Examining the link between placental pathology,growth restriction,and stillbirth

Stillbirth, often defined as death of a fetus ≥20 weeks of gestation, is emotionally devastating for families and caregivers. It is often associated with fetal growth restriction (FGR). Indeed, FGR or small-for-gestational age fetus (SGA) is a major risk factor for stillbirth. In rare cases, this is due to genetic abnormalities or infections. However, in most cases, it is linked to placental insufficiency. This may be due to abnormal placental development or placental damage, thereby resulting in decreased blood flow, oxygen, and nutrients to the fetus. Several placental histological abnormalities are associated with stillbirth, FGR, or both. Most involve vascular abnormalities but some are inflammatory lesions. This paper reviews evidence regarding the relationships between placental function and pathology, FGR, and stillbirth. Issues with clinical relevance, knowledge gaps, and areas for further research are highlighted.     

死胎原因分析及管理对策探讨

死胎是妊娠最严重的并发症之一。文章总结死胎的危险因素、病因、管理及再次妊娠的对策。强调死胎管理中查找死胎原因的重要性，建议应尽可能对所有病例进行尸体解剖、胎盘病检及基因检测。以期更有针对性的指导后续妊娠。     

The Stillbirth Collaborative Research Network (SCRN) placental and umbilical cord examination protocol

The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.     

Prediction and prevention of recurrent stillbirth

Stillbirth is one of the most common adverse pregnancy outcomes in the United States, occurring in one out of every 200 pregnancies. There is a paucity of information on the outcome of pregnancies after stillbirth. Prior stillbirth is associated with a twofold to 10-fold increased risk of stillbirth in the future pregnancy. The risk depends on the etiology of the prior stillbirth, presence of fetal growth restriction, gestational age of the prior stillbirth, and race. Categorization of the cause of the initial stillbirth will allow better estimates of individual recurrence risk and guide management. A history of stillbirth also increases the risk of other adverse pregnancy outcomes in the subsequent pregnancy such as placental abruption, cesarean delivery, preterm delivery, and low birth weight infants. Prospective studies have revealed an increased risk of stillbirth with low pregnancy-associated plasma protein A, elevated maternal serum alpha fetoprotein, abnormal uterine artery Doppler studies, and antiphospholipid antibodies. However, the positive predictive value of these factors individually is poor. Because fetal growth restriction is associated with almost half of all stillbirths, the correct diagnosis of fetal growth restriction is essential. The use of individualized or customized growth standards will improve prediction of adverse pregnancy outcome by distinguishing growth-restricted fetuses from constitutionally small, healthy fetuses. Antepartum fetal surveillance and fetal movement counting are also mainstays of poststillbirth pregnancy management.     

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.     

Late stillbirths and long-term mortality of mothers

OBJECTIVE: To assess whether women who experienced stillbirths have an excess risk of long-term mortality. METHODS: We conducted a cohort study in the setting of the Jerusalem Perinatal Study, a population-based database of all births to West Jerusalem residents. Through data linkage with the Israeli Population Registry, we followed mothers who gave birth at least twice between 1964 and 1976 and compared the survival of women who had at least one stillbirth (n=595) with that of women who had only live births (n=24,523), using Cox proportional hazards models. RESULTS: During the study period, 78 (13.1%) mothers with stillbirths died, compared with 1,518 (6.2%) women without stillbirth (crude hazard ratio 2.08, 95% confidence interval [CI] 1.65-2.61). The mortality risk remained significantly increased after adjustments for sociodemographic variables, maternal diseases at pregnancy, placental abruption, and preeclampsia (hazard ratio 1.40, 95% CI 1.11-1.77). Stillbirth was associated with an increased risk of death from coronary heart disease (adjusted hazard ratio 2.00, 95% CI 1.02-3.93), all circulatory (adjusted hazard ratio 1.70, 95% CI 1.02-2.84) and renal (adjusted hazard ratio 4.70, 95% CI 1.47-15.0) causes. Stratifying by country of origin, an increased risk was evident particularly among women of North African origin (all-cause mortality, adjusted hazard ratio 2.47, 95% CI 1.69-3.63). CONCLUSION: Stillbirth may be a risk marker for premature mortality among parous women.     

死胎的预测及其高危人群的管理

死胎是各种高危因素下母体、胎儿、胎盘疾病的终末期结局。早中孕期联合母体病史、超声胎儿生长及子宫动脉多普勒血流评估、母体血清胎盘生长因子,对胎盘受损所致死胎的预测价值较高,但对足月死胎的预测价值有限。正确识别死胎的高危因素,加强高危人群的孕前及孕期管理,有效利用各种产前监护手段以及适时分娩,可降低死胎的发生率。     

Stillbirth: tissue findings with environmental and genetic links

This article discusses stillbirth from a pathologist's perspective. Stillbirth may be caused by many different mechanisms. There are specific maternal and fetal disorders leading to stillbirth, and some of these have genetic and environmental associations. Frequently, an autopsy examination may determine the specific cause of the fetal death. We illustrate tissue findings in stillbirth to put individual faces on this condition.     

A case of confined placental mosaicism with double trisomy associated with stillbirth

We present a case of stillbirth in which the fetus was well grown and karyotypically normal, but the placenta was morphologically abnormal and had confined placental mosaicism (CPM) for a double trisomy of chromosomes 12 and 15. A compilation of published cases of CPM reveals that whilst approximately 80% of pregnancies progress normally, there is an association with abnormal placental morphology, intrauterine growth restriction, fetal abnormalities and stillbirth. This case highlights the potential adverse effects of CPM and the benefit of placental examination in determining the cause of stillbirth.     

The stillbirth collaborative research network postmortem examination protocol

After reviewing the state of knowledge about the scope and causes of stillbirth (SB) in a special workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the participants determined that there is little guidance regarding the best use of postmortem examination (PM) to address the pathogenesis of stillbirth. In this report, we describe the PM procedure designed and used in the NICHD-supported Stillbirth Cooperative Research Network (SCRN). Perinatal pathologists, clinicians, epidemiologists, and biostatisticians at four tertiary care centers, a data coordinating center, and NICHD developed a standardized approach to perinatal PM, which was applied to a population-based study of stillbirth as part of the SCRN. The SCRN PM protocol was successfully instituted and used at the four medical centers. A total of 663 women with stillbirth were included: 620 delivered a single stillborn infant, 42 delivered twins, and one delivered triplets for a total of 676 stillborn infants. Of these women, 560 (84.5%) consented to PM (572 stillborn infants) that was conducted according to the SCRN protocol. A standardized PM protocol was developed to evaluate stillbirth consistently across centers in the United States. Novel testing and approaches that increase the yield of the PM can be developed using this model.     

Major risk factors for stillbirth in different trimesters of pregnancy—A systematic review

Stillbirth remains an event that has an important impact on global health issues. Different levels of health care between countries suggest that the stillbirth rate may be one of the indicators of the quality of a country's medical system. In this review, major risk factors for stillbirth will be discussed, especially in different trimesters of pregnancy. Early identification of risk factors for stillbirth and appropriate antenatal management may reduce preventable stillbirths and improve general outcomes of pregnancy.     

Guidelines for Investigating Stillbirths: An Update of a Systematic Review

ObjectiveTo identify formal, publicly available guidelines for stillbirth investigation and to identify the most appropriate clinical practice guideline (or component of a guideline) for use in Alberta.MethodsA systematic literature search was conducted to identify primary and secondary research studies published between January 1985 and August 2006 and formal, publicly available guidelines on the subject of stillbirth investigation. The Cochrane Library, PubMed, EMBASE, CINAHL, HealthSTAR, Science Citation Index, BIOSIS, and the NHS and CRD databases were searched. The methodological quality of the selected primary research studies was assessed according to specific criteria.ResultsAll six of the publicly available clinical practice guidelines selected for this review outlined similar steps in the stillbirth investigation but differed about which tests to include and which components should be core or additional investigations. They agreed on including several elements for routine investigation, such as complete autopsy and detailed examination of the cord and placenta.Of 61 retrieved primary research studies, only seven met the inclusion criteria. No studies compared the value of specific guidelines. Although reviewed evidence highlights the value of fetal autopsy and placental examinations as integral components of stillbirth investigation, the value of other components is still not clear.ConclusionsNo firm scientific judgement could be made about which clinical practice guideline for stillbirth investigation is the most appropriate or which components are essential. Currently there is no generally accepted reference guideline for stillbirth investigation. Fetal autopsy and placental examination remain important components, assuming the postmortem examination is of high quality. These data may be helpful in counselling parents who are considering whether or not to consent to a postmortem examination.     

Systematic review of placental pathology reported in association with stillbirth

Introduction

Histopathological examination of the placenta is recommended to determine the cause of stillbirth. Although some reports find causal or contributory placental abnormalities in up to 60% of stillbirths, the significance of such findings in this clinical setting remains uncertain. A systematic review was conducted to i) investigate the likelihood of diagnosing a cause of stillbirth from placental examination and ii) to identify the specific causes of death that can be diagnosed from placental pathology.

Methods

Medline, Embase, Biosis, and Web of Science were searched using the terms “stillbirth”, “histopathology”, “pathology”, and “placenta”. Case-reports, narrative review articles and studies that failed to define diagnostic sub-groups were excluded. 473 potential studies were identified. Relevant studies (n = 41) were subdivided into those that investigated causes of stillbirth (n = 13), and those that identified conditions associated with stillbirth (n = 5). The contributory value of placental examination to stillbirth classification was evaluated in 10 studies and the role of specific placental abnormalities in the aetiology of stillbirth in 20 studies.

Results

The proportion of stillbirths attributed to a placental cause ranged from 11 to 65%. Classification systems which included multiple placental categories and allowed placental findings to supersede other disorders reported higher rates of placental causes and fewer unexplained stillbirths. Diagnoses were frequently based on qualitative, non-specific terminology.

Conclusions

The utility of histopathological examination of the placenta is affected by the classification system used. International consensus is required for both diagnostic criteria and terminology to describe placental abnormalities and on classification of stillbirths..     

Investigation and management of stillbirth

Stillbirth describes the delivery of a baby with no signs of life in relation to thresholds of either gestational age or birthweight. In the UK, a stillbirth is legally defined as the delivery of a baby at or after 24 weeks’ gestation or 500 g where gestation is unknown. A history of previous stillbirth remains one of the strongest risk factors for subsequent stillbirth and other adverse outcomes in a subsequent pregnancy. According to World Health Organization (WHO), there are nearly 2 million stillbirths globally every year. There is a drive to reduce the rate of stillbirths by 50% in England by 2025 and a global target of 12 or fewer stillbirths per 1000 total births in every country by 2030. The significant psychological burden placed on parents following a stillbirth and the associated increased risk of complications in subsequent pregnancies need appropriate management. This article covers the investigation and management of stillbirth reflecting current UK practice.     

A Comprehensive Update on Stillbirth Prevention: from Preconception to Postpartum,Individuals to Public Health Administrations

Purpose of Review

Stillbirth is a devastating event for the pregnant woman, families, and care providers alike. No preventable stillbirths should be tolerated, no matter how low the incidence is. The rate of reducing stillbirth rate is less than satisfactory and warrants continued efforts. Indeed, massive researches from all specialties bloomed in recent years. Some interventions are with good evidence and feasible to be practiced, while others are preliminary but exciting to be investigated further. The purpose of this review is a comprehensive overview of the recent studies on stillbirth prevention. An emphasis is placed on novel ideas or areas to be improved on that might interest prospective readers.

Recent Findings

For pregnant women, optimized healthy lifestyle including body weight, blood sugar, and blood pressure control is warranted. Vigilance on fetal movement is important for detecting fetal distress. Sudden vigorous movement means no less than reduced movement and should prompt timely evaluations. Sleep in supine position compromises maternal vena cava and poses increased stillbirth risks; thus, mothers are advised to sleep on their left side. For health professionals, biomarkers are studied to detect early placental insufficiency. Doppler velocimetry, fetal cardiotocography, and biophysical profile are helpful in evaluating fetal well-being but require adequate training and careful interpretation. Timely iatrogenic delivery is effective in lowering perinatal deaths but should be balanced against newborn prematurity. Precision medicine, utilizing genetic studies, microarrays to analyze causes of death or fetal hypoxia severity in utero is promising in filling the knowledge gaps about stillbirth. Special effort should be allocated to bereavement services, follow-up clinics, and social support to minimize the psychological impact on stillbirths. Moreover, care bundles that set specific goals, algorithms, including stillbirth investigations and cause classifications should be implemented, followed by auditing and data analysis. In the long run, health promotion in women by empowerment through gender equality and access to medical resources should be strived for.

Summary

Stillbirth prevention is a work undone but has received ongoing attention and massive research efforts. Individuals, healthcare providers, and policy makers alike should stay interested and up to date.

     

The influence of maternal smoking habits on the risk of subsequent stillbirth: is there a causal relation?

Objective  Maternal smoking has previously been associated with risk of stillbirth. If women who quit smoking reduce their risk of stillbirth, the hypothesis of a causal association would be supported.
Design  Prospective cohort study.
Setting  Nationwide study in Sweden.
Population  All primiparous women who delivered their first and second consecutive single births between 1983 and 2001, giving a total number of 526 691 women.
Method  A population-based Swedish study with data from the Medical Birth Registry, the Immigration Registry and the Education Registry. Logistic regression analyses were used to estimate odds ratios, using 95% confidence intervals.
Main outcome measure  Stillbirth in the second pregnancy.
Results  Compared with nonsmokers in both pregnancies, women who smoked during the first pregnancy but not during the second do not have an increased risk of stillbirth (OR 1.02; 95% CI 0.79–1.30), while corresponding risk among women who smoked during both pregnancies was 1.35 (95% CI 1.15–1.58).
Conclusion  The result supports that maternal smoking during pregnancy is causally associated with stillbirth risk. Smoking is a preventable cause of stillbirth, and smoking interventions is an important issue in antenatal care.     

死胎的病因与预防

死胎是妊娠最严重的并发症之一。死胎的病因多样且复杂,但仍有部分死胎原因不明。一般人群筛查包括监测胎动、胎儿生长发育和生化指标。降低死胎风险的措施包括识别高危人群、产前监测和适时分娩。从死胎病因着手发现高危人群、加强监测并及时干预,有可能减少死胎的发生。     

胎儿生长受限与死胎

死胎的发生与胎儿生长受限(FGR)有关。FGR是死胎发生的重要原因之一,两者病因和发病危险因素相似。但发生FGR因素复杂而非单一。识别FGR潜在的危险因素及早期发现、早期诊断、早期干预是降低各类因素FGR发生死胎的关键。     

Thrombophilic risk factors for placental stillbirth

Objectives

To define the characteristics of placental stillbirth and the possible contribution of thrombophilic risk factors.

Study design

A prospective cohort study was performed. Women diagnosed with antenatal stillbirth (>20 weeks) of singleton pregnancies between 2006 and 2008 were referred postpartum for evaluation. Maternal risk factors, fetal, placental and cord abnormalities, and a detailed thrombophilia screening, including inherited and acquired thrombophilia, were evaluated. Fetal autopsy and placental pathology were encouraged.Placental stillbirth was defined as death of a normally-formed fetus with evidence of intrauterine fetal growth restriction, oligohydramnios, placental abruption and/or histological evidence of placental contribution to fetal death. Pregnancy characteristics and thrombophilia profiles were compared between placental and non-placental stillbirth cases.

Results

Sixty-seven women with stillbirth comprised the study group. Placental stillbirth was evident in 33/67 (49.3%). Significantly more women with placental stillbirth were nulliparous, when compared with non-placental stillbirth women (21/33 vs. 9/34, p = 0.002). Mean gestational age was lower for placental, compared with non-placental stillbirth (31.1 ± 6.1 weeks vs. 33.9 ± 4.8 weeks, p = 0.04), as was birth weight. Thirty-six of the 67 women (53.7%) tested positive for at least one thrombophilia. The prevalence of maternal thrombophilia was higher for placental stillbirth women (63.6%), and even higher (69.6%) for women after preterm (<37 weeks) placental stillbirth. Factor V Leiden and/or prothrombin G20210A mutation were much more prevalent in placental versus non-placental stillbirth women (OR 3.06, 95% CI 1.07-8.7).

Conclusions

Placental stillbirth comprises a unique subgroup with specific maternal characteristics. Maternal thrombophilia is highly prevalent, especially in preterm placental stillbirth. This may have implications for the management strategy in future pregnancies in this subgroup.     

The Stillbirth Collaborative Research Network neuropathologic examination protocol

We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations.