Plasma fibulin-1 levels during pregnancy and delivery: a longitudinal observational study.

BACKGROUND: Fibulin-1 is an extracellular matrix protein expressed at high levels in the placenta. Elevated circulating fibulin-1 have been observed in women with severe pre-eclampsia, whereas low levels have been found in the fetal membranes, prior to membrane rupture. The aim of the study was primarily to evaluate plasma fibulin-1 during expected normal pregnancy and delivery, and secondarily to explore fibulin-1 levels in women developing pre-eclampsia or preterm premature rupture of fetal membranes (PPROM). METHODS: From the historical longitudinal cohort originally consisting of 801 healthy Danish women with a singleton pregnancy, 128 women (632 samples) were selected. Of these, 107 women had normal pregnancies, nine experienced PPROM, and 12 pre-eclampsia. All samples were analyzed for fibulin-1, and levels were compared with blood donors. Differences in mean fibulin-1 between groups were estimated using a linear mixed model. RESULTS: The mean concentration of fibulin-1 in 120 blood donors was 15.7 µg/mL, (25th-75th-percentiles, 12.3-18.2), with no significant difference in groups stratified by gender or age. Compared to baseline levels in week 12-20, fibulin-1 levels increased significantly from week 29-34 (estimated difference, 5.6 µg/mL; standard error, 1.7; p < 0.001) and 35-42 (12.5 µg/mL; 1.6; p < 0.001) and normalized after birth. The decrease at delivery tended to be more pronounced after elective (-7.0 µg/mL; 2.3; p = 0.002) and emergency (-5.6 µg/mL; 2.9; p = 0.05) cesarean section than after vaginal delivery (reference group). Women who developed PPROM had lower fibulin-1 levels throughout their pregnancies (-11.6 µg/mL; 4.2; p = 0.006). We did not observe a correlate between late pre-eclampsia and fibulin-1 (-0.2 µg/mL; 3.0; p = 0.9). CONCLUSIONS: Fibulin-1 was above non-pregnant levels at week 12 and increased significantly throughout pregnancy. We observed an association between low levels of fibulin-1 and PPROM. Further studies are needed to examine if fibulin-1 could serve as biomarker for the risk of PPROM. However, its role in late preeclampsia is doubtful. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki. The participants provided written informed consent, including storage for future use. The study was approved on July 18, 2005 by The Danish National Committee on Bioethics (No. KA 05065 and S-20,090,061) and the Danish Data Protection Agency.

Variation in plasma 25-hydroxyvitamin D2 and D3 in normal pregnancy with gestational age, sampling season, and complications: A longitudinal cohort study.

INTRODUCTION: Low levels of vitamin D in pregnancy have been associated with the risk of a variety of pregnancy outcomes. Few studies have investigated vitamin D concentrations throughout pregnancy in healthy women, and most guidelines recommend high vitamin D levels. In the present study, we investigated 25-hydroxyvitamin D concentrations in healthy Caucasian Danish women in relation to season, gestational age and possible vitamin D-linked complications. MATERIALS AND METHODS: Eight hundred and one healthy Caucasian Danish women with an expected normal pregnancy were recruited among 2147 women attending first trimester screening. Seven blood samplings were planned throughout the pregnancy and delivery period. The 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) concentrations were measured by LC-MS/MS and total 25-hydroxyvitamin D (25(OH)D) were calculated. RESULTS: A total of 3304 samples from 694 women were available for 25(OH)D measurements. The mean (25th-75th percentiles) concentrations of 25(OH)D, 25(OH)D3, and 25(OH)D2 were 54.6 (38.8-68.6) nmol/L, 52.2 (36.4-66.4) nmol/L, and 2.4 (2.2-2.2) nmol/L, respectively. Season was the strongest predictor of 25(OH)D concentration, with the lowest values observed in winter and spring, where only 42% and 41% of samples, respectively, were above 50 nmol/L. Nearly all women had values below the suggested optimal level of 75 nmol/L, independent of season. 25(OH)D peaked at gestational weeks 21-34. Plasma 25(OH)D2 levels were low in all seasons. Women with complications during pregnancy had higher 25(OH)D (estimated difference 9.8 nmol/L, standard error 2.7, p<0.001) than did women without complications, and women giving birth vaginally had lower 25(OH)D than did those delivering via elective (10.0 nmol/L, standard error 2.1, p<0.001) or emergency cesarean section (6.8 nmol/L, standard error 2.2, p<0.001). CONCLUSION: The 25(OH)D concentrations vary with both season and gestational age. Healthy women had lower 25(OH)D concentrations than recommended, without an association with an increased risk of pregnancy complications. Guidelines for vitamin D in pregnancy may require revision.