Understanding causes of stillbirth: moving in the right direction
Authors: Elizabeth M McClure, Robert L Goldenberg
Journal: The Lancet Global Health (2019)

Stillbirth is an important adverse pregnancy outcome, especially in low-income and middle-income countries (LMICs). The challenges in ascertaining the incidence of stillbirth and in classifying its causes in low-resource settings have been well documented.1Reinebrant HE Leisher SH Coory M et al.Making stillbirths visible: a systematic review of globally reported causes of stillbirth.BJOG. 2018; 125: 212-224Crossref PubMed Scopus (95) Google Scholar, 2Goldenberg RL Muhe L Saleem S et al.Criteria for assigning cause of death for stillbirths and neonatal deaths in research studies in low-middle income countries.J Matern Fetal Neonatal Med. 2018; (published online Aug 23.)DOI:10.1080/14767058.2017.1419177PubMed Google Scholar These challenges include late registration of pregnancy, insufficient prenatal care to assess maternal conditions, and lack of low-cost technologies to evaluate the placenta, conduct an autopsy, or identify harmful organisms. Therefore, to date, the causes of stillbirth in LMICs have been mostly derived from verbal autopsy or clinical symptoms reported by the mother or caregiver,3Alliance for Maternal and Newborn Health Improvement (AMANHI) mortality study groupPopulation-based rates, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: a multi-country prospective cohort study.Lancet Glob Health. 2018; 6: e1297-e1308Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar which can largely overlook the underlying and important conditions contributing to stillbirth. Additionally, no uniform system to classify the causes of stillbirth have been adopted.4Flenady V Wojcieszek AM Ellwood D et al.International Stillbirth Alliance Collaborative for Improving Classification of Perinatal DeathsClassification of causes and associated conditions for stillbirths and neonatal deaths.Semin Fetal Neonatal Med. 2017; 22: 176-185Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar In a prospective observational study published in The Lancet Global Health, Shabir Madhi and colleagues5Madhi SA Briner C Maswime S et al.Causes of stillbirths among women from South Africa: a prospective, observational study.Lancet Glob Health. 2019; 7: e503-e512Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar address the causes of stillbirth in a low-resource setting in South Africa. For 354 stillbirths born to 350 women, the investigators reviewed maternal medical records as well as placental macroscopic and histological examination and fetal blood culture results. Obstetricians individually reviewed cases, using a validated methodology developed by the Stillbirth Collaborative Research Network6Dudley DJ Goldenberg R Conway D et al.A new system for determining the causes of stillbirth.Obstet Gynecol. 2010; 116: 254-260Crossref PubMed Scopus (93) Google Scholar (SCRN), to classify causes of stillbirth. Among the 298 cases with complete samples available, maternal medical conditions (64 [21%] cases; primarily hypertensive disease), infections of the placenta and fetus (58 [19%]), pathological placental conditions (57 [19%]), and obstetric complications (54 [18%]) were the most common causes of fetal death, contributing to roughly equal numbers of stillbirths. Numerous specific bacteria were also implicated, most commonly Enterococcus faecalis (41 [14%] cases) and Escherichia coli (31 [10%]). Only 2 (1%) of stillbirths were attributed to fetal asphyxia. Other stillbirth studies have found different distributions of these causes. Studies in high-income countries, especially from the Netherlands, have attributed up to 65% of all stillbirths to placental causes.7Ptacek I Sebire NJ Man JA Brownbill P Heazell AE Systematic review of placental pathology reported in association with stillbirth.Placenta. 2014; 35: 552-562Crossref PubMed Scopus (99) Google Scholar In other studies from low-resource settings, such as from the Global Network, stillbirths were most commonly (in 46·6% of cases) attributed to intrauterine fetal asphyxia.8McClure EM Garces A Saleem S et al.Global Network for Women's and Children's Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system.BJOG. 2018; 125: 131-138Crossref PubMed Scopus (36) Google Scholar These differences between studies might result from differences in classification rather than any important differences in pathological processes. Events leading to fetal asphyxia often start with a maternal condition such as preeclampsia. Placental lesions such as fibrosis, infarction, or necrosis are present in many cases of preeclampsia. In most cases of preeclampsia that result in fetal death, the final cause of death is asphyxia. However, attribution of the cause of fetal death is somewhat dependent on the focus of the investigation: if one's investigative orientation starts with the mother, the cause of stillbirth will often be attributed to the maternal condition; whereas, if one focuses on the placenta, these stillbirths are more likely to be attributed to a placental condition, as observed in the study from the Netherlands.7Ptacek I Sebire NJ Man JA Brownbill P Heazell AE Systematic review of placental pathology reported in association with stillbirth.Placenta. 2014; 35: 552-562Crossref PubMed Scopus (99) Google Scholar Furthermore, if one focuses on the fetus, many of these deaths would be attributed to asphyxia, as in the Global Network study.8McClure EM Garces A Saleem S et al.Global Network for Women's and Children's Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system.BJOG. 2018; 125: 131-138Crossref PubMed Scopus (36) Google Scholar Although the reasons for the substantial discrepancies between the various studies are clear, these discrepancies create challenges for the global health community's efforts to identify strategies to reduce stillbirths. The discrepancies also highlight divisions in the field itself that can impede progress. Use of more than 30 different systems for classifying causes of stillbirth contributes to the confusion.3Alliance for Maternal and Newborn Health Improvement (AMANHI) mortality study groupPopulation-based rates, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: a multi-country prospective cohort study.Lancet Glob Health. 2018; 6: e1297-e1308Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar Madhi and colleagues' study5Madhi SA Briner C Maswime S et al.Causes of stillbirths among women from South Africa: a prospective, observational study.Lancet Glob Health. 2019; 7: e503-e512Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar adapted an approach developed for the SCRN study in the USA.6Dudley DJ Goldenberg R Conway D et al.A new system for determining the causes of stillbirth.Obstet Gynecol. 2010; 116: 254-260Crossref PubMed Scopus (93) Google Scholar However, that system required one probable cause to be identified, although other contributing causes were noted. The authors did not address how to select a single primary cause when potential maternal, placental, and fetal causes were all present. To reduce confusion, any classification system should report maternal causes if present, placental causes if present, and fetal causes. The new WHO classification of perinatal mortality includes both maternal and fetal causes, but leaves the placental causes within the maternal conditions.9Allanson ER Tunçalp Ö Gardosi J et al.The WHO application of ICD-10 to deaths during the perinatal period (ICD-PM): results from pilot database testing in South Africa and United Kingdom.BJOG. 2016; 123: 2019-2028Crossref PubMed Scopus (44) Google Scholar If the roles of all three potential cause sites are included in the example of preeclampsia, although preeclampsia might have initiated the sequence and would be considered the maternal cause, placental fibrosis, infarction, and necrosis would be considered the placental cause and fetal asphyxia the fetal cause. Limiting causal classification to one of these and making the reporter choose among them would be unnecessary. This study is a large improvement over many cause-of-stillbirth studies already published, especially from LMICs. As the authors note, few, if any, previous studies of cause of stillbirth had placental evaluations, and adequate microbiological testing was rare. Without these tests, in our opinion, ascertaining an actual cause of stillbirth provides, at best, a rough estimate of the causes of death. Because Madhi and colleagues' study included placental histological examinations and microbiological assessments by culture, we now have more insight into the conditions contributing to stillbirths in this region. To expand our understanding of stillbirth further, several ongoing LMIC-based studies are using minimally invasive tissue sampling techniques to obtain pathological specimens from the placenta and multiple fetal organs for histology and microbiology, often using multiplex PCR technology, which will help to further elucidate the causes of stillbirths.10Menendez C Castillo P Martínez MJ et al.Validity of a minimally invasive autopsy for cause of death determination in stillborn babies and neonates in Mozambique: an observational study.PLoS Med. 2017; 14: e1002318Crossref PubMed Scopus (56) Google Scholar Ultimately, to reduce stillbirths worldwide, improved investigations of stillbirth as well as a harmonised approach for evaluating the available information to ascertain the primary causes of these stillbirths are needed. This type of information will be crucial to provide the information that the global health leadership needs to reduce stillbirth rates. We declare no competing interests. Causes of stillbirths among women from South Africa: a prospective, observational studyTargeted investigation of stillbirths (even without fetal autopsy) can ascertain a cause of stillbirth in most cases. Further studies using such investigations are needed to inform the prioritisation of interventions to reduce stillbirths globally. Full-Text PDF Open Access