Objective Using a 3-year nationwide population-based database (2001–3), this study aims to examine the relationship between rheumatoid arthritis (RA) and adverse pregnancy outcomes.
Methods The study used the Taiwan National Health Insurance Research Dataset and birth certificate registry. In total, 1912 mothers with RA and 9560 matched comparison mothers were included. Separate conditional logistic regression analyses were carried out to explore the risk of low birthweight (LBW), preterm births, small for gestational age (SGA) infants, preeclampsia and delivery mode (vaginal vs caesarean section (CS)) for the study and comparison groups.
Results Regression analyses showed that the adjusted odds of LBW, SGA infants, preeclampsia and CS for women with RA were 1.47 (95% CI 1.22 to 1.78), 1.20 (95% CI 1.05 to 1.38), 2.22 (95% CI 1.59 to 3.11) and 1.19 (95% CI 1.07 to 1.31) times, respectively, that of comparison mothers.
Conclusion Women with RA had an increased risk of LBW, SGA babies, preeclampsia and CS compared with unaffected women.
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Rheumatoid arthritis (RA) is one of the most common chronic arthritides which predominates in women, commonly affects women of childbearing age and may complicate pregnancy.1,–,3 RA, the autoimmune inflammatory arthritis principally attacking the joints and affecting many tissues and organs, may complicate pregnancy.
Studies have shown increased premature births,4 5 caesarean sections (CS),4 6 low birthweight (LBW),4 infants small for gestational age (SGA)4 and perinatal death7 in pregnant women with inflammatory arthritis. In particular, using a birth registry, women with rheumatic disease had increased risks of preeclampsia, premature delivery, SGA infants and CS, compared with unaffected women.4 In a population-based retrospective cohort, significant effects of maternal RA on the risk of prematurity and CS were observed.6
Nevertheless, contradictory findings were reported. For example, while some displayed an increased risk of LBW infants among women with RA,4 8 others identified a null association.6 These inconsistencies might be attributed to various limitations experienced by the existing studies, such as recruiting relatively small study samples,5 9 using selective data of hospitals or population subgroups,6 analysing obstetric but not infant-specific outcomes,10 or lacking a specific RA diagnosis.4 To date, few studies have addressed pregnancy outcomes specifically for women with RA.
This study thus aimed to examine whether maternal RA was associated with an increased risk of adverse pregnancy outcomes, compared with unaffected mothers, in an unselected nationwide population-based dataset.
Two datasets were used. The first was the Taiwan National Health Insurance Research Dataset (NHIRD), covering inpatient and ambulatory care claims during 1996–2003. The second database came from the 2001–3 national birth certificate registry (NBCR) supervised by the Ministry of the Interior in Taiwan. The data consisted of certain pregnancy outcomes and parental characteristics. The validity of Taiwan's birth registry was verified.11
The mothers' and infants' unique personal identification numbers provided links between the NHIRD and NBCR. Because all personal identifiers were then encrypted, this study, using de-identified secondary data, was exempt from full review by the Internal Review Board.
Of 473 529 women having live singleton births between 2001 and 2003, 1959 received a diagnosis of RA (International Classification of Disease version 9-CM code 714.0) either during ambulatory care visits or hospitalisation from 1998 to 2003 (inclusive). The RA was usually diagnosed by specialists in rheumatology based on clinical symptoms, radiographic changes and the identification of serum rheumatoid factor. We excluded women who had been diagnosed with any type of chronic diseases (including hypertension, diabetes, systemic lupus erythematosus, gout, sarcoidosis or ankylosing spondylitis) that could increase the risk of adverse pregnancy outcomes (n=47), leaving 1912 mothers with RA for analysis.
In the remaining 471 570 mothers, women who had been diagnosed with the same chronic disease as RA mothers during ambulatory care visits between 1996 and 2003 were excluded. We then randomly selected 9560 mothers (five for each RA woman) matched with the RA group in age (<20, 20–24, 25–29, 30–34 and ≥35 years), parity (1, 2 and ≥3) and year of delivery, as our comparison group.
Variables of interest
The independent variable was whether or not a woman had been diagnosed with RA between 1998 and 2003. The outcome variables of interest were all dichotomous, including LBW (<2500 g), preterm gestation (<37, <32 and <28 completed weeks of gestation, respectively), SGA (birth weight below the 10th percentile for gestational age-specific birthweight distribution), preeclampsia and delivery mode (CS vs vaginal delivery). Outcomes of spontaneous abortion, stillbirth and congenital abnormality were not selected because of lacking corresponding records in the NBCR.
Potential confounders were considered, including maternal and infant characteristics, together with family monthly income as a socioeconomic indicator. Parental age difference was also included as it might be associated with adverse pregnancy outcomes.12
The SAS statistical package (SAS System for Windows, version 8.2) was used for analyses. The χ2 tests were conducted first. Then, separate conditional logistic regression analyses were carried out to explore the risk of adverse pregnancy outcomes in relation to RA, simultaneously adjusting for potential confounders. Since maternal highest education level was highly correlated with family monthly income, we only included family monthly income in the regression modelling. Crude and adjusted odds ratios (OR) are presented with 95% CI. A two-sided p value of less than 0.05 was considered statistically significant.
Table 1 shows that there were significant differences in the incidence of infant LBW, SGA, preeclampsia and CS, comparing the two groups. In addition, the mean birthweight for all sampled mothers was 3136 g (range 1205–4200); the mean birthweights for mothers with and without RA were 3101 g (range 1205–4160) and 3141 g (range 1330–4200), respectively. The mean gestational age for all sampled mothers was 38.4 weeks (range 27–43); the mean gestational ages for mothers with and without RA were 38.3 weeks (range 27–43) and 38.5 weeks (range 29–41), respectively (not shown in table 1).
Table 2 describes the crude and adjusted OR of adverse pregnancy outcomes in relation to RA. Compared with unaffected mothers, mothers with RA were more likely to have LBW infants (OR 1.47, 95% CI 1.22 to 1.78), SGA babies (OR 1.20, 95% CI 1.05 to 1.38), preeclampsia (OR 2.22, 95% CI 1.59 to 3.11) and undergo CS (OR 1.19, 95% CI 1.07 to 1.31), after adjusting for potential confounding factors. Mothers with RA had no higher odds of preterm births than unaffected mothers, regardless of the definition of preterm cut-off points.
Further treating infant birthweight as a continuous variable, multivariate linear regression analysis revealed that infants of mothers with RA had, on average, 26.5 g (p<0.001) lower birthweight than those of unaffected mothers, after adjusting for the same covariates as the above-mentioned models.
This nationwide population-based study demonstrated that after adjusting for potential confounders, mothers with RA were 1.47, 1.20, 2.22 and 1.19 times more likely than unaffected mothers to have LBW, SGA babies, preeclampsia and undergo CS, respectively. Our findings were parallel with some previous studies that found that mothers with RA had an increased risk of preeclampsia,4 delivery by the caesarean method4 6 10 and LBW infants,4 13 compared with unaffected women. Nevertheless, a study by Reed et al6 failed to observe a significant effect of maternal RA on the risk of LBW. Furthermore, several studies also observed a significant relationship between preterm birth and RA in mothers,4 6 13 14 although we found mothers with RA had no higher odds of having preterm births than unaffected mothers, regardless of the definition of preterm cut-off points. Such inconsistent results may be due to differences in patient selection, the number of patients included in the series, methodological differences in study design, the presence or lack of a comparison group and the availability of advanced obstetric care. For example, Reed et al6 analysed inpatient data with predominantly non-Hispanic white women. Skomsvoll et al4 recruited women with various diagnoses, including RA, juvenile RA and ankylosing spondylitis. The relationship between maternal RA and adverse pregnancy outcomes cannot be specifically addressed.
To our knowledge, our study is the most complete nationwide population-based study ever conducted to assess the risk of adverse pregnancy outcomes among women with RA. Unlike earlier studies that included participants from diverse ethnic groups, over 98% of Taiwan's residents are of Chinese Han ethnicity. Whereas the homogenous population may exempt our study from potential confounding by race, it also limits the generalisability to other ethnic groups. In addition, we used nationwide population-based datasets linking the NHIRD with NBCR, which leaves little room for selection and non-response biases. The very large sample size in this study provides ample statistical power to detect differences in the risk of adverse birth outcomes comparing pregnant women with and without RA.
However, four limitations merit attention. First, the NHIRD lacks clinical information and therefore did not allow us to differentiate study participants according to the severity of their RA. Second, NHIRD uses discharge diagnoses provided by treating physicians, and no standardised criteria were used to define cases, which could leave some room for bias due to case misclassification. Furthermore, because women with RA might be miscategorised as unaffected mothers if they had been diagnosed long before being pregnant (ie, earlier than 1997 but not 1998–2003), our results would probably be biased towards the null. Third, multiple pregnancies may be a concern in the association investigated. However, due to the similar results observed among women in their first pregnancy and among all pregnancies, we chose to report all pregnancies to possess ample statistical power for examining a rarer outcome of preeclampsia. Finally, effects of pharmacotherapy in women with RA may be significant.15 Because the NHIRD does not include complete information regarding medications taken during pregnancy, it is not possible for us to assess the confounding role of medications in the relationship between RA and adverse birth outcomes.
Our findings suggest a need for more intensive prenatal care among pregnant mothers with RA. In addition, early intervention should be considered to counter potential adverse obstetric outcomes for pregnant women with RA. Future studies are needed to examine the potential mechanisms by which RA produces adverse pregnancy outcomes. Future studies exploring the association between adverse birth outcomes and the severity of RA and medications taken during pregnancy are also warranted, to enable more specific interpretation of these findings.
This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.