Maternal folate, one-carbon metabolism and pregnancy outcomes.

Single nucleotide polymorphisms and pre- and peri-conception folic acid (FA) supplementation and dietary data were used to identify one-carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 µg daily FA at 15-week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 µg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L-1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre- and early-pregnancy dietary factors, are independent risk factors for pregnancy complications.

Anti-Müllerian hormone levels in recurrent embryonic miscarriage patients are frequently abnormal, and may affect pregnancy outcomes.

This prospective cohort study measured anti-Müllerian hormone (AMH) levels in recurrent miscarriage (RM) patients, compared them to a normal population, and assessed the pregnancy outcomes. The RM patients demonstrated AMH levels that were significantly lower than the normal population, both in women aged ≤35 years, and those aged >35 years. AMH percentiles were found to be significantly lower in the study group of RM patients ≤35 years (p< .004) in the 5th and 50th percentiles, and in all percentiles in women >35 years (p< .03), were compared to women from a normal population. Serum AMH levels may reflect quality, and quantity of the remaining oocytes in these patients, and RM patients may have a low ovarian reserve, and a potentially poor oocyte quality, as shown by low circulating AMH. The evaluation of AMH levels in a RM work up may allow realistic counselling and possible ART referral in RM patients. Impact statement What is already known on this subject? There is some evidence to show that low AMH levels are associated with recurrent miscarriages and this is thought to be due to a decreased oocyte quality. The AMH levels are lower in the patients with endometriosis, and are often significantly higher in the patients with polycystic ovarian syndrome. Both conditions are independently associated with miscarriages. What the results of this study add? Anti-Müllerian hormone (AMH) levels were found to be significantly lower in recurrent miscarriage patients, compared to a normal population. This may be another factor contributing to miscarriages. The spontaneous pregnancy rates in the miscarriage group significantly improved with increasing AMH levels. This may confirm that patients with low AMH levels have poorer quality oocytes, and thus may be considered 'sub-fertile'. It was also found that the utilisation of assisted reproductive technologies (ART) to achieve a pregnancy was significantly reduced in the groups with a higher serum AMH. What the implications are of these findings for clinical practice and/or further research? Serum AMH levels should be offered to all patients as part of a recurrent miscarriage work up. Detecting the low AMH levels and counselling the patients on these findings may allow them the option of accessing ART. ART may have the ability to expedite conception rates, and with pre-implantation genetic analyses, could possibly select the embryos with the greatest chance of survival. Further research is needed to establish how the decreased AMH levels contribute to recurrent miscarriages.

The association of parental methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C > T and 1298A > C) and fetal loss: a case-control study in South Australia.

Objective: To determine the association between parental MTHFR 677C > T (RS1801133) and 1298A > C (RS1801131), and fetal loss (FL).Design: Case-control study.Setting: Department of Obstetrics and Gynecology, Lyell McEwin Hospital (LMH), and the Women's and Children's Hospital (WCH) in Adelaide, Australia.Patients: A total of 222 couples with FL and 988 couples with uncomplicated pregnancies.Measurements: The main outcomes were FL and hyperhomocysteinemia (HHcy). All couples were tested for MTHFR 677C > T and 1298A > C. Fasting homocysteine was measured in the women with FL.Results: The main finding was a significant difference between the FL group and controls in couples with ≥4 abnormal alleles compared to <4 [p=.0232, OR 1.9 (95% CI 1.1-3.3)]. None of the couples with FL had zero abnormal alleles (both parents 677CC/1298 AA). However, this was also rare amongst the controls. Maternal carriage of both 677C > T and the 1298A > C polymorphisms was similar between the FL group and controls. The prevalence of paternal 677TT/1298AA and 677CC/1298AC was significantly higher in the FL group compared with controls. HHcy was significantly more common in the FL group compared with controls.Conclusion: The presence of parental MTHFR 677C > T and 1298A > C is associated with FL. The association between maternal MTHFR genotypes with FL is less pronounced than in previously published articles investigating first trimester miscarriages. Maternal HHcy is a significant risk factor for FL.

One-carbon metabolism enzyme polymorphisms and uteroplacental insufficiency.

OBJECTIVES: This study was undertaken to test novel genetic polymorphisms involved in 1-carbon metabolism for a potential association with increased risk of developing pregnancy complications associated with uteroplacental insufficiency. STUDY DESIGN: This was a prospective cohort study consisting of 50 women at low risk and 93 women at high risk for having a pregnancy complication develop. Maternal and fetal DNA samples were genotyped for methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G and methylenetetrahydrofolate dehydrogenase (MTHFD1) G1958A. A chi squared or chi(2) analysis was used to compare genotypes and pregnancy outcome, 1-way analysis of variance and linear regression were used to compare genotype with continuous variables. RESULTS: The fetal MTR 2756 G allele was associated with uteroplacental insufficiency (P = .022, likelihood ratio = 10.4) and maternal homocysteine (P = .017). The maternal MTR A2756G polymorphism was associated with uteroplacental insufficiency (P = .049, likelihood ratio = 6.0), but only in mothers not supplementing with high-dose B-vitamins. The maternal MTHFD1 AA genotype was associated with intrauterine growth restriction (P = .047, likelihood ratio = 5.8). CONCLUSION: This study suggests the maternal and fetal MTR 2756 G allele is an important risk factor in the development of uteroplacental insufficiency. In addition, the maternal MTHFD1 1958 AA genotype may be associated with intrauterine growth restriction.

3D ultrasound findings in women attending a South Australian recurrent miscarriage clinic.

BACKGROUND: Women who suffer recurrent miscarriage are a heterogeneous group. Known causes include genetic and endocrine abnormalities, anti-phospholipid syndrome and autoimmune disease. Congenital uterine abnormalities (CUAs) such as bicornuate, unicornuate, septate and arcuate uterine abnormalities are known to negatively impact on pregnancy rates, and to increase the miscarriage rates of genetically normal pregnancies. In some countries, such as Britain, 3D ultrasound of the pelvis is offered routinely to women with recurrent miscarriages. AIM: To determine the prevalence of CUAs and other pelvic pathology, in women attending a South Australian recurrent miscarriage clinic. MATERIALS AND METHODS: 3D transvaginal ultrasounds performed during the luteal phase of the menstrual cycle were offered to all patients attending the recurrent miscarriage clinic, who had not previously had a hysteroscopy, laparoscopy, HyCoSy or MRI study of their pelvis. A Philips IUI 8 MHz transvaginal probe for freehand sweep, and dedicated 3D transvaginal probe was used. 3D scans provide a coronal view of the uterus, ideal for detecting abnormalities which may be missed during routine conventional 2D scanning. RESULTS: A total of 210 women were recruited, 200 results were available, and 29% were found to have a CUA. 15% had polycystic ovaries detected, 15% were found to have fibroids, 12% adenomyosis and 1.5% Asherman's syndrome. CONCLUSIONS: 3D ultrasound evaluation of patients attending a recurrent miscarriage clinic detects CUAs, and has a high detection rate of other pelvic abnormalities that may contribute to recurrent miscarriages.

Maternal red blood cell folate concentration at 10-12 weeks gestation and pregnancy outcome.

OBJECTIVE: To determine if maternal circulating red blood cell (RBC) folate concentration in early pregnancy is associated with late gestation pregnancy complications including small for gestational age (SGA) infants, preeclampsia and preterm birth (PTB) in a socioeconomically disadvantaged population. METHOD: This was a retrospective case control study, conducted at Lyell McEwin Health Service, South Australia, including 400 primiparous women. RBC folate and demographic data were collected at 10-12 weeks gestation. Pregnancy outcome data were obtained from patient case notes. RESULTS: Patients who were folate deficient were more likely to develop pregnancy complications, specifically SGA (OR 6.9, 95% CI 2-24.3) and PTB (OR 5.4 95% CI 1.4-21.2). Those who were folate insufficient were also at increased risk of SGA (OR 3.0, 95% CI 1.3-7.7). No association between folate and preeclampsia was found. Women who were supplementing with folic acid delivered infants who were 179 g heavier (5.5% increased birth weight, P = 0.003) and 4.5 days later, compared to those who did not supplement. Furthermore, low RBC folate was associated with cigarette smoking (P < 0.001). CONCLUSIONS: Maternal RBC folate concentration in early pregnancy is associated with SGA and PTB, but not with preeclampsia.