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Describe patterns of Disease-Modifying Antirheumatic Drug (DMARD) use during pregnancy in a population-based cohort, and evaluate the association between autoimmune disease (AD), DMARDs, corticosteroids and NSAIDs, and preeclampsia.
Using healthcare utilization databases from British Columbia (1997–2006), we compared the risk for preeclampsia among 44,786 women with and without AD with study drug dispensings before pregnancy (past users) and before and during the first 20 gestational weeks (continuous users). Relative risks (RR) and 95% confidence intervals (CI) were estimated.
Only 414 (0.1%) women had a DMARD dispensing during pregnancy. The incidence of preeclampsia was 2.3% for past DMARD, 2.7% for past corticosteroid, and 2.9% for past NSAIDs users. Compared to past users, the continuous DMARD user RR was 2.29 (CI: 0.81–6.44), and was 0.89 (CI: 0.51–1.56) for corticosteroid and 0.84 (CI: 0.63–1.10) for NSAID users. Compared to women without AD, the delivery year-adjusted RR was 2.02 (CI: 1.11–3.64) for women with systemic lupus erythematosus (SLE). The DMARD results were attenuated when antimalarials were excluded and the delivery-year adjusted RR was 0.95 (CI: 0.25–3.55) when the DMARD analysis was restricted to women with AD.
Few women were exposed to DMARDs during pregnancy. We observed a two-fold increased risk of preeclampsia among women with SLE and a non-significant increase in the risk in DMARD users. The DMARD and preeclampsia association was attenuated when anti-malarials were excluded and null when restricted to women with AD, which suggests the association is likely due to greater AD severity in DMARD users.
Preeclampsia is a serious complication of pregnancy that can compromise the health of pregnant women and neonates1. Studies have consistently shown that women with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have an increased risk for preeclampsia; SLE is associated with a 2 to 6-fold increase in risk and RA is associated with a 1.4 to 2-fold increase in risk2–6. Limited data exist on the association of other autoimmune diseases, such as multiple sclerosis and inflammatory bowel disease, and preeclampsia7–8.
Disease-Modifying Antirheumatic Drugs (DMARD) are a part of standard treatments for autoimmune disease, and their use during pregnancy may be necessary to avoid flares of disease that may compromise the health of the expectant mother and fetus9–10. It is possible that DMARDs may decrease the risk of preeclampsia by diminishing the maternal immune response to the placenta, which may play a role in the development of preeclampsia11. However, it is critical to account for underlying autoimmune disease when assessing the relation between DMARD use and preeclampsia given the well-reported association between various autoimmune diseases and preeclampsia2–6.
Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pregnant women with autoimmune disease9–10, 12. Corticosteroids may mitigate the systemic inflammatory response associated with preeclampsia13 and aspirin, a non-selective NSAID, modestly decreases the risk for preeclampsia14.
In the study, we first described DMARD, oral corticosteroid, and NSAID use during pregnancy in a population-based cohort. We then assessed the impact of DMARDs, oral corticosteroids and NSAIDs on the risk for preeclampsia adjusting for autoimmune diseases and factors related to autoimmune disease severity.
Comprehensive health insurance is provided to nearly all residents in the province of British Columbia (BC)15. BC Ministry of Health administrative databases contain diagnostic and procedure information from all physician services and hospitalizations. These population-based healthcare utilization databases were used to identify a cohort of pregnant women and infants. Databases were linked to the PharmaNet database, which contains all non-hospital pharmacy dispensing claims in BC. This study was approved by the Brigham and Women’s Hospital Institutional Review Board and signed data use agreements were in place.
Women were linked to infants by family insurance number and by delivery month and year. Delivery date was estimated from inpatient delivery discharges. Women who had more than one infant with the same delivery date were identified as having a multifetal gestation. Of all identified deliveries, 94% were successfully linked to infants. Because neither gestational length nor date of the last menstrual period (LMP) are available in healthcare utilization databases, the LMP was assigned as 245 days prior to delivery for preterm deliveries, identified from the International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) codes: 644.0x, 644.2x, 765.x, P05.x, P07.x, or O60.1. For all other deliveries, we assigned the LMP as 280 days prior to the date of delivery; 280 days is the mean duration of human gestation16. This method accurately classifies gestational age within 2 weeks for nearly 70% of preterm and 93% of term deliveries in this database17. The baseline period was the year before the estimated LMP (Figure 1).
Only pregnancies in which women had a live birth between October 1, 1997 and January 31, 2006 and had continuous healthcare enrollment from 1 year prior to their LMP until 2 months after their delivery date were eligible for the study. We described baseline characteristics and patterns of DMARD, corticosteroid, and NSAID use for the 306,831 pregnancies from 224,827 women that met these criteria. To minimize the number of women who were taking DMARDs for non-autoimmune disease indications, women with an ICD-9 or ICD-10 code for organ transplant (V42.x or Z94.x-Z95.x), malaria (084.x or B50.x-B64.x), or cancer (140.x-208.x or C00.x-C97.x) were excluded from subsequent analyses that assessed the association between study drugs and preeclampsia18–20.
Autoimmune disease was defined by the presence of an inpatient or outpatient diagnosis for a specific autoimmune disease on at least two dates during the baseline period. We used ICD-9 or ICD-10 codes 714.x or M05.x-M09.x for RA, 696.x or L40.x-L44.x for psoriasis, 710.x or M32.x, M34.x, M35.x for SLE, 555.x or K50.x for Crohn’s disease, 556.x or K51.x for ulcerative colitis, and 340.x or G35.x for multiple sclerosis (MS). Previous studies suggest that the risk for preeclampsia in RA and psoriasis is similar2–3 and therefore were grouped together as RA/psoriasis. Similarly, Crohn’s disease and ulcerative colitis were grouped together as inflammatory bowel disease (IBD).
Preeclampsia is clinically defined as hypertension and proteinuria after the 20th week of gestation21. We identified preeclampsia using inpatient or outpatient ICD-9 codes 642.4x, 642.5x, 642.6x, 642.7x or ICD-10 codes O11.x, O14.x, O15.x between gestational week 20 and one month after delivery. Most cases of preeclampsia were identified with at least one inpatient code for the condition (94.2%). The positive predictive value (PPV) for specific forms of preeclampsia and eclampsia ranged from 41.7–84.8% in a validation study of ICD-9 hospital discharge code22 and was reported to be 84% for superimposed and severe preeclampsia23. The PPV for preeclampsia based on ICD-9 codes for mild and severe disease was 93% in the Swedish Medical Birth Register24.
DMARD use including biologics, and oral corticosteroid and NSAID use (Appendix lists the generic names) was determined by the presence of a pharmacy dispensing record during the baseline period and between gestational weeks 0 to 20. Minocycline is an antibiotic that is also used as a DMARD25; the drug was not considered as a DMARD in this study because minocycline was often prescribed in conjunction with a diagnosis of acne. Infusible DMARDs were not considered. We hypothesized that DMARDs affect the maternal immune response to implantation and placentation, therefore the exposure window covered these stages of pregnancy26. The exposure window ended just before 20 gestational weeks when preeclampsia, by definition, can be diagnosed. We anticipated that autoimmune disease would be less common and less severe among women who never used the study drugs than women who did. Therefore, we compared the risk for preeclampsia in three groups of users categorized by the timing of use rather than by use/non-use to reduce confounding by the presence of autoimmune disease and disease severity. Women who were exposed to a study drug only during the baseline were classified as past users and served as the reference group for these analyses. Continuous users were women who were exposed to study drugs during the baseline and between gestational weeks 0–20, whereas first-time users were women who were exposed to study drugs only between gestational weeks 0–20. Based on timing of treatment, disease activity is likely to be lowest in past users27–28.
Potential confounders included known risk factors for preeclampsia29 and factors related to autoimmune disease severity30 during the baseline: age (<24, 24–29, 30–34, ≥35), primiparity (no prior deliveries recorded in the database for a woman; multiparas are only identified when prior deliveries are recorded), multifetal gestation, hypertension defined by the presence of diagnosis codes and/or dispensing for antihypertensive medications, pre-gestational diabetes mellitus, obesity, asthma, renal disease, type of autoimmune disease, ≥2 rheumatology visits, ≥1 joint radiograph and ≥1 platelet count ordered (as markers of RA severity), type of autoimmune disease, and total baseline days supply of study drug prescriptions: DMARD (a continuous, linear variable), corticosteroid (0, 1 to 6, 7–89, ≥90) or NSAIDs (0, 1 to 6, 7–89, ≥90). Number of distinct prescription drugs dispensed excluding the study drugs (<2, 2–3, ≥4) and physician visits (0–8, 9–14, 15–24, ≥25) during the baseline were considered as markers of comorbidity31.
First, we described the number of women who were dispensed DMARDs in 3 month intervals before pregnancy and in each trimester. We also described the number of women who were dispensed study drugs during pregnancy and the median days supply of study drugs dispensed during pregnancy.
We used modified Poisson regression models to estimate relative risks (RR) and 95% confidence intervals (CI); this method directly estimates the RR for binary outcomes whereas logistic regression, an alternative, only approximates the RR32. All models were adjusted for delivery year and robust variances accounted for correlations among women who had more than one pregnancy in the database33. To support the validity of our outcome definition, we assessed the association between well-established risk factors for preeclampsia and preeclampsia. The primary analysis compared the risk of preeclampsia among continuous DMARD, corticosteroid, and NSAID users to the risk among past users, separately. We also compared first-time users with past users; because only one first-time DMARD user case was identified, the RR for DMARD first-time versus past use was not reported. We conducted multiple sensitivity analyses. First, we considered baseline drug use as part of the exposure and consequently did not adjust for baseline days supply of the study drug of interest in the continuer vs past user analysis. Second, we excluded women who used only antimalarial DMARDs and were therefore likely to have less severe autoimmune disease. Finally, we assumed that all pregnancies had an error in gestational age of +/− 2 weeks so we shortened the exposure window to between 2–18 gestational weeks and we set the past use window to end 2 weeks prior to the LMP. Models were additionally adjusted for preeclampsia risk factors. The fully-adjusted models also were adjusted for type of autoimmune disease and for factors related to autoimmune disease and healthcare utilization.
To understand the role of autoimmune disease in the association between DMARDs and preeclampsia, we first compared the delivery year-adjusted risk for preeclampsia among women with specific types of autoimmune disease to women without autoimmune disease. In an attempt to disentangle the association between autoimmune disease and study drugs with preeclampsia, we assessed the association between the study drugs dispensed between the LMP and gestational week 20 and preeclampsia only among women with autoimmune disease, adjusting for preeclampsia risk factors, type of autoimmune disease, factors related to autoimmune disease and healthcare utilization. In this analysis, the reference group was comprised of women who did not use the study drugs between the LMP and week 20. All analyses were conducted with SAS 9.2, for Windows (SAS Institute, Inc., Cary, NC).
Among 306,831 pregnancies, the median age was 30 and chronic conditions such as pre-gestational hypertension and diabetes mellitus were rare (Table 1). Only 0.3% of women had RA or psoriasis. Within this cohort, 1,226 (0.4%) women used a DMARD in the year before pregnancy, and 414 (0.1%) women were dispensed a DMARD during pregnancy. When accounting for days supply and the dispensing date, a maximum of 555 (0.2%) women were exposed to DMARDs during pregnancy. The number of women dispensed DMARDs decreased from periods before pregnancy through the third trimester (Figure 2). The most common DMARDs used during pregnancy were hydroxylchloroquine (n=114), chloroquine phosphate (n=109), azathioprine (n=91), and sulfasalazine (n=60). Only 4 women had dispensing records for biologic DMARDs during pregnancy (all for etanercept). There were 2,444 (0.8 %) women with at least one dispensing for corticosteroids during pregnancy and 6,315 (2.1%) women with at least one dispensing for NSAIDs during pregnancy. The median days supply for a DMARD prescription during pregnancy was 42 days while it was 12 days for corticosteroids and 10 days for NSAIDs. Compared with multiparous women, primiparous women had a RR for preeclampsia of 2.03 (95% CI: 1.90–2.17). Compared with singleton pregnancies, women with multifetal pregnancies had 3.97-fold increased risk (95% CI: 3.56–4.43). Women with pre-gestational diabetes mellitus had a 3.64-fold increased risk (95% CI: 3.09–4.29) compared with women without diabetes mellitus. Women ages 40 and above also had an increased risk for preeclampsia.
In the subsequent analyses, 18,867 pregnancies were excluded because of a record for organ transplant (n=76), malaria (n=406), or cancer (n=18,385), leaving 287,964 pregnancies. After restriction, hydroxylchloroquine (n=100), chloroquine phosphate (n=91), azathioprine (n=71), and sulfasalazine (n=55) were still the most commonly used DMARDs during pregnancy. Between the LMP and gestational week 20, 302 pregnancies were exposed to a DMARD, 1,342 were exposed to a corticosteroid, and 4,728 were exposed to an NSAID. Among these women, 213 used multiple study drugs: 59 pregnancies were exposed to a DMARD and corticosteroid, 16 to a DMARD and NSAID, 129 to a corticosteroid and NSAID, and 9 to all three drugs categories.
Few women taking corticosteroids and NSAIDs had autoimmune disease diagnoses but many had other indications such as osteoarthritis, back/neck disorders, soft tissue disorders, sprains/strains, headache/migraine, and premenstrual tension syndrome/other menstruation disorders (Table 2).
The incidence of preeclampsia among women who continued DMARD use after the LMP was 7.7%, while it was 4.4% for corticosteroid users and 2.6% for NSAID users. The corresponding risks for past users of these medications were 2.3% for DMARDs, 2.7% for corticosteroids, and 2.9% for NSAIDs. The incidence of preeclampsia among first-time corticosteroid users was 3.7% and it was 3.2% among NSAID users. The risk was 2.4% among non-users of these medications.
Known risk factors for preeclampsia such as older age, multifetal gestation, and hypertension were more common among continuous users compared to past and first-time study drug users (Table 2). Of the 302 women exposed to a DMARD during the first 20 weeks of gestation, 34.4% had at least two diagnoses for an autoimmune disease. RA/psoriasis, SLE, and IBD were more common among DMARD and corticosteroid continuous users compared to past and first-time users. Rheumatology visits occurred more frequently and health care utilization was the highest among the continuous users of study drugs.
Compared to past DMARD users, the delivery year-adjusted RR for preeclampsia among those who continued DMARD use was 3.22 (CI: 1.56–6.66) and the fully-adjusted RR was 2.29 (CI: 0.81–6.44); adjustment for autoimmune disease/factors related to autoimmune disease, particularly SLE, renal disease and baseline corticosteroid use, attenuated the RR. When women who used only antimalarial DMARDs were excluded, the fully-adjusted RR was 1.23 (CI: 0.30–5.02). We observed non-significant decreases in the risk for preeclampsia when comparing corticosteroid and NSAID continuous users to past users after adjusting for potential confounders (Table 3). If prior study drug use affects the risk of preeclampsia it would be inappropriate to adjust for baseline use; the results did not change greatly when we did not adjust for baseline days supply of the study drug of interest. Comparing first-time to past users, the fully-adjusted RR for preeclampsia among corticosteroid users was 1.35 (CI: 0.94–1.94), and it was 1.17 (CI: 0.94–1.45) for NSAID users. The results from the alternative exposure window sensitivity analysis were not very different from the original analysis with the exception of that from the DMARD continuer vs past user analysis which was greatly attenuated (RR: 0.93, CI: 0.31–2.80).
Of the 1,744 women with at least 2 diagnoses of autoimmune disease, 49.8% had RA/psoriasis, 29.4% had IBD, 11.2% had SLE, and 10.6% had MS. Compared to women with no autoimmune disease, women with SLE were more likely to have preeclampsia (delivery year-adjusted RR: 2.02, CI: 1.11–3.64), but women with IBD did not have a higher risk for preeclampsia (Table 4). The delivery year adjusted-RR for RA/psoriasis was 1.26 (CI: 0.87–1.81).
In the autoimmune disease cohort, 6.0% were exposed to DMARDs, 7.1% were exposed to corticosteroids and 4.1% were exposed to NSAIDs between the LMP and week 20. The delivery year-adjusted RR comparing DMARD exposure between weeks 0–20 to no DMARD exposure during this period was 0.95 (CI: 0.25–3.55) and the fully-adjusted RR was 0.62 (CI: 0.10–3.77); there were only three exposed cases. The fully-adjusted RR for corticosteroid exposure was 1.25 (CI: 0.44–3.56) and there was only 1 NSAID exposed case among women with autoimmune disease.
In this population-based cohort, we observed that use of DMARDs was rare during pregnancy and that DMARD use decreased as pregnancy advanced. Antimalarials were the most commonly used DMARD during pregnancy. Preeclampsia occurred in 2.4% of pregnancies, which is similar to the incidence in other cohorts34–36. Compared to women who used DMARDs only before pregnancy (past users), women who used DMARDs before pregnancy and between the LMP and week 20 (continuous users) had a non-significant increase in risk for preeclampsia. SLE was associated with a 2-fold increased risk for preeclampsia, after adjusting for delivery year. The DMARD and preeclampsia association was attenuated when women who used only antimalarials were excluded from the analysis and when the population was restricted to women with autoimmune disease, suggesting that the observed risk for preeclampsia in DMARD users was likely due to underlying autoimmune disease.
We observed some patterns of DMARD utilization in our population-based cohort from BC that were similar to those among a cohort of pregnant women with RA from the United States12. Both cohorts had a decrease in DMARD exposure from the months prior to pregnancy through the third trimester. Hydroxychloroquine was the most commonly used DMARD during pregnancy in our cohort; it was the second most commonly used DMARD during pregnancy behind corticosteroids and biologics in the Kuriya et al. study. In contrast, biologics were only dispensed to 4 pregnant women in our cohort.
There appeared to be an increased risk for preeclampsia among corticosteroid and NSAID first-time users compared to past users. Inspection of the baseline characteristics by timing of study drug use indicated that the comparison groups were dissimilar with respect to factors related to autoimmune disease. Although we adjusted for factors related to autoimmune disease, clinical measures of disease severity were not available. Because first-time user groups may contain women with new onset autoimmune disease, proxies for severity may not be captured during the baseline. Therefore, the increased risk for preeclampsia among first-time corticosteroid and NSAID users may reflect residual confounding by post-conception disease severity.
Prior studies have reported a 1.4 to 2-fold increased risk for preeclampsia among women with RA2–6. Increased RA disease activity during pregnancy is also associated with lower birth weight and cesarean delivery37. If preeclampsia risk is dependent on disease severity, an association between RA and preeclampsia in this study may have been diluted by unintentionally combining active and less active cases of RA. We did not observe a uniform increase in risk for preeclampsia among all autoimmune disease subtypes. We found no association between IBD and preeclampsia, and there was a small but non-significant increase in preeclampsia in RA/psoriasis patients, whereas we observed a strong association with SLE. Future studies that evaluate the association between DMARDs and preeclampsia should consider interactions with autoimmune disease subtype and severity.
We observed no difference in risk for preeclampsia between continuous and past corticosteroid and NSAID users. These results contrast with a non-significant increased risk for preeclampsia in the DMARD continuous/past user analysis. However, the association between DMARDs and preeclampsia was attenuated somewhat after adjustment for autoimmune disease, and the point estimate became null when the cohort was restricted to those with autoimmune disease. The difference between the results from adjustment and restriction by autoimmune disease is explained by low sensitivity but high specificity of ICD-9 and ICD-10 diagnosis codes for autoimmune disease. Autoimmune disease diagnoses were likely under-recorded because the physician services file only allows one diagnosis, and only one-third of women who used DMARDs during pregnancy were classified as having autoimmune disease, even after excluding non-autoimmune disease DMARD indications. Because of the low sensitivity for the ICD-9 and ICD-10 codes, power was low in the restricted analysis. However, due to the high specificity, those who were included in the restricted analysis are likely to have true disease and probably have more severe disease than those who were misclassified as not having disease. Results from the restricted analysis likely reflect less residual confounding by autoimmune disease, whereas results adjusted for misclassified autoimmune disease likely reflect residual confounding. These analyses indicated that the non-significant positive association between DMARDs and preeclampsia is likely due to underlying autoimmune disease or its severity.
Maternal decidual natural killer cells may impede early trophoblast invasion, leading to reduced placental profusion38 which may set the stage for preeclampsia. A proinflammatory cytokine profile triggered by placental hypoxia may contribute to systemic inflammation observed in women with preeclampsia38. Furthermore, regulatory T (Treg) cells down regulate self-reactive T cells and protect against autoimmune disease39, and a paucity of Treg cells may trigger autoimmune disease and has also been proposed to play a role in the development of preeclampsia40. Therefore, autoimmune disease and disease severity is a theoretical confounder for the relation between DMARD use and preeclampsia. It is plausible that DMARDs may actually decrease the risk for preeclampsia among women with autoimmune disease by mitigating immune responses. Although our results did not show beneficial effects of DMARDs, a small beneficial effect cannot be ruled out.
Exposure assessment was based on prescription fills, therefore we could not verify that cohort members were taking the prescriptions as assumed41–43. Because some of the study drugs are contraindicated during pregnancy9–10 and women with RA tend to decrease thier use during pregnancy12, 37, we anticipate that some women who were classified as study drug users during pregnancy actually discontinued use. Under-recording of over-the-counter NSAID use and intermittent corticosteroid use likely resulted in exposure misclassification. These sources of misclassification would likely attenuate the relative risks. Alternatively, case-control surveillance studies rely on patients’ recall to assess exposure; these studies suffer from differential misclassification where the direction and magnitude can be difficult to predict. Furthermore, misidentification of the LMP due to preterm deliveries would also result in exposure misclassification44. This source of misclassification is more likely among women with preeclampsia because preterm delivery is more common among preeclamptic pregnancies45–46. However, the estimated date of the LMP was within 2 weeks of the true LMP for most preterm deliveries in our study, therefore this source of exposure misclassification was likely minor. With the exception of the DMARD analysis, the results were not very sensitive to the alternative exposure definition that assumed a 2 week error in gestational age.
The use of population-based data is a major strength of our study; it allowed us to identify women who used DMARDs before or during pregnancy. The size of the population enabled us to assess the association between DMARDs and a maternal outcome, and to study the relation between specific autoimmune diseases and preeclampsia. We observed the well-established associations between age, parity, multifetal gestations, and diabetes mellitus and preeclampsia29, which supports the validity of our outcome definition.
In conclusion, DMARD use during pregnancy was rare in this population-based cohort. DMARD continuation during pregnancy was associated with a non-significant increase in risk for preeclampsia, however corticosteroid and NSAID continuation were not. The non-significant risk was attenuated when women with anti-malarial use only, i.e. those likely to have less severe disease, were excluded suggesting that the relation between DMARD use and preeclampsia is likely due to underlying disease or severity of autoimmune disease. Larger studies with detailed clinical data are needed to confirm our findings and should investigate the relation between DMARD use and preeclampsia among women with specific autoimmune diseases and should account for clinical measures of disease severity.
Sources of Funding: This study was funded by National Institute of Child Health and Human Development (NICHD) and Agency for Healthcare Research and Quality (AHRQ) grants R21HD055479 (PI: Soko Setoguchi) and R01HS018533 (PI: Sonia Hernández-Díaz). Kristin Palmsten is supported by training grant T32HD060454 from the NICHD. Dr. Setoguchi is supported by a mid-career development award grant K02-HS017731 from the AHRQ, U.S. DHHS. Daniel Solomon receives support from the NIH (K24-AR055989). The NIH and the AHRQ had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
The authors would like to thank Claire F. Canning, MA for compiling the analytic datasets.
Potential Conflict of Interest: The Pharmacoepidemiology Program at the Harvard School of Public Health receives funding from Pfizer and Asisa. Dr. Setoguchi received honoraria from Sanofi-Aventis and research support from Johnson and Johnson. Dr. Hernández-Díaz has consulted for AstraZeneca, Novartis, and GlaxoSmithKline Biologicals. Dr. Solomon has received research support from Abbott, Amgen, and Lilly.