Stillbirth: a review.

Stillbirth occurs in nearly 1% of all births in the USA, and is one of the most common but least studied adverse pregnancy outcomes. The many risk factors for and causes of stillbirth are presented. Over the past several decades, the rate of stillbirth has been substantially reduced, with the reduction most apparent in those stillbirths previously occurring at term and/or in labor. Reductions have occurred because of reductions in risk factors (i.e. prevention of Rh disease and better control of diabetes), better antepartum monitoring of those with risk factors followed by early delivery for those fetuses found to be at risk (i.e. growth restriction, maternal pre-eclampsia), better intrapartum fetal monitoring, increases in Cesarean section for those at risk, and early detection of congenital anomalies followed by termination prior to the time that these early fetal deaths are classified as stillbirths. Finally, the value of using fetal autopsy and placental examination to determine the cause of death accurately, both for research purposes and for patient counseling in future pregnancies, is explored.     

Population-based investigations to study the association of cardiovascular polymorphisms and adverse pregnancy outcome

Adverse pregnancy outcome refers to placenta-mediated complications that may share a common etiopathogenesis in some cases. Unraveling associations between prothrombotic genetic predispositions and these pregnancy disorders, namely recurrent fetal loss, stillbirth, severe preeclampsia, intrauterine growth restriction, and placental abruption, requires rigorous epidemiological studies involving large cohorts of patients with sufficient numbers of the adverse pregnancy outcomes in question. Such is the case with the Denmark National Birth Cohort, which was initiated in 1996 and followed pregnant women giving birth from the years 1996 to 2002. In addition, national registers exist which can be linked together. Two studies have been initiated. One is a retrospective cohort study concerning primiparous women, with singleton pregnancy and with no identifiable congenital malformation. The purpose of this study is to determine the long-term cardiovascular risk of women whose pregnancies were complicated by adverse pregnancy outcome. Preliminary evidence suggests that the presence of an adverse pregnancy outcome augments the cardiovascular disease risk by an odds ratio of 1.21 (P < 0.001). The second study focuses on pro-thrombotic and cardiovascular genetic polymorphisms in a nested-case control study comparing pregnancies with and without an adverse pregnancy outcome in the index pregnancy. This study will be adequately powered to determine the relationship between adverse pregnancy outcome and pro-thrombotic and cardiovascular genetic polymorphisms. These studies are urgently needed to accurately assess the linkage between family history, presence of adverse pregnancy outcome, and long-term cardiovascular risk.     

First trimester origins of fetal growth impairment

The timing of factors that lead to disorders of fetal growth have been studied for many years. Previous studies have focused on disorders of the "second wave" of trophoblast invasion of myometrial arterioles and on fetal weight gain in the third trimester. Over the last 5 years, clinical studies have shown associations between first trimester ultrasound and biochemical parameters and the risk of later adverse perinatal outcome. First trimester growth restriction is associated with an increased risk of low birth weight, low birth weight percentile for gestational age and extremely preterm birth. This may reflect a defect in early pregnancy placentation and later adverse outcome. Consistent with this hypothesis, low first trimester circulating maternal concentrations of pregnancy-associated plasma protein A, a trophoblast-derived regulator of the insulin-like growth factor system, are associated with an increased risk of later stillbirth, growth restriction, pre-term birth and pre-eclampsia. Even among healthy women having normal pregnancies, first trimester circulating concentrations of pregnancy-associated plasma protein A correlate with the timing of spontaneous labor and the eventual birth weight. These analyses suggest that in some women complications of late pregnancy have their origins in the very earliest weeks of gestation and precede first attendance for prenatal care.     

Association between first trimester maternal serum pregnancy associated plasma protein-A and adverse pregnancy outcome

AIMS: To investigate whether low pregnancy associated plasma protein-A (PAPP-A) levels in the first trimester of pregnancy are associated with subsequent intrauterine fetal growth restriction, stillbirth and preterm delivery. METHODS: A retrospective review of pregnancy outcomes was undertaken in women who had PAPP-A carried out in the first trimester of pregnancy at the time of nuchal translucency scan. Pregnancy outcomes were assessed by the review of medical records, and postal questionnaires. Delivery details were collected, including livebirth, neonatal birthweight and gestational age at delivery. The chi2 test was used to investigate the association between low first trimester serum PAPP-A levels and adverse fetal outcomes. Unpaired t-test was used for continuous variables. Sensitivities and specificities were then calculated. RESULTS: A total of 894 women who had blood collected for PAPP-A were identified, and data was obtained for 827 deliveries. Each had a normal karyotype. There were six intrauterine deaths, 13 babies with birthweights below the 3rd centile, 55 babies weighing below the 10th centile, and 96 women who delivered prematurely. Four of six intrauterine deaths had low PAPP-A levels (<0.5 multiples of the median), with a relative risk of 13.75. Low PAPP-A levels were associated with fetal weight below the 10th centile (P = 0.01) but not the 3rd centile. There was no statistically significant association between low maternal serum PAPP-A levels and preterm delivery. CONCLUSION: At 11-13 weeks' gestation, low maternal serum PAPP-A levels are associated with fetal death in utero and birthweight below the 10th centile. First trimester PAPP-A may be a useful tool for identifying pregnancies at risk of adverse fetal outcomes.     

Pregnancy and perinatal outcomes of first-trimester crown−rump length discordant IVF dichorionic twin pregnancies – a retrospective cohort study

Research QuestionThis study aimed to evaluate the association between discordance in crown–rump length (CRL) and adverse pregnancy and perinatal outcomes in dichorionic twin pregnancies.DesignThis was a retrospective cohort study of dichorionic twin pregnancies after IVF that showed two live fetuses at the first ultrasound scan between 6 ⁺⁵ and 8 weeks gestational age from 1 January 2015 to 31 December 2016. Study groups were defined by the presence or absence of 20% or more discordance in CRL. The primary outcomes were early fetal loss of one or both fetuses before 12 weeks and birthweight discordance. Secondary outcomes included fetal anomalies, fetal loss between 12 and 28 weeks, stillbirth, small for gestational age (SGA) at birth, low birthweight (LBW), very low birthweight (VLBW), admission to the neonatal intensive care unit (NICU) and preterm delivery (PTD).ResultsCRL-discordant twin pregnancies were more likely to end in the loss of one fetus before 12 weeks’ gestation (odds ratio [OR] 15.877, 95% confidence interval [CI] 10.495–24.019). Discordant twin pregnancies with twin deliveries had a significantly higher risk of birthweight discordance (OR 1.943, 95% CI 1.032–3.989). There was no significant difference in perinatal outcomes including fetal anomalies, PTD, LBW, VLBW, SGA, neonatal death and admission to NICU between singleton or twin deliveries.ConclusionsDiscordant twin pregnancies were at increased risk of one fetal loss prior to 12 weeks’ gestation. Except for birthweight discordance, there was no significant difference between CRL discordance and other adverse perinatal outcomes.     

Maternal,Fetal, and Neonatal Outcomes of Elective Fetal Reduction Among Multiple Gestation Pregnancies: A Systematic Review

ObjectiveTo review the existing literature on fetal and maternal health outcomes following elective pregnancy reduction.Data SourcesMEDLINE, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, and the Cochrane Controlled Trials Register.Study SelectionStudies involving women pregnant with dichorionic twins, trichorionic triplets, or quadra-chorionic quadruplets who underwent elective fetal reduction of 1 or more fetuses to reduce the risks associated with multiple gestation pregnancies.Data ExtractionThe main fetal health outcomes measured were gestational age at delivery, preterm birth, miscarriage, birth weight, and small for gestational age at delivery. The main maternal health outcomes measured were gestational diabetes, hypertensive disorders of pregnancy, and cesarean delivery.Data SynthesisOf 7678 studies identified, 24 were included (n = 425 dichorionic twin pregnancies, n = 2753 trichorionic triplet pregnancies, and n = 111 quadra-chorionic quadruplet pregnancies). Fifteen studies (62.5%) did not report maternal health outcomes, while every study reported at least 1 fetal health outcome. Fetal reduction was associated with higher gestational age at birth, lower preterm birth, higher birth weight, and lower rates of small for gestational age infants and intrauterine growth restriction. No consistent pattern was observed for miscarriage and neonatal mortality rates. Following fetal reduction, cesarean delivery rates were lower in most studies. There were no appreciable trends with respect to gestational diabetes or hypertensive disorders of pregnancy.ConclusionFetal reduction reliably optimizes gestational age at birth and neonatal birth weight. Miscarriage rates and other adverse procedural outcomes did not increase following transabdominal reduction. Further research on maternal outcomes is needed given a paucity of information in the literature.     

Ambulatory management of chronic hypertension in pregnancy

Chronic hypertension in pregnancy is one of the most common medical diseases affecting pregnancy. It is associated with serious maternal and fetal complications, including superimposed pre-eclampsia, fetal growth restriction, premature delivery, placental abruption, and stillbirth. Baseline evaluation as early as possible is important to differentiate women with essential hypertension from those with severe hypertension, coexisting end-organ damage, and secondary causes of hypertension, as their risks of poor outcomes are increased. An optimal plan for maternal treatment and fetal surveillance can then be formulated. Coordination of care after delivery is important for long-term maternal health and future pregnancies.     

Fetal growth potential and pregnancy outcome

Although the association of fetal growth restriction and adverse pregnancy outcomes is well known, lack of sensitivity limits its clinical value. To a large extent, this limitation is a result of traditionally used method to define growth restriction by comparing fetal or birth weight to population norms. The use of population norms, by virtue of their inability to fully consider individual variation, results in high false positive and negative rates. An alternative, calculating fetal individually optimal growth potential, based on physiological determinants of individual growth, is superior in predicting adverse outcomes of pregnancy. Impairment of fetal growth potential identifes some adverse pregnancy outcomes that are not associated with growth restrction defined by population norms. When compared with traditional population-based norms, fetal growth potential is a better predictor of several important adverse outcomes of pregnancy which include: stillbirth, neonatal mortality and morbidity, and long-term adverse neonatal outcomes like neonatal encephalopathy, cerebral palsy and cognitive abilities. Impairment of individual growth potential is also strongly associated with spontaneous preterm delivery. Although definitive interventional trials have not been conducted as yet to validate the clinical value of fetal growth potential, many observational studies, conducted in various populations, indicate its significant promise in this respect.     

Discordance in twins: Association versus prediction

Weight discordance is among the major determinants of perinatal outcome in twin pregnancies. Weight discordance can occur in each trimester of pregnancy, though the clinical meaning of such finding and the association with adverse perinatal outcome can vary according to the gestational age (GA) at detection of growth discrepancy. Discrepancy in fetal size in the first trimester of pregnancy is associated with an increased risk of anomalies, aneuploidy, and fetal loss, though the predictive accuracy of using discordance to predict perinatal outcome is low. Conversely, discordance in the third trimester of pregnancy can be associated with fetal growth restriction, perinatal mortality, and morbidity. In view of these associations, twin pregnancies should be monitored for the occurrence of growth discrepancy. The present review aims to provide an up-to-date critical appraisal of the diagnosis and clinical management of twin pregnancies complicated by growth discordance according to the trimester at presentation.     

Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine – Section on Maternal Disorders

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.Key words: stillbirth, induction of labour, bile acids, liver disease, ursodeoxycholic acid, pruritus     

Clinical significance of true umbilical knots: a population-based analysis

The objective of this study is to determine the risk of adverse pregnancy outcomes resulting from a true umbilical knot. We analyzed 288 singleton pregnancies with a true umbilical knot among the women who gave birth at Kuopio University Hospital from January 1990 to December 1999. Logistic regression analysis was used to compare pregnancy outcomes of the affected cases with those of the general obstetric population (n = 23,027). The incidence of true knot was 1.25% and it was associated with advanced maternal age, multiparity, previous miscarriages, obesity, prolonged gravidity, male fetus, long cord, and maternal anemia. The women having a fetus with a cord knot underwent cesarean delivery less frequently than unaffected controls. Fetal death and low Apgar score at 1 min occurred significantly more frequently in the study group than in the general obstetric population, the adjusted odds ratios being 3.93 (95% CI, 1.41-11.0) and 1.73 (95% CI, 1.10-2.72), respectively. Otherwise, the pregnancy outcome measures were comparable in the two groups. Fetuses with true umbilical knots are at a four-fold increased risk of stillbirth, but little can be done to prevent fetal deaths during pregnancy. Surviving fetuses with true knots are likely to suffer temporary distress during delivery, but affected newborns recover soon after birth. Thus, monitored vaginal delivery appears to be a safe option for fetuses with true knots.     

妊娠期细颗粒物的暴露对胎儿影响的研究进展

近年来,已有大量临床研究、流行病学调查资料、动物研究结果等表明妊娠期孕妇细颗粒物（PM2.5）的暴露导致了死胎、流产、胎儿生长受限、低体质量儿、早产等不良妊娠结局,其具体致病机制目前尚不清楚。现有的研究表明,PM2.5导致的死胎、流产、先天畸形可能与其遗传毒性损伤作用有关,胎儿生长受限与PM2.5造成的胎盘功能障碍密切相关,而PM2.5所致的胎膜结构改变是未足月胎膜早破及早产的一个重要原因。以国内外发表的大量流行病学调查资料为基础,对妊娠期母体PM2.5的暴露对胎儿生长发育的影响进行综述。     

Fetal gender and pregnancy outcome

Objective.?To assess the effect of fetal gender on pregnancy outcome.

Methods.?Retrospective study of all singleton pregnancies at a tertiary hospital during 1995–2006.

Results.?Of the 66,387 women studied, 34,367 (51.8%) delivered male and 32,020 (48.2%) delivered female neonates. The rate of preterm delivery (as early as 29 weeks) was higher for male fetuses and was attributed to an increased incidence of spontaneous preterm labor and preterm premature rupture of membranes. Women carrying male fetuses were at increased risk for operative vaginal delivery (OVD) for non-reassuring fetal heart rate, failed OVD and cesarean delivery. Female fetuses were more likely to experience fetal growth restriction (FGR).

Conclusion. Fetal gender is independently associated with adverse pregnancy outcome. Although the added risk is relatively small, further investigation of the mechanisms underlying this association may contribute to our understanding of the pathophysiology of pregnancy complications such as preterm delivery and FGR.     

Management of decreased fetal movements

Maternal perception of decreased fetal activity is a common complaint, and one of the most frequent causes of unplanned visits in pregnancy. No proposed definitions of decreased fetal movements have ever been proven to be superior to a subjective maternal perception in terms of identifying a population at risk. Women presenting with decreased fetal movements do have higher risk of stillbirth, fetal growth restriction, fetal distress, preterm birth, and other associated outcomes. Yet, little research has been conducted to identify optimal management, and no randomized controlled trials have been performed. The strong associations with adverse outcome suggest that adequate management should include the exclusion of both acute and chronic conditions associated with decreased fetal movements. We propose guidelines for management of decreased fetal movements that include both a nonstress test and an ultrasound scan and report findings in 3014 cases of decreased fetal movements.     

Investigation and management of the small for gestational age fetus

The desire to identify the small for gestational age fetus is due to its association with stillbirth and poorer neonatal outcomes. The difficulty lies in determining which of these babies are just constitutionally small and healthy and which are growth restricted fetuses that are at significant risk of poor outcomes. Fetal growth restriction is often mediated through placental disease and shares a similar aetiological pathway to preeclampsia. Placental malperfusion results in impaired nutrient and oxygen delivery to the fetus. Appropriate risk assessment in early pregnancy and monitoring with symphysis fundal height measurement or ultrasound scans is a crucial part of the screening pathway. There is no effective treatment for growth restriction, so management is based on close monitoring and early delivery. Fetal growth restriction has better defined monitoring and delivery timing guidelines whereas it is more unclear and variable for fetuses considered only to be small for gestational age.     

PlGF in a clinical setting of pregnancies at risk of preeclampsia and/or intrauterine growth restriction

Placental growth factor (PlGF) is an angiogenic molecule produced by the placenta and implicated in the pathogenesis of preeclampsia (PE) and intrauterine growth restriction (IUGR). We have evaluated utility and applicability of the PlGF test in a clinical setting of pregnancies at risk of PE or complicated by IUGR in order to assess its relationship with pregnancy outcomes. Seventy-three pregnancies were enrolled between 19 and 35 weeks: 57 pregnancies at risk of PE and 16 at diagnosis of IUGR. Maternal circulating PlGF levels were measured by the Triage PlGF test (Alere, San Diego, CA). Pregnancy outcomes were evaluated in relation to three categories of plasma PlGF levels: very low (<12?pg/ml), low (12–100?pg/ml) and normal (≥100?pg/ml). Uterine artery Doppler velocimetry (UADV) pulsatility index (PI) was measured in the same patients on the day of maternal sampling. Pregnancies at risk with very low plasma PlGF levels had significantly lower gestational age at delivery than patients with low or normal PlGF. The rate of emergency C-section was significantly higher in the group with PlGF?<12?pg/ml. IUGR pregnancies with very low and low PlGF delivered earlier than patients with normal PlGF. All IUGR with very low and low PlGF had UADV PI?>?95th percentile. Our data indicate that PlGF may provide useful information to identify fetuses requiring increased surveillance and possibly urgent delivery in pregnancies at risk of adverse outcomes. Furthermore, in IUGR, PlGF can predict adverse pregnancy outcomes that may be secondary to placental insufficiency.     

Prenatal diagnosis and obstetric outcomes in triplet pregnancies in relation to chorionicity

OBJECTIVE: This study describes the frequency, pregnancy complications and outcomes of non-trichorionic triplet pregnancies. DESIGN: A retrospective observational study. SETTING: Two tertiary level referral centres of Obstetrics and Prenatal Medicine, Germany. POPULATION: All women booked to receive targeted ultrasound screening between January 1998 and June 2003. The mixed low and high risk population included 36,430 women with ultrasound examinations between 11 and 24 weeks of gestation. Of those with available outcome, 176 were triplet pregnancies with three viable fetuses. METHODS: Analysis of ultrasound data and perinatal outcome in triplet gestations who had first and second trimester targeted ultrasound examination. Pregnancies with monochorionic or dichorionic placentation were identified and pregnancy outcome was compared to trichorionic triplets. MAIN OUTCOME MEASURES: Intrauterine fetal death, fetal growth restriction (FGR), mean discordance and survival rate in non-trichorionic versus trichorionic triplets. RESULTS: Triplets were trichorionic in 81.8% and had a monochorionic or dichorionic placentation in the remaining 18.2%. The rate of monochorionicity and dichorionicity was significantly higher after spontaneous conception than after assisted reproductive technologies (44.8%vs 12.9%, P < 0.001). In non-reduced monochorionic and dichorionic triplets compared with non-reduced trichorionic triplets, there was a higher rate of intrauterine fetal death (8.8%vs 1.5%, P < 0.01), FGR (33.3%vs 25.5%), mean discordance (20.5%vs 12.7%, P < 0.01), discordance >30% (26.3%vs 2.9%, P < 0.01) and delivery <32 weeks of gestations (47.4%vs 32.2%). There was a lower survival rate in non-trichorionic triplets (84.2%) than in trichorionic ones (91.7%). CONCLUSION: Triplet pregnancies with a monochorionic or dichorionic placentation are at significantly higher risk of adverse pregnancy outcome compared with trichorionic pregnancies. First trimester evaluation of chorionicity is strongly emphasised.     

Uterine and umbilical artery Doppler are comparable in predicting perinatal outcome of growth-restricted fetuses

Objective  To compare umbilical and uterine artery Doppler in predicting outcome of pregnancies suspected of fetal growth restriction (FGR).
Design  A prospective study included 353 singleton pregnancies complicated by an FGR fetus.
Setting  University Hospital setting.
Sample  Pregnancies suspected of FGR diagnosed by ultrasound fetal biometry during a 5-year period.
Main outcome measure  Perinatal outcome in relation to uterine and umbilical artery Doppler.
Methods  The women underwent Doppler examination of the umbilical and uterine arteries. Results from the uterine, but not the umbilical artery, were blind to the woman and managing obstetrician. The Doppler results were related to perinatal outcomes including small for gestational age newborns, caesarean delivery, premature delivery (<37 weeks of gestation) and admission of the newborn to a neonatal intensive care unit.
Results  Abnormal uterine artery Doppler velocimetry was seen in 120 (33.4%) pregnancies and abnormal umbilical artery Doppler in 102 (28.4%). There was a statistically significant correlation between abnormal Doppler of both the umbilical and uterine arteries and adverse outcome of pregnancy. The two vessels were comparable in predicting adverse outcome. Women with normal umbilical artery Doppler (251) were analysed separately. Abnormal uterine artery Doppler, seen in 61 (24.3%) of those women, showed a statistically significant correlation for adverse outcome of pregnancy.
Conclusions  Doppler examinations of the uterine and/or the umbilical arteries seem to be comparable as predictors of outcome in pregnancies complicated by FGR. Including uterine artery Doppler in the surveillance of growth-restricted fetuses might detect a group of pregnancies at high risk, even though the umbilical artery Doppler was normal.     

A kick from within--fetal movement counting and the cancelled progress in antenatal care

Interest for maternal fetal movement counting as a method of screening for fetal well-being boomed during the 1970's and 1980's. Several reports demonstrated that the introduction of counting charts significantly reduced stillbirth rates. However, in 1989, a large study appeared in The Lancet that annihilated research in this field by deeming charts ineffective. In retrospect, it seems evidence was lacking. This review revisits the subject of the significance of fetal movement counting in predicting outcome and reducing stillbirth rates. A structured search was performed to identify studies relating to pregnancy outcome and its association with maternal perception of fetal movements. Suspected preliminary or redundant material was excluded. Only publications from Western countries dating from after 1970 were included. Twenty-four studies were identified. Available data demonstrate that reduced fetal movements are associated with adverse pregnancy outcome, both in high and low risk pregnancies. Increased vigilance towards maternal perception of movements (e.g. by performing movement counting studies) reduces stillbirth rates, in particular stillbirths deemed avoidable. While screening for fetal well-being by maternal fetal movement counting can reduce fetal mortality rates, a resurrection in research activity is urgently needed to optimize its benefits.     

Antepartum fetal health

Delivery of a healthy full term baby following an uneventful antenatal period occurs in the majority of pregnancies. These are classified as a low-risk pregnancy group. There are, however, some pregnancies that are complicated due to maternal or fetal disease that can increase the risk of perinatal morbidity and mortality. This is classified as a high-risk group. The aim of fetal surveillance is to identify these threatened fetuses with the prospect of altering the timing of delivery to prevent the worst outcome, stillbirth. This article looks at the tools available to assess antenatal fetal health in all pregnancies and their ability to identify the at-risk pregnancies that require extra surveillance to improve outcomes. This article does not address fetal surveillance during labour.