Elevated mid-trimester hCG and maternal lupus anticoagulant

An association is described between women with lupus anticoagulant and abnormal prenatal serum screening results. Three cases of positive second-trimester serum screening for Down syndrome, with karyotypically normal fetuses, in women demonstrated to have lupus anticoagulant are presented. Serum screening positivity was principally due to a disproportionately elevated maternal serum human chorionic gonadotrophin (hCG) level. In each case, early, severe intrauterine growth restriction was documented, with only one fetus surviving the neonatal period. As maternal lupus anticoagulant may have a profoundly adverse effect on the course of pregnancy, we suggest that an elevated hCG level on prenatal screening prompt consideration of maternal lupus anticoagulant testing if ultrasonography demonstrates an otherwise normal singleton gestation and the fetal karyotype is normal.     

Maternal genetic disorders and fetal development

With improvements in early diagnosis and management of genetic diseases, more women with genetic disorders are reaching reproductive age and becoming pregnant. While pregnancy can have a significant impact on a woman's health when there is an underlying genetic disorder, there can also be fetal effects, including embryopathy, fetal growth restriction, and brain injury. Some maternal genetic disorders are associated with adverse perinatal outcomes, including a high risk of perinatal loss and preterm birth. In this article, we review several maternal genetic disorders associated with fetal risk that are important for clinicians and patients to understand and manage appropriately. These include phenylalanine hydroxylase (PAH) deficiency and other inborn errors of metabolism, tuberous sclerosis complex, myotonic dystrophy, cystic fibrosis, Turner syndrome, sickle cell disease, and connective tissue disorders.     

First trimester screening cannot predict adverse outcomes yet

The use of first trimester screening to detect aneuploidy has become an integral part of prenatal care. The application of similar screening algorithms to identify women at the highest risk for other adverse pregnancy outcomes in the first trimester could potentially have a major clinical impact. There has been much investigation into the ability to identify patients early in pregnancy at high risk for adverse pregnancy outcomes who may benefit from further surveillance and/or intervention. For this to be the case, however, as is true of any useful screening test, effective interventions need to be available. Unfortunately, for fetal growth restriction and stillbirth, no such interventions exist short of delivery. For preeclampsia, low dose aspirin has been demonstrated to be of benefit in specific subgroups. For preterm birth, although there are efficacious treatments, first trimester serum markers or cervical length measurements do not add significantly beyond historical or demographic factors, in prediction of preterm birth. Given the current evidence, first trimester screening, via serum or ultrasound markers, does not have sufficiently high enough positive predictive values for the development of preeclampsia, fetal growth restriction, preterm birth or stillbirth. In order to develop effective screening algorithms for adverse pregnancy outcomes in the first trimester, understanding the heterogeneous phenotype of these complications and the underlying pathophysiology is needed. © 2014 John Wiley & Sons, Ltd.     

Treatment of poor placentation and the prevention of associated adverse outcomes – what does the future hold?

Poor placentation, which manifests as pre-eclampsia and fetal growth restriction, is a major pregnancy complication. The underlying cause is a deficiency in normal trophoblast invasion of the spiral arteries, associated with placental inflammation, oxidative stress, and an antiangiogenic state. Peripartum therapies, such as prenatal maternal corticosteroids and magnesium sulphate, can prevent some of the adverse neonatal outcomes, but there is currently no treatment for poor placentation itself. Instead, management relies on identifying the consequences of poor placentation in the mother and fetus, with iatrogenic preterm delivery to minimise mortality and morbidity. Several promising therapies are currently under development to treat poor placentation, to improve fetal growth, and to prevent adverse neonatal outcomes. Interventions such as maternal nitric oxide donors, sildenafil citrate, vascular endothelial growth factor gene therapy, hydrogen sulphide donors, and statins address the underlying pathology, while maternal melatonin administration may provide fetal neuroprotection. In the future, these may provide a range of synergistic therapies for pre-eclampsia and fetal growth restriction, depending on the severity and gestation of onset. © 2014 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.     

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with higher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32 weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified as part of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal care and delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.     

Overview of low molecular weight heparin for preventative treatment of adverse obstetric outcomes related to abnormal placentation

Different proportions of cases of preterm and severe preeclampsia, placental abruption, fetal growth restriction, and fetal death share a common causal pathway of abnormal placental implantation. Documentation of an association between the risk of such adverse pregnancy outcomes (APOs) and inherited thrombophilias prompted initial studies to evaluate the benefit of anticoagulants for the prevention of recurrences both in patients with and without inherited thrombophilias. Prenatal administration of low molecular weight heparin (LMWH) has been evaluated in case control, cohort and randomized clinical trials. The evidence suggests a benefit of LMWH in the reduction of recurrences of APOs, with a number needed to treat of 6 (95% confidence interval: 4–10) to prevent one case of recurrent APOs. Such benefit is independent of the presence of inherited thrombophilias or the administration of low dose aspirin. Further studies are needed to establish the optimal duration for the prophylaxis, to better delineate the mechanism of action of LMWH and to explore the role, if any, of maternal serum markers and uterine artery Doppler findings in the modulation of the LMWH prophylaxis. © 2014 John Wiley & Sons, Ltd.     

Association between fetal nuchal translucency thickness in first trimester and subsequent gestational hypertension and preeclampsia

Increased fetal nuchal translucency (NT) in the first trimester is associated with adverse pregnancy outcomes. Whether the increased NT is also associated with an increased frequency of pregnancy-associated hypertension (PAH) is not known. Seven hundred and seventy-nine pregnant women who received NT-based Down syndrome screening and delivered their babies at our hospital by September 2000 were enrolled into this study. Among these women, there are 46 cases of preeclampsia, 68 cases of gestational hypertension (GH); 665 women without any adverse pregnancy outcomes served as controls. Correlation analysis demonstrated that NT MoM (multiples of median) level had a positive association with maternal diastolic blood pressure at the time of admission for delivery (r = 0.104; p < 0.01). The severity of PAH was concordant with the stepwise increase of mean NT MoM level, which was 0.88 in control, 1.07 in gestational hypertension, and 1.13 in preeclampsia (p < 0.001). Using the 95th (1.52 MoM) and 90th (1.31 MoM) percentiles of NT thickness as cut-offs, the sensitivities and odds ratios of the women at risk for developing GH after 20 weeks of gestation were 8.8%, 19.1% and 1.98, 2.15 respectively, while for preeclampsia were 10.9%, 28.3% and 2.49, 3.58 respectively. It is concluded that the pathological changes in the placenta responsible for the development of PAH may also influence the physiological decrease of NT thickness in late first trimester. However, the sensitivity of fetal NT measurement in first trimester is not sufficient as a single marker for predicting the pregnant women at risk for subsequent PAH. Copyright © 2002 John Wiley & Sons, Ltd.     

First trimester screening can predict adverse pregnancy outcomes

There has been an increasing drive over the last two decades to push the detection of women at risk of adverse pregnancy outcomes into the first trimester. This has led to a plethora of techniques, risk assessments and biomarkers, both fascinating and bewildering in its breadth. Despite the vast amount of knowledge available, it is often difficult to determine what is practicable and valuable for clinical practice. This is especially true as earlier diagnosis does not necessarily equate to improved outcomes for mother and child. We suggest that, at least for preeclampsia, fetal growth restriction, spontaneous preterm birth and gestational diabetes, there are effective first trimester tests available to identify the women at risk of subsequently developing complications. Unfortunately, there are no currently reliable first trimester tests available for identifying women at risk of stillbirth. It is likely that this field will continue to develop over time, and we hope that new and better strategies will continue to emerge to target these clinically important pathologies. © 2014 John Wiley & Sons, Ltd.     

Population screening for gestational hypertensive disorders using maternal,fetal and placental characteristics: A population-based prospective cohort study

Objective

To determine screening performance of maternal, fetal and placental characteristics for selecting pregnancies at risk of gestational hypertension and preeclampsia in a low-risk multi-ethnic population.

Method

In a prospective population-based cohort among 7124 pregnant women, we collected maternal characteristics including body mass index, ethnicity, parity, smoking and blood pressure in early-pregnancy. Fetal characteristics included second and third trimester estimated fetal weight and sex determined by ultrasound. Placental characteristics included first and second trimester placental growth factor concentrations and second and third trimester uterine artery resistance indices.

Results

Maternal characteristics provided the best screening result for gestational hypertension (area-under-the-curve [AUC] 0.79 [95% Confidence interval {CI} 0.76-0.81]) with 40% sensitivity at 90% specificity. For preeclampsia, the maternal characteristics model led to a screening performance of AUC 0.74 (95% CI 0.70-0.78) with 33% sensitivity at 90% specificity. Addition of second and third trimester placental ultrasound characteristics only improved screening performance for preeclampsia (AUC 0.78 [95% CI 0.75-0.82], with 48% sensitivity at 90% specificity).

Conclusion

Routinely measured maternal characteristics, known at the start of pregnancy, can be used in screening for pregnancies at risk of gestational hypertension or preeclampsia within a low-risk multi-ethnic population. Addition of combined second and third trimester placental ultrasound characteristics only improved screening for preeclampsia.

     

Maternal thyroid disease and its effects on the fetus and perinatal outcomes

Thyroid disease is common in women of childbearing age and can have significant effects on the development of the fetus and perinatal outcomes. Maternal thyroid hormone is critical for proper fetal neurodevelopment, and the fetus relies on thyroid hormone from its mother for the first half of pregnancy. Both overt maternal hypothyroidism and overt maternal hyperthyroidism have been shown to be associated with adverse effects on central nervous system gray matter and neurocognitive development of offspring as well as increased obstetrical risks. Treatment of overt thyroid conditions improves outcomes. Subclinical maternal hypothyroidism may increase adverse neurocognitive and obstetrical outcomes although data are conflicting. To date, treatment of subclinical hypothyroidism has not shown benefit. Subclinical hyperthyroidism is well tolerated in pregnancy. Thyroid autoantibodies alone may also affect neurodevelopment and obstetrical outcomes; however, recent data have shown no improvement with levothyroxine treatment. Several rare maternal genetic thyroid conditions can affect the fetus including a thyroid-stimulating hormone receptor mutation leading to hypersensitivity to human chorionic gonadotropin and thyroid hormone resistance. The thyroid plays a crucial role in fetal health and understanding it is important for optimal care.     

Fetal therapies for cytomegalovirus: What we tell prospective parents

Congenital CMV is the most common congenital infection in the developed world. Infection results in congenital disease ranging from asymptomatic infection to severe neurodevelopmental impairment, and occasionally fetal or neonatal death. Fetal infection can occur through maternal-fetal transmission during primary maternal infection or maternal reactivation or re-infection. Awareness among maternal health care providers and parents is low. The prevention of maternal CMV infection currently relies on hygiene measures, with no effective CMV vaccine or prophylactic therapies. No licensed treatment options are available to prevent maternal-fetal transmission or fetal disease. Hyperimmunoglobulin and valaciclovir have been investigated for prevention of maternal-fetal transmission or fetal treatment, with some evidence supporting consideration of maternal administration of hyperimmunoglobulin or valaciclovir therapy in certain circumstances. This article outlines the clinical evidence regarding proven preventative behavioral measures and experimental hyperimmunoglobulin and valaciclovir therapies, that is structured around common questions asked by pregnant women about CMV infection. It is aimed to help maternity health care providers counsel prospective parents about congenital CMV disease and the preventative and therapeutic strategies currently available.     

First-trimester fetal sex determination in maternal serum using real-time PCR

An Erratum has been published for this article in Prenatal Diagnosis 22(13) 2002, 1241. Fetal sex prediction can be achieved using PCR targeted at the SRY gene by analysing cell-free fetal DNA in maternal serum. Unfortunately, the results reported to date show a lack of sensitivity, especially during the first trimester of pregnancy. Therefore, determination of fetal sex by maternal serum analysis could not replace karyotype analysis following chorionic villus sampling. A new highly sensitive real-time PCR was developped to detect an SRY gene sequence in maternal serum. Analysis was performed on 121 pregnant women during the first trimester of pregnancy (mean gestational age: 11.8 weeks). Among them, 51 had at least one previous male-bearing pregnancy. Results were compared with fetal sex. SRY PCR analysis of maternal serum was in complete concordance with fetal sex. Among the 121 pregnant women, 61 were bearing a male fetus and 60 a female fetus. No false-negative results were observed. Furthermore, no false-positive results occurred, even though 27 women carrying a female fetus during the current pregnancy had at least one previous male-bearing pregnancy. This study demonstrates that a reliable, non-invasive sex determination can be achieved by PCR analysis of maternal serum during the first trimester of pregnancy. This non-invasive approach for fetal sex prediction should have great implications in the management of pregnant women who are carriers of an X-linked genetic disorder. Prenatal diagnosis might thus be performed for male fetuses only, avoiding invasive procedures and the risk of the loss of female fetuses. Copyright © 2001 John Wiley & Sons, Ltd.     

The use of imaging technology in the assessment of the fetal inflammatory response syndrome—imaging of the fetal thymus

The fetal inflammatory response syndrome (FIRS) describes a state of extensive fetal multi organ involvement during chorioamnionitis, and is associated with grave implications on perinatal outcome. The syndrome has been linked to the preterm parturition syndrome and is associated with inflammation/infection processes in most of the fetal organs. The fetal thymus, a major organ in the developing immune system involutes during severe neonatal disease and has been shown to be smaller in fetuses with FIRS. Various methods for imaging of the fetal thymus and measurement are described. Currently the only method to diagnose FIRS prenatally is through amniocentesis. We suggest that women who are admitted with preterm labor with intact membranes and those with PPROM should have a detailed sonographic examination of the fetal thymus as a surrogate marker of fetal involvement in intrauterine infection/inflammation processes. © 2015 John Wiley & Sons, Ltd.     

Congenital syphilis: A contemporary update on an ancient disease

Congenital syphilis (CS) rates reached a 20-year high in the United States in 2018. Unlike previous years, most babies diagnosed with CS were born to mothers who received prenatal care, indicative of the need for better provider education and guideline adherence. Current rates suggest that screening for syphilis should be performed at the first prenatal care visit and twice during the third trimester. There are two diagnostic algorithms available for use in the United States (traditional and reverse) and providers must understand how to perform each algorithm. Treatment should be administered according to stage of syphilis per Centers for Disease Control recommendations with best neonatal outcomes seen when treatment is initiated >30 days before delivery. Benzathine Penicillin G remains the only recommended treatment of syphilis during pregnancy. In viable pregnancies, a pretreatment ultrasound is recommended to identify sonographic evidence of fetal infection and treatment should be initiated with continuous fetal monitoring to evaluate for the Jarisch-Herxheimer reaction which can cause preterm labor and fetal distress. After adequate syphilotherapy, a fourfold decline in maternal nontreponemal titers may not be observed by delivery and does not correlate with rates of CS.     

Should we ‘open the kimono’ to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing?

The metaphor ‘open kimono’ has been applied in the business world to connote transparency via the release of all available data to an external party. Here, the author uses this term to discuss the relative advantages and disadvantages of reporting on the presence of rare autosomal aneuploidies detected by massively parallel sequencing of placental cell-free DNA in the plasma of pregnant women. Newly presented data sets from multiple laboratories suggest that autosomal aneuploidies such as trisomies 7, 15, 16, 22, and 8 are easily detectable and are potentially associated with fetal growth restriction, pregnancy loss, and maternal preeclampsia. Furthermore, they may explain false positive results for the common autosomal trisomies (13, 18, and 21) as well as test failures. Thus, release of this information may result in improved clinical utility. At the present time, however, professional societies in various parts of the world differ in their recommendations as to whether or not to release expanded autosomal aneuploidy results beyond the common trisomies. © 2016 John Wiley & Sons, Ltd.     

Effects of mid-trimester induced abortion on the subsequent pregnancy

The outcome of the pregnancy following (a) a mid-trimester termination of pregnancy (TOP) for fetal neural tube defect (NTD) (77 women=group 1); (b) mid-trimester TOP for fetal Down's syndrome (13 women=group 2); (c) delivery of a baby with NTD (119 women=group 3) was studied. The prenatal fetal loss was relatively high in all groups. In group 1 it was similar to that found in other studies after first trimester TOP, in group 2 it was associated with advanced maternal age and the unexpected finding in group 3 was not attributable to advanced maternal age. It is suggested that a previous NTD per se might increase the risk of fetal loss in the next pregnancy. A previous mid-trimester TOP for NTD was not associated with an increase in premature labour, small for dates babies or congenital abnormality in the next pregnancy, but there was a slight increase in the number of babies weighing less than 2500 g.     

Amiodarone treatment in pregnancy for dilatative cardiomyopathy with ventricular malignant extrasystole and normal maternal and neonatal outcome

Amiodarone treatment in pregnancy might be difficult to handle because of the long half-life of the drug (14–28 days up to 2 months) and because it reduces maternal and neonatal thyroid activity. Although short-term use in pregnancy has been described in cases of fetal supraventricular tachycardia, there are few reports on the chronic use of the drug. In this paper we describe our experience with amiodarone treatment in two pregnant sisters with familial dilatative cardiomyopathy and ventricular malignant extrasystole. Prolonged administration of amiodarone (400–200 mg/die) since the beginning of pregnancy did not have any adverse effects; maternal and neonatal thyroid function was normal, as was the neurological and motor development of the neonates.     

First trimester chorionic villus sampling versus mid-trimester genetic amniocentesis-preliminary results of a controlled prospective trial

This controlled prospective study assesses the relative risks of first trimester chorionic villus sampling (CVS) versus mid-trimester gentic amniocentesis (GA). CVS subjects and amnio-centesis controls were comparable with regard to several confounding variables which might influence the risk of pregnancy loss including maternal age, smoking, alcohol consumption, gestational age at study entry, and history of vaginal bleeding or poor prior reproductive outcome. The most common indication for prenatal diagnosis was advanced maternal age (n = 511). In this subgroup, spontaneous abortion (<24 weeks) occurred in 2·9 per cent of CVS subjects versus 4−3 per cent of amniocentesis controls. The sum of spontaneous and therapeutic abortions (<24 weeks) was identical (5·3 per cent) in both groups. Therefore, intervention in the CVS group (i.e., therapeutic abortion for cytogenetic abnormalities) did not influence the observed risk of pregnancy loss. Overall perinatal mortality rates were also similar in both groups. No significant differences were identified for a number of pregnancy outcome parameters including 5 min Apgar score, birth weight, body length, head circumference, gestational age at delivery, preterm delivery, fetal growth retardation, congenital malformations, and neonatal complications. Preliminary results of this controlled prospective study suggest that chorionic villus sampling carries a low and acceptable risk.