Fetal Safety of Chloroquine and Hydroxychloroquine Use During Pregnancy

A Nationwide Cohort Study

Niklas Worm Andersson; Lone Skov; Jon Trærup Andersen

Disclosures

Rheumatology. 2021;60(5):2317-2326. 

In This Article

Abstract and Introduction

Abstract

Objective: The antimalaria 4-aminoquinoline drugs chloroquine and HCQ are used in the treatment of a wide range of CTDs. Data to inform on the safety of their use in pregnancy are limited.

Methods: In a Danish nationwide cohort study from 1996 through 2016, we identified 4-aminoquinoline–exposed pregnancies from a cohort of 1240875 pregnancies to investigate the associated risks of major birth defects, preterm birth, and small size for gestational age (SGA). Distinct study cohorts of propensity-score–matched 4-aminoquinoline-exposed and unexposed pregnancies (in a 1:1 ratio) were established for each outcome analysis. The association with the outcomes was assessed by prevalence odds ratios (ORs) estimated through logistic regression. The associated risks for chloroquine and HCQ were individually assessed through additional analyses.

Results: A total of 1487 pregnancies exposed to 4-aminoquinolines (1184 chloroquine- and 303 HCQ-exposed) were identified. Among the 983 pregnancies exposed to 4-aminoquinolines in the first trimester, 34 infants (3.5%) were diagnosed with major birth defects as compared with 36 (3.7%) among the matched unexposed pregnancies (prevalence OR, 0.94; 95% CI: 0.59, 1.52). Exposure to 4-aminoquinolines in pregnancy was neither associated with an increased risk of preterm birth (prevalence OR, 0.97; 95% CI: 0.73, 1.28) or SGA (prevalence OR, 1.18; 95% CI: 0.93, 1.50), compared with unexposed pregnancies. No significant associations between exposure to chloroquine or HCQ individually and risk of the outcomes were identified.

Conclusion: Among pregnancies exposed to 4-aminoquinolines (chloroquine and HCQ), no increased risk of major birth defects, preterm birth, or SGA was identified.

Introduction

The 4-aminoquinoline drugs chloroquine phosphate and HCQ are antimalarial agents used in the treatment of a wide range of CTDs, including lupus erythematosus and RA. Other uses of the 4-aminoquinoline drugs include prophylactic (as well as active) treatment of non-chloroquine-resistant strains of Plasmodium falciparum malaria and photodermatosis.[1,2]

Despite 4-aminoquinoline drugs being used for many decades for disorders that also require treatment during pregnancy, data used to evaluate the potential fetal risk are limited. Current guidelines recommend the continuation of the use of HCQ in pregnancy to prevent clinical flares of disease (such as for patients with lupus erythematosus) that otherwise may increase the risk of maternal and fetal complications.[3–6] However, the previous literature examining the potential teratogenic effect of 4-aminoquinoline use in pregnancy consists of case reports and observational studies, which are very limited in size (resulting in a relatively wide CI) and are thus unable to exclude more than moderate increased risks.[7–15] Both chloroquine and HCQ pass through the placenta,[16–18] and although animal data may be of uncertain applicability to humans, administration of chloroquine at ~3–16 times the maximum dosage recommended for human therapeutic use showed embryo and fetal development toxicity.[19] As such, data to adequately evaluate the potential fetal risk of 4-aminoquinoline use in pregnancy are needed.

We conducted a nationwide registry-based cohort study to investigate the fetal safety of 4-aminoquinoline (i.e. chloroquine and HCQ) use among live-birth pregnancies. Pregnancies exposed to 4-aminoquinolines were matched with unexposed pregnancies in a propensity-score–matched design to compare the risks for the primary outcome of major birth defects and the secondary outcomes of preterm birth and small size for gestational age (SGA).

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