Most medications being tested today in clinical trials for the treatment of coronavirus disease 2019 (COVID-19) have been repurposed from other indications. These are typically not tested in pregnant women. A new study, published in the journal PLOS ONE, summarizes what is known about the safety of these drugs in this group.
Background
Pregnant women with COVID-19 are at a higher risk for hospitalization, intensive care unit (ICU) admission and mechanical ventilation, compared to their non-pregnant peers, according to the US Centers for Disease Control and Prevention (CDC). A multi-continent study from the World Association of Perinatal Medicine Working Group on COVID-19 reported the risk of ICU admission to be 11%, and the mortality 0.8%, in this group.
Pregnant women are not always eligible for COVID-19 vaccines due to the absence of trial data, though several reports have confirmed the safety and efficacy of this intervention. Similarly, medications such as dexamethasone, interferons, heparin, hydroxychloroquine and azithromycin are undergoing clinical trials for use in COVID-19.
Disturbing issues include a higher risk of cleft palate with dexamethasone use in early pregnancy in some older studies; preterm birth with steroid use; and multiple problems including major congenital anomalies, reduced fetal growth, or renal failure, with the use of angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs).
Thus, data on their use in pregnancy with COVID-19 remains to be evaluated. This is the focus of this paper.
Study details
The women came from a population-based study called the Quebec Pregnancy Cohort. All had delivered a singleton and had a live birth. There were over 231,000 women altogether.
The medications used on an outpatient basis were assessed, as well as the period of gestation at the time of use, and the use of any combination of medications.
The researchers classified the cohort into four case-control groups to analyze the effects of medication exposure in pregnancy on outcomes such as preterm birth, low birth weight (LBW), small for gestational age (SGA), and major congenital anomalies.
The researchers tried to exclude confounding factors such as urban vs. rural area, comorbidities, drugs or other addictive substance use, folic acid use, prior pregnancy history, medical care during pregnancy, and other medications in pregnancy.
Other illnesses that could call for the same medications were also identified, such as malaria, lupus, arthritis, thrombotic conditions, digestive tract disorders, urinary tract infections and human immunodeficiency virus (HIV).
What were the findings?
Of the more than 230,000 pregnant women in the study, over 8,000 were treated with one of the drugs now being used in the treatment of COVID-19. By far, the greatest number had been exposed to azithromycin, at ~6,000, and 1,400 to anticoagulation.
Over 200 had taken the antiviral oseltamivir, and almost the same number received chloroquine. More than a hundred each had received hydroxychloroquine, dexamethasone, and HIV medications.
Less than fifty each had been exposed to interferons, or to the ARBs losartan and telmisartan.
Those who used these medications were more likely to be on social welfare, on high doses of folic acid, and to have high blood pressure, asthma or diabetes. In general, they used more healthcare services.
Outcomes of pregnancy
Preterm delivery occurred in 6.5% (or over 15,000) pregnancies. The adjusted risk with dexamethasone or HIV medications was about two-fold the baseline risk and 60% higher in those on anticoagulants.
About 5% of infants were LBW, with HIV medications pushing the risk up by 2.5-fold, while anticoagulants were associated with 72% higher risk. HIV medications were also responsible for a 2.6-fold higher risk of SGA, which occurred in a tenth of pregnancies.
Major anomalies occurred in just over a tenth of babies exposed to these drugs in the first trimester. These were largely associated with dexamethasone use (66% higher risk). The most common defects were those of the musculoskeletal and circulatory systems. Respiratory and digestive tract malformations were also identified. As expected, orofacial clefts were not associated with dexamethasone use.
Musculoskeletal anomalies were also found to occur above baseline level with hydroxychloroquine, azithromycin, HIV medications, and anticoagulants. A markedly higher incidence of cardiovascular defects was associated with these drugs, except for azithromycin, which showed a smaller increase in risk.
What are the implications?
The study shows definite risks of adverse pregnancy outcomes with specific drugs now being used to treat COVID-19. This includes HIV medication- and heparin-associated risks of preterm birth, LBW and SGA.
The use of heparin has been associated with fetal death, anomalies and prematurity in an earlier study. The current study reported both LBW and prematurity, but these findings are not corroborated by a recent Israeli study. However, the latter failed to account for the effects of gestational hypertension or diabetes, as well as for the conditions for which heparin was used. In addition, tobacco and alcohol use were not compensated for in that study.
The existing literature agrees with the risk of preterm birth associated with the use of HIV medications (indinavir, lopinavir/ritonavir, raltegravir and saquinavir) in pregnancy. Anticoagulants are also associated with a broad increase in the risk of malformations, second only to dexamethasone in the wide range of defects.
Dexamethasone use increased the risk of preterm birth and birth defects. The association with prematurity has been reported in an earlier study on women being treated with this drug for rheumatoid arthritis. The same is the case with the incidence of birth anomalies in fetuses exposed to the drug in early pregnancy.
Surprisingly, azithromycin is also linked to a higher risk of congenital anomalies. This is borne out by a study using the UK Clinical Practice Research Datalink database on macrolide use, showing the risk to be present with the use of erythromycin and clarithromycin as well. A Swedish study shows cardiovascular anomalies to be increased after exposure to erythromycin in pregnancy.
The study attempted to adjust the findings for known factors that could account for changes in the outcomes. Moreover, all the women belong to the same population, had identical health insurance, and the same level of healthcare availability.
Data on over-the-counter (OTC) drug use is missing, but this normally includes only ibuprofen and acetaminophen, or folic acid. One limitation of this study is that the incidence of birth defects is relatively high, though similar in all the comparison groups, affecting the generalizability of the study findings.
Although these available medications are being considered as treatments for COVID-19, caution is warranted in pregnancy.”
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