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BACKGROUND: To study whether the use of TNF (tumor necrosis factor) inhibitors (TNFi) by pregnant women with rheumatoid arthritis affects sFlt-1 (soluble Fms-like tyrosine kinase-1), PlGF (placental growth factor), or their impact on birthweight. METHODS AND RESULTS: sFlt-1 and PlGF were measured in all trimesters of pregnancy in the Preconception Counseling in Active Rheumatoid Arthritis study and were compared according to the use of TNFi. The association of sFlt-1 and PlGF with birthweight in relation to TNFi was determined. The study included 158 women, of whom 52.5% used TNFi during pregnancy. Both sFlt-1 and PlGF increased during pregnancy, whereas their ratio declined. Taking into consideration the trimester-related variation in levels of sFlt-1 and PlGF, after correction for relevant confounders, the sFlt-1/PlGF ratio was not significantly different between patients who did or did not use TNFi (sFlt-1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% CI, 2.54-26.29], P=0.79; sFlt-1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73-22.50], P=0.25). In women who did not use TNFi, birthweight was significantly lower (3180 versus 3302 g; P=0.03), and sFlt-1 displayed a negative correlation with birthweight (r=-0.462, P<0.001) and birthweight percentile (r=-0.332, P=0.008). In TNFi users, these correlations were absent. CONCLUSIONS: TNF inhibitor use increases birthweight in pregnant women with rheumatoid arthritis independently of the sFlt-1/PlGF ratio. REGISTRATION: http://clinicaltrials.gov. Unique identifier: NCT01345071.

Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors. Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole. Results: Mean maternal age was 30 years, and median gestational age was 30+3weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P=0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio's 0.43-0.59), while only esomeprazole inhibited placental sFlt-1 release. Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Acute fatty liver of pregnancy (AFLP) is characterized by elevated circulating sFlt-1 (soluble Fms-like tyrosine kinase-1), although the free circulating levels of its ligand, PlGF (placental growth factor) are not decreased. Here, we hypothesized that women with AFLP exhibit elevated PlGF production in comparison to women with preeclampsia or hemolysis elevated liver enzymes and low platelet count syndrome. Making use of the well-known mathematical formulas describing drug-receptor interactions, we established that serum total PlGF could be accurately predicted from sFlt-1 and free PlGF levels (n=42; mean calculated KD of 50 pmol/L), yielding similar values as the previously published method of thermal dissociation of the sFlt-1-PlGF complexes (r=0.94, P<0.0001). We found that median levels of free PlGF were significantly lower in women with preeclampsia (n=13; 117pg/mL) or hemolysis elevated liver enzymes and low platelet count syndrome (n=12; 59 pg/mL) compared with women without preeclampsia (n=11; 349pg/mL, P<0.0001). In contrast, median total PlGF did not differ between women with no preeclampsia, preeclampsia, and hemolysis elevated liver enzymes and low platelet count syndrome (354 versus 435 versus 344pg/mL), whereas it was markedly elevated in AFLP compared with all groups (2054 pg/mL, P<0.0001). Furthermore, in AFLP, both sFlt-1 and total PlGF declined rapidly postdelivery, with significantly higher predelivery total PlGF (n=12; median, 2054 pg/mL) than postpartum levels (n=14; median,163pg/ mL, P<0.0001), suggesting that in AFLP, PlGF is largely placenta-derived. Collectively, our findings indicate that like sFlt-1, PlGF production is significantly upregulated in AFLP, mainly originating from the placenta. Importantly, total PlGF can now be easily calculated from already available free PlGF and sFlt-1 levels, allowing subsequent evaluation of other groups in whom PlGF is altered.

Objectives: Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery. Methods: This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement. Results: Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27–33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2–4.4], p = 0.97). Conclusion: Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia.