Maternal Rheumatoid Arthritis During Pregnancy: Understanding the Adverse Effects on Children

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Maternal Rheumatoid Arthritis During Pregnancy: Understanding the Adverse Effects on Children

Author: Rong Li 1, Dan Ma2, Ya-Zhen Su1,2, Gai-Lian Zhang2, Ke Xu2, Li-Yun Zhang2

Author Affiliations:

  • 1Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030032, China

  • 2Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, China

Corresponding Author: Li-Yun Zhang, Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan 030032, Shanxi, China. E-Mail: 1315710223@qq.com

DOI: 10.1097/CM9.0000000000001374

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately 1% of the global population. Young and middle-aged women are particularly prone to RA, and many of them may experience pregnancy during the course of the disease. The developmental origins of health and disease concept suggests that early-life health hazards can impact later-life health. In this context, RA exposure during pregnancy can potentially influence the health of the offspring. This article delves into the pregnancy status of women with RA and explores the possible effects of RA on the health of their children.

Pregnancy and Fertility in Women with RA

Women with RA often face challenges related to pregnancy. They tend to have longer pregnancy periods and reduced pregnancy rates. This could be due to their individual medical conditions and the use of medications such as non-steroidal anti-inflammatory drugs, glucocorticoids, etc., during treatment. The relationship between RA and abortion is still debated. Some believe that the abortion rate is relatively high among women with RA, and improper medication during pregnancy can contribute to this.

Assisted reproductive technology (ART) offers hope to infertile women with RA. A study found that the frequency of ART in women with RA was significantly higher (23.0% vs. 5.1%, P < 0.001) than in the general population, and the average maternal age was also relatively higher (34.7 vs. 31.8 years). However, even with successful conception via ART, the live birth rate of transplanted embryos in women with RA was lower than in non-RA women. Therefore, rheumatologists and obstetricians/gynecologists should work together to guide RA patients, standardize drug use to maintain disease stability, and consider ART for RA patients before the age of 35 to improve fertility rates.

Impact of Pregnancy on RA Patients

Pregnancy can have a significant impact on the condition of RA patients. During pregnancy, the condition of women with RA may partially improve, but there is a risk of postpartum deterioration. The balance between proinflammatory and anti-inflammatory mechanisms shifts during pregnancy in RA women. A combined improved disease activity rate between 48% and 65% has been observed. Fetal antigens and high levels of estrogen, progesterone, and human chorionic gonadotropin are important factors inducing this beneficial immune regulation.

During pregnancy in RA women, disease activity is more likely to improve if rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are negative. Also, pregnant RA women with low disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) and hormone use in the first trimester are likely to experience remission of RA disease activity. In contrast, the risk of elevated disease activity in RA women throughout the 6-month postpartum period increases (62% – 90%), peaking around 12 weeks postpartum. Changes in immune cells, cytokine patterns, and hormones mediate this elevated postpartum disease activity. Prolonged breastfeeding (>17 months) is associated with an increased risk of RA disease activity. Additionally, hypertension and pre-eclampsia are more common in pregnant RA women than in the general population.

Effects on Offspring

Intrauterine Growth and Birth Outcomes

Mothers with elevated RA activity during pregnancy face an increased risk of intrauterine growth restriction, preterm birth, and low birth weight. Tsuda et al. surveyed pregnant women in a Japanese hospital and 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. The concentration of circulating cytokines in the blood of pregnant RA women can affect fetal growth. In the first trimester, even after adjusting for disease activity, high interleukin-6 levels were associated with decreased birth weight. As disease activity (DAS28 score) in RA women increases during pregnancy, infant birth weight tends to decrease. Low infant weight may lead to a period of compensatory growth, but cardiovascular and metabolic conditions are more likely to deteriorate in adulthood. Disease activity in RA women also increases the risk of cesarean section.

Drug Use and Its Consequences

Drug use during pregnancy can lead to premature birth, low birth weight, and an increased risk of infection. Pregnant women with RA who received daily doses of prednisone >7.5 mg had higher preterm birth rates and lower fetal weight rates than those taking lower doses or no prednisone, likely due to the hormonal effects on pregnancy.

Placental transfer of biologic disease-modifying anti-rheumatic drugs (bDMARDS) may result in intrauterine drug exposure for up to 12 months. The median clearance time is 6 months, and some drugs like ublituximab or adalimumab have longer clearance times than infliximab. The timing of maternal biologics is important in assessing risk to the infant, with the late trimester increasing the risk. Berkhout et al. reviewed literature on the impact of perinatal exposure to bDMARDS on infant immune response, live vaccine safety, and vaccine efficacy. Currently, it is recommended that healthy infants exposed to bDMARDS during perinatal periods receive a rotavirus vaccine as scheduled. However, there are concerns, such as an infant exposed to bDMARDS dying of disseminated tuberculosis after BCG vaccination. For infants receiving intrauterine tumor necrosis factor inhibitor (TNFi) treatment, postponing all live vaccines until 6 months after birth is recommended, and BCG vaccination in the first 12 months is not advised. Methotrexate, leflunomide, mycophenolate mofetil, and cyclophosphamide are teratogenic and should be halted before conception. Cyclophosphamide also accumulates in breast milk, so its use is forbidden during breastfeeding. Sulfasalazine (up to 2000 mg/day), hydroxychloroquine (200 – 400 mg/day), azathioprine (up to 2 mg·kg⁻¹·d⁻¹), and cyclosporine are safe during pregnancy.

Long-Term Health Risks for Children

Mothers with RA increase the risk of chronic diseases in their children. Cytokine-mediated inflammation in the maternal circulatory system can affect fetal development, especially in sensitive organs like the lungs, brain, and intestines. Rom et al. conducted a nationwide epidemiological study based on the Danish Health Register and found that children of RA mothers had a statistically significant increase in disease incidence in eight out of 11 diagnostic groups. Type 1 diabetes incidence increased by 30%, juvenile idiopathic arthritis incidence increased threefold, and the risk of autism spectrum disorder (ASD) increased by approximately 30%. However, Tsai et al. found no significant difference in the risk of ASD in newborns born to RA mothers compared to non-RA mothers. Jølving et al. found that infants of RA mothers had a 61% elevated risk of epilepsy and a three-fold increase in RA. Knudsen et al. reported a higher incidence of cryptorchidism in boys born to RA mothers.

Epigenetic Changes

Ince-Askan et al. explored epigenetic changes in children born to RA mothers. They collected blood samples from 80 children of RA mothers and 354 children from the general population. Using the illuminated 450K gene chip method to detect cytosine-phosphate-guanine (CpG) sites, they found 147 CpG sites with differential DNA methylation patterns. Some CpG sites were related to type 2 diabetes, cardiovascular disease, obesity, or near key disease genotypes. After expression quantitative trait DNA methylation (eQTM) analysis, cg11220663 was associated with decreased expression of the ADD2 gene, which has been linked to the pathogenesis of many diseases. An analysis of RA patients based on Taiwan’s National Health Insurance Database showed that a family history of RA increased the risk of RA and other autoimmune diseases, and about two-thirds of the phenotypic variation in RA patients was explained by familial factors.

Conclusion

Women with RA face fertility challenges, and pregnancy can both improve and worsen their condition. Maternal RA disease activity and drug use during pregnancy increase the risk of adverse birth outcomes. Epigenetic changes in children of RA mothers may have long-term implications. Mothers with RA should use drugs reasonably during pregnancy to control disease activity, and children of RA mothers should be monitored for cardiovascular and metabolic disease indicators. Further research with larger sample sizes is needed to fully understand the epigenetic features and their correlations with disease in children of RA mothers.

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