NICHD Stillbirth Research Information

NICHD’s research goals related to stillbirth include the following:

• Understanding the causes of stillbirths
• Detailing the demographic and population factors related to stillbirth
• Improving understanding and prediction of stillbirth risk
• Improving stillbirth postmortem examination and reporting
• Outlining evidence-based measures to prevent or reduce stillbirth
• Linking in utero developmental phenotypes to gene expression, epigenetic changes, maternal physiology, and environmental exposures
• Improving our understanding of the morphology, function, genetics, and metabolism of the placenta and uterine blood flow
• Improving methods for antenatal diagnosis of placental disease or fetal health conditions that increase the risk of stillbirth

NICHD conducts and supports a broad range of research on stillbirth. Some recent findings from this research include the following:

• An antibody treatment in early pregnancy for women infected with cytomegalovirus does not appear to reduce the risk of infection or death among their newborns.
• Placental disorders are linked to fetal death (PMID: 32238609).
• Gestational and pregestational diabetes may influence stillbirth (PMID: 33156199).
• Stillbirth is associated with gene variations.
• Certain infections are more common than others in cases of stillbirth (PMID: 31764728).
• Sleeping on the back or side through the 30th week of pregnancy does not appear to increase the risk of stillbirth, reduced size at birth, or high blood pressure disorders of pregnancy.
• High blood pressure in the first trimester can increase the risk for stillbirth, preterm birth, and low birth weight.

A large portion of the institute’s support for research on stillbirth is provided through the extramural Pregnancy and Perinatology Branch (PPB), whose interests encompass all research that seeks to improve health outcomes associated with pregnancy, birth, and early infancy. The branch supports the Maternal-Fetal Medicine Units (MFMU) Network, which NICHD established to support well-designed clinical trials in maternal-fetal medicine and obstetrics. The network aims to reduce maternal, fetal, and infant morbidity related to preterm birth, fetal growth abnormalities, and maternal complications and to provide the rationale for evidence-based, cost-effective obstetric practice.

PPB also supports the Global Network for Women’s and Children’s Health Research, which tests cost-effective, sustainable interventions to improve maternal and infant health outcomes, including stillbirth, in resource-poor settings. Other research the Global Network has supported includes finding that women in low- and middle-income countries (LMICs) who were less educated and had less access to antenatal and obstetric care had the highest risk of stillbirth (PMID: 33256783) and that the common causes of stillbirth in LMICs are asphyxia, pre-eclampsia, and hemorrhage (PMID: 28139875).

The Global Network’s FIRST BREATH trial, which was designed to provide skilled birth attendants to babies wherever they are born, became the foundation for the American Academy of Pediatrics’ (AAP) Helping Babies Breathe (HBB) initiative. NICHD was one of several international partners that led this newborn-care education project, which taught health care providers resuscitation techniques and other basics of newborn care for the first minute of life. HBB is now part of AAP’s more comprehensive Helping Babies Survive initiative.

To examine the etiology and epidemiology of stillbirth, PPB supported the Stillbirth Collaborative Research Network (SCRN). Researchers continue to analyze the data from the SCRN to understand more about stillbirth. Some important SCRN findings include the following:

• Researchers analyzing cord blood collected through the SCRN found that the presence and abundance of pathogens causing infection were significantly higher in stillbirths than live births (PMID: 35993728).
• A secondary analysis of the SCRN data found information that might provide insight into specific genetic abnormalities associated with placental dysfunction and stillbirth (PMID: 35876766).
• In a comparison of exposures between women with stillbirth due to placental disease and stillbirth due to other causes, SCRN researchers found that a significant number of stillbirths had a probable or possible cause of death due to placental disease (PMID: 31087311).
• Researchers using whole exome sequencing to map the genes of 246 stillborn infants in the SCRN found a significant link between stillbirth and various genetic mutations.
• SCRN researchers studied records from stillbirths and live births, looking at umbilical cord abnormalities, and found that these abnormalities were an important risk factor for stillbirth (PMID: 32028503).
• Another secondary analysis of SCRN data revealed that, of infection-related stillbirth cases, Escherichia coli, group B streptococcus, and enterococcus species were the most common bacterial pathogens; cytomegalovirus (CMV) was the most common viral pathogen (PMID: 31764728).
• An SCRN study examined the relationship between inflammation, body mass index (BMI), and stillbirth. The study found that inflammation could not account for the higher rates of stillbirth among women with higher BMIs (PMID: 29609190).

Another previously supported PPB initiative was the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network, which investigated the role of prenatal exposure to alcohol in SIDS and adverse pregnancy outcomes, such as stillbirth and fetal alcohol spectrum disorders. A 2021 analysis of PASS data found that drinking alcohol and smoking cigarettes throughout the first trimester of pregnancy was associated with nearly three times the risk of late stillbirth.

The Division of Population Health Research (DiPHR) also conducts research on factors affecting the risk for stillbirth:

• Longitudinal Investigation of Fertility and the Environment (LIFE) Study
  The LIFE Study examines the relationship between ubiquitous environmental chemicals, lifestyle, and human fecundity and fertility, including stillbirth and other pregnancy outcomes.
• Effects of Aspirin in Gestation and Reproduction (EAGeR) Study
  This multisite, randomized, placebo-controlled clinical trial evaluated the effect of daily low-dose aspirin (LDA) on rates of live birth, with a focus on pregnancy loss/miscarriage more than on stillbirth. Overall, this research found that daily LDA did not prevent subsequent pregnancy loss among women with a history of one or two prior pregnancy losses. However, among women who had experienced a single recent pregnancy loss, LDA increased the likelihood of becoming pregnant and having a live birth and reduced the risk of preterm birth. Additionally, researchers who analyzed data from the EAGeR study found that elevated blood pressure before pregnancy may increase the chances for pregnancy loss.
• Consortium on Safe Labor
  This observational study of more than 200,000 deliveries aimed to explore contemporary labor progression and the use of cesarean section. Although stillbirth was not a primary focus of the study, the researchers have collected and published data on risk factors for stillbirth.

In addition to the efforts of PPB and DiPHR, other NICHD organizational units support or conduct research with relevance to stillbirth. For example:

• The Fertility and Infertility Branch (FIB), as part of its portfolio on the mechanisms of fertility and treatments for infertility, supports research on the very early processes in embryonic development that result in aneuploidy, which can cause stillbirth.
• The Maternal and Pediatric Infectious Disease Branch (MPIDB) focuses on HIV and other infectious diseases (including CMV) in pregnant women and children. MPIDB supports research on the effects of antiretroviral drugs during pregnancy on pregnancy outcomes such as stillbirth.
• The Romero Lab (Mechanisms of Disease in Preterm Labor and Complications of Prematurity; Prenatal Diagnosis of Congenital Anomalies) studies intra-amniotic infection and inflammation, vascular disorders, maternal anti-fetal rejection (such as chronic inflammatory lesions of the placenta), cervical disease, and a decline in progesterone action.

• Human Placenta Project (HPP)
  HPP is a collaborative research effort to understand the role of the placenta in health and disease. HPP aims to develop new tools to study the placenta in real time to learn how it develops and functions throughout pregnancy.
• Prevention research
  NICHD conducts and supports research on preventing health problems, including stillbirth.
• Stillbirth Working Group of Council
  NICHD formed the Stillbirth Working Group of Council in 2022 in response to a request from the U.S. Department of Health and Human Services (HHS) to lead a congressionally mandated task force to examine stillbirth in the United States and report its findings back to HHS.