On December 9, 2022, the NICHD Stillbirth Working Group of Council (the WG) convened its third meeting. The meeting, which was held virtually, was open to the public; the video recording is available online.
WG Members Present:
- Lucky Jain, M.D., Emory University, co-chair
- Uma M. Reddy, M.D., M.P.H., Columbia University Irving Medical Center, co-chair and representative of the American College of Obstetricians and Gynecologists (ACOG)
- RADM Wanda D. Barfield, M.D., M.P.H., Centers for Disease Control and Prevention (CDC)
- Deborah Conway, M.D., University of Texas Health Science Center at San Antonio
- Carla DeSisto, Ph.D., M.P.H., CDC
- Ada Dieke, Dr.P.H., M.P.H., CDC
- Donald Dudley, M.D., University of Virginia
- Andrew Fullerton, M.P.P., March of Dimes
- Isabelle Horon, Dr.P.H., CDC
- Stephanie Leonard, Ph.D., Stanford University
- Monica Longo, M.D., Ph.D., Maternal-Fetal Medicine Units Network, Pregnancy and Perinatology Branch, NICHD
- Jenna Nobles, Ph.D., University of Wisconsin–Madison
- Tina Pattara-Lau, M.D., Indian Health Service
- Sonja Rasmussen, M.D., M.S., Johns Hopkins School of Medicine
- Jennita Reefhuis, Ph.D., CDC
- Robert M. Silver, M.D., University of Utah Health Sciences Center and representative of the Society for Maternal-Fetal Medicine (SMFM)
- Catherine Vladutiu, Ph.D., M.P.H., Health Resources & Services Administration
- Maeve Wallace, Ph.D., M.P.H., Tulane University School of Public Health and Tropical Medicine
- Monica H. Wojcik, M.D., Boston Children’s Hospital
WG Members Absent:
- CAPT Amanda Cohn, M.D., CDC
- Denise Jamieson, M.D., M.P.H., Emory University
- Diana W. Bianchi, M.D., NICHD
- Joanne Cacciatore, Ph.D., Arizona State University
- Alison Cernich, Ph.D., NICHD
- Katherine Gold, M.D., M.S.W., M.S., University of Michigan
- Drucilla Roberts, M.D., Harvard University
- Hyagriv Simhan, M.D., M.S., University of Pittsburgh
- Joanne Stone, M.D., M.S., Mount Sinai
- Other NICHD staff members
Welcome and Introductions
Diana W. Bianchi, M.D., Director, NICHD
Lucky Jain, M.D., Chair, Department of Pediatrics, Emory University School of Medicine
Dr. Bianchi welcomed attendees to the meeting.
Dr. Jain explained that the meeting’s aim was to hear from experts on the topics in the second half of the WG’s mandate: psychological impact and treatment for mothers following stillbirth and known risk factors for stillbirth.
Task Force Charge and Role of Federal Agencies
Alison Cernich, Ph.D., Deputy Director, NICHD
Dr. Cernich reviewed the mandate of the WG, which NICHD formed in 2022 at the request of the U.S. Department of Health and Human Services (HHS). The WG’s charge is outlined in a House report, and Congress appropriated $750,000 for the WG’s work, which is motivated by the unrelieved burden of stillbirth in the United States. About 24,000 babies are stillborn each year, and the stillbirth rate has remained constant for the last 3 decades. The WG’s composition, also outlined in the House report, includes members from CDC, NIH, specialty organizations, and maternal-fetal medicine specialists. The group is also tasked with providing a report focusing on four areas: current barriers to collecting data on stillbirths, communities at higher risk of stillbirth, the psychological impact and treatment for mothers following stillbirth, and known risk factors for stillbirth.
Dr. Cernich also summarized the roles of the organizations participating in the WG. HHS is a large ecosystem, and each agency plays a role on the issue of stillbirth:
- NIH, an agency of 27 institutes and centers, including NICHD, is the largest funder of medical and behavioral research. NIH’s goal is to fund research that provides the evidence that other agencies can use.
- CDC’s role is to prevent, detect, and respond to diseases and preventable conditions and to respond to public health emergencies. The agency collects epidemiological evidence, conducts surveillance, and develops public health campaigns, such as Hear Her, an effort led by Wanda D. Barfield, M.D., M.P.H. Representatives from two CDC divisions—the National Center on Birth Defects and Developmental Disabilities and the National Center for Chronic Disease Prevention and Health Promotion’s Division of Reproductive Health—are on the WG.
- CDC’s National Center for Health Statistics collects, analyzes, and disseminates health data and statistics, including vital statistics. The center’s staff have considerable expertise with birth certificates and mortality reporting.
- The Health Resources and Services Administration (HRSA) provides healthcare and services to isolated and vulnerable communities and offers training for healthcare professionals. Its programs for training healthcare providers in child and maternal health are often funded through state block grant programs.
- The Indian Health Service (IHS) provides American Indian and Alaska Native communities with comprehensive health services. The IHS collaborates with federal and community resources to optimize patient access to care, whether the care is provided at IHS facilities or at other locations.
In addition, nongovernmental organizations, including ACOG, SMFM, pediatric providers, and the March of Dimes, issue clinical guidelines, ensure access to educational resources and training for both patients and providers, facilitate knowledge sharing, serve as focal points on key topics, and advocate for resources, which government agencies cannot do.
Session I: Psychological Impact and Treatment for Mothers Following Stillbirth
CDC’s Pregnancy Risk Assessment Monitoring System (PRAMS) and Study of Associated Risks of Stillbirth (SOARS) Projects
RADM Wanda D. Barfield, M.D., M.P.H., Director, Division of Reproductive Health (DRH), National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP), CDC
Ada Dieke, Dr.P.H., M.P.H., PRAMS Team, DRH, NCCDPHP, CDC
Dr. Barfield thanked the organizers for the opportunity to talk about DRH’s contributions on the issue of stillbirth and introduced two of her colleagues: Dr. Dieke, an epidemiologist and project officer in the Women’s Health and Fertility Branch, and Carla DeSisto, Ph.D., M.P.H., an epidemiologist on the Perinatal and Infant Health Team in the Maternal and Infant Health Branch. Dr. Dieke introduced CDC’s efforts to use PRAMS and SOARS to listen to and capture the voices of those who have experienced stillbirth.
PRAMS is a population-based surveillance system established in 1987 as part of CDC’s Safe Motherhood and Infant Health Initiative. The current 5-year funding cycle runs through 2025. PRAMS collects information from mothers in 46 states and 4 cities or territories about their experiences before, during, and shortly after a live birth and is thus a source of near-national estimates of many maternal and child health indicators. PRAMS data represent 81% of live births.
Each jurisdiction contacts families when their baby is 2 to 6 months old, for a sample of 1,000 to 3,000 women each year. Data are collected on a range of topics, including preconception and prenatal care, oral health, cigarette and alcohol use, health insurance, physical abuse, breastfeeding, depression, and infant sleep environment. The ninth phase of the PRAMS questionnaire will be released in April 2023 and will include new questions on vaccinations, disability, stressors, blood pressure monitoring, and experiences of discrimination. PRAMS follows a standard data collection protocol, including contact by mail and by phone, to facilitate comparison across sites. Five jurisdictions have also pilot-tested a web module that CDC expects all sites to be using by fall 2023.
PRAMS has also contributed to the study of stillbirth. Its 13-item questionnaire assessing stressors and significant life events was used in a Stillbirth Collaborative Research Network (SCRN) study that identified increased risk of stillbirth associated with such events (PMID: 23531847). From 2012 to 2013, researchers at Emory University used PRAMS methodology to assess the feasibility of data collection following stillbirth; surveillance was conducted through Georgia fetal death certificates (PMID: 27166788). In 2016, CDC funded one PRAMS site, in Utah, for 3 years to develop stillbirth data collection as a new component. Site staff developed questions for SOARS, worked to resolve data collection issues over several years, then collected data from 2018 to 2019. In 2020, Utah’s efforts were funded by a PRAMS partner. In the 2021–2025 CDC funding cycle, the state was the only applicant; data collection from 2021 has been completed, and 2022 data collection is ongoing. Staff in Utah have also helped create similar projects in Ohio and North Dakota, also funded separately. The SOARS questionnaire covers many of the same questions as PRAMS, with the addition of questions about tests and services received in the hospital after the stillbirth and grief and bereavement support.
The success of the Utah SOARS program is due in part to its strong advisory committee, which includes women who have experienced pregnancy loss. The committee provided advice on survey questions and facilitated free provider consultations, which are offered to each patient. The SOARS questionnaire includes questions on decreased fetal movement, whether an autopsy was offered, reasons an autopsy was not done, mental health conditions, and social determinants of health (SDOH) indicators, such as healthcare access, housing insecurity, and incarceration exposure.
Dr. DeSisto led a study in 2018 and 2019 examining the feasibility of introducing SOARS at existing PRAMS sites, based on data collected from about 300 Utah residents who experienced stillbirth (PMID: 33673777). The results showed a higher response rate (58%) for SOARS than for PRAMS (54%). Parents wanted to complete the survey and preferred the option of doing it by mail, not in person or by phone. Even sensitive questions, such as those about what tests were offered and performed, had low nonresponse rates, as did questions closer to the end of the survey. The study demonstrated feasibility for women experiencing stillbirth.
Data from the first year of Utah SOARS (PDF 273 KB) showed that most of the women received support after the stillbirth (such as being given the opportunity to hold their baby or get an impression of the infant’s footprint). Most (97%) were given a chance to ask questions and felt adequately supported by hospital staff in their grief (86%–97%). Fewer (78%) received information on what to do when their breastmilk came in. Although 24% reported that they were not adequately supported by grief counselors at the hospital, more than half (52%) received grief counseling in later months. A majority (56%) who did not receive grief counseling said they felt they did not need it, but 15% felt they were not ready for it, and 14% did not know where to get grief counseling.
CDC will continue to analyze the existing and incoming data. Staff will also consider possible revisions to SOARS questions and continue to monitor data collection, which is now done with REDCap. CDC is also hopeful that other sites can be funded to support stillbirth studies at PRAMS sites.
Dr. Dieke also highlighted the Hear Her campaign, which lists decreased fetal movement as a sign that should prompt women to seek immediate medical care. The Hear Her campaign also encourages partners, providers, and friends to listen to women when they say something does not feel right.
When Birth and Death Collide
Joanne Cacciatore, Ph.D., Professor, School of Social Work, Watts College of Public Service and Community Solutions, Arizona State University
Dr. Cacciatore introduced work on traumatic grief, including the nonprofit organization she founded to support families whose children have died and her farm , featured in the Apple TV series “The Me You Can’t See,” and identified herself as the mother of Cheyenne, who died during birth in 1994. She explored some of the defining experiences of stillbirth, including its psychological and emotional, social and interpersonal, economic, existential and spiritual, and physical aspects.
In terms of stillbirth’s psychological and emotional effects, research has documented many characteristics of traumatic grief and post-traumatic stress disorder (PTSD) with stillbirth, including sudden and unexpected loss, loss of control, and fear. Fear is a core experience in the death of a baby.Childbirth itself can be terrifying, but when the outcome is the death of the baby, the level of terror is exponentially higher. Stillbirth also challenges core assumptions and identity. Fathers and mothers, especially those who lose their first child, wonder whether they can still call themselves parents. They must repeatedly tell acquaintances who ask about the baby what happened. Others in society do not see the child or see them as a parent, and reconciling this with the need to parent the dead child can be a core challenge. Siblings too can struggle with their identity. In their prenatal care, many families are not advised about the possibility of stillbirth, and there is a general reluctance in society to talk about babies dying. Mothers commonly feel guilt and shame (PMID: 28214156), including a sense that their own body was responsible for the death of their child. Rumination is common, and parents may express regrets about their care decisions. They also face substantial stigma . The world believes a parent feels less grief if the child was not yet born than if an older baby or child had died and also makes more general assumptions about grief, such as when it is “time to move on.” These assumptions can be isolating for parents who have experienced a stillbirth, and many withdraw socially. Parents still want to care for their lost baby, and some want to die to be with them. At the same time, the parents may be afraid to share these thoughts because others might think they are not coping or because they fear being hospitalized. Anger and jealousy toward others, even family or friends, who gave birth to a living child are also common (PMID: 11380384).
In social and interpersonal interactions, marital conflict can follow a stillbirth. Research suggests that women who have experienced a perinatal death or the death of an older child had a higher risk of marital dissolution . This is not true for families who experience miscarriage. In addition, each partner’s experience of grief is personal (PMID: 22863238). Stillbirth can also affect parenting style (PMID: 20175019), produce intergenerational trauma, and have other impacts on other children in the family, including influencing the way they cope with their grief and how they see the family birth order and their role within the family. Experiencing the stillbirth of a sibling or being born into a family that has experienced pregnancy loss continues to affect these children as adults, including when they have their own children (PMID: 24499387). Research shows that pressure to move on and other social constraints predict poor psychological and physical outcomes, including more depressive symptoms and poorer overall health (PMID: 25708231). Such pressure can become a cycle as parents try to engage more in their familiar circles and integrate their loss into their daily lives but feel compelled to withdraw by the pressure. Schools, churches, and communities need to learn how to provide better grief support, and there is a need for better pedagogical models to do this.
The economic impacts of stillbirth are significant and can be long-lasting. A Lancet study showed that 10% of parents experiencing stillbirth remain off work for 6 months (PMID: 26794073). Another analysis conservatively estimated that the economic burden of child death in the United States is $1.6 billion per year (PMID: 24588841).
Stillbirth also has a deep existential and spiritual impact. With the death of a baby, a part of the parent dies, too. Parents are wired to nurture their baby, and when the baby dies, they have nowhere to put their maternal or paternal energy. Stillbirth is a challenge to one’s identity and faith. Parents may lose their sense of trust in themselves or their body and wonder what they or their body did wrong. People need to feel safe to talk about these feelings. Giving birth is a seminal human experience, and when it ends in death, parents face an existential conundrum.
Birth is also a significant physical experience, and the body goes through complex changes after birth, whether the baby lives. The fear and pain of labor and childbirth can predict PTSD (PMID: 9585714). In addition, postpregnancy hormones urge the mother to care for and feed the baby, and breastmilk starts to come in. Physical pain can also result from emotional pain—for example, seeing the car seat set up in the car or having to tell everyone expecting the good news of a birth that the baby has died. Such experiences represent the somatic aspects of grief trauma.
To provide effective support, it is important to understand parents’ priorities. Many parents are faced with insensitivity, and there is a general lack of understanding about traumatic grief. Even hospital staff and others providing crisis care and therapists may be insensitive or lack compassion. Parents want people to talk in way that is sensitive and tender. They want people to acknowledge their baby and the death as having as much significance as any other child’s death. In previous decades’ research, stillbirth was grouped with miscarriage and abortion, but this does not reflect people’s actual experiences. Although there may be meaning in families’ loss, it is unhelpful for other people to try to find that meaning for the families. Research also shows that parents do not want their normal grief to be diagnosed as pathological.
Things that do help grieving parents include having unrushed time with the baby. Most states allow families to take the baby home, and there are a growing number of death doulas. Rituals and artifacts, which could be just about anything that the baby touched, are meaningful. Having a compassionate provider and a single point of contact for the parentsalso helps ensure that staff know how to care for people whose baby has just died (PMID: 18077296). Notes on the door, in-hospital rituals, and sensitive language are practical ways to help. The experience can be lonely and terrifying, and having something tangible to hold on to, such as a card, lets parents reflect in their own time. Finding good trauma-informed grief counseling can be challenging. Support groups, mindfulness-based bereavement interventions , meditation, and yoga can be effective intervention for stillbirth (PMIDs: 17877082; 30292774; and 28694991). A recent study showed that having emotional support and active emotional caring from many sources was the most helpful (PMID: 34043716). A surprising result was that most respondents (89%) considered animals one of the best sources of grief support, easily outstripping neighbors (31%), colleagues (32%), faith leaders (40%), family (41%), friends (53%), counselors (57%), and grief support groups (58%–67%). Animals are nonjudgmental, do not need to talk, are always there, provide tactile comfort, and will approach rather than avoid someone who is grieving. They are a witness to grief and alleviate loneliness and isolation. Animals offer a refuge from fears of how other people will respond to their grief. These results show the importance of just being there when there is no fix.
Dr. Cacciatore dedicated her presentation to all of the babies gone too soon. She reflected on the lack of conversation like this one when she lost Cheyenne, thanked NIH for convening the WG, and honored those gathered to advance its important work.
Mental Health After Stillbirth: What Do We Know, and What Are the Gaps?
Dr. Katherine Gold, M.D., M.S.W., M.S., Associate Professor, Family Medicine and Obstetrics and Gynecology, University of Michigan (Psychological Impact and Treatment)
In discussing the challenges of grieving families and the research needs regarding bereavement, Dr. Gold underscored the magnitude of the need, highlighting the fact that the more than 20,000 stillbirths that occur in the United States each year, far outnumber other priority maternal and child health concerns, such as sudden unexpected infant death (3,400 cases per year) and maternal death (700 per year).
Stillbirth is a unique loss, given that two life-changing events happen at once. There is rarely time for anticipatory grief or closure, and the experience can be traumatic not only for patients and families but also for medical staff. Dr. Gold said that bereavement is normal and not a linear process; many families recover after stillbirth, but some struggle. It is important to pay attention to families at the greatest risk of poor outcomes, including those with prior losses, mental health struggles, experiences of interpersonal violence, and poor social support. Stillbirth is unexpected and receiving poor care after their loss can increase families’ trauma.
Dr. Gold introduced her work conducting a population-level survey of mothers in Michigan. Bereaved families, identified from fetal death certificates, were matched with mothers who gave birth to a living child. The researchers found that mental health outcomes were similar among mothers experiencing stillbirth and those dealing with early childhood death and similar by race (PMID: 26258870). After 9 months, these mothers showed a much higher risk for depression, PTSD, anxiety, and social phobia (PMID: 25305711). Mental health is a high-risk area for families after a loss .
Endocrinology and neurobiology research suggests that mental health also affects future reproductive health, including subsequent pregnancies. This connection was further substantiated by an analysis showing that having a mental health diagnosis increased the risk of a subsequent stillbirth or miscarriage, and a finding that emphasizes the importance of emotional support following a stillbirth (PMID: 17484937).
When examining partner relationships over time, the researchers found that half of couples in a relationship were still together 15 years after a live birth (PMID: 20368319). Miscarriage increased the risk of a relationship dissolving in the first 2 years after the loss. There was a 22% increased risk of separation within 10 years of a miscarriage and a 40% increased risk after stillbirth. Struggling relationships are more likely to be at risk for a poor outcome after a pregnancy loss.
Few of the women with a mental health condition in the Michigan stillbirth study sought treatment (PMID: 25305711). Of mothers with a positive screen for a mental health condition, only 42% with depression and 36% with PTSD reported seeking treatment. There were no differences by race in the rates of these disorders, but White women were twice as likely to get treatment (43%) as African American women (20%).
There are serious barriers to health equity in mental health treatment. African American women are less likely to get traditional forms of support, including medication and psychotherapy. Medicaid support to women who receive Medicaid before a child’s birth ends after birth, and the mother may not visit a physician who will look after her mental health or may not have time to go for treatment. Childcare and transportation can pose additional barriers.
Parents experience stillbirth as trauma; it comes as a shock. Certain memories from that experience play over and over in their thoughts, which makes it especially important that providers show sensitivity. Minor missteps can add up. Good care matters clinically, and parents say it matters a lot, but there is little documentation of what types of care hospitals offer. There is a need for research tying specific interactions to data on outcomes.
A survey of bereavement counselors at hospitals of various sizes showed that at only 75% of hospitals is it typical for providers to discuss normal grieving with parents who have experienced a stillbirth. Only 69% offer families the name of someone to contact for follow-up, and about half discuss the impact of loss on fathers (55%) or support options available online (49%). Less than half talk about the increased risk of mental health problems or substance use (48%). Just 43% of hospitals required bereavement training for prenatal clinic nurses; 51% for labor and delivery nurses; and only 14% for physicians. These figures demonstrate a significant gap in research and clinical care.
A separate study examining the emotional impact on providers of delivering babies who die showed that many obstetricians (34%) blame themselves or have a sense of guilt, even when there is no known cause of death. Stillbirth is also the second leading cause of lawsuits against obstetricians, so it can also bring up legal fears: 43% of obstetricians said they worried about disciplinary or legal action. When asked whether they received adequate training to deal with the emotional impact of losses, 53% of providers said yes, but only 29% agreed that their colleagues did. Clearly a large gap between research and clinical care remains and should be addressed.
Priorities for bereavement research include intervention trials for bereavement care and studies that specifically aim to understand the experience of African American women. Recruitment also needs to be reconsidered, given that most studies have recruited participants from support groups (PMID: 21907592) and ultimately end up surveying mostly well-educated White women with private insurance (PMID: 27562824).
Rethinking cohorts to group maternal, infant, and stillbirth outcomes to ensure stronger studies is another priority. There are common causes of death across women who die during birth or labor and babies who die either before or after they are born; considering all three groups together would benefit research. Researchers should also consider how to expand bereavement cohorts to encompass the continuum of loss from early pregnancy to a child’s first year. There are similar grief outcomes with losses between 14 weeks of gestational age and 1 month after birth, and these outcomes differ from those for both early miscarriages and sudden infant death syndrome deaths after the first month. Having NIH communicate clearly about which institute has funding for mental health after stillbirth would also be helpful; researchers have been pointed to, variously, the National Institute of Mental Health, the National Institute of Nursing Research, and NICHD. It would also be helpful to investigate how best to quantify stillbirth’s cost, which at present is not measured well. We need to understand the cost to families and to society when a baby dies—and not just after a baby is born.
Establishing a Rainbow Clinic at Mount Sinai in the Department of Obstetrics, Gynecology, and Reproductive Science
Joanne Stone, M.D., M.S., President of the Society for Maternal-Fetal Medicine (SMFM), Chair of the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology, and Reproductive Science at the Icahn School of Medicine at Mount Sinai
Dr. Stone introduced the work of Mount Sinai’s Rainbow Clinic, which offers pregnancy planning and care for families who hope to have a rainbow child, a baby that someone carries after experiencing a stillbirth. The goal of the clinic is to support women and families, improve the patient experience, reduce fear and anxiety, add to the body of research, and decrease the risk of stillbirth in a future pregnancy with enhanced clinical care and emotional support. In New York City, about 700 stillbirths occur each year. The clinic is modeled on the rainbow clinics in the United Kingdom and was created with considerable patient input. It shares an institutional review board with a U.K. clinic run by Alexander Heazell, M.B.Ch.B, Ph.D .
Distinctive aspects of the clinic include special attention to the heightened anxiety patients often experience, additional prenatal appointments, use of technology for surveillance during the pregnancy, and special training for providers and staff to help them understand patients’ needs, nutritional support, and social work support. Its services are free. Staff learn to be aware of potential triggers that can produce anxiety in patients, such as having an ultrasound technician ask, “Is this your first pregnancy?” or front desk staff question why a patient who schedules weekly prenatal surveillance needs so many appointments.
The concept for the clinic was designed at a meeting in February 2021; the next day, participants finalized their proposal and later that spring met with administrative leadership to discuss logistics. The strategy was finalized, and a funding source was identified later that year. The clinic is open to anyone, regardless of insurance. Funding of about $200,000 per year supports staff to schedule patients, a nutritionist, and a social worker. The nonprofit organization PUSH for Empowered Pregnancy funded the clinic for its first 3 years, and staff hope it will be sustainable after that.
PUSH developed the core curriculum, which includes 6 hours of training for front desk, billing, call center, and medical staff. PUSH offers the curriculum free to any organization opening a rainbow clinic. The clinic staff aim to individualize management and get to the initial cause of the stillbirth. Weekly appointments are scheduled after 20 weeks, with twice-weekly visits after 32 weeks, and counseling on fetal movement is provided.
In many cases, couples have not had genetic testing, and most seem to want it for peace of mind. There is also considerable patient interest in tracking placental volume, and the clinic collects data to determine whether there is any correlation with placental volume after delivery. It is also notable that many clinic patients find it difficult to wait until 39 weeks to deliver. Although the clinic providers agree with the rationale for that guidance, there is often an indication for earlier delivery—for example, because of a mother’s high levels of anxiety.
The clinic also attracts patients who have experienced other pregnancy losses, including recurrent miscarriages or neonatal death. The clinic opened to patients in April 2022, and providers have seen more than 80 patients, with 3 deliveries. Staff are tracking outcomes for future research.
Listening to ongoing feedback from patients is another important element of the clinic’s operations. The clinic has learned that ensuring repeat training and training of new staff is necessary. Patients prefer having the same sonographers to the extent possible. Clinic staff also find they have to translate their antepartum approach to labor and delivery staff, including nurses and technicians, so that patients receive appropriate care through delivery. Steps in that direction include putting rainbow footprints to put on the hospital room door and patients’ rainbow status on electronic whiteboards. To the extent possible, clinic patients are given priority for a private hospital room, and the clinic social worker and a physician visit after delivery. Delivering a healthy baby can bring up all the emotions around what the family lost and be difficult in its own way. Clinic staff also make sure to follow up with the patient within a week. Eliciting feedback from patients is an ongoing process.
Dr. Jain asked what would be required to implement SOARS nationwide and why stillbirth was not included in PRAMS from the start. Dr. Barfield explained that although the participation rate in PRAMS is high, when it was launched, no one knew whether people who had experienced infant loss or stillbirth would respond or whether the questions would be too sensitive. From its inception, PRAMS has been sensitive to infant death, sending condolences as well as incentives before asking birthing people whether they want to participate. Data collection on stillbirth presented additional concerns. CDC does surveillance on maternal mortality and sudden unexpected infant death as well as live births and stillbirth. The components are so closely interrelated that it is important to continue considering how research and data collection could be conducted more broadly. However, acknowledging that despite having common themes, each topic requires different skill sets, expertise for review panels, tools for diagnosis, and research to understand the underlying issues is also key. Dr. Dieke added that CDC has had limited funding for its pilot efforts to expand data collection to include stillbirth. The first pilot was supported with about $100,000. In the current 3-year Notice of Funding Opportunity (NOFO) round, only one site applied for funding. CDC is trying to understand from the site perspective what barriers to applying might exist. Some states have strong committees and would appear to be good candidates; it would be useful to know whether those states are open to applying for the limited CDC funding. Additional funding would also offer an opportunity to expand. Dr. Barfield said that in recent years, it has been “all hands on deck” for the maternal and child health community, limiting the capacity of some states to implement this kind of surveillance.
In a follow-up, Dr. Jain calculated that if PRAMS captures 81% of live births—or about 3 million births annually—conducting similar surveys for 24,000 stillbirths seems like a manageable addition. If it were done as part of a national initiative, states would not need to develop duplicative services. Dr. Barfield said PRAMS is conducted through cooperative agreements between the states or other jurisdictions and CDC. CDC also supports the work of maternal mortality review committees, pregnancy mortality surveillance, and SUID data collection; given additional resources, expanding PRAMS data collection to include stillbirth is a potential opportunity. It will be important to think carefully about jurisdictions with limited capacity and how to ensure that PRAMS has diverse representation. Barriers to a more diverse cadre of birthing people participating in surveys include trust and access. Any new effort would need to make sure that no groups are left behind.
Uma Reddy, M.D., M.P.H., noted that making progress requires an in-depth investigation of why stillbirth happens. This effort will require pulling together fetal death records, chart data, SOARS-like questionnaires, lab testing, and interviews with mothers and families.
Dr. Jain reflected on paternal grief as an underappreciated topic and asked how the WG can address it too. Dr. Gold noted that data on paternal grief has emerged in only in the last 5 to 10 years. In general, the data suggest that men and women have different grief and forms of expressing it. Women tend to have more prolonged outcomes. Identifying those fathers who are most at risk of poor outcomes will be important; those individuals are likely to also have risk factors such as mental health issues, prior traumatic loss, or experience of an unanticipated death. But few hospitals are talking with families about paternal grieving or what normal grief looks like. This is a neglected topic, not only for fathers but also for LGBT couples and Black women.
Monica Longo, M.D., Ph.D., asked how fetal movement could be evaluated as a risk factor without a good evidence base. Dr. Barfield explained that fetal movement is highlighted in the Hear Her campaign not as a definitive sign that something of concern is going on with the pregnancy but as an issue that is important for providers to be aware of. The Hear Her campaign is about women who seek help but are ignored, whether the issue is swollen feet, a headache, or a lack of fetal movement. Listening is essential. Many pregnant people return to the emergency room several times because of concerns about their baby’s movement. Dr. Stone added that providers cannot just dismiss pregnant people’s concerns and say that there is no evidence to back up claims about fetal movement. Offering support for these concerns is one way to build trust. Prospective studies to generate more information so providers can understand patterns better are also needed. Dr. Dieke noted that there are questions about fetal movement in the SOARS survey, but they are asked after a stillbirth has happened. Dr. Gold added that in her experience as a provider at a free clinic in Detroit, patients sent to the hospital with a specific concern are often turned away because of a lack of insurance or because their child is with them. Empowering patients to keep speaking up through campaigns like Hear Her is crucial.
Dr. Longo asked what research questions need to be asked in order to build better educational and training modules for providers on how to comfort grieving families and provide emotional support. Dr. Gold recommended using parents’ experience to train healthcare professionals: Hearing what was helpful and what was painful directly from parents can be persuasive; otherwise, physicians, midwives, and nurses may have trouble understanding their impact or knowing what is needed or helpful. It is telling that 10% of hospitals did not have a marker on the door to indicate a rainbow family; in such a situation a provider could easily walk in and offer congratulations. Facilities need to make training based on parents’ voices more common.
Dr. Jain asked Robert M. Silver, M.D., to comment on SOARS and how it has affected the psychological impact of stillbirth on mothers. If SOARS were to be modified, what changes should be made? Dr. Silver said that SOARS is useful for collecting epidemiological data and getting information that cannot be obtained from vital statistics or medical records; speaking to its effect on psychological impact is harder. Utah offer SOARS participants a no-cost consultation after a stillbirth, when staff can address psychosocial needs and make referrals. It could be improved if there were a way to make sure everyone who needed additional psychosocial support services was offered them.
Dr. Jain asked how many obstetric programs nationwide do predelivery depression screening to help predict potential postpartum issues. Dr. Silver said his assumption was that virtually every obstetric clinic in the United States does depression screening. At his clinic, it is done at every visit. Dr. Stone said that in the general obstetrics department at Mount Sinai, each patient is screened, but the screening is not repeated at every visit. Screening is also conducted after delivery. Medicaid requires screening at different time intervals, but despite its value, commercial insurance often does not require it. Providers need to do better in terms of compliance. Dr. Silver said that screening is best assigned to nurses and medical assistants; doctors do it less consistently. Dr. Reddy said that at her facility, screenings are done at the patient’s prenatal visit, at 18 weeks, and in the third trimester. She talked about the impact of a 2007 meta-analysis Dr. Gold published assessing what families value in bereavement care (PMID: 17470598). It is a model for what should be implemented. The extraordinary level of detail in the paper left a strong impression because it was so unprecedented. Families described how meaningful it was to have footprints or photos of their babies or to have a picture of twins taken together when one died and the other survived. Despite the number of bereavement training programs, it is important to make sure that all hospitals, not just private or big academic hospitals, can provide that kind of care. Dr. Gold noted that in her survey of services provided at hospitals, she specifically asked about the things families said that they want. She found pronounced differences based on the hospitals’ volume of deliveries. Academic hospitals tended to have more robust bereavement programs, but many low-cost measures could be offered at smaller hospitals. Studying the impact of such measures on families would be valuable.
Dr. Silver asked panelists to comment on whether accepted interventions for PTSD would be applicable for the subset of parents who experience PTSD after a stillbirth, including in subsequent pregnancies. Dr. Stone agreed; she noted that the Rainbow Clinic does not have psychiatrists on staff who could do a formal assessment, but the social worker does assessments and makes referrals as needed. Psychosocial support is so important for these parents because of the trauma they have experienced. Their anxiety level is high, and nothing will reduce it until delivery—yet birth causes them to relive their trauma. Staff at the Rainbow Clinic know that patients want their stillborn child to be recognized. They like it when providers mention the child’s name and know their birthdate, so that information is put into the patient’s chart. The clinic has a list of do’s and don’ts for providers. It is important to educate providers and others who interact with patients about everything that is important for the patients. Dr. Gold said that the last 30 years of research have shown that having high anxiety in the next pregnancy is a normal response, and data show that that anxiety falls after people deliver. PTSD that persists after the birth of healthy child is a more significant concern. There is little research on interventions for PTSD after stillbirth. One study showed no improvement with yoga, and another pilot study found only slight improvement with online support.
Dr. Jain said he found himself revisiting the idea of having a regional or national repository of information that captures all the relevant data so that meaningful associations can be built and tested, and a biorepository established in certain regions. Jennita Reefhuis, Ph.D., added that the research will be valuable if it is population-based, and that can only happen if the data are drawn from a population-based registry. The registry is the starting point, but it must have a foundation of documented causes of death, autopsy results, and information from medical records. The registry would allow researchers to investigate potential causes and do follow-up research to understand the experiences of the registry participants. Dr. Barfield asked other panelists to comment on what setting up a registry would involve, such as training. Getting this information is an art, not a science. Learning will require modeling and becoming familiar with the circumstances of stillbirth. The handoff between obstetricians and providers who oversee these parents’ follow-up care in other primary care settings will need to be considered, given the time needed to identify all of the relevant information. In addition, it is important to both record the experiences of diverse families and ensure the diversity of those who collect and enter data and who are involved in data collection committees. CDC has some relevant experience with data collection on maternal mortality; the maternal mortality review committees are built through community engagement and are diverse. It is important to consider how to build engagement so registry data are more robust. If the participation is not representative, data will be missing, and it will be hard to link the registry to other data sources.
Dr. Jain asked about making stillbirth a reportable event for which data gathering at the hospital level is mandated. Dr. Barfield explained that there are challenges with mandated reporting, including legal restrictions to obtaining data in some states. There is an opportunity for more data collection, but the challenge is in making the information readily available and broadly collected without making it a forced exercise. This will require resources. Data collection requires time, dedication, and training, and it has not been given the attention it deserves. Dr. Reefhuis added that data collection will require infrastructure that is sustained over several years.
Dr. Gold said that, as a researcher, she often looks for big datasets with mental health data and reproductive outcomes, but they are exceedingly rare. Finding a way to include pregnancy status, pregnancy outcomes, and mental health variables in these datasets would advance researchers’ ability to look at big, population-based datasets. Dr. Reefhuis agreed and noted that before the pandemic there had been efforts underway to establish a link between clinical databases with information about mothers and those with data about their babies; revisiting that task is a priority. Dr. Dieke added that CDC aims to make PRAMS data more widely available by providing automated research files so that researchers can download the datasets. There are data about mental health conditions for live birth deliveries, but there is no plan to add fetal deaths to that, because doing so remains a state-based decision. The qualitative data in PRAMS and SOARS can also be mined to assess outcomes.
Session II: Known Risk Factors for Stillbirth
Dr. Longo introduced the second session.
Stillbirth: Risk Factors
Robert Silver, M.D., Chair, Department of Obstetrics/Gynecology, University of Utah (Overview of Risk Factors)
Dr. Silver presented an overview of stillbirth risk factors. He noted that it can be difficult to distinguish between causes and risk factors with certainty because of significant overlap between the two. Although there are some exceptions, risk factors can generally be defined as maternal characteristics associated with stillbirth that are not part of a causal pathway.
The SCRN grouped the many individual causes of death into broader groups (PMID: 22166605). Risk factors are commonly classified into the following categories: maternal, fetal, or environmental. Grouping those factors that can be readily assessed through prenatal testing and those that require additional testing can help with prediction and management. Another useful way is to assess whether risk factors are modifiable (e.g., tobacco use) or not. Risk factors can also be classified for use in prediction, leading to risk stratification and management interventions. Risk factors can provide clues to the pathophysiology of stillbirth. Understanding what contributed to a stillbirth makes it possible to identify a pathway and targets. Another framework is to consider how common each risk factor is (PMID: 16325593). The most common risk factors and those with the highest stillbirth risk contribute more to the public health burden (PMID: 20966697).
Risk factors can also be used to examine pathophysiology in more detail. For example, the stillbirth rate for non-Hispanic Black women is more than double the overall rate. As SCRN research showed, this disparity can be attributed to higher rates of infection and obstetric complications among Black women.
Maternal age can also be a risk factor. A 2006 study showed that the risk of having a stillbirth increases between the ages of 35 and 39 (odds ratio [OR] 1.28, compared with 20- to 34-year-olds) and at 40 and above (OR 1.72) (PMID: 16522422). A recent randomized trial comparing expectant management with induction at 39 weeks for pregnant women 35 or older showed no increased risk for women whose labor was induced . The study, which found that advanced maternal age does not convey increased risk, shows how medical intervention can also alter risk. Even without a basis in evidence, it has become common to conduct nonstress tests and induce at 39 weeks, and this may have reduced risk for older mothers. Given how they can interact with each other, with exposures, and with genetic variation, it is also important to study risk factors in relation to each other.
Tobacco use is the largest preventable cause of stillbirth aside from obesity: It appears to increase the risk of stillbirth by about 50%, with higher exposure linked with greater risk. The risk is mitigated if smoking is stopped in the first trimester. An SCRN study of blood cotinine levels demonstrated a link between higher levels and increased stillbirth risk (PMID: 24463671). Toxicology analysis of the umbilical cord showed increased risk from other drugs, including a nearly threefold increased risk associated with THC (tetrahydrocannabinol).
It is difficult to study alcohol exposure and stillbirth both because there is no good biomarker for alcohol use and because people often do not accurately report how much they drink. A recent Prenatal Alcohol in SIDS and Stillbirth (PASS) Network study indicated increased stillbirth risk among participants who used both alcohol and drugs and a nearly threefold increased risk of late stillbirth associated with smoking and drinking in the first trimester (PMID: 34424306).
About 10% of stillbirths, particularly late fetal deaths, are associated with maternal diseases such as diabetes and high blood pressure, which are potentially preventable. Findings indicating that the risk is especially high at later gestational ages can also help target interventions (PMID: 14710106). Guidance to induce delivery at 39 weeks appears to have had the effect of decreasing stillbirth rates among women who have diabetes.
Cholestasis, which affects up to 2% of pregnancies, can also dramatically increase stillbirth risk. A recent meta-analysis indicated that most women with this condition—typically diagnosed when serum bile acids concentrations are 10 μmol/L or more—do not face an increased risk of stillbirth. However, with bile acids concentrations of 100 μmol/L or more, the risk more than triples (PMID: 30773280). Interventions such as preterm delivery have reduced stillbirths, but it is not clear whether this has done more harm than good. An earlier SCRN study found no association between elevated bile acids and stillbirth (PMID: 24215860).
Previous obstetric complications can also increase the risk of stillbirth in a subsequent pregnancy. The stillbirth rate in people with a previous stillbirth is 0% to 8%. Higher risk is associated with some conditions, including diabetes and antiphospholipid syndrome (APS), earlier or recurrent losses, fetal growth restriction, and being a non-Hispanic Black person. Unexplained stillbirth appears to be associated with a lower risk of recurrent stillbirth. Knowing a patient’s previous history can help when counseling them in a subsequent pregnancy.
Testing is frequently conducted for thrombophilia, a condition that leads to a predisposition for blood clots. Studies indicate thrombophilia can increase stillbirth risk fourfold. However, a prospective Maternal-Fetal Medicine Network study showed that the clotting condition factor V Leiden was not associated with any adverse pregnancy outcome, including pregnancy loss (PMID: 16135581). These conflicting results have not been reconciled. In APS, some antibodies appear to be more strongly associated with stillbirth than others (PMID: 23921873).
Fetal growth restriction is also a major risk factor for stillbirth. It may be possible to improve detection of fetuses that are not growing because of a lack of blood and oxygen and those that are small for other reasons, although improvements in diagnosis have not led to better outcomes (PMID: 26360240).
Anecdotally, reduced fetal movement is widely seen as a precursor of stillbirth. A systematic review found no significant difference in pregnancy outcomes between groups of women who reported decreases in movement and those who did not (PMID: 31923063). In the United Kingdom, the AFFIRM trial found a slight but not statistically significant reduction in stillbirths in a group offered active management of reduced fetal movement (PMID: 30269876). Decreased fetal movement deserves more study. Studies conducted to date may have been underpowered for an outcome as rare as stillbirth, or it may be possible to improve stratification of risk in combination with other factors, such as biomarkers or ultrasound results. Researchers are also pursuing the cerebroplacental ratio as an indicator and looking for better interventions. However, given that decreased fetal movement is common even in healthy pregnancies, fetal movement may turn out not to be a useful indicator.
The possible association of stillbirth and sleep position is controversial. Some studies indicate there is a more than twofold risk when a pregnant person sleeps on their back, and decreased blood flow through the inferior vena cava is a plausible mechanism (PMID: 31193832). Many people are advised to sleep on their side later in pregnancy. However, this risk factor deserves additional study. The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) study showed no association between sleep position and stillbirth (PMID: 31503146).
Using risk factors to determine optimal delivery windows is a promising area of research. Inducing labor can reduce the risk of stillbirth, but it is not always clear how to balance this benefit against the increased risk of prematurity. At 36 or 37 weeks, a 1 in 3 risk of stillbirth is a clear indication for early delivery. However, if the stillbirth risk is 1 in 5,000, early delivery could cause more harm than waiting. Despite many associations with stillbirth, risk factors overall explain little of the variance in stillbirth (PMID: 22166606). Research that targets the entire population could improve methods for identifying patients who are at highest risk. Machine learning/artificial intelligence, ultrasound, and biomarkers could be promising areas of research to improve risk stratification. Markers of placental dysfunction, fetal hypoxia or acidemia, cord compression, and oxidative stress could be useful. The ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management) has shown that delivery at 39 weeks is safe and following that guidance could reduce some stillbirths. However, many recommendations for early induction are based on weak evidence and too often are not individualized. There is an opportunity to develop individualized risk stratification.
Obesity and Stillbirth
Hyagriv Simhan, M.D., M.S., Professor, Department of Obstetrics, Gynecology & Reproductive Science; Executive Vice Chair, Obstetrical Services, University of Pittsburgh
Dr. Simhan addressed stillbirth in the context of obesity, including opportunities for research to improve outcomes. Obesity is an important contributor to the healthcare burden overall and is becoming more common. Segments of the U.S. population that carry the greatest risk of stillbirth also are at increased risk of obesity.
A systemic review and meta-analysis of studies across many populations concluded that every five-unit increase in body mass index (BMI) was associated with a 25% increase in stillbirth risk (PMID: 24737366). Separate research estimated that 8% to 18% of the stillbirth risk, or about 8,000 stillbirths each year, in a set of high-income countries could be attributed to obesity (PMID: 21496916).
Obesity is an important risk factor for cardiovascular disease, metabolic syndrome, diabetes, hypertension, and other conditions that contribute to stillbirth risk. However, obesity has been shown to increase stillbirth risk even when not associated with such comorbidities (PMID: 30983447). Studies of gestational weight gain have given conflicting results. A recent examination suggests that pre-pregnancy weight influences whether there is weight gain or weight loss during pregnancy, and the degree of weight change increases stillbirth risk. For patients with normal weight, overweight, and obesity, the highest stillbirth risk could be attributed to weight loss during pregnancy, but this was not true for patients described as having morbid obesity (PMID: 28969875).
Among women who reported decreased fetal movement, stillbirth risk was greater among patients with obesity (PMID: 29068467). In clinical practice, it is common to assess fetal well-being with a nonstress test. However, obesity may affect administration of the test and the results (PMID: 26960703). Obesity was associated with a longer time to getting a reassuring result from the test (PMID: 35026965). It is important for providers to account for this kind of data when administering these assessments.
Ultrasound is important for assessing fetal age, evaluating fetal anatomy to identify any birth defects, and obtaining reassurance of well-being. Data show that obesity presents technical limitations for ultrasound performance, because when the sound wave passes through more tissue, the image quality decreases, leading to more false positives and false negatives. There are opportunities in research and development for technologies that circumvent or minimize current limitations.
Many adverse pregnancy outcomes, including spontaneous preterm birth, abruption, preeclampsia, and fetal growth restriction, share common risk factors and might have common mechanisms. Similar conditions in one pregnancy might lead to spontaneous preterm birth and to stillbirth in another. With a high population-attributable risk like obesity, which can contribute to many adverse pregnancy outcomes, it would be useful to aggregate shared mechanisms and disaggregate distinct ones in research to better understand both common and rare outcomes. This approach could lead to better diagnosis and prevention.
Accounting for the larger context in which people live and how it affects child health outcomes will also be important. Society and individuals’ communities carry social drivers of health, which can affect individual biology. It is important to keep in mind the conceptual framework of the effects of social context on factors such as obesity and, ultimately, stillbirth risk.
Genomic Contributions to Stillbirth
Monica H. Wojcik, M.D., Newborn Medicine Medical Director, Maternal Fetal Care Center; Attending Neonatologist, Division of Newborn Medicine Division of Newborn Medicine, Boston Children’s Hospital
Dr. Wojcik, a practicing neonatologist and geneticist, gave an overview of the current state of genomic testing. In the literature on the genomics of stillbirth, about 10% to 30% of fetal deaths have been attributed to chromosomal disorders (PMID: 28898573); 10% to 50% of deaths have been attributed to monogenic conditions (PMID: 23215556). SCRN research used a variety of genetic assessments, attributing 18% of stillbirth deaths overall to genetic causes (PMID: 32786180).
Diagnoses identified by genetic testing include multiple malformation syndromes, including trisomies and single gene conditions such as autosomal recessive polycystic kidney disease, skeletal dysplasias, neuromuscular disorders, and cardiac channelopathies (PMIDs: 30293990; 23215556; 32786180; and 33100332).
Identifying such causes of stillbirth through genetic testing is increasingly being referred to as genomic autopsy. This could involve examining the coding regions (exome sequencing) from DNA, blood or tissue samples, or the entire genome to look for disease-causing variants. Coupling these results with clinical phenotyping from traditional autopsy results, photos, or imaging aids with the diagnosis. Genomic sequencing for stillbirth is conducted primarily for research. It is minimally invasive and increasingly cost-effective.
Potential benefits of a genetic diagnosis include understanding the cause of stillbirth for families and providers, being able to identify other family members at risk or prevent recurrence in a subsequent pregnancy and directing public health efforts to reduce stillbirth.
Current testing has several limitations. Sequencing more often occurs when there is suspicion of an underlying genetic condition, possibly leading to ascertainment bias in the research. Larger population-based cohorts are needed to adequately measure genomic determinants of stillbirth. Over time, genetic testing has evolved considerably; tests from 10 years ago could not find conditions that can be detected by current techniques. It is challenging to accurately interpret the results of genetic testing in the perinatal period, especially if there is no structural anomaly or if genetic information from the parents is unavailable. Another challenge is accurately capturing the results of genetic testing and making sure they are reflected in mortality statistics reporting.
In the future, genomic autopsy could be improved by collaboration to increase the size of research cohorts. In the design of future studies, a broad genetic testing approach will help increase the number of conditions that can be identified. Pairing genetic autopsy results with information from traditional autopsies and other sources is crucial for the accurate interpretation of results. It would be helpful to think of genomic sequencing as a standard element of postmortem evaluation and could help prevent stillbirth recurrence. Individually, the conditions detected might be quite rare, but taken together, they represent a common risk. Standard genomic sequencing could also help determine when genetic factors increase risk in combination with certain exposures.
The Placenta in Stillbirth
Drucilla Roberts, M.D., Professor of Pathology, Massachusetts General Hospital; Professor of Pathology, Harvard Medical School
Dr. Roberts shared a catalog of images showing how placental tissue appears after stillbirths due to various causes. She explained that the placenta reveals the most likely cause of death in about one-third of stillbirths; however, placentas are not always sent for examination. Special training is required to examine placentas, and there are few placental pathology experts. The placenta has information that can predict immediate and future maternal or pediatric outcomes.
It is difficult to conduct controlled research on placental pathology in stillbirth because there is no control set of placentas. However, studies indicate that umbilical cord anomalies, including blood clots, and parenchymal anomalies such as inflammation, fetal vascular malperfusion, and retroplacental hematoma are among the most common (PMID: 24402599).
Dr. Roberts reviewed the features of placentas from stillbirths caused by umbilical cord problems, delayed villous maturation, and maternal vascular malperfusion, as well as rarer causes, including abruption, hemorrhage, fibrin deposition, intervillositis, infection, and malignancy or molar pregnancy (PMIDs: 11275018; 30129127; and 29271494). These rarer causes are particularly important because of their high recurrence rate.
The umbilical cord is the weak link in the placenta, and injury to the umbilical cord can lead to a fatal outcome. The cord may appear flat in places, suggesting compression; be abnormally coiled; or have an insertion abnormality (PMID: 23642640). Bruises in the placenta or interruption in blood flow from the fetus, indicating umbilical obstruction, can be detected from histological examination.
With maternal vascular malperfusion, vessels in the placental decidua look similar to those in coronary artery disease. Maternal vascular malperfusion is usually associated with hypertension or diabetes and is characterized by a particularly small placenta. The effect is that the placenta cannot sustain the demands of the fetus, particularly during labor. Often the baby’s death occurs intrapartum.
Answering the what and the how with placental pathology is helpful for families and for providers, offering a chance to get closure and aid in appropriate grieving and care in future pregnancies.
Infectious Causes of Stillbirth
Robert M. Silver, M.D., Chair, Department of Obstetrics/Gynecology, University of Utah (Infection and Stillbirth)
Dr. Silver gave an overview of infection as a cause of stillbirth. Stillbirth can happen when the fetus is infected directly, damaging organs (e.g., with Group B streptococcus [GBS], pneumonia, sepsis) or causing a developmental abnormality (e.g., with rubella, cytomegalovirus [CMV], malaria, parvovirus). Infection can damage the placenta (malaria, syphilis, coronavirus), cause a critical maternal illness that is fatal for the fetus (influenza, polio, coronavirus), or trigger preterm labor, if the infection is in the uterus (ureaplasma, mycoplasma).
It can be tricky to figure out whether infection is the cause of death, even with clinical history, autopsy, and placental histology. In cases of GBS, for example, there may be no histologic evidence of inflammation. Infection may also be a contributing factor, but not the cause of death.
SCRN studies tried to evaluate the epidemiological data to see whether they supported an association between infection and the stillbirth. If an infection appears rarely with live births, it can be more confidently attributed as a cause of stillbirth. The investigator can see whether a dose–response relationship exists. One overarching question to help determine causality is whether the stillbirth would have occurred without the infection. If not, the cause has likely been found. Dr. Silver also listed various criteria for determining whether an infection was the cause of a stillbirth.
Studies conducted in high-income countries attribute 9% to 15% of stillbirths to infection, but infection can cause up to 50% of stillbirths in low-income countries, especially in areas where syphilis or malaria are endemic (PMIDs: 7900505; 1727582; and 22166606). Stillbirths occurring before 24 weeks of gestation are more common (20%) than those at later stages. In addition, data from a U.S. sample indicated that racial and ethnic disparities characterize stillbirths caused by infection.
It is unclear what proportion of stillbirths can be attributed to viral infection, in part because there is no systematic approach for finding this answer and because cultivating viruses is challenging. In addition, even if infection is detected, it may not be the cause (e.g., CMV, coxsackievirus, coronavirus). More than 130 bacterial infections have been associated with stillbirth, including listeria, syphilis, Escherichia coli, GBS, and Bacteroides. Protozoal infection should not be overlooked. Each year, 14 million pregnant women in sub-Saharan Africa are exposed to malaria, doubling their stillbirth risk. The means for preventing many of these infections are available.
It is difficult to prevent infection entirely even in high-income countries, but effective strategies could include screening for syphilis, gonorrhea, chlamydia and GBS screening; providing antibiotics for preterm premature rupture of membranes; vaccination; and public health campaigns about the risks of soft cheeses, uncooked meat, and cat litter. Research on ascending infection is another priority. In addition to these, strategies for low- and middle-income countries should include HIV and malaria prevention and treatment.
Other research priorities include assessment of the microbiome, although this will require the proper collection of tissues to allow for high-quality RNA and DNA extraction. Correlating tests for infection with clinical history and histology, international collaboration, clinical trials, and implementation of stillbirth reduction strategies should also be prioritized.
Dr. Reddy thanked the presenters and reviewed major highlights from the talks. Although there is a lot of research based on detailed investigations of stillbirth, including what risk factors are associated with it, predicting who is at risk of stillbirth is not possible. Ideally, providers would be able to predict who is at high risk and intervene without causing preterm birth. Areas for further investigation include placental biomarkers, isolating placental cells and products of maternal circulation, ultrasounds, and the microbiome. The concept introduced by Dr. Simhan, showing how BMI translates to higher risk of stillbirth through biomarkers, is key. It will also be important to consider the framework of individuals’ social context, including incorporating SDOH in research, to affect physical health as well as inequities in healthcare. Dr. Wojcik showed how important it is do genomic sequencing to understand phenotypes of stillbirth and how that understanding can help in managing pregnancies. Dr. Roberts’ review of placental lesions associated with stillbirth showed how important it is to understand how and why they form to be able to predict them.
Dr. Reddy asked each of the Session II presenters to give their thoughts on where the research needs to go.
- Dr. Silver responded to a question in the chat asking about efforts to assess placental function with imaging. He noted that such efforts have been advanced by the Human Placenta Project, including magnetic resonance imaging (MRI) to assess blood flow and metabolism. He said that he would emphasize biomarkers and ultrasound as future research priorities. Delivery is one tool currently available to clinicians; getting better data on whether delivering at 36, 37, or 38 weeks is optimal, given various combinations of stillbirth risk factors, is a promising area of research. Dr. Reddy noted that a prediction study would require an extremely large cohort and asked what study designs would make such research feasible. Dr. Silver responded that the first trimester has been the holy grail of biomarker prediction and ultrasound assessment. Risk can be modified if it is identified early, but treatments are currently limited to aspirin and progesterone. Delivery at 36 weeks is a relatively understudied approach. It is expensive to do these studies. Approaches to mitigate that cost could include defining a composite adverse pregnancy outcome, given the overlap in the pathophysiology of growth restriction, hypertensive disorders, and stillbirth. Study design also calls for creativity in combining cohorts, too, so that no single entity has to fund it all. Dr. Reddy asked whether such studies would be conducted prospectively. Dr. Silver said an association would first need to be proved in a smaller study, perhaps of a high-risk group. Many things that are not being assessed currently could be assessed with ultrasound. Findings from smaller studies would then justify larger validation research. All of these approaches need to be pursued.
- Dr. Simhan argued that it should be possible to have an impact on a variety of adverse outcomes by appreciating commonalities between them (e.g., of biology or risk factors). A study to do so could be designed—for example, by creating a case-cohort study within a cohort study by oversampling late pregnancy at the time of the adverse outcome. For stillbirth and other late pregnancy adverse outcomes, there is merit in focusing on the late pregnancy period.
- Dr. Wojcik noted how powerful today’s technology is for identifying genetic conditions, especially for nonanomalous pregnancies. Sometimes these diagnoses have implications for future pregnancies. Because of what it could reveal, the genomic aspect should be included in any stillbirth study. Dr. Jain asked whether whole genome sequencing should be done for every stillbirth. Given $1,000 for sequencing each of the 24,000 stillbirths each year, the cost should work out to about $500,000 to $1 million per state. Dr. Wojcik agreed that that is not an enormous amount of money, especially relative to other costs associated with stillbirth. Genome or exome sequencing should be offered as an option, even if not all families want it. Dr. Reddy added that NICHD is funding a study on whole genomic sequencing and trios; getting such data will be an important step to persuade insurers to cover sequencing.
- Dr. Roberts agreed that prenatal diagnosis of placental pathology should be the focus, as has been pursued in the Human Placenta Project. Many things that are possible now are not done routinely (e.g., analysis of the placenta from early ultrasound reports).
- Dr. Silver reiterated that researchers should not look at any one piece of information in a vacuum. Linking the clinical story, histology, whole genome sequencing, and other elements is important. The hope is that increased attention to stillbirth research will lead to multicenter collaboration, which can take the field farther.
- Dr. Jain said that from a research perspective, it would be wonderful to know how many stillbirths are preventable to know where to direct public health interventions. The WG needs to consider where it can be most effective.
Dr. Bianchi thanked the co-chairs, moderator, and speakers. She outlined additional details of the January 5 public listening session. The time allotted for each speaker will be determined by the total number of registrants, so organizations will need to decide whether to identify a single speaker or give several members more limited time to speak. In addition, NICHD encourages written comments to the request for information on developing strategies to strengthen research on stillbirth prevention (NOT-HD-22-054).
NICHD will review the recommendations made at all four WG meetings, and the co-chairs will present the WG’s recommendations to Dr. Bianchi for consideration at the January meeting of the National Advisory Child Health and Human Development (NACHHD) Council. Once the WG submits its written report, NIH will examine current research priorities and programs that address stillbirth to see where they align with the recommendations and where there are gaps. The WG will also share its report with federal colleagues, who can help determine action items in their scope and mission. Given the magnitude of stillbirth, there is a strong case to be made that more should be done.