Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Available medications used as potential therapeutics for COVID-19: What are the known safety profiles in pregnancy

  • Anick Bérard ,

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    anick.berard@umontreal.ca

    Affiliations Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada, Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada, Faculty of Medicine, Université Claude Bernard, Lyon, France

  • Odile Sheehy,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – review & editing

    Affiliation Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada

  • Jin-Ping Zhao,

    Roles Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada

  • Evelyne Vinet,

    Roles Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – review & editing

    Affiliation Faculty of Medicine, McGill University, Montreal, Quebec, Canada

  • Caroline Quach,

    Roles Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – review & editing

    Affiliations Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

  • Behrouz Kassai,

    Roles Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – review & editing

    Affiliation Faculty of Medicine, Université Claude Bernard, Lyon, France

  • Sasha Bernatsky

    Roles Conceptualization, Investigation, Methodology, Validation, Visualization, Writing – review & editing

    Affiliation Faculty of Medicine, McGill University, Montreal, Quebec, Canada

Available medications used as potential therapeutics for COVID-19: What are the known safety profiles in pregnancy

  • Anick Bérard, 
  • Odile Sheehy, 
  • Jin-Ping Zhao, 
  • Evelyne Vinet, 
  • Caroline Quach, 
  • Behrouz Kassai, 
  • Sasha Bernatsky
PLOS
x

Abstract

Background

Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source.

Methods

Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998–2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations.

Results

Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11–3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31–1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01–4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41–2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25–4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00–1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51–4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02–2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02–1.19; 747 exposed cases) exposures were associated with MCM.

Conclusions

Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.

Introduction

Given the changes to the cardiopulmonary and immune systems during pregnancy, pregnant women are at increased risk for severe COVID-19 [13]. In June 2020, the US Centers for Disease Control and Prevention reported that pregnant women with COVID-19 were more likely to be hospitalized and at increased risk for intensive care unit (ICU) admission and receipt of mechanical ventilation compared with non-pregnant women of reproductive age [4]. The World Association of Perinatal Medicine Working Group on COVID-19, with data from Europe, the US, South America, Asia and Australia reported a 0.8% rate of mortality and a 11.1% rate of ICU admissions among infected pregnant women; vertical transmission was negligible [5]. Although vaccination is underway in many countries, pregnant women are often advised against it due to missing data on safety and efficacy during pregnancy. Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. However, given that pregnant women are excluded from these trials, it is important to assess the current safety profile of these drugs in pregnancy. According to the WHO COVID-19, BMJ COVID-19 Hub, JAMA Network COVID-19, The Lancet COVID-19 Resource Center, New England Journal of Medicine COVID-19, and CMAJ COVID-19 registered trials, these medications include dexamethasone, interferon, heparins, angiotensin-receptor blockers (ARB), chloroquine, hydroxychloroquine, azithromycin, oseltamivir, and HIV medications [6].

At present, results from the COVID-19 RECOVERY trial showed that dexamethasone reduced the mortality rates in severe COVID-19 non-pregnant patients requiring oxygen therapy or on ventilator support [7], as the immunosuppressant dexamethasone may be counteracting the effect of the cytokine in immune dysregulated severe COVID-19 patients [811]. Cortisol is critical for embryogenesis, and endogenous fetal glucocorticoid levels remain significantly lower than maternal levels throughout gestation [12,13]; exogenous corticosteroids across the placenta could have adverse developmental effects [14]. Early pregnancy corticosteroid use has been associated with increased risk of orofacial cleft in some [1520], but not in recent studies [21,22]. Furthermore, studies have reported an increased risk of preterm birth or shorter gestational length following oral corticosteroid use during pregnancy among women with autoimmune disease [23,24].

Likewise, in a phase 2 randomized trial, the immunomodulator interferon beta-1b combined with protease inhibitors (lopinavir–ritonavir) and a nucleoside analogue (ribavirin) was superior to lopinavir–ritonavir alone in reducing the duration of the viral shedding, symptom alleviation, and hospital stay in patients with COVID-19 [25].

About 20%–55% of severe COVID-19 patients have laboratory evidence of coagulopathy [26] and the use of anticoagulant therapy with heparin showed to decrease mortality [27]. Heparin in pregnancy is widely accepted and experienced in women with a high risk of thromboembolism and other conditions; in small sample size studies, heparin use during pregnancy has not shown to be putting the fetus at risk [28].

Angiotensin-converting receptors (ACE2) are required for SARS-CoV2 to enter human cells [29,30]. ACE inhibitors and ARBs are often taken as first-line treatment for hypertension [31], which can result in increased ACE2 expression [32], and increased viral load [33]. Thus, the use of ACE inhibitors or ARBs may aggravate the severity or worsen the outcome of COVID-19 [34,35]. Although ACE inhibitors are contraindicated during pregnancy, ARBs continue to be used inadvertently [36]. At present, ACE inhibitors and ARBs have been shown to be associated with major malformations [36], intrauterine growth retardation, renal dysplasia, anuria, renal failure and death [3741].

Chloroquine and hydroxychloroquine are currently used to treat and prevent malaria, as well as treat rheumatic diseases. Although many trials have been done on their effectiveness for the treatment of COVID-19, results are conflicting with anecdotal case reports [4244]. Chloroquine and hydroxychloroquine cross the placenta with a half-life of around 50 days, which could lead to long-term effect during gestation [45]. However, when used for malaria, lupus, or rheumatoid arthritis, hydroxychloroquine was not shown to increase adverse pregnancy outcomes [46]. Other drugs such as azithromycin and oseltamivir, and HIV protease inhibitors indinavir, saquinavir and raltegravir may inhibit the replication of SARS-CoV-2 and have been used in COVID-19 clinical trials [4750]. Antiretroviral therapy, specifically protease inhibitors, use during pregnancy has been associated with increased risk of preterm birth in some studies [5159], as antiretroviral therapy produces immunologic changes [60], and interfering with maintenance of pregnancy [61]. A potential safety signal for an increased rate of neural tube defects in association with dolutegravir use in pregnancy has been identified in the surveillance study in Botswana [62], but not in other studies [6365].

Although immunomodulator dexamethasone and interferon, anticoagulant heparins, angiotensin-receptor blockers (ARB), chloroquine, hydroxychloroquine as well as azithromycin, oseltamivir, and HIV medications are being considered in clinical trials for COVID-19 treatments, their safety in pregnancy need to be determined.

As of now, all these medications have been studied independently in different pregnant populations and not for the treatment of COVID-19 during pregnancy, which makes safety comparisons difficult. Also, these studies would likely not capture pregnant women concomitantly taking more than one COVID-19 potential available treatments, which is highly likely to occur in clinical practice. Finally, different classifications of medication exposure and disease outcomes between studies would lead to imperfect comparisons with regards to safety.

We therefore aimed to quantify the effect of COVID-19 potential available therapeutics, based on the WHO list of registered medication trials, during pregnancy on the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformations (MCM) using real-world data.

Methods

Study cohort

We analyzed data from the Quebec Pregnancy Cohort (QPC), which is a population-based cohort with prospective data collection on all pregnancies covered by the province of Quebec’s universal prescription drug insurance, from 01/01/1998 to 31/12/2015 [66]. Individual-level information for all pregnant women and children are obtained from province-wide databases and linked using unique personal identifiers (S1 Fig). We defined the first day of the last menstrual period (LMP) using data on gestational age, which has been validated against ultrasound measures from each patients’ charts within the QPC [67]. Prospective follow-up is available from 1 year before LMP, during pregnancy, and until 31/12/2015 (S2 Fig).

The QPC data sources include the medical claims database (‘Régie de l’assurance maladie du Québec’ (RAMQ): diagnoses, medical procedures, socio-economic status), Quebec’s outpatient prescription drug insurance database (drug name, start date, dosage, duration), hospitalization archives database (MedEcho: in-hospital diagnoses and procedures, gestational age), and the Quebec birth certificates database (‘Institut de la statistique du Québec’ (ISQ): patient socio-demographics, gestational age, birth weight). Birth weight in ISQ, and MCM and other diagnoses in the RAMQ and MedEcho databases have been found to be valid when compared to patient charts [67,68].

Pregnant women in the QPC were eligible for this study if they were i) more than 18 years old; ii) continuously covered by the Quebec prescription drug insurance for ≥12 months before pregnancy and during pregnancy; and iii) had given birth to a liveborn singleton. This was done because twin pregnancies are at increased risk of adverse pregnancy outcomes regardless of gestational medication exposures. We also excluded pregnancies exposed to known teratogens as described by Kulaga et al. [69] (S1 Table), and those resulting in minor malformations alone or chromosomal abnormalities in the newborns for analyses on MCM. Minor malformations are selectively identified and do not reflect the true prevalence; chromosomal abnormalities are not related to medication use.

Ethics statement.

The study was approved by the Sainte-Justine’s Hospital Ethics Committee. The Quebec “Commission d’accès à l’information” authorized database linkages. All data were fully anonymized before we accessed them, and the Ethics Committee of CHU Sainte-Justine as well as the ‘Commission d’accès à l’information’ waived the requirement for informed consent.

Study medication exposures

Study medications included outpatient filled prescriptions of immunomodulator dexamethasone, interferon for multiple sclerosis (beta-1a, beta-1b, and alfa-2b), antithrombotic heparin and heparin derivatives (enoxaparin, dalteparin, and tinzaparin), ARB (losartan and telmisartan), chloroquine, hydroxychloroquine, azithromycin, oseltamivir, and HIV medications (indinavir, lopinavir/ritonavir, saquinavir and raltegravir). We identified study medication prescription fillings from the Quebec prescription drug insurance database (prescribed over-the-counter medications were also included), using timing of exposure determined by the dispensed date and duration of treatment. Pregnancies were dichotomously defined as exposed within each of the study medication groupings if women had filled at least one study medication during pregnancy or if they had filled a prescription with a duration that overlapped the beginning of pregnancy (yes/no). Pregnant women could use more than one study medications during the gestational period, and thus were considered in each corresponding study medication grouping when that was the case. The exposure time window for analyses on prematurity, LBW and SGA was any time during pregnancy; only first trimester exposure (organogenesis) was considered for analyses on MCM.

Data on prescription fillings have been validated and compared to maternal reports in the QPC; the positive predictive value (PPV) of prescription drug data was ≥87% (95%CI: 70%-100%) and the negative predictive value (NPV) was ≥92% (95%CI: 86%-98%) [70].

Outcomes

Cases of prematurity were identified from the RAMQ and MedEcho databases and defined as deliveries before the 37th week of gestation.

Cases of LBW were identified from the ISQ database as newborns with birthweight less than 2,500g.

Cases of SGA were identified from the MedEcho database (gestational age) and the ISQ database (birth weight and sex) and were defined as birthweights below the 10th percentile for newborns of the same gestational age and the same sex, according to population-based Canadian references [71]. Birth weight in ISQ and gestational age in MedEcho have been found to be valid when compared to patient charts [67,68].

Cases of MCM diagnosed in the first 12 months of life were identified from the RAMQ and MedEcho databases and defined according to ICD-9 and ICD-10 codes (S2 Table), which have been validated against patient charts with high PPV (78.1%) and NPV (94.2%) [68]. All organ systems were considered and high PPV (over 80%) have also been reported for specific MCMs [68], Twelve months after birth was needed to allow for late detection, and validation of early diagnoses.

Statistical analyses

Within the identified study cohort, we conducted 4 case-control analyses to quantify the effect of the study medication exposures during pregnancy on the occurrence of prematurity, LBW, SGA, and MCM. Although case-control analyses were performed within the study cohort, we have included all controls (no control sampling has been done), and therefore, odds ratios (OR) give the same estimate measure as relative risks.

Potential confounders considered for all analyses were: 1) sociodemographic variables on LMP including maternal age, welfare recipients (yes/no), area of residence (urban/rural); 2) maternal chronic comorbidities (in the 12 months before pregnancy and during pregnancy identified by a diagnosis code or a medication-specific filling) including diabetes, asthma, thyroid disorders (see S3 Table for diagnostic and medication codes used); 3) Tobacco, alcohol, and illicit drug use (See S3 Table); 4) Health care utilization including hospitalizations or emergency department visits during pregnancy (yes/no), number of general practitioner visits and specialist visits (12 months pre-pregnancy); 5) Pregnancy related variables including folic acid use (prescribed high dose (>5 mg/d) and prescribed over-the-counter (OTC) dosage only) in the 6-months prior to LMP and during pregnancy (S3 Table), and previous pregnancy (spontaneous or planned abortion, delivery) in the year prior to LMP (yes/no). We also considered whether pregnant women were followed by an obstetrician (yes/no), and if other medications were used during pregnancy (besides the study medications and medication used to identify comorbidities).

Finally, to control for potential confounding by indication, we adjusted for the presence of the following indications during pregnancy (a pregnant women could have multiple comorbidities): malaria (ICD-9 code 084 and ICD-10 codes B50-B54), lupus (ICD-9 codes 695.4, 710.0 and ICD-10 codes L93, M32), arthritis (ICD-9 codes 274, 696.0, 710.3, 710.4, 714 and ICD-10 codes L40.5, M05, M06, M08, M10, M33.10, M33.20), respiratory tract infections and disorders (ICD-9 codes 011.90, 135, 381, 382, 461, 466, 491.21, 503, 518.3 and ICD-10 codes A15.0, D86, H65-H67, J01-J03, J17, J18, J63.2, J44.1, J82), sexually transmitted diseases and urinary tract infection (ICD-9 codes 077, 099.0, 310, 597–599, 614, 616.0 and ICD-10 codes A31, A54-A57, N34, N37, N70-N77), thrombosis and antiphospholipid syndrome (ICD-9 codes 289.81, 415.19, 444, 453 and ICD-10 codes D68.61, I23, I26, I74, I82), skin disorders (ICD-9 codes 202.1, 694.0, 694.4, 695.1, 695.9 codes and ICD-10 codes C84.0, L10, L13.0, L51.1, L53.9), endocrine disorders (ICD-9 codes 245.0, 255.2, 255.4, 275.4 and ICD-10 codes E06.9, E25.0, E27, E83.52), gastro-intestinal disorders (ICD-9 code 555.9 and ICD-10 codes K50, K51), other hematologic disorders (ICD-9 codes 283, 284, 287.31, 287.4 and ICD-10 codes D59, D60, D61, D69.3, D69.59), human immunodeficiency virus (HIV) (ICD-9 codes 042, 043, 044 and ICD-10 code B20), hepatitis B or C (ICD-9 codes 070.2, 070.3, 070.7 and ICD-10 code B18.2), hypertension (ICD-9 code 401 and ICD-10 code I10), influenza (ICD-9 code 487 and ICD-10 codes J09-J11).

All study medication groupings were always included in analyses, which ensured that estimates were adjusted for concomitant study medication use.

The unit of analysis was a pregnancy. Means and proportions for continuous and dichotomous variables were calculated, respectively. Crude and adjusted odds ratios (aOR) with 95% confidence intervals (95%CI) were calculated for each outcome separately. Multivariable generalized estimating equations were used to estimate the association between the study medications and the risk of prematurity, LBW, SGA, and MCM, independently, accounting for clustering by family (mother). All above mentioned potential confounders and covariables were included in all analyses. All statistical analyses were performed using SAS (SAS Institute Inc., Version 9.2, Cary, NC, USA).

Results

Of the 248,787 pregnancies with a delivery within the QPC, 231,075 met inclusion criteria and were considered for analyses; 8,213 pregnancies were exposed to at least one COVID-19 repurposed drug (Fig 1). We identified 182 pregnancies exposed to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 107 to dexamethasone (0.05%), 1,398 to anti-thrombotics (enoxaparin, dalteparin, and tinzaparin, 0.60%), 31 to multiple sclerosis study medications (interferon beta-1a, beta-1b, and alfa-2b, 0.01%), 6,206 to azithromycin (2.70%), 114 to HIV medications (indinavir, lopinavir/ritonavir, raltegravir and saquinavir, 0.05%), 230 to oseltamivir (0.10%), and 24 to the study ARB (losartan and telmisartan, 0.01%) (Fig 1, Table 1).

thumbnail
Fig 1. Cohort selection within the Quebec Pregnancy Cohort.

https://doi.org/10.1371/journal.pone.0251746.g001

Study medication users were slightly older; welfare recipients (33.3% vs. 22.5% in non-users); more likely to use high dose (>5 mg/d) folic acid; more likely to have hypertension, diabetes or asthma; and had a higher prevalence of health services utilization including other medication use (Table 1).

Within the study population, 6.5% (15,032) pregnancies resulted in a premature delivery. Adjusting for potential confounders, dexamethasone (aOR 1.92, 95%CI 1.11–3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31–1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01–4.11; 20 exposed cases) use during pregnancy were statistically significantly associated with an increased risk of prematurity (Table 2A).

thumbnail
Table 2.

A. Association between study medication exposures during pregnancy and the risk of prematurity. B. Association between study medication exposures during pregnancy and the risk of low birth weight (LBW) (birthweigh <2500 grams). C. Association between study medication exposures during pregnancy and the risk of being born small for gestational age (SGA) (birthweight below the 10th percentile for newborns of the same gestational age and same sex). D. Association between study medication exposures during the first trimester of pregnancy and the risk of overall major congenital malformation.

https://doi.org/10.1371/journal.pone.0251746.t002

LBW has been identified in 5.0% (11,606) of newborns. Adjusting for potential confounders including indication for use, anti-thrombotics (aOR 1.72, 95%CI 1.41–2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25–4.90; 21 exposed cases) were statistically significantly associated with an increased risk of LBW (Table 2B).

Nine percent (9.6%, 22,280) of pregnancies resulted in an SGA newborns. Adjusting for potential confounders including indication for use, anti-thrombotics (aOR 1.20, 95%CI 1.00–1.44; 176 exposed cases), and HIV medication use (aOR 2.61, 95%CI 1.51–4.51; 30 exposed cases) were statistically significantly associated with an increased risk of SGA (Table 2C).

Overall MCM were identified in 10,4% (23,991) of pregnancies. Adjusting for potential confounders, dexamethasone (aOR 1.66, 95%CI 1.02–2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02–1.19; 747 exposed cases) use during pregnancy were statistically significantly associated with an increased risk of MCM (Table 2D).

Table 3 presents organ specific defects identified with the use of the study medications. Musculoskeletal defects and circulatory malformations including heart defects were the most prevalent in each of the study medication groups. No orofacial defects were found in newborns exposed to dexamethasone in-utero.

thumbnail
Table 3. Organ-specific malformations stratified by first-trimester exposures to the study medications.

https://doi.org/10.1371/journal.pone.0251746.t003

Discussion

Using the population-based Quebec Pregnancy Cohort, we quantified the risk of adverse perinatal outcomes associated with available medications presently considered as COVID-19 treatments. Indeed, after adjusting for potential confounders including current indications for use, and concomitant COVID-19 potential therapeutic use, we found that anti-thrombotics, mostly heparins, and HIV medication use during pregnancy were associated with the risk of prematurity, LBW and SGA. Dexamethasone was associated with increasing risks of prematurity and MCM; and azithromycin was associated with the risk of MCM.

This study adjusted for all known and measurable potential confounding variables and estimates are comparable given that they emerge from the same source population, health insurance coverage, and access to care.

Our results on dexamethasone are consistent with the literature with regards to prematurity [23,24]. Palmsten et al. [24] showed that oral corticosteroid use during pregnancy was associated with a doubling of the risk of preterm birth in women with rheumatoid arthritis recruited within teratogen information services (MotherToBaby). Early pregnancy corticosteroid use has also been associated with increased risk of MCM [1520] similar to what we have shown. We found no orofacial defect with dexamethasone use as was reported in more recent pregnancy studies [21,22].

Our findings on anti-thrombotics (mostly heparins) use and pregnancy are different from what has been published recently. The increased prevalence of adverse fetal/infant outcomes including death, prematurity and MCM have been reported following heparin use [72]. However, in another more recent study performed by Shlomol et al. [28], no such associations were found within an Israeli cohort of pregnant women. While heparin does not appear to cross the placenta, it may affect embryo and fetal development through interactions with the trophoblast and placental vasculature [73]. Differences between our findings and those from Shlomol et al. [28] could be partly explained by their lack of adjustment for potential confounders such as gestational hypertension and diabetes, indications for heparin use, and lifestyles such as tobacco and alcohol use.

Our findings on the association between indinavir, lopinavir/ritonavir, raltegravir and saquinavir (HIV drugs) use during pregnancy and the risk of prematurity, LBW and SGA [51]; and on chloroquine, and hydroxychloroquine with regards to prematurity, LBW or MCM are also consistent with the literature [46].

We found that azithromycin use was increasing the risk of MCM. A recent population-based cohort study using data from the Clinical Practice Research Datalink in the United Kingdom has shown that use of macrolide antibiotics, including erythromycin, clarithromycin, or azithromycin, during pregnancy was associated with an increased risk of overall major congenital malformations in children [74]. Similarly, a population based cohort study using data from the Swedish Medical Birth Register has shown an association between early pregnancy erythromycin use and infant cardiovascular defects [75].

Strengths and potential limitations

Study strengths include the use of population-based prospective pregnancy cohort with linkage of data at the individual level, which minimized selection and recall biases; this also allowed for analyses on a large number of pregnancies with detailed information regarding exposure, outcomes, and potential confounders. The fact that all potential available medications for COVID-19 treatments were studied within a unique and single population allowed for comparative safety assessments. QPC data on filled prescriptions [70], gestational age [67], birth weight [67], and MCM [67] have all been validated. Adjustment on all known and measurable potential confounders for adverse pregnancy outcomes was made, including maternal comorbidities, indications for medication uses, lifestyles including smoking, alcohol, illicit drug use, and high dose folic acid intake; adjustment was also made on health services utilization, which is considered a proxy for severity of diseases.

One potential limitation is missing information on over-the-counter (OTC) medication use, and use of medications during in-hospital deliveries. Other than for ibuprofen and acetaminophen use and non-prescribed folic acid use, all other medications will be prescribed. It is possible that some women took folic acid OTC. However, this would lead to non-differential misclassification as it is unlikely that those exposed to the study medications would differ in terms of prevalence of folic acid OTC compared to those who were not exposed. Since the databases only include pregnant women insured by the Prescription Drug Insurance program, generalizability of results to those insured by private drug insurance could be affected. However, validation studies have shown that publicly insured pregnant women have similar characteristics and co-morbidities than those who have private medication insurance [76]. We considered filled prescriptions and not actual intake, but Zhao et al. [70] have shown that prescription filling data in the QPC were valid when compared to maternal report. Although health services utilization was adjusted for and considered a proxy for disease severity, residual confounding by severity of disease could remain. Our estimates could be slightly biased upwards since we only considered deliveries in our analyses as is done in the majority of studies on medications and pregnancy. Finally, the MCM prevalence of 10.3% is higher than what is routinely reported (3–5%) [77]. This could be partly explained by the Founders’ effect in the province of Quebec. [78,79]. It can also be partly explained by the fact that we have included all pregnancies between 1998 and 2015, and we have required that all pregnant women and children be insured by the RAMQ public medication insurance program in order to fully measure medication exposures during pregnancy (we only have medication data on those insured by the RAMQ public medication insurance program). This, in addition to the Founders’ effect, could explain the MCM prevalence. Although our baseline prevalence of MCMs is high, it does not differ among our compared groups, and therefore does not invalidate our findings. This, however, could limit the generalizability of our results.

Conclusions

Using the population-based Quebec Pregnancy Cohort, gestational exposure to dexamethasone was associated with an increased risk of prematurity and MCM; azithromycin exposure was associated with the risk of MCM, and exposure to anti-thrombotics (mostly heparins), and indinavir, lopinavir/ritonavir, raltegravir and saquinavir (HIV drugs) use during pregnancy were associated with increased risks of prematurity, LBW and SGA. Although these available medications are being considered as treatments for COVID-19, caution is warranted in pregnancy.

Supporting information

S1 Fig. Quebec Pregnancy Cohort database linkage.

https://doi.org/10.1371/journal.pone.0251746.s001

(DOCX)

S2 Fig. Quebec Pregnancy Cohort outcomes and babies.

https://doi.org/10.1371/journal.pone.0251746.s002

(DOCX)

S1 Table. List of known fetotoxic prescribed medications excluded.

https://doi.org/10.1371/journal.pone.0251746.s003

(DOCX)

S2 Table. ICD-9 and ICD-10 diagnostic codes of major congenital malformations.

https://doi.org/10.1371/journal.pone.0251746.s004

(DOCX)

S3 Table. List of diagnostic codes (ICD-9 and ICD-10) and medications used for the covariates.

https://doi.org/10.1371/journal.pone.0251746.s005

(DOCX)

References

  1. 1. Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010;63:425–33. pmid:20367629
  2. 2. Ramsey PS, Ramin KD. Pneumonia in pregnancy. Obstet Gynecol Clin North Am 2001;28:553–69. pmid:11512500
  3. 3. Rasmussen SA, Kissin DM, Yeung LF, MacFarlane K, Chu SY, Turcios-Ruiz RM, et al. Preparing for influenza after 2009 H1N1: special considerations for pregnant women and newborns. Am J Obstet Gynecol 2011;204:S13–20. pmid:21333967
  4. 4. Ellington S, Strid P, Tong VT, Woodworth K, Galang RR, Zambrano LD, et al. Characteristics of Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status—United States, January 22-June 7, 2020. MMWR Morb Mortal Wkly Rep 2020;69:769–75. pmid:32584795
  5. 5. COVID WWGo. Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection. Ultrasound Obstet Gynecol 2021;57:232–41. pmid:32926494
  6. 6. https://clinicaltrials.gov/ct2/who_table.
  7. 7. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Landary MJ, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv June 22,2020. preprint. pmid:32690491
  8. 8. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe 2020;27:992–1000 e3. pmid:32320677
  9. 9. Johnson RM, Vinetz JM. Dexamethasone in the management of covid -19. BMJ 2020;370:m2648. pmid:32620554
  10. 10. Singh AK, Majumdar S, Singh R, Misra A. Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective. Diabetes Metab Syndr 2020;14:971–8. pmid:32610262
  11. 11. Magro G. COVID-19: Review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus Res 2020;286:198070. pmid:32569708
  12. 12. Brown RW, Diaz R, Robson AC, Kotelevtsev YV, Mullins JJ, Kaufman MH, et al. The ontogeny of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology 1996;137:794–7. pmid:8593833
  13. 13. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term. Pediatr Res 1973;7:509–19. pmid:4704743
  14. 14. Reinisch JM, Simon NG, Karow WG, Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978;202:436–8. pmid:705336
  15. 15. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242–4. pmid:10482873
  16. 16. Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ, National Birth Defects Prevention S. Maternal corticosteroid use and orofacial clefts. Am J Obstet Gynecol 2007;197:585.e1–7; discussion 683–4, e1-7. pmid:18060943
  17. 17. Pradat P, Robert-Gnansia E, Di Tanna GL, Rosano A, Lisi A, Mastroiacovo P, Contributors to the Md. First trimester exposure to corticosteroids and oral clefts. Birth Defects Res A Clin Mol Teratol 2003;67:968–70. pmid:14745915
  18. 18. Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998;58:2–5. pmid:9699238
  19. 19. Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385–92. pmid:11091360
  20. 20. Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. Rheum Dis Clin North Am 2017;43:489–502. pmid:28711148
  21. 21. Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 2011;183:796–804. pmid:21482652
  22. 22. Skuladottir H, Wilcox AJ, Ma C, Lammer EJ, Rasmussen SA, Werler MM, et al. Corticosteroid use and risk of orofacial clefts. Birth Defects Res A Clin Mol Teratol 2014;100:499–506. pmid:24777675
  23. 23. Norgard B, Pedersen L, Christensen LA, Sorensen HT. Therapeutic drug use in women with Crohn’s disease and birth outcomes: a Danish nationwide cohort study. Am J Gastroenterol 2007;102:1406–13. pmid:17437503
  24. 24. Palmsten K, Bandoli G, Vazquez-Benitez G, Xi M, Johnson DL, Xu R, et al. Oral corticosteroid use during pregnancy and risk of preterm birth. Rheumatology (Oxford) 2020;59:1262–71. pmid:31566229
  25. 25. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020;395:1695–704. pmid:32401715
  26. 26. Lee SG, Fralick M, Sholzberg M. Coagulopathy associated with COVID-19. CMAJ 2020;192:E583. pmid:32357997
  27. 27. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094–9. pmid:32220112
  28. 28. Shlomo M, Gorodischer R, Daniel S, Wiznitzer A, Matok I, Fishman B, et al. The Fetal Safety of Enoxaparin Use During Pregnancy: A Population-Based Retrospective Cohort Study. Drug Saf 2017;40:1147–55. pmid:28733971
  29. 29. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450–4. pmid:14647384
  30. 30. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020;581:221–4. pmid:32225175
  31. 31. Whelton PK, Carey RM. The 2017 Clinical Practice Guideline for High Blood Pressure. JAMA 2017;318:2073–4. pmid:29159375
  32. 32. Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens 2015;28:15–21. pmid:24842388
  33. 33. Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 2020;41:1801–3. pmid:32196087
  34. 34. Sommerstein R, Kochen MM, Messerli FH, Grani C. Coronavirus Disease 2019 (COVID-19): Do Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? J Am Heart Assoc 2020;9:e016509. pmid:32233753
  35. 35. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;8:e21. pmid:32171062
  36. 36. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443–51. pmid:16760444
  37. 37. Quan A. Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early Hum Dev 2006;82:23–8. pmid:16427219
  38. 38. Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 2012;60:444–50. pmid:22753220
  39. 39. Moretti ME, Caprara D, Drehuta I, Yeung E, Cheung S, Federico L, et al. The Fetal Safety of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers. Obstet Gynecol Int 2012;2012:658310. pmid:22203847
  40. 40. Cox RM, Anderson JM, Cox P. Defective embryogenesis with angiotensin II receptor antagonists in pregnancy. BJOG 2003;110:1038. pmid:14592593
  41. 41. Barr M. Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 1994;50:399–409. pmid:7778045
  42. 42. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020:105949.
  43. 43. Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 Mar. 31. pmid:33165621
  44. 44. Meo SA, Klonoff DC, Akram J. Efficacy of chloroquine and hydroxychloroquine in the treatment of COVID-19. Eur Rev Med Pharmacol Sci 2020;24:4539–47. pmid:32373993
  45. 45. Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020;16:155–66. pmid:32034323
  46. 46. Lacroix I, Benevent J, Damase-Michel C. Chloroquine and hydroxychloroquine during pregnancy: What do we know? Therapie 2020;75:384–5. pmid:32418732
  47. 47. Vatansever EC, Yang K, Kratch KC, Drelich A, Cho CC, Mellot DM, et al. Targeting the SARS-CoV-2 Main Protease to Repurpose Drugs for COVID-19. bioRxiv 2020. pmid:32511370
  48. 48. Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222. pmid:31924756
  49. 49. Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396–403. pmid:32623082
  50. 50. Lagier JC, Million M, Gautret P, Colson P, Cortaredona S, Giraud-Gatineau A, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Travel Med Infect Dis 2020:101791. pmid:32593867
  51. 51. Powis KM, Kitch D, Ogwu A, Hughes MD, Lockman S, Leidner J, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011;204:506–14. pmid:21791651
  52. 52. Watts DH, Williams PL, Kacanek D, Griner R, Rich K, Hazra R, et al, Pediatric HIVACS. Combination antiretroviral use and preterm birth. J Infect Dis 2013;207:612–21. pmid:23204173
  53. 53. Gagnon LH, MacGillivray J, Urquia ML, Caprara D, Murphy KE, Yudin MH. Antiretroviral therapy during pregnancy and risk of preterm birth. Eur J Obstet Gynecol Reprod Biol 2016;201:51–5. pmid:27060543
  54. 54. Chen JY, Ribaudo HJ, Souda S, Parekh N, Ogwu A, Lockman S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012;206:1695–705. pmid:23066160
  55. 55. Cotter AM, Garcia AG, Duthely ML, Luke B, O’Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis 2006;193:1195–201. pmid:16586354
  56. 56. Patel K, Shapiro DE, Brogly SB, Livingston EG, Stek AM, Bardeguez AD, et al, Group PtotIMPAACT. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. J Infect Dis 2010;201:1035–44. pmid:20196654
  57. 57. Duryea E, Nicholson F, Cooper S, Roberts S, Rogers V, McIntire D, et al. The Use of Protease Inhibitors in Pregnancy: Maternal and Fetal Considerations. Infect Dis Obstet Gynecol 2015;2015:563727. pmid:26617456
  58. 58. Slyker JA, Patterson J, Ambler G, Richardson BA, Maleche-Obimbo E, Bosire R, et al. Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants. BMC Pregnancy Childbirth 2014;14:7. pmid:24397463
  59. 59. Sibiude J, Warszawski J, Tubiana R, Dollfus C, Faye A, Rouzioux C, et al. Premature delivery in HIV-infected women starting protease inhibitor therapy during pregnancy: role of the ritonavir boost? Clin Infect Dis 2012;54:1348–60. pmid:22460969
  60. 60. Fiore S, Ferrazzi E, Newell ML, Trabattoni D, Clerici M. Protease inhibitor-associated increased risk of preterm delivery is an immunological complication of therapy. J Infect Dis 2007;195:914–6; author reply 6–7. pmid:17299724
  61. 61. Hanna N, Bonifacio L, Weinberger B, Reddy P, Murphy S, Romero R, et al. Evidence for interleukin-10-mediated inhibition of cyclo- oxygenase-2 expression and prostaglandin production in preterm human placenta. Am J Reprod Immunol 2006;55:19–27. pmid:16364008
  62. 62. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med 2018;379:979–81. pmid:30037297
  63. 63. Rasi V, Cortina-Borja M, Peters H, Sconza R, Thorne C. Brief Report: Surveillance of Congenital Anomalies After Exposure to Raltegravir or Elvitegravir During Pregnancy in the United Kingdom and Ireland, 2008–2018. J Acquir Immune Defic Syndr 2019;80:264–8. pmid:30531300
  64. 64. Shamsuddin H, Raudenbush CL, Sciba BL, Zhou YP, Mast TC, Greaves WL, et al. Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy. J Acquir Immune Defic Syndr 2019;81:247–50. pmid:30908331
  65. 65. Scevola S, Tiraboschi JM, Podzamczer D. Nothing is perfect: the safety issues of integrase inhibitor regimens. Expert Opin Drug Saf 2020;19:683–94. pmid:32356477
  66. 66. Berard A, Sheehy O. The Quebec Pregnancy Cohort—prevalence of medication use during gestation and pregnancy outcomes. PLoS One 2014;9:e93870. pmid:24705674
  67. 67. Vilain A, Otis S, Forget A, Blais L. Agreement between administrative databases and medical charts for pregnancy-related variables among asthmatic women. Pharmacoepidemiol Drug Saf 2008;17:345–53. pmid:18271060
  68. 68. Blais L, Berard A, Kettani FZ, Forget A. Validity of congenital malformation diagnostic codes recorded in Quebec’s administrative databases. Pharmacoepidemiol Drug Saf 2013;22:881–9. pmid:23616437
  69. 69. Kulaga S, Zargarzadeh AH, Berard A. Prescriptions filled during pregnancy for drugs with the potential of fetal harm. BJOG 2009;116:1788–95. pmid:19832828
  70. 70. Zhao JP, Sheehy O, Gorgui J, Berard A. Can We Rely on Pharmacy Claims Databases to Ascertain Maternal Use of Medications during Pregnancy? Birth Defects Res 2017;109:423–31. pmid:28398706
  71. 71. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, et al, Fetal/Infant Health Study Group of the Canadian Perinatal Surveillance S. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;108:E35. pmid:11483845
  72. 72. Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 1989;61:197–203. pmid:2665171
  73. 73. Alvarez AM, Balcazar N, San Martin S, Markert UR, Cadavid AP. Modulation of antiphospholipid antibodies-induced trophoblast damage by different drugs used to prevent pregnancy morbidity associated with antiphospholipid syndrome. Am J Reprod Immunol 2017;77. pmid:28132398
  74. 74. Fan H, Gilbert R, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ 2020;368:m331. pmid:32075790
  75. 75. Kallen B, Danielsson BR. Fetal safety of erythromycin. An update of Swedish data. Eur J Clin Pharmacol 2014;70:355–60. pmid:24352632
  76. 76. Berard A, Lacasse A. Validity of perinatal pharmacoepidemiologic studies using data from the RAMQ administrative database. Can J Clin Pharmacol 2009;16:e360–9. pmid:19553702
  77. 77. Egbe AC. Birth defects in the newborn population: race and ethnicity. Pediatr Neonatol 2015;56:183–8. pmid:25544042
  78. 78. Laberge AM. [Prevalence and distribution of genetic diseases in Quebec: impact of the past on the present]. Med Sci (Paris) 2007;23:997–1001. pmid:18021714
  79. 79. Zhao JP, Sheehy O, Berard A. Regional Variations in the Prevalence of Major Congenital Malformations in Quebec: The Importance of Fetal Growth Environment. J Popul Ther Clin Pharmacol 2015;22:e198–210. pmid:26567551