Most of the drugs tested today in clinical trials for the treatment of 2019 coronavirus disease (COVID-19) have been reused from other indications. These are usually 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.
Pregnant women with COVID-19 have a higher risk of hospitalization, intensive care unit (ICU) admission, and mechanical ventilation, compared to their non-pregnant peers, according to the Centers for Disease Control and Prevention ( CDC) from the United States. A multi-continental study by the World Association of Perinatal Medicine Working Group on COVID-19 reported that the risk of ICU admission was 11% and mortality 0.8% in this group.
Pregnant women are not always eligible for COVID-19 vaccines due to the lack of test data, although several reports have confirmed the safety and effectiveness of this intervention. Likewise, drugs such as dexamethasone, interferons, heparin, hydroxychloroquine, and azithromycin are currently in clinical trials for use in COVID-19.
Worrisome issues include a higher risk of cleft palate with the use of dexamethasone in early pregnancy in some older studies; premature birth with the use of steroids; and multiple problems, including major birth defects, reduced fetal growth, or kidney failure, with the use of angiotensin converting enzyme (ACE) inhibitors and receptor antagonists angiotensin (ARA).
Thus, the data on their use during pregnancy with COVID-19 remains to be evaluated. This is the subject of this article.
The women were from a population-based study called the Quebec Pregnancy Cohort. All of them had given birth to a singleton and had a live birth. There were a total of over 231,000 women.
Medicines used on an outpatient basis were evaluated, as well as the gestation period at the time of use and the use of any combination of drugs.
The researchers classified the cohort into four case-control groups to analyze the effects of drug exposure during pregnancy on outcomes such as prematurity, low birth weight (LBW), short stature for the gestational age (GAS) and major birth defects.
The researchers attempted to rule out confounding factors such as urban versus rural, co-morbidities, drug or other addictive substance use, folic acid intake, pregnancy history, medical care during pregnancy and other drugs during pregnancy.
Other diseases that may require the same drugs have also been identified, such as malaria, lupus, arthritis, thrombotic diseases, digestive tract disorders, urinary tract infections, and human immunodeficiency virus ( HIV).
What were the results?
Of more than 230,000 pregnant women in the study, more than 8,000 were treated with any of the drugs currently used to treat COVID-19. By far the greatest number had been exposed to azithromycin, ~ 6,000, and 1,400 to anticoagulation.
More than 200 had taken the antiviral oseltamivir, and almost the same number had received chloroquine. Over a hundred had each received hydroxychloroquine, dexamethasone and anti-HIV drugs.
Less than fifty each had been exposed to interferons, or to losartan and telmisartan ARBs.
Those who used these drugs were more likely to receive social assistance, take high doses of folic acid, and have high blood pressure, asthma or diabetes. In general, they used more health services.
Premature birth occurred in 6.5% (or more than 15,000) pregnancies. The risk adjusted with dexamethasone or anti-HIV drugs was about twice the baseline risk and 60% higher in those on anticoagulants.
About 5% of infants were underweight, with anti-HIV drugs increasing the risk 2.5 times, while anticoagulants were associated with a 72% higher risk. Anti-HIV drugs were also responsible for a 2.6 times higher risk of GAS, which occurred in one tenth of pregnancies.
Major abnormalities have occurred in just over a tenth of babies exposed to these drugs during the first trimester. These were largely associated with the use of dexamethasone (66% higher risk). The most common defects were those of the musculoskeletal and circulatory systems. Respiratory and digestive malformations have also been identified. As expected, orofacial clefts have not been associated with the use of dexamethasone.
Musculoskeletal abnormalities were also found to be greater than baseline with hydroxychloroquine, azithromycin, anti-HIV drugs, and anticoagulants. A significantly higher incidence of cardiovascular abnormalities has been associated with these drugs, with the exception of azithromycin, which has shown a smaller increased risk.
What are the implications?
The study shows certain risks of adverse pregnancy outcomes with specific drugs currently used to treat COVID-19. This includes the risks associated with anti-HIV and heparin drugs related to preterm birth, stroke and GAS.
Heparin use was associated with fetal death, abnormalities, and prematurity in an earlier study. The current study reported both low weight and prematurity, but these results are not supported by a recent Israeli study. However, the latter did not take into account the effects of gestational hypertension or diabetes, as well as the conditions for which heparin was used. In addition, the consumption of tobacco and alcohol was not compensated for in this study.
The existing literature is consistent with the risk of preterm delivery associated with the use of anti-HIV drugs (indinavir, lopinavir / ritonavir, raltegravir and saquinavir) during pregnancy. Blood thinners are also associated with a large increase in the risk of malformations, just behind dexamethasone in the wide range of defects.
The use of dexamethasone has increased the risk of premature birth and birth defects. The association with prematurity was reported in an earlier study in women treated with this drug for rheumatoid arthritis. The same is true for the incidence of birth defects in fetuses exposed to the drug in early pregnancy.
Surprisingly, azithromycin is also linked to a higher risk of birth defects. This is confirmed by a study using the UK Clinical Practice Research Datalink on the use of macrolides, showing the risk to be also present with the use of erythromycin and clarithromycin. A Swedish study shows an increase in cardiovascular abnormalities after exposure to erythromycin during pregnancy.
The study attempted to adjust the results for known factors that might explain the changes in the results. In addition, all women belong to the same population, have identical health insurance and the same level of health care availability.
Data on over-the-counter (OTC) drug consumption is missing, but this normally only includes ibuprofen and acetaminophen, or folic acid. One of the limitations of this study is that the incidence of birth defects is relatively high, although similar in all comparison groups, which affects the generalizability of the study results.
Although these available drugs are considered treatments for COVID-19, caution is advised during pregnancy. “