Background
The anti-malarial drugs Hydroxychloroquine (HCQ) is widely used to treat various rheumatic diseases [
1]. The mechanism of action of this drug is to increase the pH in acidic vesicles, inhibiting receptor mediated endocytosis that affects many cellular functions including antigen presentation, toll receptor signaling and post-transcriptional modification of proteins [
2‐
4]. Convincing evidence has accumulated over the past years demonstrating the efficacy of HCQ in the treatment of auto-immune diseases including systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE) and rheumatoid arthritis (RA) [
5,
6]. Since many rheumatic diseases affect women of child bearing age, there have been concerns regarding potential teratogenic and toxic effects of the drug on the developing fetus [
7,
8].
Malformations and other abnormalities after treatment with higher than the recommended dose of (Chloroquine) CQ through pregnancy were reported after intrauterine exposure to 500 mg daily of CQ in 3 siblings [
9]. In animal model systems the drug accumulates in the pigmented cells in the eye [
10,
11]. Dose-dependent retinal toxicity has long been recognized as the major side effect of HCQ [
10,
11]. CQ crosses the placenta during pregnancy [
12]. In an evidence-based guideline evaluating the risks and benefits of drug therapies during pregnancy, it was recommended to continue HCQ during pregnancy and lactation [
13]. Although there have been a number of reviews regarding the use of HCQ during pregnancy [
14‐
16], to date there has been no meta-analysis analyzing the effect of HCQ on fetal outcomes in women with various auto-immune diseases. This systematic review contains a meta-analysis of the available clinical studies investigating the use of HCQ during pregnancy and will focus on the risk of congenital defects, number of live births, spontaneous abortions, fetal deaths and pre-maturity in fetuses born to women taking HCQ.
Discussion
Our systematic review provides evidence for the use of HCQ during pregnancy for women with auto-immune diseases. We identified 3 cohort studies [
27‐
29] and 1 case-controlled study [
30] comparing HCQ treatment with no HCQ treatment in pregnant women with auto-immune diseases (Figure
1 and Additional file
1, Tables S1 and S2). We attempted to identify all relevant studies regarding HCQ and pregnancy by not restricting our literature search to the English language. It is still possible that we may have inadvertently omitted other studies that were not identified in the literature searches of the different databases.
Although the Harbord test for dichotomous variables did not indicate publication bias, citation bias, and database bias, the number of studies included in our meta-analysis was only 4 so that it is possible that it may not be able to distinguish chance from real asymmetry in the funnel plot. The quality of the studies that were included in this meta-analysis as determined by the Downs and Black checklist was excellent despite the fact that they were no randomized placebo-controlled clinical trials [
19,
20]. The scores are listed in Additional file
1, Table S1.
We did not observe any heterogeneity in the results of the different studies (Figures
2a, b,
3a, and
4) that could have arisen because of differences in doses of HCQ (200 mg compared to 400 mg), length of follow up after birth, and between auto-immune diseases (SLE, DLE, RA, Sjogren's syndrome), allowing the use of a fixed effect model for. The only significant heterogeneous result between the studies was the increased risk of fetal deaths (Figure
3b) noted where the results were analyzed by using a random-effects model.
Our study was limited by the lack placebo controlled double-blinded studies that compared HCQ therapy with a control group. The patient populations included in the studies were fairly homogenous. All of the studies included pregnant females of child bearing age with autoimmune disease predominantly Lupus who met the ACR criteria for diagnosis, all of the patients and the fetuses were exposed to HCQ at the time of conception and throughout the pregnancy, all of the studies had a control group who were not exposed to the drug, and all reported similar outcomes.
We did not include the 1 RCT [
31] because of the difficulties of combining different study designs in meta-analysis as noted above [
17,
18]. This study also found no differences in congenital defects, number of live births, fetal death, and pre-maturity in patients who were treated with HCQ compared to those who were not treated with HCQ. Despite the fact that we performed a meta-analysis, our studies were underpowered to detect an association between congenital defects congenital defects, spontaneous abortions, fetal deaths, pre-maturity and live births, if the effect of HCQ is less than 0.2 [
48]. We did consider adding isolated case reports in our analysis given the rarity of the occurrence of congenital malformations and other obstetrical complication of this drug [
35‐
40]. However, we did not include these patients in the statistical analysis because there were no control groups.
There have been numerous studies using CQ prophylaxis for malaria during pregnancy. CQ, a pharmacologic analogue of HCQ has been used in Europe to treat auto-immune diseases and its mechanism of action is identical to HCQ. In general the doses used for malarial prophylaxis are less than those used to treat auto-immune diseases. There is a large meta-analysis published by the Cochrane database that included 12,638 patients focused on malaria prevention [
32]. No increase in congenital malformations, live births, spontaneous abortions, fetal deaths or pre-maturity was noted in patients who used CQ compared to controls. Although these studies do not directly prove that CQ is safe for pregnant women with auto-immune diseases, it is further evidence of the safety of anti-malaria drugs during pregnancy.
Two of the included studies by Clowse et. al. [
27] and Frassi et al [
30] had an increase in fetal death (OR 4.79 95% CI 0.78, 29.57 and OR 5.40 95% CI 0.26,114.28) in the placebo while another study by Costedoat-Chalumeau et al [
28] had an OR of 0.08 (95% CI 0.01, 0.60) that favored HCQ. One possible explanation for this discrepancy is the increased number of patients with anti-cardiolipin antibodies in the HCQ group of Clowse et al [
27] and Frassi et al [
30] that may have contributed to the high incidence of fetal deaths seen in both studies.
Since anti-malarials cross the placenta, they have the potential to cause congenital defects [
12]. The first reports documenting congenital abnormalities and accumulation of the drug in the eye were described in infants whose mothers received chloroquine (CQ) [
9,
33]. However, recent reports including a Cochrane meta-analysis have demonstrated that CQ in low doses is safe as malaria prophylaxis during pregnancy [
34]. In addition to the 4 studies that we included in this report, there have been several uncontrolled studies that have examined the effect of HCQ therapy on ocular toxicity in babies born to women taking the drug during pregnancy [
35‐
37]. Two of these studies performed comprehensive ophthalmologic examinations of infants whose mothers took HCQ during pregnancy and found no evidence of ocular toxicity [
29,
31]. All of these studies have documented the safety of HCQ in infants whose mothers took the medication during pregnancy. The total number of infants examined in these 3 studies is 96.
Another benefit of HCQ during pregnancy is its effect on reducing disease activity. Of note Clowse et al. [
27] and Levy et al. [
31] made observations of lupus outcomes in a cohort of women with SLE and reported the impact of HCQ treatment cessation on SLE activity during pregnancy. Clowse et al. [
27] found that women who stopped taking HCQ had increased lupus activity and increased lupus flares during pregnancy. High activity lupus was defined as a physician's estimate of activity (PEA) greater than 2 occurred in twice as many pregnancies in which HCQ treatment was stopped as in those in which HCQ was continued. The rate of flare was also higher among women who stopped the medication compared with those who either continued taking it or who never took it. These flares occurred throughout pregnancy. More women who discontinued HCQ treatment had SLEDAI scores greater than 4 during pregnancy and this remained elevated when adjusted for year of delivery, anti-phospholipid antibody syndrome (APS), age, ethnicity, and prior history of lupus nephritis.
The types of lupus activity that were best controlled by HCQ were arthritis and constitutional symptoms. HCQ did not prevent the more severe complications of proteinuria or thrombocytopenia. Furthermore, the authors also evaluated the use of Prednisone and fewer women who continued HCQ required high-dose corticosteroids, defined as either a daily dose of Prednisone of at least 20 mg or pulse steroids. Similar to the observation of Clowse et al. [
27], Levy et al. [
31] noted that after delivery Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores of the placebo group were not significantly different from pre-treatment scores while in the HCQ group a statistically significant improvement in the score was found; in the HCQ group there were no flares, and there was a statistically significant improvement in the SLEDAI score at delivery when compared to the placebo group.
Competing interests
None of the authors have a financial interest in Sanofi-Winbthrop Pharmaceuticals or any other laboratory that manufactures HCQ.
Authors' contributions
KS did the literature search, the statistical analysis, and wrote the paper. CH and CPC did the blinded grading and quality assessments of the studies. JA and DS wrote the manuscript.