Adverse Effects of Maternal Rheumatoid Arthritis During Pregnancy on Children
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by invasive arthritis, affecting approximately 1% of the global population. It predominantly affects young and middle-aged women, many of whom may experience one or more pregnancies during the course of the disease. The developmental origins of health and disease (DOHaD) concept suggests that health hazards occurring early in life can have long-term effects on an individual’s health. In this context, maternal RA during pregnancy can significantly influence the health of the offspring. This article comprehensively discusses the impact of maternal RA on pregnancy outcomes, the health of children, and the underlying mechanisms involved.
Pregnancy Outcomes in Women with Rheumatoid Arthritis
Women with RA often face challenges related to fertility and pregnancy. They tend to have longer conception periods and reduced pregnancy rates, which may be attributed to their medical condition and the use of medications such as non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and other disease-modifying antirheumatic drugs (DMARDs). The relationship between RA and abortion remains controversial, with some studies suggesting a higher abortion rate among women with RA, particularly if medications are improperly managed during pregnancy.
Assisted reproductive technology (ART) has become a viable option for women with RA who struggle with infertility. ART includes follicular stimulation, improved estrogen levels, artificial insemination, and in vitro fertilization-embryo transfer. A study found that the frequency of ART use in women with RA was significantly higher than in the general population (23.0% vs. 5.1%, P < 0.001). Additionally, the average maternal age of women with RA was higher (34.7 years) compared to the general population (31.8 years). Despite successful conception through ART, the live birth rate of transplanted embryos in women with RA was lower than in women without RA. This highlights the importance of early intervention and proper management of RA to improve fertility outcomes.
Disease Activity During and After Pregnancy
Pregnancy can have a complex impact on the disease activity of women with RA. Some women experience partial remission during pregnancy, with improved disease activity rates ranging between 48% and 65%. This improvement is thought to be driven by fetal antigens and elevated levels of estrogen, progesterone, and human chorionic gonadotropin, which promote immune regulation. Women who are negative for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are more likely to experience disease improvement during pregnancy. Additionally, pregnant women with low disease activity scores (DAS28-CRP) and those using glucocorticoids in the first trimester are more likely to achieve remission.
However, the postpartum period poses a significant risk for disease exacerbation. The risk of elevated disease activity increases between 62% and 90% during the six months postpartum, peaking around 12 weeks after delivery. Changes in immune cells, cytokine patterns, and hormonal shifts contribute to this increased disease activity. Prolonged breastfeeding (>17 months) has also been associated with a higher risk of RA exacerbation. Furthermore, pregnant women with RA are more likely to experience complications such as hypertension and pre-eclampsia. Data from the Norwegian Birth Registry indicate that the risk of pre-eclampsia in RA patients is 5.0%, compared to 3.4% in the general population.
Impact on Fetal and Neonatal Health
Maternal RA during pregnancy is associated with adverse fetal and neonatal outcomes. Elevated disease activity increases the risk of intrauterine growth restriction, preterm birth, and low birth weight. A study conducted in Japan found that women with RA had higher rates of preterm birth (27.5% vs. 5.6%, P < 0.001), reduced offspring birth weight (51.6% vs. 9.5%, P < 0.001), and increased fetal growth restriction (28.6% vs. 4.1%, P < 0.001) compared to the general population. Circulating cytokines in the maternal blood, particularly high levels of interleukin-6 in the first trimester, are associated with decreased birth weight. As disease activity (DAS28 score) increases during pregnancy, the birth weight of infants tends to decrease.
Low birth weight can lead to compensatory growth in childhood, but it is also associated with an increased risk of cardiovascular and metabolic conditions in adulthood. Additionally, high disease activity in pregnant women with RA increases the likelihood of cesarean section. In a parallel cohort, the cesarean section rate was 22% in women with high disease activity (DAS28-CRP >3.2) compared to 10% in those with low disease activity (DAS28-CRP <3.2).
Medication Use During Pregnancy
The use of medications during pregnancy in women with RA can also impact fetal health. High doses of prednisone (>7.5 mg/day) are associated with higher preterm birth rates and lower fetal weight compared to lower doses or no prednisone use. Biologic DMARDs (bDMARDs) can cross the placenta, leading to intrauterine drug exposure that may last up to 12 months, with a median clearance time of six months. The timing of maternal biologics during pregnancy is crucial in assessing potential risks to the infant, with late-trimester exposure posing a higher risk.
Live vaccines, such as the bacille Calmette-Guerin (BCG) vaccine, should be avoided in infants exposed to bDMARDs during the perinatal period due to the risk of disseminated infections. For infants exposed to tumor necrosis factor inhibitors (TNFi), it is recommended to postpone all live vaccines until six months after birth and avoid BCG vaccination in the first 12 months. Methotrexate, leflunomide, mycophenolate mofetil, and cyclophosphamide are confirmed teratogens and should be discontinued before conception. Cyclophosphamide can also accumulate in breast milk and is contraindicated during breastfeeding. In contrast, sulfasalazine (up to 2000 mg/day), hydroxychloroquine (200–400 mg/day), azathioprine (up to 2 mg/kg/day), and cyclosporine are considered safe during pregnancy.
Long-Term Health Risks for Children
Children born to mothers with RA are at an increased risk of developing chronic diseases. Cytokine-mediated inflammation in the maternal circulatory system can affect fetal development, particularly in sensitive organs such as the lungs, brain, and intestines. A nationwide epidemiological study based on the Danish Health Register found that children of mothers with RA had a significantly higher incidence of several chronic diseases. For example, the incidence of type 1 diabetes increased by 30%, and the risk of juvenile idiopathic arthritis increased threefold. Additionally, the risk of autism spectrum disorder (ASD) was found to be approximately 30% higher in children of mothers with RA, although another study in Taiwan found no significant increase in ASD risk.
Children of mothers with RA also have a higher risk of epilepsy (61% increase) and a threefold increased risk of developing RA themselves. A retrospective study in Denmark found that 3.9% of boys born to mothers with RA had cryptorchidism, compared to 2.82% in the general population.
Epigenetic Changes in Children of Mothers with RA
Epigenetic modifications, such as DNA methylation, may play a role in the increased disease risk observed in children of mothers with RA. A study using the Illumina 450K gene chip method identified 147 CpG sites with differential DNA methylation patterns in children born to mothers with RA compared to the general population. Five CpG sites (cg06642177, cg08867893, cg06778273, cg07786668, and cg20116574) were most significantly associated with methylation differences. Some of these CpG sites are linked to conditions such as type 2 diabetes, cardiovascular disease, and obesity. For example, the CpG site cg11220663 was associated with decreased expression of the ADD2 gene, which is implicated in hypertension, cancer, and systemic lupus erythematosus.
These findings suggest that maternal RA may induce epigenetic changes in the offspring, potentially contributing to their increased risk of chronic diseases. However, further research with larger sample sizes is needed to fully elucidate these mechanisms.
Conclusion
Maternal RA during pregnancy has significant implications for both maternal and child health. Women with RA face challenges related to fertility, pregnancy, and postpartum disease activity. Elevated disease activity and medication use during pregnancy increase the risk of adverse fetal outcomes, including intrauterine growth restriction, preterm birth, and low birth weight. Children born to mothers with RA are at an increased risk of developing chronic diseases, potentially due to epigenetic modifications induced by maternal inflammation. Proper management of RA during pregnancy, including the careful use of medications, is essential to minimize these risks. Additionally, children of mothers with RA should be monitored for indicators of cardiovascular and metabolic diseases.
doi.org/10.1097/CM9.0000000000001374
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