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.     

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.     

Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation

Meta-analysis of randomized studies on the use of low-dose aspirin in women at high risk of preeclampsia (PE) has demonstrated that if treatment is initiated at ≤16 weeks' gestation, there is significant reduction in the risk of PE [relative risk (RR) 0.47, 95% confidence interval (CI) 0.36–0.62], fetal growth restriction (RR 0.46, 95% CI 0.33–0.64), preterm birth (RR 0.35, 95% CI 0.22–0.57) and perinatal death (RR 0.41, 95% CI 0.19–0.92), whereas the effect of treatment after 16 weeks is substantially less (RR 0.78, 95% CI 0.61–0.99; RR 0.98, 95% CI 0.88–1.08; RR 0.90, 95% CI 0.83–0.97; and RR 0.93, 95% CI 0.73–1.19, respectively). Moreover, the decrease in the risk of PE from early onset treatment seems to be related to the dose of aspirin, and a dose of >80 mg daily should be considered for optimal benefits. © 2014 John Wiley & Sons, Ltd.     

A review of fetal and neonatal consequences of maternal systemic lupus erythematosus

Systemic lupus erythematosus (SLE) primarily affects women of childbearing age and is commonly seen in pregnancy. The physiologic and immunologic changes of pregnancy may alter the course of SLE and impact maternal, fetal, and neonatal health. Multidisciplinary counseling before and during pregnancy from rheumatology, maternal fetal medicine, obstetrics, and pediatric cardiology is critical. Transplacental passage of autoantibodies, present in about 40% of women with SLE, can result in neonatal lupus (NL). NL can consist of usually permanent cardiac manifestations, including conduction system and myocardial disease, as well as transient cutaneous, hematologic, and hepatic manifestations. Additionally, women with SLE are more likely to develop adverse pregnancy outcomes such as preeclampsia, fetal growth restriction, and preterm birth, perhaps due to an underlying effect on placentation. This review describes the impact of SLE on maternal and fetal health by trimester, beginning with prepregnancy optimization of maternal health. This is followed by a discussion of NL and the current understanding of the epidemiology and pathophysiology of anti-Ro/La mediated cardiac disease, as well as screening, treatment, and methods for prevention. Finally discussed is the known increase in preeclampsia and fetal growth issues in women with SLE that can lead to iatrogenic preterm delivery.     

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.     

Aortic isthmus Doppler velocimetry: role in assessment of preterm fetal growth restriction

Intrauterine fetal growth restriction (IUGR) is an important pregnancy complication associated with significant adverse clinical outcome, stillbirth, perinatal morbidity and cerebral palsy. To date, no uniformly accepted management protocol of Doppler surveillance that reduces mortality and cognitive morbidity has emerged. Aortic isthmus (AoI) evaluation has been proposed as a potential monitoring tool for IUGR fetuses. In this review, the current knowledge of the relationship between AoI Doppler velocimetry and preterm fetal growth restriction is reviewed. Relevant technical aspects and reproducibility data are reviewed as we discuss AoI Doppler and its place within the existing repertoire of Doppler assessments in placental insufficiency. The AoI is a link between the right and left ventricles which perfuse the lower and upper body, respectively. The clinical use of AoI waveforms for monitoring fetal deterioration in IUGR has been limited, but preliminary work suggests that abnormal AoI impedance indices are an intermediate step between placental insufficiency-hypoxemia and cardiac decompensation. Further prospective studies correlating AoI indices with arterial and venous Doppler indices and perinatal outcome are required before encorporating this index into clinical practice. Copyright © 2010 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.     

Confined placental mosaicism for trisomy 14 and maternal uniparental disomy in association with elevated second trimester maternal serum human chorionic gonadotrophin and third trimester fetal growth restriction

A case of confined placental mosaicism (CPM) and maternal uniparental isodisomy 14 identified after placental karyotype revealed trisomy 14 in a newborn with intrauterine growth restriction (IUGR) and minor dysmorphic features is reported. During the second trimester of the pregnancy, multiple marker screening revealed an increased risk for Down syndrome of >1 in 10. The maternal serum human chorionic gonadotrophin (MShCG) was markedly elevated at 4.19 MoM. Amniocentesis revealed a normal 46,XX karyotype. Fetal growth restriction has been associated with elevated MShCG and placental aneuploidy with CPM for chromosomes 2, 7, 9 and 16. The present case of CPM for chromosome 14 was also associated with fetal growth restriction and elevated second trimester MShCG, suggesting a common link. Further studies need to be done to determine if indeed elevation of second trimester MShCG is associated with increased risk of CPM. The present case again demonstrates the need to perform placental karyotype in unexplained fetal growth restriction. Copyright © 2001 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.     

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.     

Stage-based approach to the management of fetal growth restriction

Fetal growth restriction (FGR) is among the obstetrical entities with the greatest variation in clinical practice. The first clinically relevant step in the management of FGR is the distinction of ‘true’ FGR, associated with signs of abnormal feto-placental function and poorer perinatal outcome, from small for gestational age fetuses, which do not present abnormal Doppler and have near normal perinatal outcome. Such distinction should not be only relied on umbilical artery Doppler, as this parameter identifies only severe, early-onset, forms of placental insufficiency. Instead, FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio and uterine artery Doppler, a growth centile below the third centile. Upon diagnosis, differentiating into early-onset and late-onset FGR is useful to distinguish two clear phenotypes, with differences in severity, association with preeclampsia, and sequence of fetal deterioration. Finally, management of FGR aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration, and establishes follow-up intervals and optimal delivery timings, which may facilitate decision-making and minimize variability in the clinical management. © 2014 John Wiley & Sons, Ltd.     

Do first-trimester screening algorithms for preeclampsia aligned to use of preventative therapies reduce the prevalence of pre-term preeclampsia: A systematic review and meta-analysis

Objective

Traditional obstetric practice relies upon history-based assessment to screen for preeclampsia and guide preventative therapies but is hampered by low sensitivity, high false-positive rates and low treatment rates. First-trimester screening algorithms represent the most efficacious approach for risk prediction and could target early initiation of aspirin to well-defined high-risk populations. A large randomised controlled trial has demonstrated the clinical benefits of this approach, but widespread practice implementation has remained elusive.

Methods

We performed a systematic review and meta-analysis summarising studies linking first-trimester preeclampsia screening algorithms with the initiation of preventative therapy and examined their effect on pre-term preeclampsia rates compared with standard maternity care. Odds ratios were calculated together with 95% confidence intervals.

Results

7 studies with a total of 377,790 participants were included. Within singleton populations, early initiation of aspirin in response to a high-risk screening algorithm result reduced the prevalence of pre-term preeclampsia by 39% compared with routine antenatal care (odds ratio 0.61; 95% CI: 0.52–0.70). There were significant reductions in the prevalence of preeclampsia at <32–34 weeks, preeclampsia at any gestation and stillbirth.

Conclusion

First-trimester screening algorithms for preeclampsia aligned with early initiation of preventative therapy with aspirin reduce the prevalence of pre-term preeclampsia.     

Altered levels of insulin-like growth factor binding protein proteases in preeclampsia and intrauterine growth restriction

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are leading causes of perinatal and maternal morbidity and mortality. Many studies have found association between low levels of insulin-like growth factor binding protein (IGFBP) proteases in the first trimester maternal circulation and the risk of subsequent development of PE and/or IUGR. These results are generally interpreted to reflect decreased production of the proteases by the placenta, leading to reduced proteolysis of IGFBPs and lower free levels of insulin-like growth factor (IGF), resulting in diminished feto-placental development. However, the association between low circulating levels of placental proteins early in pregnancy and the subsequent development of IUGR and/or PE could be due to low exchange in the placenta and not due to reduced production. In contrast, late in pregnancy, the circulating levels of these proteins and their expression in the placenta are often elevated in PE, which may reflect upregulation to compensate for abnormal placental development, that is an adaptive mechanism to increase IGFBP proteolysis, increase local IGF levels and promote feto-placental growth. Further research into the biological mechanisms underlying these associations will aid the identification of high-risk pregnancies and the development of therapeutic targets for diseases for which there are presently no preventative measures. Copyright © 2010 John Wiley & Sons, Ltd.     

Intrauterine growth restriction (IUGR): biometric and Doppler assessment

Intrauterine growth restriction (IUGR) is a common complication in pregnancy and influences morbidity and mortality at all stages of life. Historically, the management of IUGR has been dependent on antenatal biophysical testing and umbilical artery Doppler studies. With recent Doppler studies of the fetal central circulation, including intracardiac flows and the ductus venosus, better timing of delivery to minimize morbidity may be possible. This review will provide the reader with tools to diagnose IUGR, more accurately date the IUGR pregnancy with poor dating criteria, and better assess the condition of the IUGR fetus. A brief review of animal models of IUGR is presented to demonstrate research directions for answering human clinical questions and potentially carrying therapeutic intervention from the bench to the bedside. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

Ionizing radiation for maternal medical indications

Ionizing radiation should be considered an avoidable exposure although all pregnant women receive some radiation from their environment. The potential effect of ionizing radiation on the fetus is determined by the dose and the timing of the exposure with growing interest in the potential risks of transgenerational effects of radiation as an epigenetic phenomenon. High dosage exposure is very unlikely in routine situations such as occupational, diagnostic, or therapeutic exposures. Individual diagnostic radiation procedures (fetal dosage <50 mGy), are not associated with any increase in lethality (miscarriage or stillbirth), genetic damage, teratogenicity, growth impairment, mental retardation, or sterility. More recent modeling has suggested that a 10 mGy fetal dose is associated with an excess risk of childhood cancer risk as low as 1 in 4545, well below historical estimates.When the mother's condition necessitates diagnostic radiation it is necessary to balance the risks of the procedure with the benefits to be gained. As almost all diagnostic imaging involves doses below the 50 mGy threshold, clinically indicated investigations should not be withheld because of concerns regarding fetal radiation exposure. Even radiotherapy directed away from the abdomen or pelvis may be considered during pregnancy, if the benefits outweigh the risks and no suitable alternative is available.     

Can anomalies of fetal brain circulation be useful in the management of growth restricted fetuses?

Assessment of the fetal cerebral circulation provides important information on the hemodynamic changes associated with chronic hypoxia and intrauterine growth restriction. Despite the incorporation of new US parameters, the landmark for the fetal brain hemodynamic evaluation is still the middle cerebral artery. However, new vascular territories, such as the anterior and posterior cerebral arteries, might provide additional information on the onset of the brain sparing effect. The fractional moving blood volume estimation and three-dimensional power Doppler ultrasound indices are new techniques that seem to be promising in indentifying cases at earlier stages of vascular deterioration; still, they are not available for clinical application and more information is needed on the reproducibility and advantages of three-dimensional power Doppler ultrasound blood flow indices. In the past, the brain sparing effect was considered as a protective mechanism; however, recent information challenges this concept. There is growing evidence of an association between brain sparing effect and increased risk of abnormal neurodevelopment after birth. Even in mild late-onset intrauterine growth restriction affected fetuses with normal umbilical artery blood flow, increased cerebral blood perfusion can be associated with a substantial risk of abnormal neuroadaptation and neurodevelopment during childhood. © 2012 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.

     

Fetal diaphragmatic hernia and upper limb anomalies suggest Brachmann-de Lange syndrome

We describe two independent cases of Brachmann-de Lange syndrome (BDLS) in which second trimester fetal sonographic studies showed the presence of a diaphragmatic hernia and upper limb anomalies. In both cases the karyotypes were normal. Intrauterine growth restriction (IUGR) developed in the third trimester. Postnatal and postmortem physical examinations demonstrated typical physical findings associated with BDLS. The prenatal diagnosis of diaphragmatic hernia with associated anomalies should prompt consideration of an underlying genetic etiology. Copyright © 2002 John Wiley & Sons, Ltd.