COVID‐19 and stillbirth: direct vs indirect effect of the pandemic

• DOI: 10.1002/uog.24846
• Publication Date: 2021-12-24T16:04:46Z
• Authors: A. Khalil; H. Blakeway; A. Samara; P. O'Brien
• Keywords: Pandemic

The coronavirus disease 2019 (COVID-19) pandemic has had devastating effects on mortality and morbidity, including in pregnant women. Epidemiological studies have reported an association between COVID-19 stillbirth. Despite the initial conflicting evidence, this is now accepted. Recently, USA Centers for Disease Control Prevention (CDC) that risk of stillbirth was 2-fold higher women with compared to those without (adjusted relative risk, 1.90; 95% CI, 1.69–2.15)1. Among 1 249 634 birth hospitalizations from March 2020 September 2021, rate 13 per 1000 births 6 without. Moreover, during period which Delta variant severe acute respiratory syndrome 2 (SARS-CoV-2) predominant pre-Delta period. A national cohort study published May 2021 a sample size over 340 000 England found occurred more frequently SARS-CoV-2 infection2. Spanish Obstetric Emergency Group study, incidence who infection pregnancy non-infected (10/1347 (0.7%) vs 3/1607 (0.2%); P = 0.023)3. In USA, analysis 406 446 hospitalized childbirth April November (6380 whom tested positive SARS-CoV-2), Premier Healthcare Database, all-payer database encompassing approximately 20% hospitalizations, demonstrated significantly (5 3 births; 0.003)4. recent large India doubling second wave (34 February 2021) first (15 January 2021)5. systematic review effect outcomes evidence increase before pandemic6. analyzing data UK Surveillance System (UKOSS), included admitted hospital 2020, three stillbirths among 247 women, around times (4–5 births)7. than (13.9 births)8. However, June same months did not find any pandemic9. Of note, Global Pregnancy Neonatal (PAN-COVID) registry (1 25 July 2020) American Academy Pediatrics (AAP) Section Neonatal–Perinatal Medicine (SONPM) National Perinatal (4 8 August report stillbirth10. Several reports highlighted direct impact pregnancy. Netherlands, 58 9620 known SARS-CoV-2-infected pregnancies, 7 December resulted stillbirth, according most figures Netherlands System; however, number pregnancies reported11. Studies increased SARS-CoV-2-positive experience infection1–4,12 (Table 1). controversial, several smaller reporting no significant COVID-19. Possible reasons are lack statistical power show difference failure discriminate indirect pandemic, differences access availability healthcare services, whether duration overlapped lockdown, nature severity social restrictions or isolation lockdown. It important consider due pandemic. Direct caused by maternal infection, while resulting changes behavior clinicians observed time-trend likely be combination effects. Although case–control examined primarily may also contributed. An early St George's Hospital London, UK, prepandemic period13. small. Notably, none COVID-1913, raising possibility pathogenesis their explanations include late presentation hesitancy attend fear exposure altruistic desire further over-burden already stretched health service (a subject receiving considerable coverage media at time). ambulance under huge pressure, documented long delays attendance both emergency and, particular, non-emergency callouts2. Many outpatient appointments were converted face-to-face visits virtual (telephone video call) appointments, services reduced across board as staff redeployed help wards14. Postnatal length stay reduced, been proactive discharge leave earlier, either reduce chances nosocomial see loved ones allowed visit hospital15. Melbourne, Australia, restriction measures setting very low levels infection16. follow-up confirmed maternity triage (where seen range concerns, such fetal movements, vaginal bleeding abdominal pain) pandemic17. This pattern reflected nationally internationally. admissions dramatically many present routine appointments18. retrospective substantially lower referred tertiary care19. As extensive public-health campaigning, encouraging people home avoid infection. Public transport made particularly challenging living rural areas19. Women high-risk greater pregnancy-related morbidity Given these would normally receive intensive antenatal care surveillance low-risk they disproportionately disadvantaged reduction attendance. Another possible explanation testing negative time admission rate, asymptomatic earlier stage symptomatic when limited available, case pandemic20. Asymptomatic cases estimated account 25% all cases21. Paradoxically, although non-pregnant counterparts11. result, unaware pregnancy21. likely, given high prevalence worldwide 202022. INTERCOVID Multinational Cohort Study, analyzed 18 countries perinatal 706 1424 controls, much (17.0% 7.9%)23. contributed rise highlight fact likely. Pregnant developing complications COVID-1924; twice counterparts require care, assisted ventilation extracorporeal membrane oxygenation die COVID-1925. Evidence emerging adverse other because itself Wei et al. outcome associated pre-eclampsia; there 'dose–response' relationship, pre-eclampsia26. mechanism underlying unclear; it hypothesized bind angiotensin-converting enzyme receptors, leading dysfunction renin–angiotensin system vasoconstriction27-29. can cause clinical manifestations similar pre-eclampsia, but measurements biomarkers indicated distinguishable distinct pathologies30. gestational diabetes preterm birth, mild COVID-1926. They could systemic inflammatory response SARS-CoV-2, creating suboptimal environment placental growth development. observation yet groups. birth23, 31-36, (mainly medically birth)23. potentially confound stillbirth; iatrogenic reduces underestimation Conversely, baby stillborn, delivered regardless age; therefore, part explained 40 mental worse evidenced mean Edinburgh postnatal depression score6. result felt isolated lacked usual support networks. Maternal disorder factor stillbirth37. understand inequalities highlighted, population, black, Asian minority ethnic groups suffer COVID-1938. Even white million showed disparity widen pandemic39. Table lists key histopathological findings infection40-63. Pulinx (2020)40 15 third trimester that, histology one features vascular malperfusion, abnormal vessels intervillous thrombi41. There malperfusion hypertensive disorders, pre-eclampsia. despite association, whose placenta exhibited only pregnancy-induced disorder41, 64. commonly identified stillbirth48. Placental patients studied. infiltrates longer active though signs malperfusion65. 64 influenced histology66. When control placentae, macro- microscopic morphology. placentae treated antiviral medication, molecular weight heparin, hydroxychloroquine antibiotics delayed villous maturation66. still being researched, so far, available small samples. Further research needed fully contribute (Figure On 16 Joint Committee Vaccination Immunisation (JCVI) released updated guidance advising should offered vaccination age67. based where 169 vaccinated, nearly 100 safety concerns raised indication harm fetus68, 69. government 24 759 received least dose vaccine prior delivery 8-month 202170, 71 (355 299 gave period). 3.35 vaccinated 3.60 unvaccinated significant. Similarly, rates unvaccinated. Prior this, advised having if condition working areas involving SARS-CoV-267. CDC vaccine. 29 31% against COVID-1972. latest uptake 22% 202171. During rollout, prioritized peers age. age giving 30.7 years73. Assuming average invited until younger later (over 18s 2021)69, 74. shielding throughout pandemic75, risks own accumulated. woman, combined outcome, particular COVID-19, suggest doses vaccine, booster high-income population equivalent discussed above, impacted shield. Vaccinating free them shielding, thus reducing restoring women; survey 53% intention getting vaccine76. ongoing77, reassured about supporting encouraged soon possible. increases implications discussed, vaccination. offering induction labor test beneficial, trimester, exists. implication treating rest disorders pregnancy, closer monitoring blood pressure None interventions currently supported robust evidence. Therefore, prospective multicenter urgently needed. often asymptomatic, consideration introduction weekly early. into factors women78, 79, at, of, enable identification facilitating development targeted intervention, ensure appropriate offer strategy need clear, research-backed guidelines best mother achieved. We recently developed internally validated prediction model critical unit women80. secondary two models categorization using death. These used define criteria target prioritize vaccination80. Mechanistic studies, larger investigating will clarify mechanisms occur. mounting association. Once clarified, practice adapted babies mitigated.