Keywords
Stillbirth, cause of stillbirth, useful investigations, minimally invasive tissue sampling, pathology
Stillbirth, cause of stillbirth, useful investigations, minimally invasive tissue sampling, pathology
The views expressed in this article are those of the author(s). Publication in Gates Open Research does not imply endorsement by the Gates Foundation.
Stillbirths are one of the most common adverse pregnancy outcomes in low and middle-income countries (LMIC). In some high-income countries, stillbirth rates of 2–3 per thousand births are seen, while in some LMICs, reported stillbirth rates are 10 to 15-fold higher and may range from 30 to 50 per 1000 births1,2. The Every Newborn Action Plan (ENAP) has set a goal for each country to have a stillbirth rate of <12/1000 births by 20303. Many LMICs appear unlikely to achieve that goal.
In high-income countries, cause of death (COD) in stillbirths has been evaluated using several different methods, 35 by one count4, but because of differences in methodologies, there is still little consensus about the major causes. There is even less consensus about causes of stillbirths in LMICs, in part because until recently, evaluating the causes of stillbirths or reducing stillbirths in those locations has not been a major priority5. In addition, most useful tools to inform cause of stillbirth have not generally been available in many LMICs. The tools that are traditionally used for assigned cause of stillbirth in LMICs, (i.e., verbal autopsy) do not provide an accurate cause of stillbirth6. Thus, until recently, limited data have been available to inform cause of stillbirths in LMICs.
However, given that most stillbirths occur in LMICs, and because of the increased advocacy for reducing stillbirths in LMICs, determining accurate cause of stillbirth has assumed greater importance7. New tools to evaluate the cause of stillbirth, which are feasible in many LMICs, are now available. These tools include minimally invasive tissue sampling (MITS) – a method using needle biopsies to obtain internal organ tissue from deceased fetuses for histology and pathogen identification8–10, and multiplex polymerase chain reaction (PCR) to identify a wide range of pathogens in those tissues11. While the ability to study placental histology has been available for some time, the development and publication of the Amsterdam Criteria in 2016 has provided a useful framework to categorize placental lesions12. In addition, to reduce the bias from individual physician observation, many newer studies on stillbirth cause of death have used an independent panel to assess cause of death13,14.
Given the range of tools now available to inform cause of stillbirth and the limited resources available, we believe the next phase is a determination of which investigations are most informative for stillbirth causation. From a United States’ study of the usefulness of diagnostic tests to determine cause of stillbirth, placental pathology was found to be useful in 64.6% of the cases and fetal autopsy in 42.4%, with other tests far less useful15. Studies from the Netherlands confirm the usefulness of placental pathology in determining COD in the majority of stillbirths16.
More recently, several groups are trying to understand which information, and which specific tests, are useful in determining stillbirth COD in specific LMIC areas17–19. For the purpose of this exercise, we defined ‘useful’ tests as 1) data that are feasible to obtain accurately and 2) data that help determine a cause of death, or 3) help eliminate a cause of death15. One of the challenges to determine the most informative tests is that for many studies, an expert panel is the final arbiter of the cause of death. The specific information the panel has available can vary by project or case, and it is usually not clear which information individual panel members used to develop their opinion on COD, and how this information was used overall by the panels to designate a specific cause of death. Thus, we have summarized some of the main observations of the authors of this commentary from these panel discussions.
Our first observation is that in these studies conducted in LMIC, even under the best of circumstances, there is usually incomplete information available to panel members. The information may be unavailable due to prohibitive costs, because the technology was unavailable, or because the delivery occurred at home, and as a result the full complement of potentially useful information may not have been available to the panel.
In our view, the full complement of information to determine cause of stillbirth, at best, would include information from several domains (Table 1). The first domain is maternal clinical history. Useful information in this domain includes a large variety of maternal conditions and especially hypertension, diabetes, and anemia. The second domain includes obstetric conditions that arise during the prenatal period or during labor and delivery including placental abruption, fetal distress, fetal malposition, and uterine rupture. The third domain includes data describing the placenta. These data would include a gross examination, with special emphasis on infarction and hemorrhage, some measures of placental size or weight compared to a reference standard, histology of the placental body, chorioamniotic membranes, and umbilical cord, focusing on signs of inflammation and malperfusion lesions20. The fourth domain, examination of the fetus, first using external observation, includes measurements and weight. Then, using one of several approaches to examine internal organs is important. These approaches may include full diagnostic autopsy, or more recently, MITS, to obtain internal organ tissue samples for histological examination and pathogen PCR for organism identification. We have found it especially useful to present all available data to the panel using a standard computerized approach21.
Clinical Conditions | Pregnancy conditions | Placental evaluation | Fetal physical and histology evaluation | Polymerase chain reaction (PCR) | |
---|---|---|---|---|---|
Key Elements | Hypertension, Diabetes, Anemia | Abruption, Fetal distress, Fetal malposition Uterine rupture | Gross examination Weight Histology (body, membranes umbilical cord) Inflammation, malperfusion lesions Meconium* | Gross examination Fetal weight Lung histology Meconium* | Placenta Lungs Brain/Cerebral spinal fluid Fetal blood |
Source | Clinical history | Clinical history | Placenta | Physical exam MITS** or Autopsy | Various tissues |
Our next observation is that some of these data are more useful to the panel members than other data. Determining the usefulness of information is critical since a low-cost and efficient approach is necessary in order for stillbirth COD investigations to become routinely performed. Based on all available data and observations, several types of data will be most useful. The first of these is the relevant maternal clinical and obstetric history. The second is a careful placental evaluation starting with a gross examination including measurement of placental weight (with a comparison to an accepted standard to define small and large placentas), and including histology of the chorioamniotic membranes, umbilical cord and placental body with a focus on inflammation, hemorrhage and malperfusion. The third is an external examination of the fetus, (including weight in comparison to some standard to determine fetal growth restriction)22 and especially for congenital anomalies. While an approach using MITS will likely miss some internal organ anomalies, this outcome is relatively rare.
Finally, we consider potential data from MITS examinations of internal organ histology and PCR for pathogen evaluation of these same tissues and the placenta. Our first observation is that for organ histology, lungs are the most informative organs, while liver and CNS histology provides the least information. Findings of amniotic fluid debris or meconium in the lung, likely due to fetal gasping, is present in somewhat less than half the stillbirths, and often helped the panels determine a diagnosis of fetal asphyxia23. Regarding microbiological analyses, PCR evaluation of blood, CSF, and brain tissue provided the most information17. Microbiological analysis of the placenta and membranes were also informative, as was the finding of meconium on any examination.
In summary, the most common causes of stillbirth in LMICs based on available reports include fetal asphyxia, infection, and congenital anomalies24. In individual cases, the panels used various types of data to choose one or several conditions as the most likely cause(s) of stillbirth. To define the most useful, efficient, and cost-effective data to collect in LMICs to define stillbirth COD, the authors recommend focusing on the clinical history, the placental evaluation, the external examination of the fetus, and when available, fetal tissue evaluation (obtained by MITS) of lung (focused on histology and microbiology) and brain/CSF and fetal blood (focused on microbiological analysis). We recognize that this approach will not identify some causes of stillbirth, including some genetic abnormalities and internal organ anomalies, but we believe it will identify the most common causes of stillbirth, most of the preventable causes25 of stillbirth, and will be the most cost-efficient approach for use in LMICs.
The authors thank the project staff who collected and analyzed the data discussed in this commentary as well as the families who participated in studies referenced in this report.
PURPOSe Study Investigators: RTI: McClure EM; Columbia University: Goldenberg RL; KLE Academy of Higher Education and Research’s J N Medical College, Belagavi, India: Goudar SS, Dhaded SM, Nagmoti MB, Somannavar MS, Yogesh Kumar S, Harakuni SU: JJM Medical College, Davangere, India: Guruprasad G, Aradhya GH, Nadig, Kusgur VB, Raghoji CR, Siddartha ES, Patil LC, Pujar S, Dhananjaya S, Sarvamangala B, Veena GR, Mangala GK, Rajashekhar SK, Sunilkumar KB, Kulkarni VG, Nagaraj TS, Jeevika MU, Joish UK, Harikiran RR: Aga Khan University: Saleem S, Sunder S, Zafar A, Ahmed I, Uddin Z, Ghanchi N, Mirza W, Jinnah Post Graduate Medical Center: Yasmin H, Bano K, National Institute of Child Health; Raza J, Prakash J, Haider F.
ISGlobal/CaDMIA Plus Study Investigators: ISGlobal: Ordi J, Rakislova N, Bassat Q, Menéndez C, Martínez MJ, Maixenchs M, Hurtado JC, Marimón L, Navarro M, Casas I; Maputo Central Hospital: Carla Carrilho C, Ismail MR, Fernandes F, Lorenzoni C, Lovane L, Luis E; Centro de Investigaçao em Saude de Manhiça: Mandomando I, Macete E, Nhampossa T, Munguambe K, Cossa A, Chicamba V.
The CHAMPS Network Investigators: Blau D; CHAMPS Bangladesh: El Arifeen S, Gurley E; CHAMPS Ethiopia: Assefa N, Scott JA; CHAMPS Kenya: Onyango D, Akelo V; CHAMPS Mali: Sow S, Kotloff K; CHAMPS Mozambique: Bassat Q, Mandomando I, CHAMPS Sierra Leone: Jambai A, Ogbuanu I: CHAMPS South Africa: Madhi S
The MITS Surveillance Alliance Investigators: RTI International: Goco N, Paganelli C, Aceituno A, Parlberg L, Plotner D; ISGlobal: Ordi J, Centers for Disease Control Infectious Disease Pathology Branch: Martines R, Ritter J; Ohio State University: Clark S; CHAMPS Program Office: Blau D, Whitney C; University of Nairobi: Walong E.
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Is the rationale for the Open Letter provided in sufficient detail?
Yes
Does the article adequately reference differing views and opinions?
Yes
Are all factual statements correct, and are statements and arguments made adequately supported by citations?
Yes
Is the Open Letter written in accessible language?
Yes
Where applicable, are recommendations and next steps explained clearly for others to follow?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Public health, infectious diseases, immunization and vaccines.
Is the rationale for the Open Letter provided in sufficient detail?
Yes
Does the article adequately reference differing views and opinions?
Yes
Are all factual statements correct, and are statements and arguments made adequately supported by citations?
Yes
Is the Open Letter written in accessible language?
Yes
Where applicable, are recommendations and next steps explained clearly for others to follow?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Low and middle income countries, perinatality, children, epidemiology, cause of death, infectious disease, precarity
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | ||
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Version 1 04 Jul 23 |
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Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
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