key: cord-1003912-apnvy34e
authors: Hedley, P. L.; Hedermann, G.; Hagen, C. M.; Baekvad-Hansen, M.; Hjalgrim, H.; Rostgaard, K.; Laksafoss, A. D.; Hoffmann, S.; Jensen, J. S.; Breindahl, M.; Melbye, M.; Hviid, A.; Hougaard, D. M.; Krebs, L.; Lausten-Thomsen, U.; Christiansen, M.
title: Preterm birth, stillbirth, and early neonatal mortality during the Danish COVID-19 lockdown
date: 2021-06-12
journal: nan
DOI: 10.1101/2021.06.09.21258622
sha: 8eb9c9f9ad46bfe6774b623a79279b8899c8a985
doc_id: 1003912
cord_uid: apnvy34e

Abstract Importance: Using provisional or opportunistic data, three nationwide studies (The Netherlands, USA, and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, these findings have been challenged as none of the studies accounted for perinatal deaths. Objective: To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be a result of an increase in number of perinatal deaths; and to assess the impact of extended COVID-19 restrictions on the prevalence of preterm birth and perinatal death. Design: The study is a nationwide Danish register-based prevalence proportion study using detailed data to capture all births (induced abortions were excluded) throughout Denmark. We assessed the prevalence of stillbirth, preterm birth, and early neonatal death. Setting: Population-based study Participants: All singleton pregnancies delivered in Denmark, between February 27, and September 30, 2015-2020. COVID-19 lockdown was studied in 31,164 births and the extended period of COVID-19 restrictions in 214,862 births. Exposure: COVID-19 restrictions broadly (February 27, to September 30, 2020) or COVID-19 lockdown specifically (March 12, to April 14, 2020). Main Outcome: Prevalence of preterm births, stillbirths and early neonatal deaths across the periods under study. Results: The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period, while perinatal mortality was not significantly different. During the extended period of restrictions, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found. Conclusion and Relevance: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes.

The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the 30 strict lockdown period, while perinatal mortality was not significantly different. During the 31 extended period of restrictions, the extremely preterm birth rate was marginally reduced, and a 32 significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early 33 neonatal mortality rates were found. 34 Conclusion and Relevance: Stillbirth and extremely preterm birth rates were reduced in Denmark 35 during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of 36 these containment and control measures confer an element of protection. The present 37 observational study does not allow for causal inference; however, the results support design of 38 studies to ascertain whether behavioural or social changes for pregnant women may improve 39 pregnancy outcomes. 40 Introduction 42 COVID-19 containment and control policies were implemented worldwide in response to the 43 SARS-Cov-2 pandemic. The preventative and protective measures placed on communities in order 44 to reduce viral transmission created an opportunistic experiment 1 which may add to our future 45 understanding of what causes preterm birth (PTB). 2 A Danish nationwide study first described a 46 dramatic reduction in extremely PTBs (xPTB) during the strict lockdown period. 3 Following this 47 finding, similar reductions in PTBs were reported from the Netherlands, 1 Japan, 4 Italy, 5 48 Tennessee, 6 New York, 7 Israel, 8 and the USA 9 and a report from Ireland described a reduced 49 proportion of very low birth weight babies. 10 However, smaller studies from California, 11 50 Philadelphia, 12 Israel, 13 Spain, 14 and London, 15 as well as a recent nationwide Swedish study 16 51 could not confirm these findings. 52 A recent meta-analysis indicated that during the COVID-19 pandemic high-income countries 53 generally saw a reduction in PTBs and stillbirths, while low-to -middle-income countries (LMIC) 54 saw increases. 17 Notably there are very few reports from LMIC. The conflicting findings can in part 55 be explained by health system inefficiencies and/or an inability to deal adequately with the 56 pandemic. 17 In Nepal, for instance, the number of women giving birth in institutions dropped 57 precipitously. 18 These regional differences are further supported by a prepublication reporting 58 data from 17 countries, 19 where the xPTB rate was reduced between 11 % and 22 % in the 59 European region, and increased by 48 % in China and India. Furthermore, some studies have 60 reported elevated stillbirth rates 5, 13, 15 and a study from Nepal reported an increase in both PTBs 61 and stillbirths during their lockdown periods. 18 62 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint Stillbirths and early neonatal mortality rates were not assessed in the three nationwide studies 63 from The Netherlands, USA, and Denmark 1, 3, 9 . Since PTB rates could be reduced in response to 64 increasing perinatal mortality rates 20 there is a need to assess live birth rates alongside perinatal 65 mortality rates (stillbirth and early neonatal death) during the different periods studied. 66 Accordingly, this study aimed to use data pertaining to all Danish pregnancies and births, captured 67 in the extensive nationwide electronic registers to study the prevalence of PTB, stillbirth, and early 68 neonatal mortality from singleton pregnancies during the first strict lockdown period in Denmark 69 and during the continuous period of COVID-19 restrictions. Furthermore, we describe the 70 stringency of Danish COVID-19 policies and the timeline of their implementation in order to 71 contextualise our findings. 72 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in (Table 1) . 111 However, the xPTB rate was significantly reduced (OR 0.27, 95% CI 0.07 -0.86) while the other 112 PTB groups were not changed (Table 2 ). There were no differences in gestational age dependent 113 stillbirth rates, perinatal mortality and neonatal mortality rates (Table 2) . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint birth rate, for all PTB groups, was not different in 2020 (Table 2) . Furthermore, the proportion of 123 term pregnancies was increased (OR 1.38, 1.29 -1.46), whereas the proportion of late term 124 pregnancies was reduced (OR 0.85, 0.71 -1.01) ( Table 2) . Importantly, the total stillbirth rate was 125 reduced (OR 0.69, 0.50 -0.95), resulting in a corresponding reduction in perinatal mortality (OR 126 0.76, 0.20 -0.98) ( Table 1 ). The very early and early neonatal mortality rates were not different 127 between 2020 and 2015 -2019 (Table 1) .

The monthly combined stillbirth and live birth rates for infants delivered with gestational age 130 between 22+0 and 28+0 weeks (extremely preterm), are illustrated in Figure Using population-based Danish register data, we have documented that the strict lockdown period 147 is associated with a ~70 % reduction in singleton xPTBs, while no difference was noted for the 148 other PTB groups (Table 2 ). This result is compatible with the previously reported ~90 % reduction 149 in xPTBs assessed from the Danish Neonatal Screening Biobank (DNSB), 3 taking into account that 150 three out of four extremely preterm infants died during the first day of life (very early neonatal 151 death) -precluding their appearance in the DNSB (Table 1 ). The proportion of very PTBs was 152 slightly, ~20 %, reduced, but there is no evidence for a protective effect of the lockdown in this 153 group. It is important to note that the reduction in xPTBs during the lockdown period does not 154 appear to be mirrored by an increase in stillbirths (Table 1 & perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint stillbirth rate does not account for the reduction in xPTBs during the Danish lockdown and is itself 183 reduced as a possibly unintended beneficial consequence of the COVID-19 restrictions generally. 184 The reduction in combined extremely preterm stillbirth and live birth rates is statistically 185 significant in February and March, while the increase in May and June is not (Figure 3 ). This seems 186 to reflect that the improvement in perinatal health started prior to the lockdown, during which (Table 1) . Early, and very early, neonatal mortality was not changed during these periods 192 (Table 1) 53 We cannot exclude that the 227 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint psychosocial and behavioural changes during lockdown, i.e., more people working from home, 228 could have affected the risk of xPTB in specific groups of pregnant women. 229 The observational nature of this study precludes causal inference, but the sizeable effect on the 230 xPTB rate indicates that it will be worthwhile to identify the elements of the lockdown that have 231 conferred this unintended protective effect regarding xPTB. One might speculate that it will be 232 possible to identify a specific psychosocial phenotype in mid-pregnancy that may benefit from 233 specialised care. However, the complex causality of PTB 30 suggests that defining controllable 234 protective factors will require a cross-disciplinary effort. 235 The use of national registers allowed us to examine all Danish pregnancies, thus avoiding selection 236 bias and allowing us to provide a complete assessment of birth and mortality rates. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted June 12, 2021. ; https://doi.org/10.1101/2021.06.09.21258622 doi: medRxiv preprint 

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