Associations between fetal HLA-G genotype and birth weight and placental weight in a large cohort of pregnant women - Possible implications for HLA diversity.

Birth weight and placental weight are crucial parameters for the survival of fetuses and newborns in mammals. High variation in the MHC is important for an effective adaptive immune response. The maternal immune system must be controlled in relation to the semi-allogenic fetus. The immunoregulatory HLA/MHC class Ib gene, HLA-G, is strongly expressed on extravillous trophoblast cells. We investigated birth weight and placental weight of the newborns in mothers heterozygous for an HLA-G 14bp insertion (Ins)/deletion (Del) gene polymorphism. Separate analyses for pregnancies without preeclampsia (n=185), pregnancies complicated by preeclampsia (n=101), and both groups combined, were performed. Interestingly, we observed the highest mean birth weight and placental weight in homozygous 14bp Del/Del newborns, and the lowest in 14bp Ins/Ins newborns (P=0.008 and P=0.009). The 14bp Del/Del genotype is also associated with high expression of HLA-G on the trophoblast membrane. In theory, fetuses and newborns with intermediate weights and sizes would be an optimal compromise for both the fetus/father and the mother compared with very high and low weights. If such fetuses/newborns more often are heterozygous at the HLA-G gene locus, then newborns with two distinct HLA haplotypes are favored, leading to a higher degree of HLA diversity. The results of the study may indicate that a compromise between an intermediate birth weight and placental weight, induction of maternal tolerance by a fetal-derived non-polymorphic HLA class Ib molecule, and favoring of HLA heterozygous offspring, have evolved in humans.

Human leukocyte antigen (HLA)-G during pregnancy part I: correlations between maternal soluble HLA-G at midterm, at term, and umbilical cord blood soluble HLA-G at term.

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on trophoblast cells and has been proposed to have immunomodulatory functions during pregnancy. Soluble HLA-G1 (sHLA-G1) can be generated by the shedding of membrane-bound HLA-G molecules; however, three soluble isoforms also exist (HLA-G5 to -G6). During pregnancy, it is unknown whether there is a correlation between sHLA-G levels in maternal and fetal blood. In 246 pregnancies, we have measured the levels of sHLA-G1/-G5 in maternal blood plasma samples from gestational week 20 (GW20) and at term, as well as in umbilical cord blood samples. Soluble HLA-G levels declined by 38.4% in maternal blood from GW20 to term, and sHLA-G levels were significantly lower in maternal blood at term than in GW20 (P<0.001). At term, the sHLA-G levels were significantly higher in maternal blood than in umbilical blood (P<0.001). HLA-G levels in maternal blood in GW20 and at term, and in maternal blood at term and umbilical cord blood, were correlated (P<0.001 and P<0.01, respectively). This is the first large study simultaneously measuring sHLA-G in both maternal and umbilical cord blood. The finding that sHLA-G levels are significantly lower in fetal compared with maternal blood at term documents for the first time that sHLA-G is not freely transferred over the placental barrier. Soluble HLA-G levels in maternal and fetal blood were found to be correlated, which may be due to shared genetic factors of importance for production of sHLA-G in the mother and child, or it may support the theory that sHLA-G in the pregnant woman and the fetus is partly derived from a "shared organ", the placenta.

Human leukocyte antigen (HLA)-G during pregnancy part II: associations between maternal and fetal HLA-G genotypes and soluble HLA-G.

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on the extra-villous trophoblast and seems to have immunomodulatory functions during pregnancy. Studies have linked HLA-G polymorphisms to pregnancy complications such as preeclampsia and recurrent miscarriage. Levels of soluble HLA-G (sHLA-G) in blood plasma from non-pregnant donors seem to be associated with these polymorphisms. In the current study, we have genotyped 246 mothers and their offspring for HLA-G polymorphisms in the 3'-untranslated region (3'UTR) and measured sHLA-G in maternal blood plasma samples from gestational week 20 and at term, as well as in fetal umbilical cord blood samples. This is the first large study simultaneously performing HLA-G genotyping of mother and offspring and measuring sHLA-G in both maternal and umbilical cord blood. The results showed that increasing numbers of 14bp ins (rs66554220) alleles in the mother-child genotype combinations were associated with higher maternal sHLA-G levels at term when restricting the analysis to 14bp ins/del heterozygous mothers (p=0.015). Furthermore, increasing numbers of 14InsG haplotypes (14bp ins/del and +3142C/G (rs1063320) polymorphism) in mother-child genotype combinations were associated with higher levels of sHLA-G at term in heterozygous 14DelC/14InsG mothers (p=0.005). In conclusion, the results indicate that there is an association between combined feto-maternal HLA-G genotypes and sHLA-G levels in maternal blood plasma.

Freestanding midwifery unit versus obstetric unit: a matched cohort study of outcomes in low-risk women.

OBJECTIVE: To compare perinatal and maternal morbidity and birth interventions in low-risk women giving birth in two freestanding midwifery units (FMUs) and two obstetric units (OUs). DESIGN: A cohort study with a matched control group. SETTING: The region of North Jutland, Denmark. PARTICIPANTS: 839 low-risk women intending FMU birth and a matched control group of 839 low-risk women intending OU birth were included at the start of care in labour. OU women were individually chosen to match selected obstetric/socio-economic characteristics of FMU women. Analysis was by intention to treat. MAIN OUTCOME MEASURES: Perinatal and maternal morbidity and interventions. RESULTS: No significant differences in perinatal morbidity were observed between groups (Apgar scores <7/5, <9/5 or <7/1, admittance to neonatal unit, asphyxia or readmission). Adverse outcomes were rare and occurred in both groups. FMU women were significantly less likely to experience an abnormal fetal heart rate (RR: 0.3, 95% CI 0.2 to 0.5), fetal-pelvic complications (0.2, 0.05 to 0.6), shoulder dystocia (0.3, 0.1 to 0.9), occipital-posterior presentation (0.5, 0.3 to 0.9) and postpartum haemorrhage >500 ml (0.4, 0.3 to 0.6) compared with OU women. Significant reductions were found for the FMU group's use of caesarean section (0.6, 0.3 to 0.9), instrumental delivery (0.4, 0.3 to 0.6), and oxytocin augmentation (0.5, 0.3 to 0.6) and epidural analgesia (0.4, 0.3 to 0.6). Transfer during or <2 h after birth occurred in 14.8% of all FMU births but more frequently in primiparas than in multiparas (36.7% vs 7.2%). CONCLUSION: Comparing FMU and OU groups, there was no increase in perinatal morbidity, but there were significantly reduced incidences of maternal morbidity, birth interventions including caesarean section, and increased likelihood of spontaneous vaginal birth. FMU care may be considered as an adequate alternative to OU care for low-risk women. Pregnant prospective mothers should be given an informed choice of place of birth, including information on transfer.