Stillbirths: contribution of preterm birth and size-for-gestational age for 119.6 million total births from nationwide records in 12 countries, 2000 to 2020

Objective To examine the contribution of preterm birth and size-for-gestational age in stillbirths using six ‘newborn types’. Design Population-based multi-country analyses. Setting Births collected through routine data systems in 12 countries. Sample 119,644,788 total births from 22+0 to 44+6 weeks gestation identified from 2000 to 2020. Methods We included 605,557 stillbirths from 22+0 weeks gestation from 12 countries. We classified all births, including stillbirths, by six ‘newborn types’ based on gestational age information (preterm, PT, <37+0 weeks vs term, T, ≥37+0 weeks) and size-for-gestational age defined as small (SGA, <10th centile), appropriate (AGA, 10th-90th centiles), or large (LGA, >90th centile) for gestational age, according to the international newborn size for gestational age and sex INTERGROWTH-21st standards. Main Outcome Measures Distribution of stillbirths, stillbirth rates and rate ratios according to six newborn types. Results 605,557 (0.50%) of the 119,644,788 total births resulted in stillbirth after 22+0 weeks. Most stillbirths (74.3%) were preterm. Around 21.0% were SGA types (PT+SGA (16.0%), T+SGA (5.0%)) and 14.3% were LGA types (PT+LGA (10.1%), T+LGA (4.2%)). The median rate ratio (RR) for stillbirth was highest in PT+SGA babies (RR=78.8, interquartile range (IQR), 68.2, 111.5) followed by PT+AGA (RR=24.5, IQR, 19.3, 29.4), PT+LGA (RR=23.0, IQR,13.7, 29.0) and T+SGA (RR=5.5, IQR, 5.0, 6.0) compared with T+AGA. Stillbirth rate ratios were similar for T+LGA vs T+AGA (RR=0.7, IQR, 0.7, 1.1). At the population level, 21.5% of stillbirths were attributable to small-for-gestational-age. Conclusions In these high-quality data from high/middle income countries, almost three quarters of stillbirths were born preterm and a fifth were small-for-gestational age, with the highest stillbirth rates associated with the coexistence of preterm and SGA. Further analyses are needed to better understand patterns of gestation-specific risk in these populations, and also patterns in lower-income contexts, especially those with higher rates of intrapartum stillbirth and SGA. Funding The Children’s Investment Fund Foundation, 1803-02535 WHAT WAS KNOWN? Stillbirth (pregnancy loss after 22+0 weeks) is a devastating outcome. Global estimates indicating 1.9 million late gestation stillbirths (≥28+0 weeks) worldwide in 2021 underestimate the overall burden. Many of the pathways to stillbirth result in fetal death before term (preterm stillbirth, <37+0 weeks of gestational age). In addition, babies with fetal growth restriction (frequently assessed using the proxy small for gestational age (SGA, <10th centile)) are at higher risk of stillbirth than their appropriately grown peers. Stillbirths are therefore more likely to be low birthweight (LBW, <2,500g). Being large for gestational age (LGA, >90th centile) at term may also be associated with increased risk of stillbirth. WHAT WAS DONE THAT IS NEW? Combining information on gestational age (preterm (PT), or term (T)) and attained size for-gestational-age (small-for-gestational-age (SGA), appropriate-for-gestational age (AGA), large-for-gestational age (LGA)) we defined six ‘newborn types’: four small (PT+SGA, PT+AGA, PT+LGA, T+SGA), one large (T+LGA), and one reference (T+AGA). We compiled livebirth and stillbirth data from 15 high- and middle-income countries as part of the Vulnerable Newborn Collaboration. A total of 119,039,231 livebirths and 605,557 stillbirths ≥22+0 weeks from 12 countries between 2000 and 2020 met the inclusion criteria. We examined the distribution of stillbirths by these ‘newborn types’, and calculated type-specific stillbirth rates and rate ratios. WHAT WAS FOUND? Most stillbirths (74.3%) were preterm, compared to fewer than 1-in-10 (9.0%) livebirths. A fifth (21.0%) of stillbirths were SGA compared to 1-in-20 (5.4%) livebirths. Preterm SGA had 78.8 times higher stillbirth rates compared to term AGA (Rate ratio (RR)=78.8, interquartile range (IQR), 68.2,111.5). Overall, preterm types had a 25 times higher stillbirth rate than term types (RR=25.0, IQR,20.1, 29.5). At the population level, over a fifth of stillbirths (21.5%) were attributable to being SGA, indicating a substantial impact of growth restriction on stillbirth in these settings. 14.3% of stillbirths and 17.5% of livebirths were LGA. There was no evidence of increased stillbirth rates for LGA types. The distribution of these ‘newborn types’ are similar amongst stillbirths and neonatal deaths. WHAT NEXT? Categorisation of all births, including stillbirths, into these ‘newborn types’ was analytically possible using routinely collected data in these 12 upper-middle- or high-income contexts and led to programmatic relevant findings. However, as the majority (98%) of the world’s stillbirths are in low-and middle-income countries, more data are needed to improve understanding of patterns in stillbirths in a wider range of contexts, especially in settings with higher rates of intrapartum stillbirth and those with very high SGA rates such as South Asia. Further analyses, including assessing gestational age-specific risk, could provide more information on pathways to stillbirth and enable targeted interventions to underlying causes such as infection and obstetric complications. When analysing these vulnerability pathways, omitting stillbirths neglects an important part of the burden and its effects on families and society. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Childrens Investment Fund Foundation, prime grant 1803-02535. The funders had no role in the study design, data collection, analysis, interpretation of the data, or the decision to submit for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval London School of Hygiene & Tropical Medicine (LSHTM)LSHTM - Observational / Interventions Research Ethics Committee2285817th May 2021 EstoniaEthics Committee of National Institute for Health Development77009th August 2021 Iran Iran University of Medical Sciences, Tehran, IranIR.IUMS.REC.1400.75821st November 2021 LebanonInstitutional Review Board, American University of BeirutPED.KY.0113th July 2021 MalaysiaMedical Research & Ethics Committee, Ministry of Health MalaysiaKKM/NIHSEC/ P21-718 (4)5the May 2021 MexicoCentre of Investigation in Health Sciences, Anahuac University, Mexico20221431st March 2022 QatarMedical Research Centre, Hamad Medical Corporation, Doha-QatarMRC-01-21-27725th April 2021 Kentland and Wales1. National Information Governance Board 2. Confidentiality Advisory Group of the Health Research Authority 3. Health & Social Care Information Centre (HSCIC), Data Access Advisory Group1. ECC 5-05 (f)/2012 2. 15/CAG/0119 3. DARS-NIC-359651-H3R1P-v5.2. 10th October 2012 and 1st May2015 UK ScotlandPublic Health Scotland20210218-Vulnerable Newborn Measurement30th March 2021 Exemptions (e.g., IRB approval not required for public or aggregate data, existing ethics approval in place, etc) Argentina Denmark Netherlands Sweden Uruguay USA publicly available data from I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sharing and transfer agreements were jointly developed and signed by all collaborating partners. The pooled summary table data generated during the current study are deposited online with data access subject to approval at except for those from countries where data sharing is not permitted.