Rheumatoid arthritis (RA)is defined as a systemic autoimmune disorder associated with a chronic inflammatory process that can damage joints and extra-articular organs, including the heart, kidneys, lungs, digestive system, eyes, skin, and nervous system (1, 2). The pathophysiological process of RA is closely related to cytokines such as interleukin 6 (IL-6) (3). Studies have shown that RA is a global disease irrespective of race, sex, ethnicity, nationality, and age, but prevalence and incidence measurements vary according to population characteristics and over time (2). Notably, gender differences have been observed in the prevalence of RA. Women are two to three times more likely to suffer from this disease than men, with most cases appearing during the childbearing years (4, 5). The global prevalence of RA is approximately 1%, fluctuates less consistently, and increases significantly from south to north, rural to metropolitan areas (6).

Small for gestational age (SGA) is defined as birth weight below the 10th percentile for gestational age (GA) (7). Perinatal mortality is higher in infants with SGA compared to newborns of appropriate gestational age at birth. This association exists for both full-term and preterm infants (8–12). SGA accounts for about 22% of neonatal deaths in low- and middle-income countries (13). It is also a cause of multiple short- and long-term complications (14). Infants with SGA are at higher risk of morbidity and developmental delay in childhood. They are susceptible to chronic diseases such as obesity, type 2 diabetes, coronary artery disease, and stroke into adulthood (15). Cytokines such as IL-6 have been reported to be higher in mothers of newborns who gave birth to SGA (16). As mentioned above, maternal RA potentially impacts SGA in offspring, but the risk of maternal RA increasing SGA in offspring is controversial. Five cohort studies of 936,030 participants found a significant association between maternal RA and risk of SGA (17–21), compared to two studies that showed no statistically significant association between maternal RA and risk of SGA (22, 23). Given the increasing incidence of RA in women over the years and the inconsistent association between maternal and risk of SGA in offspring, a Meta-analysis to assess this association would be of great value.

The association between maternal RA and the risk of SGA in offspring is a controversial topic. Based on previous studies, this meta-analysis of seven cohort studies of patients from different backgrounds found an association between maternal RA and increased risk of SGA in offspring. The results show that newborns of women with RA are more likely to be SGA compared to women with normal pregnancies. In addition, subgroup analyses confirmed the such association. The pooled estimated effects of the included subgroups were almost similar to the overall results. Statistical significance was found for subgroups grouped by country, study quality, age with or without restrictions, sample size, and adjustment factors. Sensitivity analysis showed no substantial change in the results when we used the retention method, suggesting that the results of this meta-analysis are robust. Considering the progressive increase in the prevalence of RA among women, this article will make much sense.

The potential mechanisms between maternal RA and SGA of the newborn remain obscure. It has been shown that oxidative stress markers are significantly higher in neonates with SGA than in infants of appropriate gestational age (AGA) and that prolonged excessive oxidative stress and intrauterine malnutrition can lead to SGA in offspring (31). Oxidative stress plays a crucial role in the pathophysiology of RA. In RA patients, the antioxidant system is altered, and serum and synovial fluid lipid peroxidation levels are elevated (32). Since the last decade, studies have shown a positive correlation between the level of ROS and the severity of RA (33). The findings suggest that maternal RA can affect SGA in offspring through reactive oxygen species.

In another study, IL-10 was found to be detectable in 23.4% of RA patients and IL-6 in 76.6% of patients in late pregnancy. When IL-6 levels were high, the risk of neonatal SGA was increased, suggesting that increased levels of IL-6 are associated with neonatal SGA (16). In addition, vitamin D is also involved. Vitamin D deficiency increases levels of pro-inflammatory cytokines and leads to oxidative stress. Lower 25(OH)D status is associated with increased vascular endothelial cell expression of interleukin six and reduced expression of vitamin D receptors and 1-alpha hydroxylase (34). One study reported significantly higher levels of pro-inflammatory cytokines in the cord blood of SGA infants than in the cord blood of non-SGA infants (35). Maternal rheumatoid can increase the risk of SGA in newborns through cytokines. In clinical studies, patients with RA were found to have low sleep quality and severe sleep disturbances (36). A short duration of pregnancy and poor sleep quality were associated with an increased risk of preterm birth and SGA (37). This result supports the effect of maternal rheumatoid on neonatal SGA. Our study confirms the results, but more profound and more comprehensive mechanisms remain to be explored further.

This meta-analysis has several limitations. First, heterogeneity existed between included studies, so a random effects model was applied to combine ORs and RRs. Although subgroup analysis could explain some of the heterogeneity, sufficient data from the included original studies, such as different ethnicities of female RA patients and different rheumatoid disease characteristics (duration, severity, with or without treatment), were lacking to investigate other potential sources. Second, although the sensitivity analysis results were robust and ensured the accuracy and persuasiveness of the results, the limited number of studies conducted outside of Europe and the Americas suggests the need for more data on populations of different backgrounds. The substantial heterogeneity (I² = 89.6%) of the pooled effects may reflect the significant variation in sample size. Considering the limited number of studies in our review and the high heterogeneity, more and higher quality studies are needed. Our results should be interpreted cautiously due to the limited number of included studies. Finally, our study is the absence of correlation analysis between maternal RA disease activity and the risk of neonatal SGA. Unfortunately, we could not investigate this potential association due to the need for more sufficient data in the included studies. However, we acknowledge this limitation and encourage future research to explore the relationship between maternal RA disease activity and the risk of SGA. Despite these limitations, the following strengths of this study should be acknowledged. This is the first meta-analysis to elucidate the relationship between maternal RA and the risk of SGA in offspring. In addition, sensitivity analyses showed that the meta-analysis results did not change substantially using the leave-one-out method. The results were robust, and there was no publication bias.

Accurate knowledge of maternal RA and neonatal SGA risk is valuable for early intervention to reduce the frequency of these adverse events. Further studies are needed to investigate the underlying causes of RA and SGA, which may improve clinical care and lead to a more informed prognosis for future pregnant mothers with RA.

In summary, maternal RA increases the risk of SGA in offspring. Healthcare providers should be aware of the high risk of adverse maternal and neonatal outcomes. Medical staff should develop an individualized and continuous pregnancy screening program for pregnant women with RA, record their family history, medical history, and physical examination data in detail, and provide health education on daily precautions for pregnant women. Before pregnancy, women with RA should be encouraged to maintain optimal health and manage their RA and other chronic diseases. Pregnant women with RA should schedule detailed and regular pregnancy tests according to the actual situation. By increasing the number of pregnancy tests, we can dynamically monitor the mother and fetus’s physiological changes and effectively reduce the risk of SGA.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

LT: data curation, formal analysis, and writing original draft. ZZ: investigation. YM: resources and supervision. MZ: project administration, visualization, writing-review, and editing. All authors contributed to the article and approved the submitted version.

This study was supported by the Natural Science Foundation of Jilin Province (grant number: YDZJ202201ZYTS062, 20200201127JC).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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