TNF Inhibitors Increase Birthweight in Pregnant Women with RA

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Birthweight was significantly lower in women who were not treated with a TNF.

Treatment with a tumor necrosis factor inhibitor (TNF) was associated with increases in birthweight in pregnant patients with rheumatoid arthritis (RA), which were independent of the soluble Fms‐like tyrosine kinase‐1 (sFlt-1)/placental growth factor (PlGF) ratio, according to a study published in Journal of the American Heart Association.1

PlGF and sFlt-1 are common biomarkers of placentation and placental function, with a high sFlt-1/PlGF ratio considered to be indicative of adverse pregnancy outcomes including fetal growth restriction, preeclampsia, and lower birthweight.2

“A tight balance between proinflammatory (eg, TNFα [tumor necrosis factor α]) and interleukin (IL)‐6 and anti‐inflammatory (eg, IL‐10) cytokines is required for adequate placentation, with the anti‐inflammatory cytokines predominating,” wrote a team of investigators led by Cornelia H Quaak, MD, associated with the Department of Rheumatology at Erasmus Medical Center Rotterdam in the Netherlands. “In RA, proinflammatory cytokines, such as TNFα and IL‐6, are increased. High levels of IL‐6 are associated with a reduced birthweight. This high inflammatory state could be related to poor pregnancy outcome in terms of a lower birthweight as a result from disturbed placentation.”

Data from the prospective Preconception Counseling in Active RA (PreCARA) study, performed in the Erasmus Medical Center, a tertiary referral hospital in Rotterdam, the Netherlands, was used to analyze a possible correlation between sFlt-1 and PlGF with birthweight in women treated with TNF. sFlt-1 and PlGF were collected via blood samples in all trimesters and then compared according to TNF usage. Eligible patients regularly visited the hospital prior to conception, once every trimester during pregnancy, and scheduled periodic postpartum follow-ups to week 26.

A total of 158 women were included in the analysis, of whom 52.5% (n = 83) received a TNF during pregnancy. Forty-six women (29.1%) were treated with a TNF for the entirety of their pregnancy. Relevant confounders included maternal age, diabetes, gestational age at delivery, and the Disease Activity Score of tender and swollen joints in the third trimester.

Although sFlt-1 and PlGF levels increased during pregnancy, their ratio declined. After accounting for relevant confounders and considering trimester-related variation in levels, the sFlt-1/PlGF ratio was similar among patients who were treated with TNF and those who were not (sFlt‐1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% confidence interval (CI), 2.54–26.29], P = .79; sFlt‐1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73–22.50], P = .25).

Birthweight was significantly lower in women who were not treated with a TNF (3180g vs 3302 g; P = .03). Among these patients, sFlt-1 levels were associated with a negative correlation with birthweight (r = −.462, P <.001) and birthweight percentile (r = −.332, P = .008). These correlations were not present in patients receiving a TNF during pregnancy.

The study was the first to explore the correlation between sFlt, PlGF, and TNF treatment and included a large sample of women with well-defined homogeneous disease. However, investigators note limitations including being unable to obtain laboratory samples for all patients from all trimesters. Additionally, they were unable to determine the effect of TNF treatment per trimester as patients who received a TNF in one trimester were likely to use this treatment in other trimesters as well.

“TNF inhibitors could be explored as a therapeutic intervention in women with clinical conditions characterized by increased sFlt‐1 levels, such as preeclampsia,” investigators concluded.


  1. Quaak CH, Kluivers ACM, Baart SJ, et al. Tumor Necrosis Factor Inhibitor Use Increases Birthweight in Pregnant Women With Rheumatoid Arthritis Independently of the Soluble Fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio. J Am Heart Assoc. Published online March 27, 2024. doi:10.1161/JAHA.123.032655
  2. Chen W, Wei Q, Liang Q, Song S, Li J. Diagnostic capacity of sFlt‐1/PlGF ratio in fetal growth restriction: a systematic review and meta‐analysis. Placenta. 2022; 127:37–42. doi: 10.1016/j.placenta.2022.07.020