COVID‐19‐related medicine utilization study in pregnancy: The COVI‐PREG cohort

The objective of this study was to describe the use of COVID‐19‐related medicines during pregnancy and their evolution between the early/late periods of the pandemic.


Funding information
This research was funded by a grant from the Swiss Federal Office of Public Health. The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, The Netherlands. The project named CONSIGN has received support from the European Medicines Agency under the Framework service contract No. EMA/2018/28/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
Aim: The objective of this study was to describe the use of COVID-19-related medicines during pregnancy and their evolution between the early/late periods of the pandemic.
Methods: Pregnant women who tested positive for SARS-CoV-2 from March 2020 to July 2021 were included using the COVI-PREG registry. Exposure to the following COVID-19-related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti-interleukin-6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID-19 severity level and early/late period of the pandemic (before and after 1 July 2020). intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID-19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period.
Conclusion: Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID-19-related medicines in pregnancy.

| INTRODUCTION
During this unprecedented COVID-19 crisis, pregnant women were particularly at risk of severe disease compared to non-pregnant women of the same age, with up to 9% requiring intensive care unit admission. [1][2][3] Pregnant women were also at higher risk of preterm birth, mostly induced. 2,4 Newborn transmission ranged from 1 to 4% among SARS-CoV-2 positive pregnant women close to delivery, mainly after birth, with exceptional severe adverse neonatal outcome directly caused by the virus. [5][6][7] Repurposed medicines have been proposed to treat COVID-19.
Corticosteroids, remdesivir, anakinra, tocilizumab and other anti-SARS-CoV2 monoclonal antibodies are currently authorized to treat COVID-19 in the European Union. 8 Other medicines have been used off-label, including lopinavir-ritonavir, and high doses of hydroxychloroquine.
Since the beginning of the pandemic, guidelines have drastically changed, as new treatments and data have emerged over time. 9 Additionally, clinical guidelines specifically dedicated to the pregnant women population were drawn from information collected in the general population as most studies excluded pregnant women. 10 Information on the safety of several repurposed medicines to treat COVID-19 in pregnancy is scarce and insufficient to draw conclusions about potential risks.
The use of the anti-interleukin 6 (anti-IL6), tocilizumab and the antiviral remdesivir remains reassuring but extremely limited in pregnant women. 11,12 Corticosteroids have been well studied during the late pregnancy period 13 but first trimester administration raised questions about the potential increased risk of cleft lips and gestational diabetes incidence, but no evidence exists to rule this out. 14 Recommendations for COVID-19 have been drawn from the RECOVERY trial reporting a decreased mortality in the general population requiring oxygen and was first reported on 16 June 2020. 15,16 The use of lopinavir/ritonavir has been studied in pregnant patients outside COVID-19 (e.g., Human Immunodeficiency Viruses or Hepatitis B virus), and no concerns have been raised to date. 17 Chloroquine/ hydroxychloroquine has been used during pregnancy for treating lupus or rheumatoid arthritis with contradictory results regarding birth defects. 18,19 There is insufficient evidence on the safety of the use of ivermectin for treating parasitosis during pregnancy. 20 The majority of observational studies regarding azithromycin use in pregnancy have not found an increased risk of major congenital anomalies. 21 However, due to their lack of efficacy and potential side effects, chloroquine/hydroxychloroquine alone or combined with azithromycin, or ivermectin are no longer recommended for the treatment of COVID-19. 22,23 It is therefore important to assess how pregnant women were exposed to COVID-19-related medicines given the complexity and the evolving evidence and recommendations during this pandemic. In this study, we aimed to describe the use of COVID-19-related medicines during pregnancy from March 2020 until July 2021 using the COVI-PREG international registry. 24 What is already known about this subject • Pregnant women are at high risk of severe forms of COVID-19 leading to higher risks of preterm birth.
• Repurposed drugs have been used to treat COVID-19 even with scarce safety information.
• Pregnant women have been excluded from the majority of COVID-19 clinical trials.

What this study adds
• COVID-19 medicine use in pregnancy increased with disease severity.
• The management of COVID-19 in pregnancy has changed over time, with a decrease in the use of medicines which are no longer recommended, and an increase in the use of corticosteroids, especially for cases requiring oxygen, which is recommended.
• Further studies are urgently needed to assess the effectiveness and safety of COVID-19 medicines in pregnancy.

| Design and settings
This study used the data collected from 24 March 2020 to 1 July 2021 in the COVI-PREG registry database which is a prospective cohort study aiming to assess the impact of SARS-CoV-2 infection in pregnant women and their fetuses/newborns. 24 Pregnant women tested for SARS-CoV-2 during pregnancy, with the exception of those under 18 or declining/not able to consent, were eligible in this multicentre international study. Any health facility with an antenatal clinic or labour ward worldwide was able to contribute to the registry. The study was approved by both the Swiss Ethical Board (CER-VD-2020-00548) and the local ethics boards at each participating centre.     Table S1). Symptomatic treatments defined as any medicine not intended to treat directly COVID-19, such as antipyretic and antithrombotic treatments, were not recorded. No information was available on the timing of COVID-19-related medicine intake.

| Co-variables
Sociodemographic characteristics of patients such as marital status, ethnicity, region of the world and educational level were collected.

| Statistical analysis
Descriptive statistics were used to present baseline demographics and characteristics of the study population. Prevalence of reported medicine use for the COVID-19 event overall and stratified by pregnancy trimesters was categorized by early or late pandemic period, and by severity level of maternal COVID-19. Prevalence of medicine use was defined as the proportion of patients exposed to at least one medication, divided by the total number of included pregnancies. The 95% confidence intervals (95% CI) were calculated for each reported prevalence using the exact Clopper-Pearson method. Statistical analyses were performed using Stata 16 (StataCorp., College Station, TX, USA).

| Exposure to COVID-19-related medicines
A description of patient characteristics with and without exposure to COVID-19-related medicines is presented in Finally, HCQ was used by 1.4% (27/1964) of patients, anti-IL6 (tocilizumab) by 0.3% (5/1964) and no one was exposed to immunoglobulins. Among all medicine categories, antibiotics represented 56.0% The prevalence of exposure to COVID-19-related medicines by pregnancy trimester is reported in Table S4. The proportion of patients who received a COVID-19-related medicine was 6.6% (18/72), 11.2% (70/627) and 10.8% (112/1040) in trimesters 1, 2 and 3, respectively. The prevalence of exposure to COVID-19-related medicines by world regions is presented in Table S5.  Table 3. Individual medicine names are presented in Table S6. When stratified by trimester of infection, 1.5% (4/272) of patients infected in the first trimester required standard oxygen (level 3 or more). This figure increased to 6.9% (43/627) and 6.5% (67/1040) patients in second and third trimester infections, respectively.  Table S7. A description of pregnant patients who tested positive for SARS-CoV-2 over time is presented in Figure S1. COVID-19-related medicine use over time is presented in Figure S2 and shows a decrease in the recorded use of medicines over time. The proportion of patients who received at least one medicine to treat COVID-19 during the early period was higher (16.7%, 95% CI 13.8-20.0) compared to the late period (7.7%, 95% CI 6.3-9.2) ( A stratified analysis by severity of the disease is also reported in

| DISCUSSION
To our knowledge, this is one of the first studies to report use of COVID-19-related medicines among pregnant women who tested positive for SARS-CoV-2. 26 More than 10% of pregnant women in our study population used at least one COVID-19-related medicine.
Despite the lack of robust safety and efficacy information for antivirals in pregnancy, 39 patients (2%) were exposed to this medicine category. Remdesivir, the only antiviral treatment recommended to be used for COVID-19 on a 'case by case' basis according to the NIH 22 and not recommended by the WHO, 23    differed across geographical regions, potentially due to different local protocols for screening and/or patient management. Third, due to its design, this study cannot estimate the safety and efficacy of COVID-19-related medicines among pregnant women and this needs to be urgently assessed in this population at high risk from severe COVID-19.
This study brought evidence that pregnant women were not spared from the COVID-19 pandemic and specific recommendations regarding pregnancy were crucial in this public health crisis situation.
Lessons learned from this pandemic should support the development of rapid clinical practice guidelines specific to this special population in the future. 33

| CONCLUSION
Medicine use in pregnant women was low but increased with the levels of severity of symptoms. The observed decrease in use of medicines that were not recommended for the treatment of COVID-19 after the publication of the first scientific evidence (e.g., antivirals, hydroxychloroquine) and the tendency for an increased use of corticosteroids seem to be aligned with the evolution of guidelines. Finally, there is a large lack of evidence regarding the effectiveness and safety of COVID-19-related medicines in pregnant women, which calls for further and large studies in different settings that are able to stratify by severity.
G.F. and E.G. drafted the manuscript. E.M., M.S. and A.P. critically revised the manuscript. A.P. provided supervision and mentorship.
The COVI-PREG group contributed to data collection. Each author made a contribution in reviewing the manuscript drafting or revision and accepts accountability for the overall work. All authors approved the final version of the report.

DATA AVAILABILITY STATEMENT
Data are available through joint research agreements from the corresponding authors.