|Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases
|Sperber K, Hom C, Peng Chao C, Shapiro D, Ash J
This review concluded that hydroxychloroquine use in pregnant women with autoimmune diseases was not associated with increased risk of congenital defects, spontaneous abortions, live births, fetal death or prematurity. This was a well-conducted review, but the limitations of the included studies acknowledged by the authors should be borne in mind when interpreting the results.
To compare the incidence of congenital defects, spontaneous abortions, number of live births, fetal death and pre-maturity in women with autoimmune diseases taking hydroxychloroquine (HCQ) during pregnancy.
MEDLINE, Current Contents Clinical Medicine, Embase Drugs and Pharmacology, EBSCO, Web of Science, SCOPUS, ClinicalTrials.gov and The Cochrane Library were searched from 1980 to 2007 without language or publication restrictions; search terms were reported. Reference lists of included studies were searched for additional articles.
Comparative studies of any design that described hydroxychloroquine during pregnancy were eligible for inclusion. Eligible studies comprised pregnant patients in a non-hydroxychloroquine treatment group and reported clinical outcomes in the fetus; studies without a non-hydroxychloroquine group were excluded. Included studies were observational and hydroxychloroquine doses ranged from 200mg to 400mg; all studies had a control group not exposed to the drug. The outcomes considered in the review were congenital defects, spontaneous abortions, fetal deaths, prematurity (birth before 37 weeks of gestation) and live births. Included studies comprised pregnant females of child-bearing age with autoimmune disease; predominantly Lupus patients who met the American College of Rheumatology (ACR) criteria for diagnosis. Study duration ranged from five to 15 years.
The authors did not state how many reviewers performed the selection
Assessment of study quality
Two reviewers independently assessed study quality using the Downs and Black Study checklist based upon five subscales: reporting, internal validity bias, internal validity confounding, external validity and power. The maximum possible score was 31; higher scores suggested better quality studies. Where disagreements occurred a third reviewer again assessed the study quality.
Two reviewers extracted predefined dichotomous outcomes of interest (congenital defects, spontaneous abortions, fetal deaths, prematurity and live births) onto a standardised form to calculate odds ratios (OR). The data extraction was confirmed by a third reviewer.
Methods of synthesis
Pooled OR and their 95% confidence intervals (CI) were calculated using a fixed-effects model if significant heterogeneity was absent; a random-effects model was used if significant heterogeneity was present. Heterogeneity was assessed using the Χ2 and I2 tests. Significant heterogeneity was defined as p<0.1 or an I2 value of 50%. Publication bias was assessed using funnel plots.
Results of the review
A total of five studies were included in the review (n=645, range 20 to 206): four observational and one randomised controlled trial (RCT). The RCT was not incorporated within the meta-analysis, the reason for which was not made explicitly clear). Study quality scores ranged from 20 to 25. There was no evidence of publication bias.
For patients with auto-immune diseases, hydroxychloroquine was not significantly associated with an increased risk of congenital defects (OR 0.66, 95% CI 0.25 to 1.75), spontaneous abortions (OR 0.92, 95% CI 0.49 to 1.72), fetal death (OR 0.97, 95% CI 0.14 to 6.54), premature birth (OR 1.10, 95% CI 0.75 to 1.61) or decreased numbers of live births (OR 1.05, 95% CI 0.58 to 1.93). The fetal death comparison was the only significant statistical heterogeneity detected.
Hydroxychloroquine was not associated with any increased risk of congenital defects, spontaneous abortions, fetal death, prematurity or decreased numbers of live births in patients with autoimmune diseases; hydroxychloroquine was safe for use during pregnancy.
The review addressed a clear question with well-defined inclusion criteria; details for participants were limited. The thorough literature search was undertaken without language or publication restrictions, which reduced the likelihood of language bias and chance of missed studies. The authors stated that one study was undertaken in USA; it was not reported where the other studies were conducted, therefore, it was unclear how generalisable the findings were. Publication bias was assessed and found to be absent. Both data extraction and validity assessment were undertaken by multiple reviewers, which reduced the possibility of error and bias; it was unclear whether such rigour extended to study selection. Appropriate criteria were used to assess the quality of the included studies, which were of good quality. The small number of included studies was underpowered, as acknowledged by the authors. Suitable methods were used for the meta-analysis. Statistical heterogeneity was assessed and found to be absent from most analyses; for some outcomes the confidence intervals were wide. This was generally a well-conducted review. The authors conclusions appeared to accurately reflect the evidence presented, but the limitations of the included studies (acknowledged by the authors) regarding limitations in study design and underpowered studies should be borne in mind when interpreting the results.
Implications of the review for practice and research
The authors did not state any implications for practice or further research.
Sperber K, Hom C, Peng Chao C, Shapiro D, Ash J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatric Rheumatology 2009; 7:9
Subject indexing assigned by CRD
Autoimmune Diseases; Humans; Hydroxychloroquine /adverse effects; Pregnancy
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.