Abstract
Objective:
Limited data exists on the effect of rheumatoid arthritis (RA) on maternal postpartum outcomes. Using a real-world, electronic health record (EHR) cohort, we assessed maternal postpartum outcomes in RA.
Methods:
In a large, de-identified EHR, we identified possible RA deliveries using ≥1 delivery ICD-9 or ICD-10-CM codes and a validated RA algorithm. RA cases were required to be diagnosed by a rheumatologist on chart review. Maternal postpartum outcomes included rates of blood transfusion, rates of infection up to 6 weeks postpartum defined by a clinician, and length of hospital stay. We also identified deliveries to women without autoimmune diseases.
Results:
We identified 202 deliveries occurring after RA diagnosis and 596 deliveries to controls without autoimmune diseases. Postpartum infection rates were similar among RA patients and controls (8% vs. 4%, p = 0.10), as were red blood cell transfusion rates (2% vs. 2%, p = 1.00). RA case status was not significantly associated with postpartum infection (OR = 2.10, 95% CI 0.88 – 4.98, p = 0.09) but was significantly associated with preterm birth (OR = 2.11, 95% CI 1.38 – 3.23, p = 0.001). Corticosteroid use during pregnancy was common at 41%, while tumor necrosis factor inhibitor use was 13%. After adjusting for age at delivery and race, corticosteroid use at delivery was not associated with postpartum maternal infections but was associated with a significantly lower birthweight in RA cases.
Conclusion:
Women with RA have an increased risk of adverse pregnancy outcomes, particularly preterm birth. Our study highlights, however, that maternal postpartum outcomes such as postpartum infection and blood transfusion are not significantly increased in RA patients.
Keywords: rheumatoid arthritis, pregnancy, delivery, birth, electronic health record
Introduction
Rheumatoid arthritis (RA) is a chronic, autoimmune disease commonly affecting females of child-bearing age (1). Studies on birth outcomes to women with RA are limited and conflicting. Some studies indicate that women with well controlled RA have birth outcomes similar to the general population (2). In contrast, other larger studies have noted higher rates of preterm birth, preeclampsia, eclampsia, and cesarean section (3–7). There is a gap, however, in studies assessing maternal postpartum outcomes such as postpartum infections, rates of blood transfusion, and length of hospital stay in RA. One small study of 38 patients noted that infection rates in RA were no different than controls (8), but a larger administrative database study found an increased risk for wound complications and VTE in women with RA (7).
Similarly, there is a lack of robust data on the effect of RA medications on maternal postpartum outcomes. Specifically, the effect of corticosteroid use on pregnancy outcomes in RA has been controversial. While historically prednisone use had been deemed relatively safe in pregnancy, recent studies show that prednisone use, even at low doses, may be associated with preterm birth (2, 9). Contemporary studies, however, have not investigated the effect of corticosteroid use on maternal postpartum infections.
Electronic health records (EHRs) provide an efficient and cost-effective method to study deliveries to RA patients. These methods can more quickly amass a larger sample compared to single-center, prospective cohort studies. Further, EHR-based studies have longitudinal, dense data that is more comprehensive than administrative database studies and allow for chart review for accurate phenotyping. Using a large, de-identified EHR and validated phenotypes for RA and deliveries, we assembled a cohort of RA deliveries. We assessed the impact of demographics, RA disease characteristics, and RA medications on maternal postpartum outcomes including infection, blood transfusions, and length of stay.
Methods
The Synthetic Derivative
Following approval from the Institutional Review Board of Vanderbilt University Medical Center (VUMC), we used a de-identified version of VUMC’s electronic health record (EHR) called the Synthetic Derivative. The Synthetic Derivative contains clinical information on over 3.2 million unique patients since 1990 (10). VUMC’s patient population draws from a large area of the southern United States and is a key tertiary care center in the region. The Synthetic Derivative contains all available EHR data such as diagnostic and procedure billing codes, demographics, inpatient and outpatient notes, laboratory values, and imaging and pathology reports. Outside records are not available; however, if deliveries external to our institution were documented in clinical notes, they were included in the analysis. Specifically, we included deliveries where delivery dates, mode of delivery, and gestational age were noted. If preeclampsia was not mentioned, we assumed this complication was absent for that delivery. Medication data was assessed from both inpatient and outpatient electronic prescribing systems and a natural language processing program called MedEx. MedEx recognizes medication names and prescription data such as dose, frequency, route, and duration within free-text records and is internally and externally validated (11, 12). Clinical documentation is searchable via keyword, which allows for directed chart review.
Identifying Rheumatoid Arthritis Births
To identify RA deliveries, we applied ≥ 1 delivery-related ICD-9 or ICD-10-CM codes (Supplemental Table 1) and a validated RA algorithm to the entire Synthetic Derivative that spans from 1990 to 2020 with no restrictions on date. The delivery codes have been previously validated in other chronic diseases including SLE (13–16). The RA algorithm required ≥ 1 ICD-9 (714*) or ICD-10-CM RA codes (M05*, M06.0, M06.2, M06.3, M06.8, M06.9), ever mention of a RA medication, and a keyword of “rheumatoid arthritis” and was based on a previously validated RA algorithm (17). A full list of RA medications is included in Supplemental Table 2. Our RA algorithm has a positive predictive value of 90%. We performed chart review on all potential RA deliveries identified by the RA algorithm to confirm case status. RA case status was defined by a diagnosis from an internal or external rheumatologist. From the true RA cases, we included only deliveries that occurred after RA diagnosis. A flowchart of subject selection is shown in Figure 1A. Disease characteristics were assessed via keyword search, chart review, laboratory data, and radiology reports. To be defined as seropositive, a subject could have a “seropositive” keyword, a positive rheumatoid factor, or a positive cyclic citrullinated peptide (CCP). Presence of erosive disease was determined by keyword search for “erosive” or “erosion(s)” in clinic notes, discharge summaries, and radiology reports.
Figure 1. Flow chart of patient selection.
Rheumatoid arthritis (RA) deliveries (A) were identified using a validated RA algorithm and at least one validated pregnancy or delivery-related ICD-9 or ICD-10-CM code (Supplemental Table 1). RA case status was confirmed on chart review and defined by a rheumatologist diagnosis. We identified 331 deliveries to 186 mothers with RA and with available delivery data. Births occurring before RA diagnosis were then excluded resulting in 202 deliveries to 101 mothers. Control pregnancies (B) were identified using at least one ICD-9 or ICD-10-CM delivery code, same as the codes required for RA cases (Supplemental Table 1). We excluded controls who had ICD-9 or ICD-10-CM codes for rheumatoid arthritis or other systemic autoimmune disease (full list of conditions in Supplemental Table 3). We identified approximately 855 control subjects and randomly selected 250 subjects for chart review. We performed chart review to ensure no autoimmune disease and excluded control pregnancies with autoimmune diseases.
Identifying Controls
A control population of deliveries to women without autoimmune disease was identified within the Synthetic Derivative. Control deliveries were identified as those with ≥ 1 ICD-9 or ICD10-CM delivery code, same as the codes required for RA cases (Supplemental Table 1). We also required that controls not have codes for rheumatoid arthritis or other systemic autoimmune disease including ICD-9 codes under the 710.* heading “Diffuse diseases of connective tissue,” the 714.* heading “Rheumatoid arthritis and other inflammatory polyarthropathies,” or ICD-10 codes M05.* (“Rheumatoid arthritis with rheumatoid factor”), M06.* (“Other rheumatoid arthritis”), M32 (“SLE”), M33.* (Dermatopolymyositis), M34.* (“Systemic sclerosis”), M35.* (“Other systemic involvement of connective tissue”), and M36.* (“Systemic disorders of connective tissue in diseases classified elsewhere”). Control subjects all received longitudinal care at VUMC with at least 3 outpatient visits within 5 years to ensure density of records was similar to that of cases. We identified approximately 855 control subjects and randomly selected 250 subjects for chart review. We performed chart review on control pregnancies to ensure no autoimmune disease. Control pregnancies with an autoimmune disease discovered on chart review were excluded. A full list of autoimmune diseases for controls excluded in our study is outlined in Supplemental Table 3. A flowchart of subject selection is shown in Figure 1B.
Outcomes Assessed
Medication use was defined as ever use during the pregnancy and at time of delivery. Pregnancies with missing data on medication use were excluded. Fetal and maternal outcomes were all defined based on obstetrics and gynecology diagnoses in delivery notes and discharge summaries. Preterm birth was defined as live births that were delivered at < 37 weeks. Preeclampsia was considered in pregnancies with ≥ 20 weeks gestation. Maternal postpartum outcomes including blood transfusion (red blood cells or platelets) and length of stay in days were all extracted from obstetric discharge summaries. Maternal postpartum infection (endometritis, surgical site infection, pneumonia, and others) was defined as infection diagnosed by a clinician within 6 weeks postpartum and was assessed by chart review. For infection rates, we included all pregnancies with ≥ 20 weeks gestation. Births with missing infection data were excluded.
Statistical Analysis
We compared pregnancy and postpartum outcomes in RA cases vs. controls. We compared categorial variables using chi-square or Fisher’s exact test and compared continuous variables using the Mann-Whitney U test, as there were non-normal distributions in the data. We performed logistic regression in all deliveries to estimate the association of RA case status with preterm birth, preeclampsia, and postpartum infection after adjusting for age at delivery and race. We also performed logistic regression including only RA deliveries that occurred after RA diagnosis to estimate the association of medication use with preterm birth, preeclampsia, and postpartum infection after adjusting for age at delivery and race. For logistic regression models, odds ratios (ORs) and 95% confidence intervals (95% CIs) are reported. We also performed linear regression to estimate the association of medication use with birthweight in kilograms after adjusting for age at delivery and race. For linear regression, betas and 95% CIs are reported. To assess the impact of missingness on our outcomes, we performed multiple imputation for all linear and logistic regression models. We used the aregImpute function from the Hmisc package in R to conduct multiple imputation using predictive mean matching where five imputations were performed with default settings. For sample size for models, we estimated having 42 RA pregnancies with preterm birth. Applying the rule of 10–15 outcomes per 1 covariate, we estimated having up to 4 covariates for preterm birth for RA models. For postpartum infection, we estimated having 20 RA pregnancies and 30 control pregnancies with infection with having up to 5 covariates for models with both RA and control pregnancies and up to 2 covariates for models with only RA pregnancies. Two-sided p values less than 0.05 were considered significant. Analyses were conducted using R version 4.0.2.
Results
Deliveries to Control Mothers
We initially identified 250 control mothers and excluded 2 mothers with missing delivery data and 24 mothers with autoimmune diseases discovered on chart review resulting in 224 deliveries. A list of the autoimmune diseases in the controls is included in Supplemental Table 3 with the most common conditions being type 1 diabetes (n = 9), ulcerative colitis (n = 5), and Hashimoto’s thyroiditis (n = 3). We then analyzed 224 control mothers with 596 pregnancies. Mean age at delivery was 27 ± 7 with a racial background that was predominantly White at 58% with 38% African American, 2% Asian, 1% Other, and 1% Multi-race (Table 1). Of controls with available data, 11% were of Hispanic ethnicity.
Table 1.
Maternal and Disease Characteristics of RA Pregnancies and Controls.
| Maternal characteristics | Pregnancies in RA patients (n = 202) | Pregnancies in control patients (n = 596) | p value |
|---|---|---|---|
| Mean age at delivery ± standard deviation (SD) (range) years | 31 ± 5 (18–47) | 27 ± 7 (14–46) | p < 0.001 |
| Race (%) | |||
| Caucasian | 85% (165/195) | 58% (332/574) | p < 0.001 |
| African American | 10% (19/195) | 38% (219/574) | p < 0.001 |
| Multi-race | 2% (4/195) | 1% (3/574) | p = 0.06 |
| Asian/Pacific Islander | 2% (5/195) | 2% (13/574) | p = 0.98 |
| Other | 1% (2/195) | 1% (7/574) | p = 0.98 |
| Ethnicity (%) | |||
| Hispanic/Latino | 6% (11/198) | 11% | p = 0.03 |
| Disease characteristics | |||
| Seropositive (RF or CCP) | 75% (104/139) | - | |
| Erosive disease | 39% (37/95) | - | |
| Mean age at RA diagnosis ± SD (years) | 26 ± 5 | - | |
| Mean disease duration at delivery ± SD (years) | 5 ± 4 | - | |
| Medication use during pregnancy | - | ||
| None | 46% | - | |
| Corticosteroids | 41% | - | |
| TNF inhibitors | 13% | - | |
| cDMARDs | 11% | - | |
| Antimalarials | 10% | - |
Deliveries to RA Mothers
We identified 202 deliveries to 101 mothers that occurred after RA diagnosis (Table 1). Mean age at RA diagnosis was 26 ± 5 years, and mean age at delivery was 31± 5 years. Compared to controls, RA mothers were significantly older at time of delivery (31 ± 5 vs. 27 ± 7, p < 0.001). Our RA cohort was less racially diverse than the controls and was predominantly Caucasian (84%) with 10% African American and 6% Hispanic. Of our RA cases, 75% were seropositive and 39% had erosive disease. We compared rates of Cesarean section, preeclampsia, preterm delivery, postpartum maternal infection, and transfusion in RA deliveries where the mother was seropositive vs. seronegative. These outcomes were all similar in deliveries to seropositive vs. seronegative RA mothers (Supplemental Table 4). We performed a similar analysis in RA deliveries where the mother had erosive vs. non-erosive disease. Rates of Cesarean section were significantly higher in deliveries to RA mothers with non-erosive vs. erosive disease (57% vs. 11%, p < 0.001). Rates of preeclampsia, preterm delivery, postpartum maternal infection, and transfusion were all similar in deliveries to RA mothers with non-erosive vs. erosive disease (Supplemental Table 5).
Medication use during pregnancy
Of RA deliveries that occurred after RA diagnosis, 160 deliveries had available data on medication use. Of these deliveries, 54% had medication use during the pregnancy. Corticosteroid use during pregnancy was common at 41%. Conventional disease modifying anti-rheumatic drugs (cDMARDs) and antimalarial use were both uncommon, at 11% and 10%, respectively. cDMARDs used included sulfasalazine, azathioprine, and intravenous immunoglobulin. Tumor necrosis factor inhibitor (TNF inhibitor) use was 13% with no other biologic medications prescribed.
Medication use at time of delivery
Of RA deliveries that occurred after RA diagnosis, 160 deliveries had available data on medication use at time of delivery. Of these, 38% had corticosteroid use, 9% antimalarials, and 6% cDMARDs. The mean dose of corticosteroids at delivery was the prednisone equivalent of 15 mg daily. Only 7% of RA deliveries had TNF inhibitor use at time of delivery.
Maternal and Fetal Outcomes in RA Deliveries and Controls
Cesarean section rates were significantly higher in RA vs. control deliveries (44% vs. 33%, p = 0.02) (Table 2) and higher compared to the general population at 30% (18). Preterm birth rates were significantly higher in RA deliveries vs. controls (27% vs. 13%, p < 0.001) and were also higher compared to the general population (10%) (19). Rates of preeclampsia were similar in RA vs. control deliveries (7% vs. 9% p = 0.45) but were somewhat higher than rates in the general population (3–4%) (20–22). Approximately half of all RA deliveries complicated by preeclampsia occurred preterm, as compared to only 13% in control deliveries (p = 0.001). Mean gestational age in weeks was significantly shorter in deliveries to RA cases compared to controls (37 ± 3 vs. 39 ± 3, p < 0.001). Mean birthweight in kilograms was significantly lower in RA deliveries compared to controls (2.99 ± 0.72 vs. 3.26 ± 0.71, p = 0.006). Mean Apgar scores (at 1 and 5 minutes) in RA deliveries were similar to controls.
Table 2.
Maternal and Fetal Outcomes in RA Pregnancies and Controls.
| Fetal outcomes | Pregnancies in RA patients (n = 202) | Pregnancies in control patients (n = 596) | p value |
|---|---|---|---|
| Cesarean section | 44% (68/156) | 33% (165/497) | p = 0.02 |
| Term | 71% (110/156) | 84% (419/497) | p < 0.001 |
| Preterm | 27% (42/156) | 13% (66/497) | p < 0.001 |
| Miscarriage | 17% (35/202) | 15% (90/596) | p = 0.45 |
| Stillbirth | 2% (4/202) | 1% (3/596) | p = 0.13 |
| Termination | 2% (5/202) | 1% (6/596) | p = 0.23 |
| Mean gestational age (weeks) ± SD | 37 ± 3 | 39 ± 3 | p < 0.001 |
| Mean birthweight (kilograms) ± SD | 2.99 ± 0.72 | 3.26 ± 0.71 | p = 0.006 |
| Preeclampsia | 7% (11/160) | 9% (32/362) | p = 0.45 |
| Preeclampsia occurring preterm | 55% (6/11) | 13% (9/69) | p = 0.001 |
| Apgar score at 1 minute (mean ± SD) | 8 ± 2 | 8 ± 1 | p = 0.06 |
| Apgar score at 5 minutes (mean ± SD) | 9 ± 1 | 9 ± 1 | p = 0.16 |
We performed logistic regression models for maternal and fetal outcomes in RA patients and controls (Table 3). RA case status was significantly associated with preterm birth (OR = 2.45, 95% CI 1.52 – 3.93, p < 0.001) after adjusting for age at delivery and race. Age at delivery (OR = 1.04, 95% CI 1.02–1.07, p = 0.002) was associated with cesarean section after adjusting for race and RA case status. RA case status was not significantly associated with preeclampsia (OR = 1.38, 95% CI 0.63 – 3.04, p = 0.43) after adjusting for age at delivery and race. These model findings were all upheld when we accounted for missingness using multiple imputation (Supplemental Table 6).
Table 3.
Maternal and Fetal outcomes in Rheumatoid Arthritis and Control Deliveries.
| Population | Preeclampsia | Preterm birth | Postpartum infection | |||
|---|---|---|---|---|---|---|
| Raw OR (95% CI) |
Adjusted ORa (95% CI) |
Raw OR (95% CI) |
Adjusted ORa (95% CI) |
Raw OR (95% CI) |
Adjusted ORa (95% CI) |
|
| RA vs. control pregnancies | 0.60 (0.30 – 1.22) | 1.38 (0.63 – 3.04) | 2.11 (1.38 – 3.23) | 2.45 (1.52 – 3.93) | 1.65 (0.75 – 3.61) | 2.10 (0.88 – 4.98) |
Maternal Postpartum Outcomes in RA Pregnancies and Controls
Overall, rates of adverse maternal postpartum outcomes were low among both RA and control deliveries (Table 4). Rates of red blood cell transfusion were the same in RA and control deliveries at 2%. For the 3 RA deliveries that required transfusions, none of these mothers had anemia during the pregnancy and all had postpartum hemorrhage. For the 7 control deliveries that required blood transfusions, 2 had anemia during the pregnancy with 5 having postpartum hemorrhage. Overall infection rates were similar among deliveries to RA and control mothers (8% vs. 4%, p = 0.10). Endometritis (3% vs. 1%, p = 0.27), surgical site infection (1% vs. 1%, p = 0.84), and urinary tract infections (1% vs. 0.2%, p = 0.79) all occurred at similar rates in RA vs. control deliveries. Cellulitis and mastitis each occurred in two RA deliveries (1% each), and there were no occurrences among the controls. RA case status was not significantly associated with postpartum infection (OR = 2.10, 95% CI 0.88 – 4.98, p = 0.09) after adjusting for age at delivery and race (Table 3).
Table 4.
Maternal Postpartum Outcomes in RA Pregnancies and Controls.
| Maternal postpartum outcomes | Pregnancies in RA patients (n = 202) | Pregnancies in control patients (n = 596) | p value |
|---|---|---|---|
| Transfusion (%) | |||
| Platelets | 0% (0/134) | 0% (0/345) | p = 0.93 |
| Red blood cells | 2% (3/135) | 2% (6/350) | p = 0.99 |
| Infection (%) | |||
| Any | 8% (12/148) | 4% (13/303) | p = 0.10 |
| Endometritis | 3% (5/148) | 1% (4/302) | p = 0.27 |
| Cellulitis | 1% (2/148) | 0% (0/291) | p = 0.55 |
| Surgical site infection | 1% (1/148) | 1% (3/303) | p = 0.84 |
| Pneumonia | 0% (0/148) | 1% (4/297) | p = 0.88 |
| Urinary tract infection | 1% (1/148) | 0.3% (1/291) | p = 0.79 |
| Mastitis | 1% (2/148) | 0% (0/291) | p = 0.55 |
| Mean length of stay in days (± SD) | 5 ± 7 | 3 ± 2 | p < 0.001 |
Mean length of stay in days was significantly longer in RA compared to control deliveries (5 ± 7 vs. 3 ± 2, p < 0.001). Among RA deliveries, there were outliers in terms of length of stay, at 37, 45, and 53 days with all three mothers having complications related to non-RA disease manifestations and preterm premature rupture of membranes (PPROM). All three infants required neonatal intensive care unit (NICU) stays. Median length of stay at 3 days was similar for RA and control deliveries.
Effect of RA medications on delivery outcomes
We then investigated the impact of RA medication use on delivery outcomes. In univariate analysis among RA deliveries, corticosteroid use at delivery was not associated with preeclampsia (OR = 3.04, 95% CI 0.89 – 10.39, p = 0.08) or preterm birth (OR = 1.62, 95% CI 0.80 – 3.31, p = 0.18) (Table 3). Corticosteroid use at delivery was associated with postpartum infection (OR = 3.61, 95% CI 1.09 – 11.96, p = 0.04). We found no significant difference in mean daily corticosteroid dose, expressed in mg of prednisone daily, in deliveries with maternal postpartum infection vs. no infection (24 mg vs. 13 mg, p = 0.79). We also found no significant difference in mean daily corticosteroid dose at delivery in preterm vs. term deliveries (21 mg vs. 12 mg, p = 0.11) and in deliveries with preeclampsia vs. no preeclampsia (9 mg vs. 15 mg, p = 0.41). TNF inhibitor at delivery was not associated with postpartum infection (OR = 0.80, 95% CI 0.10 – 6.57, p = 0.83).
In logistic regression models adjusting for age at delivery and race, corticosteroid use at delivery was not associated with preeclampsia (OR = 3.72, 95% CI 0.92–15.03, p = 0.07), preterm birth (OR = 1.37, 95% CI 0.66 – 2.88, p = 0.40), or postpartum infection (OR = 3.18, 95% CI 0.95 – 10.69, p = 0.06) (Table 5). These model findings were all upheld when we accounted for missingness using multiple imputation (Supplemental Table 7). In a linear regression model for birthweight in grams in RA cases, a lower birthweight was associated with corticosteroid use at delivery after adjusting for age at delivery and race (ß = −440, 95% CI −837 – −42, p = 0.03). In other terms, corticosteroid use at delivery was associated with infants weighing 444 grams less, or almost 1 pound less.
Table 5.
Maternal and Fetal Outcomes in Rheumatoid Arthritis Deliveries.
| Outcomes | Preeclampsia | Preterm birth | Postpartum infection | |||
|---|---|---|---|---|---|---|
| Raw OR (95% CI) |
Adjusted ORa (95% CI) |
Raw OR (95% CI) |
Adjusted ORa (95% CI) |
Raw OR (95% CI) |
Adjusted ORa (95% CI) |
|
| RA pregnancies only | ||||||
| Corticosteroid use at delivery vs. not | 3.04 (0.89 – 10.39) | 3.72 (0.92 – 15.03) | 1.62 (0.80 – 3.31) | 1.37 (0.66 – 2.88) | 3.61 (1.09 – 11.96) | 3.18 (0.95 – 10.69) |
Logistic regression models adjusting for age at delivery and race.
Discussion
In a large, real-world EHR study of RA and control deliveries, we examined maternal postpartum and delivery outcomes. Rates of maternal postpartum infection and blood transfusion were similar in RA compared to control deliveries, while mean but not median length of stay was significantly longer in RA deliveries. Limited data exists on maternal postpartum outcomes in RA. Our results provide reassuring data for certain postpartum outcomes and provides additional data on the risk of corticosteroids during pregnancy. This data will be useful for counseling women with RA contemplating pregnancy.
Few studies examine maternal postpartum outcomes. One large administrative database study using the National Inpatient Sample (NIS) also found that total rates of maternal postpartum infection were similar among RA pregnancies and controls (7). This study, however, did find that there were higher rates of wound complications in RA pregnancies (i.e., surgical site infections), which we did not find in our study. One possible explanation for this discrepancy is that in the NIS study outcomes were defined by billing and procedure codes. In contrast, our study defined postpartum outcomes based on extensive chart review. We found chart review to be important for accurate identification of true RA deliveries, particularly to assure RA deliveries occurred after an RA diagnosis. While the NIS study did not look specifically at blood transfusion rates, their rates of postpartum hemorrhage were similar among RA deliveries and controls, which reflects the findings of our study. A small administrative database study of 38 RA and 150 control deliveries also found no increased risk of postpartum infections among RA patients compared to controls (8).
There are few studies exploring maternal length of stay in RA deliveries, and existing data is conflicting. Two studies found that women with RA had significantly longer mean length of hospital stays compared to controls (23, 24). Another small study, however, found that women with RA had similar length of stay to controls (8). It is possible that discrepancies may arise from differences in the age of patients, the complexity of the patient population, as well as differences in study design. Our median length of stay was similar to controls, suggesting that our longer mean length of stay is likely the result of a few outlier deliveries with long lengths of stay, which were attributed to pre-existing, non-RA related maternal conditions and PPROM.
Preterm birth was significantly associated with RA case status after adjusting for age at delivery and race. Gestational age was significantly shorter, and mean birthweight was significantly lower in RA deliveries. Several studies have also reported higher rates of preterm birth in women with RA and shorter gestational age (3, 6–8, 23, 25, 26). A large national registry study showed that children born to women with RA had higher risk of preterm birth compared to children born to women without RA (3). Four other large database studies also found higher rates of preterm birth in RA pregnancies compared to control pregnancies which is consistent with our findings (7, 23, 25, 27). The majority of these studies are administrative database studies. In our real-world EHR cohort, we confirm an increased risk of preterm birth in RA.
Six studies have also shown that women with RA have a higher risk of delivering infants of lower birthweight along with a higher risk of infants that are small for gestational age and have fetal growth restriction (3, 5, 7, 23, 25, 28). Our study confirms these findings of lower birthweights in infants to RA mothers. In one study, lower birthweights were attributed to higher rates of prematurity; as this difference was no longer significant after adjusting for gestational age (24). In contrast to our study, two studies show no increased risk of low birth weight in RA patients compared to controls (27, 29). Aside from being born premature, it is not completely clear why infants born to women with RA may have lower birthweight. Another explanation for low birthweight could be corticosteroid exposure during pregnancy (2, 26). In our study, corticosteroid use at delivery was significantly associated with lower birthweights after adjusting for age at delivery and race.
Increased rates of cesarean section in women with RA have previously been reported. Three studies have found higher rates of cesarean section in women with RA compared to controls (5, 7, 23, 24, 27, 28). While we found higher rates of cesarean section in RA cases vs. controls in univariate analyses, only age at delivery was associated with cesarean section after adjusting for RA case status and race. Further, we observed higher rates of Cesarean section in RA deliveries where the mother had non-erosive vs. erosive disease. High rates of cesarean section in women with RA may stem from patient and provider concerns about physical ability to undergo labor thus leading to elective surgery (23). These concerns could arise from true disease activity or lack of provider comfort and familiarity with RA patients (23). It is difficult, however, to attribute any clear cause for higher rates of cesarean section in our study, as the indications for cesarean sections were not available in our dataset.
In our study, preeclampsia was not increased in RA deliveries compared to control deliveries. Conflicting studies exist in the literature, with three studies showing no increased risk of preeclampsia (5, 8, 24) but four studies reporting higher rates of preeclampsia in RA cases compared to controls (7, 25, 27, 28). One of these studies found almost identical rates of preeclampsia to rates in our study (7). These conflicting results could reflect differences in our study population compared to other populations including the larger NIS administrative database cohort. In one study, the small increased risk of preeclampsia was no longer significant when adjusting for maternal age. While we did not find an increased risk of preeclampsia in our study, we did find an increased risk of preterm preeclampsia compared to controls. In the general population, preeclampsia typically occurs later in pregnancy (30). Studies in SLE pregnancies show that preeclampsia occurs more frequently in the preterm setting (31). It is possible that RA pregnancies follow a similar pattern to SLE, although the mechanism is not clear.
Similar to other studies, we report that corticosteroid use during pregnancy is common in RA pregnancies (2). Historically, corticosteroids were felt to be safe during RA pregnancy; however, newer studies suggest adverse fetal effects (2, 9, 26). Studies in women with other conditions such as asthma, inflammatory bowel disease, and SLE have all found that corticosteroid use during pregnancy is associated with a significantly increased risk of preterm birth compared with women not taking corticosteroids (32–37). Higher disease activity states in RA, necessitating more frequent and higher corticosteroid doses, have also been associated with greater risk of preterm birth, lower gestational age, and lower birthweight (2, 26). One prospective cohort study found that higher daily and cumulative prednisone dose trajectories were associated with shorter gestational length (9). In our study, while corticosteroid use at delivery was not associated with preterm birth after adjusting for age at delivery and race, corticosteroid use at delivery was associated with a significantly lower birthweight of almost one pound.
Our study demonstrated that corticosteroid use at time of delivery was associated with a higher risk of maternal postpartum infections in univariate analysis but not after adjusting for age at delivery and race. Most likely we were underpowered to find an association with corticosteroid use and postpartum infection, as we observed a low number of postpartum infections in RA cases. In one NIS study, the authors proposed that their RA population may have had increased risk of wound complications due to possible corticosteroid use and impaired wound healing, but this could not be verified, as medication use could not be assessed (7). In contrast, TNF inhibitor use was not associated with increased risk of postpartum infections. This finding has important implications for medication counseling during pregnancy. Prior practice and some current practice among rheumatologists is to discontinue all medications when patients report pregnancy, with the plan to use corticosteroids for flares. There is now increasing data that this management strategy may increase the risk of adverse pregnancy outcomes, particularly preterm birth, and postpartum infections. Providers may need to advocate for continuing certain cDMARDs and biologics to limit corticosteroid exposure during pregnancy.
Our study has limitations. It is a single-center, EHR-based study in the Southeastern United States, which limits its generalizability to other RA populations in the US. As our center is a tertiary care referral center, patients in our study may be more likely to have higher complexity as compared to studies that include community-based hospital settings. These concerns are mitigated by using a non-autoimmune control cohort at the same institution. In addition, outside records from external deliveries were not available for review, which led to a proportion of pregnancies having missing data, which limited sample size in our analyses. Often, however, OBGYN and maternal fetal medicine physicians document external deliveries and outcomes in clinical notes, which were included in our analyses. Further, to assess for the impact of missingness on our models, we performed multiple imputation and found all our model results were upheld. As RA disease activity measures were not collected systematically in clinical notes, we could not assess the association of disease activity with maternal and fetal outcomes. As our EHR database is de-identified, we do not have available data on education level, zip code, income, or insurance status. We acknowledge that these social determinants can impact pregnancy outcomes. The main strength of our study is the contribution of a real-world, EHR cohort study, in which extensive chart review was performed, which builds upon administrative database studies where chart review and granular data such as medication use is not readily available. Further, we examined clinically important outcomes such as postpartum infection, blood transfusions, and length of stay that previously had been understudied.
Conclusions
In conclusion, women with RA have an increased risk of adverse fetal outcomes such as preterm birth, lower birthweight, and shorter gestational age. Our study, however, provides reassurance that maternal outcomes such as postpartum infection and blood transfusion may not be adversely affected. Corticosteroid use at time of delivery increased the risk of lower weight babies and postpartum infections in RA mothers, while TNF inhibitor use did not. Given this information, rheumatologists should educate patients on the risk of both adverse fetal and maternal outcomes with corticosteroid use and consider advocating for the continuation of TNF inhibitors and other pregnancy-safe cDMARDs during pregnancy.
Supplementary Material
Highlights:
To the best of our knowledge, our study is the only study that focuses on multiple maternal postpartum outcomes in women with RA.
To the best of our knowledge, our study is the only study documenting the risk of postpartum blood transfusion in women with RA.
We contribute a large, diverse, real-world EHR cohort study on RA fetal outcomes and maternal postpartum outcomes to the literature, which is mostly comprised of administrative database studies.
We are among the first to explore the effect of RA medications on maternal postpartum outcomes such as postpartum infections, length of stay, and blood transfusion.
Financial Support:
This work was supported by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (1K08 AR072757-01, Barnado); National Institutes of Health/National Center for Research Resources (UL1 RR024975, VUMC); National Institutes of Health/National Center for Advancing Translational Sciences (ULTR000445, VUMC); the Rheumatology Research Foundation (K Supplement Award, Barnado).
Footnotes
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Conflict of Interest: none
References
- 1.Dugowson CE, Koepsell TD, Voigt LF, Bley L, Nelson JL, Daling JR. Rheumatoid arthritis in women. Incidence rates in group health cooperative, Seattle, Washington, 1987–1989. Arthritis Rheum. 1991;34(12):1502–7. 10.1002/art.1780341205. [DOI] [PubMed] [Google Scholar]
- 2.de Man YA, Hazes JM, van der Heide H, Willemsen SP, de Groot CJ, Steegers EA, et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 2009;60(11):3196–206. 10.1002/art.24914. [DOI] [PubMed] [Google Scholar]
- 3.Rom AL, Wu CS, Olsen J, Kjaergaard H, Jawaheer D, Hetland ML, et al. Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis: a nationwide cohort study. Arthritis Rheumatol. 2014;66(12):3265–73. 10.1002/art.38874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bermas BL, Tassinari M, Clowse M, Chakravarty E. The new FDA labeling rule: impact on prescribing rheumatological medications during pregnancy. Rheumatology (Oxford). 2018;57(suppl_5):v2–v8. 10.1093/rheumatology/key010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54(3):899–907. 10.1002/art.21663. [DOI] [PubMed] [Google Scholar]
- 6.Langen ES, Chakravarty EF, Liaquat M, El-Sayed YY, Druzin ML. High rate of preterm birth in pregnancies complicated by rheumatoid arthritis. Am J Perinatol. 2014;31(1):9–14. 10.1055/s-0033-1333666. [DOI] [PubMed] [Google Scholar]
- 7.Aljary H, Czuzoj-Shulman N, Spence AR, Abenhaim HA. Pregnancy outcomes in women with rheumatoid arthritis: a retrospective population-based cohort study. J Matern Fetal Neonatal Med. 2020;33(4):618–24. 10.1080/14767058.2018.1498835. [DOI] [PubMed] [Google Scholar]
- 8.Barnabe C, Faris PD, Quan H. Canadian pregnancy outcomes in rheumatoid arthritis and systemic lupus erythematosus. Int J Rheumatol. 2011;2011:345727. 10.1155/2011/345727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Palmsten K, Rolland M, Hebert MF, Clowse MEB, Schatz M, Xu R, et al. Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: Daily and cumulative dose. Pharmacoepidemiol Drug Saf. 2018;27(4):430–8. 10.1002/pds.4410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther. 2008;84(3):362–9. 10.1038/clpt.2008.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Xu H, Stenner SP, Doan S, Johnson KB, Waitman LR, Denny JC. MedEx: a medication information extraction system for clinical narratives. J Am Med Inform Assoc. 2010;17(1):19–24. 10.1197/jamia.M3378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jiang M, Wu Y, Shah A, Priyanka P, Denny JC, Xu H. Extracting and standardizing medication information in clinical text - the MedEx-UIMA system. AMIA Jt Summits Transl Sci Proc. 2014;2014:37–42. [PMC free article] [PubMed] [Google Scholar]
- 13.Yasmeen S, Romano PS, Schembri ME, Keyzer JM, Gilbert WM. Accuracy of obstetric diagnoses and procedures in hospital discharge data. Am J Obstet Gynecol. 2006;194(4):992–1001. 10.1016/j.ajog.2005.08.058. [DOI] [PubMed] [Google Scholar]
- 14.Boulet SL, Okoroh EM, Azonobi I, Grant A, Craig Hooper W. Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population. Matern Child Health J. 2013;17(2):200–7. 10.1007/s10995-012-1216-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zhang S, Cardarelli K, Shim R, Ye J, Booker KL, Rust G. Racial disparities in economic and clinical outcomes of pregnancy among Medicaid recipients. Matern Child Health J. 2013;17(8):1518–25. 10.1007/s10995-012-1162-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Barnado A, Eudy AM, Blaske A, Wheless L, Kirchoff K, Oates JC, et al. Developing and Validating Methods to Assemble Systemic Lupus Erythematosus Births in the Electronic Health Record. Arthritis Care Res (Hoboken). 2020. 10.1002/acr.24522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Carroll RJ, Thompson WK, Eyler AE, Mandelin AM, Cai T, Zink RM, et al. Portability of an algorithm to identify rheumatoid arthritis in electronic health records. J Am Med Inform Assoc. 2012;19(e1):e162–9. 10.1136/amiajnl-2011-000583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Clapp MA, Barth WH. The Future of Cesarean Delivery Rates in the United States. Clin Obstet Gynecol. 2017;60(4):829–39. 10.1097/GRF.0000000000000325. [DOI] [PubMed] [Google Scholar]
- 19.Martin JA, Osterman MJK. Describing the Increase in Preterm Births in the United States, 2014–2016. NCHS Data Brief. 2018(312):1–8. [PubMed] [Google Scholar]
- 20.Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: age-period-cohort analysis. BMJ. 2013;347:f6564. 10.1136/bmj.f6564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31. 10.1097/01.AOG.0000437382.03963.88. [DOI] [PubMed] [Google Scholar]
- 22.Force USPST, Bibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, et al. Screening for Preeclampsia: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(16):1661–7. 10.1001/jama.2017.3439. [DOI] [PubMed] [Google Scholar]
- 23.Kishore S, Mittal V, Majithia V. Obstetric outcomes in women with rheumatoid arthritis: Results from Nationwide Inpatient Sample Database 2003–2011. Semin Arthritis Rheum. 2019;49(2):236–40. 10.1016/j.semarthrit.2019.03.011. [DOI] [PubMed] [Google Scholar]
- 24.Reed SD, Vollan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern Child Health J. 2006;10(4):361–6. 10.1007/s10995-006-0073-3. [DOI] [PubMed] [Google Scholar]
- 25.Norgaard M, Larsson H, Pedersen L, Granath F, Askling J, Kieler H, et al. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med. 2010;268(4):329–37. 10.1111/j.1365-2796.2010.02239.x. [DOI] [PubMed] [Google Scholar]
- 26.Bharti B, Lee SJ, Lindsay SP, Wingard DL, Jones KL, Lemus H, et al. Disease Severity and Pregnancy Outcomes in Women with Rheumatoid Arthritis: Results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. J Rheumatol. 2015;42(8):1376–82. 10.3899/jrheum.140583. [DOI] [PubMed] [Google Scholar]
- 27.Wallenius M, Salvesen KA, Daltveit AK, Skomsvoll JF. Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand. 2014;93(3):302–7. 10.1111/aogs.12324. [DOI] [PubMed] [Google Scholar]
- 28.Lin HC, Chen SF, Lin HC, Chen YH. Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-based study. Ann Rheum Dis. 2010;69(4):715–7. 10.1136/ard.2008.105262. [DOI] [PubMed] [Google Scholar]
- 29.Posfai E, Banhidy F, Urban R, Czeizel AE. Birth Outcomes of Children Born to Women with Rheumatoid Arthritis. Cent Eur J Public Health. 2015;23(2):128–34. 10.21101/cejph.a3968. [DOI] [PubMed] [Google Scholar]
- 30.Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013;209(6):544 e1–e12. 10.1016/j.ajog.2013.08.019. [DOI] [PubMed] [Google Scholar]
- 31.Simard JF, Arkema EV, Nguyen C, Svenungsson E, Wikstrom AK, Palmsten K, et al. Early-onset Preeclampsia in Lupus Pregnancy. Paediatr Perinat Epidemiol. 2017;31(1):29–36. 10.1111/ppe.12332. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, et al. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol. 2004;113(6):1040–5. 10.1016/j.jaci.2004.03.017. [DOI] [PubMed] [Google Scholar]
- 33.Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol. 2004;18(1):93–101. 10.1016/j.reprotox.2003.10.007. [DOI] [PubMed] [Google Scholar]
- 34.Bakhireva LN, Jones KL, Schatz M, Johnson D, Chambers CD, Organization Of Teratology Information Services Research G. Asthma medication use in pregnancy and fetal growth. J Allergy Clin Immunol. 2005;116(3):503–9. 10.1016/j.jaci.2005.05.027. [DOI] [PubMed] [Google Scholar]
- 35.Chakravarty EF, Colon I, Langen ES, Nix DA, El-Sayed YY, Genovese MC, et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol. 2005;192(6):1897–904. 10.1016/j.ajog.2005.02.063. [DOI] [PubMed] [Google Scholar]
- 36.Al Arfaj AS, Khalil N. Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia. Lupus. 2010;19(14):1665–73. 10.1177/0961203310378669. [DOI] [PubMed] [Google Scholar]
- 37.Broms G, Granath F, Stephansson O, Kieler H. Preterm birth in women with inflammatory bowel disease - the association with disease activity and drug treatment. Scand J Gastroenterol. 2016;51(12):1462–9. 10.1080/00365521.2016.1208269. [DOI] [PubMed] [Google Scholar]
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