Stefan C. Kane

A review of the mechanisms and evidence for typical and atypical twinning.

The mechanisms responsible for twinning and disorders of twin gestations have been the subject of considerable interest by physicians and scientists, and cases of atypical twinning have called for a reexamination of the fundamental theories invoked to explain twin gestations. This article presents a review of the literature focusing on twinning and atypical twinning with an emphasis on the phenomena of chimeric twins, phenotypically discordant monozygotic twins, mirror-image twins, polar body twins, complete hydatidiform mole with a coexistent twin, vanishing twins, fetus papyraceus, fetus in fetu, superfetation, and superfecundation. The traditional models attributing monozygotic twinning to a fission event, and more recent models describing monozygotic twinning as a fusion event, are critically reviewed. Ethical restrictions on scientific experimentation with human embryos and the rarity of cases of atypical twinning have limited opportunities to elucidate the exact mechanisms by which these phenomena occur. Refinements in the modeling of early embryonic development in twin pregnancies may have significant clinical implications. The article includes a series of figures to illustrate the phenomena described.

First Trimester Biomarkers in the Prediction of Later Pregnancy Complications

Adverse obstetric outcomes, such as preeclampsia, preterm birth, gestational diabetes, and fetal growth restriction, are poorly predicted by maternal history and risk factors alone, especially in nulliparae. The ability to predict these outcomes from the first trimester would allow for the early initiation of prophylactic therapies, institution of an appropriate model and location of care, and recruitment of a truly “high risk” population to clinical trials of interventions to prevent or ameliorate these conditions. To this end, development of adequately sensitive and specific predictive tests for these outcomes has become a significant focus of perinatal research. This paper reviews the biomarkers involved in these multiparametric tests and also outlines the performance of these tests and issues regarding their introduction into clinical practice.

First-Trimester Uterine Artery Doppler Analysis in the Prediction of Later Pregnancy Complications

Uterine artery Doppler waveform analysis has been extensively studied in the second trimester of pregnancy as a predictive marker for the later development of preeclampsia and fetal growth restriction. The use of Doppler interrogation of this vessel in the first trimester has gained momentum in recent years. Various measurement techniques and impedance indices have been used to evaluate the relationship between uterine artery Doppler velocimetry and adverse pregnancy outcomes. Overall, first-trimester Doppler interrogation of the uterine artery performs better in the prediction of early-onset than late-onset preeclampsia. As an isolated marker of future disease, its sensitivity in predicting preeclampsia and fetal growth restriction in low risk pregnant women is moderate, at 40–70%. Multiparametric predictive models, combining first-trimester uterine artery pulsatility index with maternal characteristics and biochemical markers, can achieve a detection rate for early-onset preeclampsia of over 90%. The ideal combination of these tests and validation of them in various patient populations will be the focus of future research.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.

Background: Preeclampsia and small‐for‐gestational‐age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low‐molecular‐weight heparin for the prevention of recurrence of preeclampsia and small‐for‐gestational‐age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. Objective: We sought to assess the effectiveness of enoxaparin in addition to high‐risk care for the prevention of preeclampsia and small‐for‐gestational‐age pregnancy in women with a history of these conditions. Study Design: This was an open‐label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6+0 and <16+0 weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1‐to‐1 ratio to standard high‐risk care or standard high‐risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36+0 weeks or delivery, whichever occurred sooner. Standard high‐risk care was defined as care coordinated by a high‐risk antenatal clinic service, aspirin 100 mg daily until 36+0 weeks, and–for women with prior preeclampsia–calcium 1000–1500 mg daily until 36+0 weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks’ gestation and later analyzed for soluble fms‐like tyrosine kinase‐1, soluble endoglin, endothelin‐1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small‐for‐gestational‐age <5th customized birthweight percentile. All data were analyzed on an intention‐to‐treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268). Results: Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high‐risk care plus enoxaparin and 77 receiving standard high‐risk care only). Seven women who miscarried <16 weeks’ gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small‐for‐gestational‐age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53–2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms‐like tyrosine kinase‐1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high‐risk care only. Conclusion: The use of enoxaparin in addition to standard high‐risk care does not reduce the risk of recurrence of preeclampsia and small‐for‐gestational‐age infants in a subsequent pregnancy.

First‐trimester maternal ophthalmic artery Doppler analysis for prediction of pre‐eclampsia

To determine the performance of a multiparametric test comprising maternal risk factors, uterine artery Doppler and ophthalmic artery Doppler in the first trimester of pregnancy for the prediction of pre‐eclampsia (PE).

OPHTHALMIC ARTERY DOPPLER ANALYSIS: A WINDOW INTO THE CEREBROVASCULATURE OF WOMEN WITH PRE-ECLAMPSIA

The neurological complications of pre-eclampsia, including eclampsia (seizures) and intracerebral haemorrhage, are responsible for much of the maternal morbidity and mortality associated with this condition. Animal models and neuroimaging in humans suggest that pre-eclampsia is associated with a loss of cerebral autoregulation, which consequent hyperperfusion and vasogenic oedema. Treatments given to pre-eclamptic women are aimed at preventing these cerebral sequelae, and include antihypertensive agents (to prevent intracranial haemorrhage) and magnesium sulphate (for seizure prophylaxis). It is likely that these agents have a direct effect on the maternal cerebrovasculature, although their precise mechanisms of action remain incompletely understood. Doppler analysis of the maternal ophthalmic artery represents a safe, well-tolerated, reproducible, readily accessible, real-time imaging modality by which cerebrovascular haemodynamic changes can be assessed. Existing research has shown pre-eclampsia to be associated with changes in the Doppler parameters of the ophthalmic artery that are consistent with increased perfusion. This sonographic technique could also be used to determine the cerebrovascular effects of anticonvulsant and antihypertensive therapies in pre-eclampsia. In time, it may prove to be a useful point-of-care tool for the individualisation of risk for neurological events in pre-eclampsia, potentially allowing for more appropriately targeted therapy, and ensuring an adequate cerebrovascular response in those deemed high risk. In so doing, ophthalmic artery Doppler studies may play an important role in ameliorating the potentially devastating short- and long-term cerebral complications of pre-eclampsia.

Doppler Assessment of Uterine Blood Flow in Pre-eclampsia: A Review

Doppler ultrasonography plays an ever-increasing role in obstetric imaging. Although commonly purported to assess blood flow, most studies in this area report purely on velocimetric parameters, rather than true volumetric flow. This review article highlights the physiological importance of this distinction, and reports on a literature review of uterine artery Doppler interrogation in the context of pre-eclampsia, which identified only four original research papers that attempted to assess blood flow. Attention is needed for true volumetric flow assessment in pre-eclampsia research, which may permit a more complete conceptualisation of the pathogenesis and haemodynamic consequences of this condition.

Cervical length as a predictor for spontaneous preterm birth in high-risk singleton pregnancy: current knowledge.

†The University of Melbourne, Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, Locked Bag 300, Parkville, Victoria 3052, Australia; ‡Pregnancy Research Centre, Department of Maternal-Fetal Medicine, The Royal Women’s Hospital, Parkville, Victoria, Australia; §Department of Obstetrics, Paulista School of Medicine Federal University of São Paulo, São Paulo, Brazil *Correspondence. (e-mail: Fabricio.Costa@thewomens.org.au)

Contemporary clinical management of the cerebral complications of preeclampsia.

The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality arising from these conditions, for women and their infants alike. This paper outlines the evidence base for contemporary management principles pertaining to the neurological sequelae of preeclampsia, primarily from the maternal perspective, but with consideration of fetal and neonatal aspects as well. It concludes with a discussion regarding future directions in the management of this potentially lethal condition.

Outcomes and predictive tests from a dedicated specialist clinic for women at high risk of preterm labour: A ten year audit

Preterm birth continues to be a major cause of infant morbidity and mortality worldwide, but advances have recently been made in its prediction and prevention. A short cervix (<25 mm) in the second trimester on transvaginal ultrasound scan and fetal fibronectin are important predictive tests. For over ten years, the Preterm Labour Clinic at the Royal Womens Hospital, Melbourne, Australia has provided care for women at high risk of preterm birth, including those with a previous preterm birth, previous cervical surgery, uterine malformation or incidental finding of short cervix at routine ultrasound. The purpose of this study was to review this clinics outcomes for the first decade.