Talk:Birth - Stillbirth and Perinatal Death

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Cite this page: Hill, M.A. (2019, June 18) Embryology Birth - Stillbirth and Perinatal Death. Retrieved from


Interventions for investigating and identifying the causes of stillbirth

Cochrane Database Syst Rev. 2018 Apr 30;4:CD012504. doi: 10.1002/14651858.CD012504.pub2.

Wojcieszek AM1, Shepherd E, Middleton P, Gardener G, Ellwood DA, McClure EM, Gold KJ, Khong TY, Silver RM, Erwich JJH, Flenady V.

Abstract BACKGROUND: Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. OBJECTIVES: To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. MAIN RESULTS: We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials. PMID: 29709055 DOI: 10.1002/14651858.CD012504.pub2

Early Pregnancy Losses: Review of Nomenclature, Histopathology, and Possible Etiologies

Fetal Pediatr Pathol. 2018 May 8:1-19. doi: 10.1080/15513815.2018.1455775. [Epub ahead of print]

Pinar MH1, Gibbins K2, He M3, Kostadinov S4, Silver R5.


Miscarriage is a frequent complication of human pregnancy: ∼50% to 70% of spontaneous conceptions are lost prior to the second trimester. Etiology of miscarriage includes genetic abnormalities, infections, immunological and implantation disorders, uterine and endocrine abnormalities, and lifestyle factors. Given such variability, knowledge regarding causes, pathophysiological mechanisms, and morphologies of primary early pregnancy loss has significant gaps; often, pregnancy losses remain unexplained. Pathologic evaluation of miscarriage tissue is an untapped source of knowledge. Although miscarriage specimens comprise a significant part of pathologists' workload, information reported from these specimens is typically of minimal clinical utility for delineating etiology or predicting recurrence risk. Standardized terminology is available, though not universally used. We reintroduce the terminology and review new information about early pregnancy losses and their morphologies. Current clinical terminology is inconsistent, hampering research progress. This review is a resource for diagnostic pathologists studying this complex problem. KEYWORDS: Early pregnancy loss; histopathology; miscarriage; nomenclature PMID: 29737906 DOI: 10.1080/15513815.2018.1455775

Risk of stillbirth, preterm delivery, and fetal growth restriction following exposure in a previous birth: systematic review and meta-analysis

BJOG. 2018 Jan;125(2):183-192. doi: 10.1111/1471-0528.14906. Epub 2017 Oct 3.

Malacova E1, Regan A1, Nassar N2, Raynes-Greenow C3, Leonard H4, Srinivasjois R5,6, W Shand A2,7, Lavin T8, Pereira G1.


BACKGROUND: Little is known about the risk of non-recurrent adverse birth outcomes. OBJECTIVES: To evaluate the risk of stillbirth, preterm birth (PTB), and small for gestational age (SGA) as a proxy for fetal growth restriction (FGR) following exposure to one or more of these factors in a previous birth. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Maternity and Infant Care, and Global Health from inception to 30 November 2016. SELECTION CRITERIA: Studies were included if they investigated the association between stillbirth, PTB, or SGA (as a proxy for FGR) in two subsequent births. DATA COLLECTION AND ANALYSIS: Meta-analysis and pooled association presented as odds ratios (ORs) and adjusted odds ratios (aORs). MAIN RESULTS: Of the 3399 studies identified, 17 met the inclusion criteria. A PTB or SGA (as a proxy for FGR) infant increased the risk of subsequent stillbirth ((pooled OR 1.70; 95% confidence interval, 95% CI, 1.34-2.16) and (pooled OR 1.98; 95% CI 1.70-2.31), respectively). A combination of exposures, such as a preterm SGA (as a proxy for FGR) birth, doubled the risk of subsequent stillbirth (pooled OR 4.47; 95% CI 2.58-7.76). The risk of stillbirth also varied with prematurity, increasing three-fold following PTB <34 weeks of gestation (pooled OR 2.98; 95% CI 2.05-4.34) and six-fold following preterm SGA (as a proxy for FGR) <34 weeks of gestation (pooled OR 6.00; 95% CI 3.43-10.49). A previous stillbirth increased the risk of PTB (pooled OR 2.82; 95% CI 2.31-3.45), and subsequent SGA (as a proxy for FGR) (pooled OR 1.39; 95% CI 1.10-1.76). CONCLUSION: The risk of stillbirth, PTB, or SGA (as a proxy for FGR) was moderately elevated in women who previously experienced a single exposure, but increased between two- and three-fold when two prior adverse outcomes were combined. Clinical guidelines should consider the inter-relationship of stillbirth, PTB, and SGA, and that each condition is an independent risk factor for the other conditions. TWEETABLE ABSTRACT: Risk of adverse birth outcomes in next pregnancy increases with the combined number of previous adverse events. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Each year, around 2.6 million babies are stillborn, 15 million are born preterm (<37 weeks of gestation), and 32 million are born small for gestational age (less than tenth percentile for weight, smaller than usually expected for the relevant pregnancy stage). Being born preterm or small for gestational age can increase the chance of long-term health problems. The effect of having a stillbirth, preterm birth, or small-for-gestational-age infant in a previous pregnancy on future pregnancy health has not been summarised. We identified 3399 studies of outcomes of previous pregnancies, and 17 were summarised by our study. What were the main findings? The outcome of the previous pregnancy influenced the risk of poor outcomes in the next pregnancy. Babies born to mothers who had a previous preterm birth or small-for-gestational-age birth were more likely to be stillborn. The smaller and the more preterm the previous baby, the higher the risk of stillbirth in the following pregnancy. The risk of stillbirth in the following pregnancy was doubled if the previous baby was born both preterm and small for gestational age. Babies born to mothers who had a previous stillbirth were more likely to be preterm or small for gestational age. What are the limitations of the work? We included a small number of studies, as there are not enough studies in this area (adverse birth outcomes followed by adverse cross outcomes in the next pregnancy). We found very few studies that compared the risk of small for gestational age after preterm birth or stillbirth. Definitions of stillbirth, preterm birth categories, and small for gestational age differed across studies. We did not know the cause of stillbirth for most studies. What are the implications for patients? Women who have a history of poor pregnancy outcomes are at greater risk of poor outcomes in following pregnancies. Health providers should be aware of this risk when treating patients with a history of poor pregnancy outcomes. © 2017 Royal College of Obstetricians and Gynaecologists. KEYWORDS: Growth restriction; meta-analysis; pregnancy; preterm birth; stillbirth; systematic review PMID: 28856792 DOI: 10.1111/1471-0528.14906


Altered fetal growth, placental abnormalities, and stillbirth

PLoS One. 2017 Aug 18;12(8):e0182874. doi: 10.1371/journal.pone.0182874. eCollection 2017.

Bukowski R1, Hansen NI2, Pinar H3, Willinger M4, Reddy UM4, Parker CB2, Silver RM5, Dudley DJ6, Stoll BJ7, Saade GR8, Koch MA2, Hogue C9, Varner MW5, Conway DL10, Coustan D3, Goldenberg RL11; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Stillbirth Collaborative Research Network (SCRN). Author information Abstract BACKGROUND: Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. METHODS AND FINDINGS: Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at ≥24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births. CONCLUSIONS: The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths. PMID: 28820889 PMCID: PMC5562325 DOI: 10.1371/journal.pone.0182874


Prediction of stillbirth from maternal factors, fetal biometry and uterine artery Doppler at 19-24 weeks' gestation

Ultrasound Obstet Gynecol. 2016 Sep 7. doi: 10.1002/uog.17295.

Akolekar R1,2, Tokunaka M3, Ortega N3, Syngelaki A3, Nicolaides KH3.


OBJECTIVES: To evaluate the performance of screening for all stillbirths and those due to impaired placentation and unexplained or other causes by a combination of maternal factors, fetal biometry and uterine artery pulsatility index (UT-PI) at 19-24 weeks' gestation and compare this performance to that of screening by UT-PI alone. METHODS: This was a prospective screening study of 70,003 singleton pregnancies including 69,735 live births and 268 (0.38%) antepartum stillbirths; 159 (59%) were secondary to impaired placentation and 109 (41%) were due to other or unexplained causes. Multivariate logistic regression analysis was used to develop a model for prediction of stillbirth based on a combination of maternal factors, fetal biometry and UT-PI. RESULTS: Combined screening predicted 55% of all stillbirths, including 75% of those due to impaired placentation and 23% of those that were due to other causes or unexplained, at false positive rate of 10%; within the impaired placentation group the detection rate of stillbirth at <32 weeks' gestation was higher than that of stillbirth at ≥37 weeks (88% vs 46%; p < 0.001). The performance of screening by the combined test was superior to that of selecting the high-risk group on the basis of UT-PI being above the 90th percentile for gestational age, which predicted 48% of all stillbirths, 70% of those due to impaired placentation and 15% of those that were due to other causes or unexplained. CONCLUSIONS: Second-trimester screening by a combination of UT-PI with maternal factors and fetal biometry can predict a high proportion of stillbirths and in particular those due to impaired placentation. This article is protected by copyright. All rights reserved. KEYWORDS: Fetal biometry; Impaired placentation; Pyramid of pregnancy care; Stillbirth; Uterine artery Doppler PMID 27601282 DOI: 10.1002/uog.17295


Stillbirth: Correlations Between Brain Injury and Placental Pathology

Pediatr Dev Pathol. 2015 Oct 22. [Epub ahead of print]

Ernst LM1, Bit-Ivan EN2, Miller ES3, Minturn L4, Bigio EH5, Weese-Meyer DE6.


BACKGROUND: Chronic placental pathologic processes such as fetal thrombotic vasculopathy have been linked to brain injury in neonates. We hypothesize that using stillbirth as a model, placental pathology can predict risk for hypoxic-ischemic brain injury. DESIGN: From a single institutional database of stillbirths {greater than or equal to}23 weeks gestational age, we included cases with full autopsy and neuropathology examination. Bivariable analyses were performed to identify whether there was an association between placental pathologic findings and neuropathologic findings. Logistic regression was used to control for potential confounders. RESULTS: Among 97 potential cases, adequate tissue was analyzable from 79 cases (mean gestational age 33 weeks). Acute CNS hemorrhage and acute neuronal necrosis were the most common neuropathologic processes seen in this cohort (57% for each). Maternal vascular underperfusion was the most common placental pathology, but was not significantly associated with a specific neuropathologic finding. High grade chronic villitis (HGCV) and fetal thrombotic vasculopathy (FTV) were significantly associated with increased risk for pontosubicular necrosis (OR 15.73 and 3.79, respectively). These associations persisted after controlling for potential confounders. CONCLUSION: Chronic placental pathologies, specifically HGCV and FTV, were associated with pontosubicular necrosis, suggesting that placental pathology involving the fetal vasculature and altered fetoplacental blood flow have the greatest likelihood of hypoxic/ischemic brain injury.

PMID 26492345

Stillbirths in Germany: Retrospective Analysis of 168 Cases between 2003 and 2011

Z Geburtshilfe Neonatol. 2015 Apr;219(2):73-80. doi: 10.1055/s-0034-1395654. Epub 2015 Apr 22.

Article in German

Hübner J1, Gast AS1, Müller AM2, Bartmann P3, Gembruch U1.


BACKGROUND: The decline in the incidence of stillbirths in Germany has remained static in recent years. This study aims to analyse the current situation of data documentation and examination of stillbirths. Furthermore, possible stillbirth prevention strategies should be developed. METHODS: Searches in the international peer-reviewed literature, retrospective data collection of 168 stillbirths in 8 hospitals, (in the area of Bonn) with subsequent statistical evaluation (descriptive statistics, t-test and binominal test) were undertaken. RESULTS: This study shows considerable deficits in data documentation, interdisciplinary communication and postmortal examination. Only in 51.8% (87/168) of the cases was a certain or uncertain cause of death found (42.3% placental, 1.2% foetal, 3.6% chromosomal, 4.8% umbilical cord abnormalities). Severe foetal growth restriction (<5(th) percentile) was observed in 29.2%; 44.9% (22/49) of them died at the age of ≥36+0 weeks of gestation. CONCLUSION: The first step to reduce the rate of stillbirths in Germany is to increase the identified causes of foetal death: Therefore, an interdisciplinary case report form was compiled to improve data collection and interdisciplinary collaboration. To standardise and complete postmortal management, an algorithm was created. The long-term aim is the development of a central data register for statistical analysis, to identify goals of research and to organise conferences with interdisciplinary reports of diagnostic findings. © Georg Thieme Verlag KG Stuttgart · New York.

PMID 25901868


Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis of Progress, Projections, and Priorities

PLoS Med. 2011 Aug;8(8):e1001080. Epub 2011 Aug 30.

Oestergaard MZ, Inoue M, Yoshida S, Mahanani WR, Gore FM, Cousens S, Lawn JE, Mathers CD; on behalf of the United Nations Inter-agency Group for Child Mortality Estimation and the Child Health Epidemiology Reference Group. Source World Health Organization, Department of Health Statistics and Informatics, Geneva, Switzerland. Abstract BACKGROUND: Historically, the main focus of studies of childhood mortality has been the infant and under-five mortality rates. Neonatal mortality (deaths <28 days of age) has received limited attention, although such deaths account for about 41% of all child deaths. To better assess progress, we developed annual estimates for neonatal mortality rates (NMRs) and neonatal deaths for 193 countries for the period 1990-2009 with forecasts into the future.

METHODS AND FINDINGS: We compiled a database of mortality in neonates and children (<5 years) comprising 3,551 country-years of information. Reliable civil registration data from 1990 to 2009 were available for 38 countries. A statistical model was developed to estimate NMRs for the remaining 155 countries, 17 of which had no national data. Country consultation was undertaken to identify data inputs and review estimates. In 2009, an estimated 3.3 million babies died in the first month of life-compared with 4.6 million neonatal deaths in 1990-and more than half of all neonatal deaths occurred in five countries of the world (44% of global livebirths): India 27.8% (19.6% of global livebirths), Nigeria 7.2% (4.5%), Pakistan 6.9% (4.0%), China 6.4% (13.4%), and Democratic Republic of the Congo 4.6% (2.1%). Between 1990 and 2009, the global NMR declined by 28% from 33.2 deaths per 1,000 livebirths to 23.9. The proportion of child deaths that are in the neonatal period increased in all regions of the world, and globally is now 41%. While NMRs were halved in some regions of the world, Africa's NMR only dropped 17.6% (43.6 to 35.9).

CONCLUSIONS: Neonatal mortality has declined in all world regions. Progress has been slowest in the regions with high NMRs. Global health programs need to address neonatal deaths more effectively if Millennium Development Goal 4 (two-thirds reduction in child mortality) is to be achieved. Please see later in the article for the Editors' Summary.

PMID 21918640

Effect of screening and management of diabetes during pregnancy on stillbirths

BMC Public Health. 2011 Apr 13;11 Suppl 3:S2.

Syed M, Javed H, Yakoob MY, Bhutta ZA. Source Division of Women & Child Health, The Aga Khan University, Stadium Road, PO Box 3500, Karachi, Pakistan.


BACKGROUND: Diabetes during pregnancy is associated with significant risk of complications to the mother, fetus and newborn. We reviewed the potential impact of early detection and control of diabetes mellitus during pregnancy on stillbirths for possible inclusion in the Lives Saved Tool (LiST). METHODS: A systematic literature search up to July 2010 was done to identify all published randomized controlled trials and observational studies. A standardized data abstraction sheet was employed and data were abstracted by two independent authors. Meta-analyses were performed with different sub-group analyses. The analyses were graded according to the CHERG rules using the adapted GRADE criteria and recommendations made after assessing the overall quality of the studies included in the meta-analyses. RESULTS: A total of 70 studies were selected for data extraction including fourteen intervention studies and fifty six observational studies. No randomized controlled trials were identified evaluating early detection of diabetes mellitus in pregnancy versus standard screening (glucose challenge test between 24th to 28th week of gestation) in pregnancy. Intensive management of gestational diabetes (including specialized dietary advice, increased monitoring and tailored dietary therapy) during pregnancy (3 studies: 3791 participants) versus conventional management (dietary advice and insulin as required) was associated with a non-significant reduction in the risk of stillbirths (RR 0.20; 95% CI: 0.03-1.10) ('moderate' quality evidence). Optimal control of serum blood glucose versus sub-optimal control was associated with a significant reduction in the risk of perinatal mortality (2 studies, 5286 participants: RR = 0.40, 95% CI 0.25- 0.63), but not stillbirths (3 studies, 2469 participants: RR = 0.51, 95% CI 0.14-1.88). Preconception care of diabetes (information about need for optimization of glycemic control before pregnancy, assessment of diabetes complications, review of dietary habits, intensification of capillary blood glucose self-monitoring and optimization of insulin therapy) versus none (3 studies: 910 participants) was associated with a reduction in perinatal mortality (RR = 0.29, 95% CI 0.14 -0.60). Using the Delphi process for estimating effect size of optimal diabetes recognition and management yielded a median effect size of 10% reduction in stillbirths. CONCLUSIONS: Diabetes, especially pre-gestational diabetes with its attendant vascular complications, is a significant risk factor for stillbirth and perinatal death. Our review highlights the fact that very few studies of adequate quality are available that can provide estimates of the effect of screening for aid management of diabetes in pregnancy on stillbirth risk. Using the Delphi process we recommend a conservative 10% reduction in the risk of stillbirths, as a point estimate for inclusion in the LiST.

PMID 21501437

Reducing stillbirths: prevention and management of medical disorders and infections during pregnancy

Neonatal morbidity and mortality secondary to premature rupture of membranes

Obstet Gynecol Clin North Am. 1992 Jun;19(2):265-80.

Klein JM.

Department of Pediatrics, University of Iowa, Iowa City. Abstract PROM is one of the most common complications of pregnancy that has a major impact on neonatal mortality and morbidity. The occurrence of PROM is either directly or indirectly responsible for a large number of premature births and the concomitant mortality and morbidity associated with preterm delivery. PROM turns a pregnancy into a high-risk situation and increases the need for neonatal resuscitation in the delivery room. The incidence of neonatal sepsis increases with PROM, but the overall outcome of the neonate, even with surfactant therapy, is still primarily dependent on the gestational age at the time of delivery. This is most relevant between 24 and 27 weeks' gestation. During this 3-week interval, survival improves by almost 2% for each additional day of in utero maturation (i.e., from 35 to 75%). Thus the benefit to the fetus of prolonging the pregnancy in cases of PROM is immensely worthwhile and should be aggressively pursued as long as there is no significant increase in maternal morbidity.

PMID: 1630737 [PubMed - indexed for MEDLINE]