and reduces the need for unnecessary investigations.

Prenatal Diagnosis of Hemoglobinopathies in Hacettepe University, Turkey

Between 1983 and 2008, prenatal diagnostic procedures for identifying hemoglobinopathies were performed in 947 at-risk fetuses. Seventy-six percent of the fetuses were at risk for β-thalassemia major and 16% for sickle cell anemia; only a small percentage (7%) were at risk for compound heterozygosity of β-thalassemia and an abnormal hemoglobin of the β chain. The results of the study showed that β gene mutations in hemoglobinopathies have a very broad spectrum. Seven hundred and thirty of the 947 fetuses examined using the DNA technique showed 88 different combinations of 27 different mutations. Although the number of fetuses evaluated was far below the desired target, the termination of 261 affected fetuses provided both psychological and economic relief for the parents and was economically beneficial for the country in the long term.

Establishment of reference ranges for ductus venosus waveform indices in the Japanese population

To establish reference ranges for ductus venosus waveform indices in the Japanese population. In this retrospective cross-sectional study, 791 singleton fetuses of healthy Japanese couples were examined from January 2004 to January 2008. Reference ranges for ductus venosus waveform indices were constructed from cross-sectional data obtained at between 18 and 41weeks of gestation. With a success rate of 84%, a total of 667 measurements in 791 women were eligible for analysis. The median pulsatility index (PI) of fetal ductus venosus decreased from 0.54 at 18weeks of gestation to 0.30 at 41weeks of gestation. The median end-diastolic velocity/peak systolic velocity (a/S) of the ductus venosus increased from 0.56 at 18weeks of gestation to 0.76 at 41weeks of gestation. In this study, we established reference ranges for the PI and a/S of the ductus venosus in the Japanese population, which differed slightly from other published reference data. The results will be useful for further studies to determine the validity of the clinical importance of the ductus venosus for at-risk fetuses.

Ultrasonographic prediction of homozygous α0‐thalassemia using placental thickness, fetal cardiothoracic ratio and middle cerebral artery Doppler: alone or in combination?

To compare the predictive values of three ultrasonographic parameters: placental thickness (PT), fetal cardiothoracic ratio (CTR) and middle cerebral artery peak systolic velocity (MCA-PSV), alone or in combination, in pregnancies affected by homozygous alpha(0)-thalassemia at 12-20 weeks' gestation. Pregnant women at risk of carrying a fetus affected by homozygous alpha(0)-thalassemia were studied from 1995 to 2006 using serial ultrasonography at 12-15 weeks, 16-20 weeks and 30 weeks' gestation. We measured CTR and PT from 1995, and MCA-PSV as well from 1997. An invasive prenatal test was offered if cardiomegaly with or without placentomegaly was detected but the MCA-PSV results were used only retrospectively for analysis. Of a total of 777 at-risk fetuses studied, 138 (17.8%) were affected by homozygous alpha(0)-thalassemia. At 12-15 weeks' gestation, 598 ultrasound examinations were performed. CTR was better than both PT and MCA-PSV in the prediction of affected pregnancies. The highest sensitivity (98.3%) was achieved by the combination of CTR and/or MCA-PSV at a false-positive rate of 15.8%. At 16-20 weeks' gestation, 410 ultrasound examinations were performed, 121 of which were at the patient's first visit and 289 of which were at a follow-up visit. Both CTR and MCA-PSV predicted the affected pregnancies equally well. The sensitivity of CTR was 100.0%, but the false-positive rate was 5.2%. In contrast, the false-positive rate of MCA-PSV alone was 1.4% and that of the combination of CTR and MCA-PSV was 0%, although their sensitivities were less than 65%. The data suggest that adding MCA-PSV to CTR in the prediction of homozygous alpha(0)-thalassemia can increase the sensitivity at 12-15 weeks and decrease the false-positive rate at 16-20 weeks' gestation.

Electronic fetal heart rate monitoring

Electronic fetal heart rate monitoring is a useful monitoring tool to assess intrapartum fetal wellbeing and has been shown to improve perinatal outcomes in at-risk fetuses. This article describes the benefits, criticisms of its use during labour, the pathophysiology and care pathway based on the cardiotocogram features.

Prenatal diagnosis of propionic acidemia by measuring methylcitric acid in dried amniotic fluid on filter paper using GC/MS

Propionic acidemia is a frequent inborn error of metabolism. Methylcitric acid, a key indicator of propionic acidemia, increases in the amniotic fluid of affected fetuses. For prenatal diagnosis, the methylcitric acid in amniotic fluid can be measured by stable-isotope dilution GC/MS. Here, we quantified this indicator in samples of amniotic fluid that had been dried on filter paper and transported at ambient temperatures, and compared the results with data obtained from the original amniotic fluid. We then used the filter-paper method to screen at-risk fetuses and obtained a clear-cut diagnosis in each case.

Fetal MRI: what is the future?

Fetal MRI: what is the future?

Targeted Extended Cystic Fibrosis Mutation Testing on Known and At-Risk Patients and Relatives

This paper reports mathematically derived residual risks of being a carrier or being affected with cystic fibrosis following various screening scenarios to assist in interpreting test results and advising patients. While parental screening with 23 American College of Medical Genetics (ACMG) cystic fibrosis mutations defines the 64% of affected U.S. Caucasian fetuses with two detectable mutations, newborn screening for elevated immunoreactive trypsinogen (IRT) and sweat chloride identifies an additional 36% of affected newborns with zero or one detected mutation. The relatives of these affected newborns with less than two detectable mutations have higher posterior (after) 23 mutation-negative test risks of carrying undetected mutations. These calculations emphasize how knowledge of the mutations in the related affected patient substantially improves upon the quality of after-test advice to patients. Furthermore, negative tests of the partner without a family history and/or more extensive cystic fibrosis transmembrane conductance regulator (CFTR) gene testing also increases the likelihood that a negative report is truly negative. When a newborn patient with zero or one detected CFTR mutation has an inconclusive sweat test result, the sweat test should be repeated before ordering additional often unnecessary CFTR gene sequencing. Given the same composite mutation panel test accuracy, a higher proportion of reported test results would be correct during parental screening than when testing at-risk fetuses or symptomatic newborns. Prenatal and newborn screening would be enhanced substantially by medical professionals offering copies of all positive parental and newborn test reports to the parents to share with their relatives. These principles are likely to be applicable to other genetic diseases as the most common mutation frequencies are reported.