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.     

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.     

First-trimester assessment of placenta function and the prediction of preeclampsia and intrauterine growth restriction

Preeclampsia and intrauterine growth restriction (IUGR) are major contributors to perinatal mortality and morbidity worldwide. Both are characterized by impaired trophoblastic invasion of the maternal spiral arteries and their conversion from narrow muscular vessels to wide non-muscular channels. Despite improvement in the understanding of the pathophysiology of these conditions, ability to accurately identify pregnant woman who will develop them is limited. This greatly impairs the development and testing of preventive interventions. While different measures of placental dysfunction have been associated with increased risk for adverse pregnancy outcomes, the ability of any single one to accurately predict these outcomes is poor. Developing predictive tests is further challenged by difficulty in the timing of the measurements, as both the structural and biochemical characteristics of the placenta change with increasing gestational age. The ideal screening test would accurately predict the development of adverse pregnancy outcomes early enough to provide a window for preventive interventions. Improvement in ultrasound technology provides potentially useful novel tools for evaluating placental structure, but measuresments need to be standardized in order to be useful. Maternal serum analyte screening is a noninvasive test of placental biochemical function, but present serum marker alone is not sufficiently accurate to suggest its routine use in clinical practice. The use of first trimester biochemical markers in combination with uterine artery Doppler screening is promising as a potential screening tool. Prospective longitudinal studies using standardized methodology are necessary to further evaluate the choice of parameters and strategies of combination to achieve the best predictive models. Copyright © 2010 John Wiley & Sons, Ltd.     

Non-invasive prenatal testing in the management of twin pregnancies

Twin pregnancies are common and associated with pregnancy complications and adverse outcomes. Prenatal clinical management is intensive and has been hampered by inferior screening and less acceptable invasive testing. For aneuploidy screening, meta-analyses show that non-invasive prenatal testing (NIPT) through analysis of cell-free DNA (cf-DNA) is superior to serum and ultrasound-based tests. The positive predictive value for NIPT is driven strongly by the discriminatory power of the assay and only secondarily by the prior risk. Uncertainties in a priori risks for aneuploidies in twin pregnancies are therefore of lesser importance with NIPT. Additional information on zygosity can be obtained using NIPT. Establishing zygosity can be helpful when chorionicity was not reliably established early in pregnancy or where the there is a concern for one versus two affected fetuses. In dizygotic twin pregnancies, individual fetal fractions can be measured to ensure that both values are satisfactory. Vanishing twins can be identified by NIPT. Although clinical utility of routinely detecting vanishing twins has not yet been demonstrated, there are individual cases where cf-DNA analysis could be helpful in explaining unusual clinical or laboratory observations. We conclude that cf-DNA analysis and ultrasound have synergistic roles in the management of multiple gestational pregnancies.     

Pregestational diabetes in pregnancy: Complications,management, surveillance,and mechanisms of disease—A review

Diabetes is an increasingly common diagnosis among pregnant women. Pregestational diabetes is associated with an increase in many adverse pregnancy outcomes, which impact both on the woman and her fetus. The models of pregnancy care for women with diabetes are based largely on observational data or consensus opinion. Strategies for aneuploidy screening and monitoring for fetal well-being should be modified in women with diabetes. There is an increasing understanding of the mechanisms by which congenital anomalies and disorders of fetal growth occur, involving epigenetic modifications, changes in gene expression in critical developmental pathways, and oxidative stress. This knowledge may lead to pathways for improved care for these high-risk pregnancies.     

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.     

Significance of adverse outcome pathways in biomarker-based environmental risk assessment in aquatic organisms

In environmental risk assessments (ERA), biomarkers have been widely used as an early warning signal of environmental contamination. However, biomarker responses have limitation due to its low relevance to adverse outcomes (e.g., fluctuations in community structure, decreases in population size, and other similar ecobiologically relevant indicators of community structure and function). To mitigate these limitations, the concept of adverse outcome pathways (AOPs) was developed. An AOP is an analytical, sequentially progressive pathway that links a molecular initiating event (MIE) to an adverse outcome. Recently, AOPs have been recognized as a potential informational tool by which the implications of molecular biomarkers in ERA can be better understood. To demonstrate the utility of AOPs in biomarker-based ERA, here we discuss a series of three different biological repercussions caused by exposure to benzo(a)pyrene (BaP), silver nanoparticles (AgNPs), and selenium (Se). Using mainly aquatic invertebrates and selected vertebrates as model species, we focus on the development of the AOP concept. Aquatic organisms are suitable bioindicator species whose entire lifespans can be observed over a short period; moreover, these species can be studied on the molecular and population levels. Also, interspecific differences between aquatic organisms are important to consider in an AOP framework, since these differences are an integral part of the natural environment. The development of an environmental pollutant-mediated AOP may enable a better understanding of the effects of environmental pollutants in different scenarios in the diverse community of an ecosystem.     

Prenatal screening and diagnosis of congenital toxoplasmosis: a review of safety issues and psychological consequences for women who undergo screening

As part of the EUROTOXO initiative, this review focuses on the potential risks associated with prenatal testing for congenital toxoplasmosis. We first review the evidence on the risks of adverse events associated with amniocentesis, which is required for definitive diagnosis of toxoplasmosis infection in the fetus, and for which the most important risk is fetal loss. To date, there has been only one randomized trial to document risks associated with amniocentesis. This trial, which was conducted in 1986, reported a procedure-related rate of fetal loss of 1.0% (95% CI, 0.3–1.5). However, evidence from available controlled studies suggests that the pregnancy loss associated with mid-trimester amniocentesis may be lower. Potential psychological consequences of prenatal testing for congenital toxoplasmosis include parental anxiety due to false positive results and uncertainties related to prognosis of children with a prenatal diagnosis of congenital toxoplasmosis. Parental anxiety may be particularly important in screening strategies that include more frequent screenings, which may in turn entail substantial, and at times unnecessary, anxiety or other negative consequences for women and their families. These negative psychological outcomes should be balanced against the benefits of testing, which can allow women to make an informed choice regarding the pregnancy. Copyright © 2007 John Wiley & Sons, Ltd.     

First-trimester screening: dealing with the fall-out

The articles collected together in this issue describe first-trimester screening for a variety of complications. With the advance of both technology and research, early pregnancy screening is becoming ever more sophisticated and complex. While there are clear benefits to most women receiving early reassurance that their baby is developing as expected, there is no evidence to suggest that an earlier prenatal diagnosis has less long-term emotional impact than at later gestations. The poignancy of ultrasound images for many parents means that it can be especially difficult to manage the anxiety when an ultrasound marker is highlighted as potential cause for concern. They can then face a journey of anxiety-laden uncertainty, which can extend through much of the pregnancy, and even beyond. Professionals involved in screening need to recognise and acknowledge such adverse side-effects and develop the skills necessary to help parents understand and cope with the uncertainties inherent in the process. Copyright © 2011 John Wiley & Sons, Ltd.     

Artificial intelligence in obstetric ultrasound: A scoping review

The objective is to summarize the current use of artificial intelligence (AI) in obstetric ultrasound. PubMed, Cochrane Library, and ClinicalTrials.gov databases were searched using the following keywords “neural networks”, OR “artificial intelligence”, OR “machine learning”, OR “deep learning”, AND “obstetrics”, OR “obstetrical”, OR “fetus”, OR “foetus”, OR “fetal”, OR “foetal”, OR “pregnancy”, or “pregnant”, AND “ultrasound” from inception through May 2022. The search was limited to the English language. Studies were eligible for inclusion if they described the use of AI in obstetric ultrasound. Obstetric ultrasound was defined as the process of obtaining ultrasound images of a fetus, amniotic fluid, or placenta. AI was defined as the use of neural networks, machine learning, or deep learning methods. The authors’ search identified a total of 127 papers that fulfilled our inclusion criteria. The current uses of AI in obstetric ultrasound include first trimester pregnancy ultrasound, assessment of placenta, fetal biometry, fetal echocardiography, fetal neurosonography, assessment of fetal anatomy, and other uses including assessment of fetal lung maturity and screening for risk of adverse pregnancy outcomes. AI holds the potential to improve the ultrasound efficiency, pregnancy outcomes in low resource settings, detection of congenital malformations and prediction of adverse pregnancy outcomes.     

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.     

Prenatal screening for Down syndrome and neural tube defects in twin pregnancies

Prenatal screening and diagnosis in a twin pregnancy is not straightforward. Once a twin pregnancy has been identified, women and their partners need time to consider the implications and decide whether they wish the pregnancy to be screened for Down syndrome or neural tube defects. We discuss here how multiple marker screening for Down syndrome and alpha-fetoprotein screening for neural tube defects can be carried out, given that this is the parents' chosen option and that the health professionals involved are capable of performing a diagnosis and selective feticide, should this arise. Copyright © 2005 John Wiley & Sons, Ltd.     

The use of magnetic resonance imaging in the prediction of birthweight

Extremes of fetal growth can increase adverse pregnancy outcomes, and this is equally applicable to single and multiple gestations. Traditionally, these cases have been identified using simple two-dimensional ultrasound which is quite limited by its low precision. Magnetic resonance imaging (MRI) has now been used for many years in obstetrics, mainly as an adjunct to ultrasound for congenital abnormalities and increasingly as part of the post-mortem examination. However, MRI can also be used to accurately assess fetal weight as first demonstrated by Baker et al in 1994, using body volumes rather than standard biometric measurements. This publication was followed by several others, all of which confirmed the superiority of MRI; however, despite this initial promise, the technique has never been successfully integrated into clinical practice. In this review, we provide an overview of the literature, detail the various techniques and formulas currently available, discuss the applicability to specific high-risk groups and present our vision for the future of MRI within clinical obstetrics.     

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.     

Toxic metals in amniotic fluid and altered gene expression in cell-free fetal RNA

Both exposures to toxic metals, as well as deficiencies in essential metals, during pregnancy has been linked to a variety of negative reproductive outcomes. The exact etiologies of such outcomes and the effects of fetal exposure to these metals are largely unknown. Therefore, the ability to assess levels of these elements is critical to determining the underlying causes of such conditions and the effects that both essential and nonessential metals have on fetal development. Thus, using cell-free fetal RNA from amniotic fluid, we set out to measure the association between amniotic fluid levels of toxic and essential metals and fetal gene expression. We find that arsenic was associated with increased expression of 3 genes known to play roles in both birth-related and reproductive effects. The results highlight the potential for detrimental health effects of prenatal metals exposure and the potential to identify biomarkers of environmental exposure during this critical developmental period.     

Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects or Down syndrome

Intrauterine fetal death occurred in four women who were ‘screen-positive’ in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore, we evaluated all ‘screen-positive’ women in whom both of these markers were ⩾ 2.0 multiples of the median. The cases fulfilling these criteria totalled 11, and only one of them had no complications. High concentrations of both MSAFP and MShCG in a number of these cases might have been caused by an increased placental volume, which, in turn, might have been induced by decreased perfusion of the placenta. We conclude that screening programmes wrongly determine a high risk of fetal NTD or DS if the concentrations of both these parameters are very high. Invasive diagnostic procedures should be avoided in these cases, particularly in view of the increased risk of an adverse pregnancy outcome.     

First trimester serum screening for down's syndrome

Screening for Down's Syndrome has been shown to be effective at 10 weeks of pregnancy. A multicentre study (the First trimester serum screening study) has shown that there are two biochemical markers of choice at this time in pregnancy, namely pregnancy associated placental protein A (PAPP-A) and the free β-sub-unit of human chorionic gonadotrophin (free β-hCG). When used together with maternal age these two biochemical markers have an estimated detection rate of 62% and a 5% false-positive rate. The results are consistent with those obtained from a systematic review of the world literature. Other markers are less predictive of Down's syndrome though there is still some uncertainty over the value of dimeric inhibin-A at 10 weeks of pregnancy. Nuchal translucency measurement, from an ultrasound examination performed at about 10 weeks of pregnancy, is associated with Down's syndrome and is emerging as an important potential screening marker. At present there is uncertainty over its quantitative performance and performance when combined with biochemical markers. The resolution of these issues is currently the subject of active research. Ten week screening for Down's syndrome is an advance that is now technically possible though there is still insufficient information to justify its use in routine screening practice.     

Perinatal outcome after maternal primary cytomegalovirus infection in the first trimester: a practical update and counseling aid

Cytomegalovirus (CMV) is the most common cause of congenital infection with approximately 0.5% of pregnant women in developed countries seroconverting during pregnancy. In utero transmission occurs in about one third of women who develop primary infection in the first trimester, and these fetuses are at risk for adverse perinatal outcomes and long-term neurological complications. The great promise of a prenatal therapy to reduce fetal infection after maternal primary CMV infection has not been realized to date. The prediction of CMV sequelae is particularly challenging for clinicians because of the heterogeneity of the published literature, the wide spectrum of perinatal outcomes, the adjustment of fetal risk at each stage of assessment, and the variable quality of published data. Given the continued lack of a proven fetal therapy, it is timely to review the natural history of congenital CMV in the modern management era. We have analyzed the recent literature, integrated findings from multiple studies, and calculated stage-specific risks for adverse perinatal outcome to assist in counseling women with first trimester primary CMV infection. © 2014 John Wiley & Sons, Ltd.     

Defining core outcomes of reproductive genetic carrier screening: A Delphi survey of Australian and New Zealand stakeholders

Objective

Understanding the value, benefits and harms of health interventions is needed to inform best practice and ensure responsible implementation of new approaches to patient care. Such value is demonstrated through the assessment of outcomes; however, which outcomes are assessed is often highly varied across studies and can hinder the ability to draw robust conclusions. The Core Outcome Development for Carrier Screening study aims to understand the outcomes that can meaningfully capture the value of reproductive genetic carrier screening (RGCS).

Method

The authors report an iterative, two-round online Delphi survey of Australian and New Zealand stakeholders to determine the degree of consensus regarding the core outcomes of RGCS. Panellists ranked 83 outcomes according to their perceived importance on a nine-point Likert scale. Using the distribution of rankings, outcomes were grouped into tiers representative of their perceived level of importance and agreement between groups.

Results

The top tier outcomes represent those agreed to be critically important for all future studies of RGCS to assess and were used to define a preliminary core outcome set encompassing the domains (1) primary laboratory outcomes, (2) pregnancy outcomes, (3) resource use and, (4) perceived utility of RGCS.

Conclusion

These findings can guide the selection of meaningful outcomes in studies aiming to demonstrate the value of RGCS. A future international consensus process will expand on these findings and guide the inclusion of diverse perspectives across the range of settings in which RGCS is offered.