Hydroxychloroquine (HCQ), an antimalarial drug containing the 4-aminoquinoline radical, is widely used in the treatment of systemic lupus erythematosus (SLE). Results of a randomized, controlled trial performed in nonpregnant patients showed that discontinuation of HCQ doubles the risk of SLE flare during the next 6 months (1). It is generally agreed that pregnancy per se increases disease activity in patients with SLE. Therefore, withdrawal of HCQ at the onset of pregnancy may result in exacerbation of SLE. Additionally, discontinuation of the drug might not prevent side effects in fetuses because of its very long terminal elimination half-life, which is estimated to be 1–2 months (2). Consequently, even though use of HCQ during pregnancy remains controversial (3), Parke (4, 5) and other investigators (6–9) have proposed continuation of this treatment throughout gestation.
We recently demonstrated that HCQ passes across the placenta, with cord blood concentrations nearly identical to those found in maternal blood, suggesting that during pregnancy the level of exposure to HCQ in mother and fetus is similar (10). These results raise the issue of potential teratogenic and toxic effects of HCQ and emphasize the need for careful evaluation of pregnancies in women being treated with HCQ. However, only small series of such pregnancies have been described, with a maximal sample size of 35 live births (7) and a total of 101 pregnancies resulting in live births (4–9). Most of these studies had no control group.
We now report our experience concerning HCQ treatment of women with SLE, at a single center, throughout 133 pregnancies that resulted in 117 live births. The results in patients receiving HCQ treatment are compared with those in a control group. Because the terminal elimination half-life of HCQ is very long (2), and because there is no information concerning the metabolism of HCQ in newborns, the children of mothers enrolled in the study were followed up for a mean of 26 months.
- Top of page
- PATIENTS AND METHODS
In women treated with HCQ, 133 pregnancies leading to 117 live births were followed up and compared with those in a control group. Malformations were carefully recorded, and all pregnancies were evaluated, including therapeutic abortion. Three malformations were observed in children of mothers in the HCQ group: hypospadias, craniostenosis, and cardiac malformation. Four malformations were observed in children of women in the control group (70 pregnancies). For comparison, the malformation rate in the general population, according to the European registry EUROCAT (European Concerted Action on Congenital Anomalies and Twins) (minor birth defects are excluded) is equal to 2.3% of all births (including fetal deaths and induced abortion) (14). Thus, the results in our study are equivalent to what would be expected in a large population of pregnancies, with the statistical power of our study being >90%.
Additionally, these results may not be imputable to HCQ, especially because of the diversity of malformations observed. In previous reports, the only congenital abnormalities observed in children of mothers who were treated with HCQ during their pregnancies were patent ductus arteriosus with atrial septal defect (8) and Down's syndrome (6). However, because these malformations are not exceptional in a general population (prevalence of 0.1% and 0.2%, respectively) (14), no firm conclusions can be drawn regarding the role of HCQ in these birth defects.
Concerning the potential toxic effects of HCQ, both retinal toxicity and ototoxicity have been reported in children born to women treated with chloroquine (15–17). These complications have never been reported in association with HCQ. Due to the difficulties encountered in assessing vision in young children, ophthalmologic examinations were not systematically performed in our series. However, although the children were not routinely checked on a prospective basis, data for each of them were carefully collected from mothers, general practitioners, and/or pediatricians. Because the terminal elimination half-life of HCQ is very long (2), clinical data on the children were collected at a mean age of 26 months. No clinical vision or hearing abnormalities have been observed, and the growth and development of these children appear to be normal. Our clinical data are in accordance with those reported by Klinger et al (8), who found that results of ophthalmologic examinations and tests were normal in 14 children who were exposed to HCQ in utero and were assessed at a mean age of 1.9 years. These results have been confirmed in 26 additional children (7, 9).
Because cardiac conduction abnormalities have been reported in adults who received long-term treatment with HCQ (18), we obtained EKGs in the children of mothers enrolled in this study. No difference was found between the HCQ group and the control group with regard to duration of the PR or QTc intervals, and the EKG findings were considered normal for age.
The limitations of our study should be noted. First, we did not systematically perform complete ophthalmologic examinations and tests in all children. Second, even though the number of pregnancies in this study is substantial in comparison with previous data, it may be insufficient to detect a discrete increase in birth defects. If so, a multicenter study including complete ophthalmologic examinations and long-term followup of the children would be recommended.
Nonetheless, our findings support preliminary evidence of the safety of HCQ use during pregnancy (4–9) and are concordant with the experience of selected experts, as reported in a national survey concerning the use of antimalarial drugs in lupus pregnancy (19). Indeed, according to results of that survey, 69% of respondents continued to prescribe antimalarial drugs sometimes, often, or always during pregnancy, and this was particularly true for those who treated a larger number of pregnant lupus patients per year (P < 0.01). Additionally, none of the respondents reported having seen any fetal toxicity related to the use of antimalarials. In conclusion, in the absence of HCQ-related adverse effects documented in pregnancy, and because SLE flares are frequently observed following HCQ discontinuation, we think this treatment should probably be maintained throughout pregnancy in patients with SLE.