Immune-Metabolic Interactions and T Cell Tolerance in Pregnancy.

Pregnancy depends on a state of maternal immune tolerance mediated by CD4+ regulatory T (Treg) cells. Uterine Treg cells release anti-inflammatory factors, inhibit effector immunity, and support adaptation of the uterine vasculature to facilitate placental development. Insufficient Treg cells or inadequate functional competence is implicated in infertility and recurrent miscarriage, as well as pregnancy complications preeclampsia, fetal growth restriction, and preterm birth, which stem from placental insufficiency. In this review we address an emerging area of interest in pregnancy immunology-the significance of metabolic status in regulating the Treg cell expansion required for maternal-fetal tolerance. We describe how hyperglycemia and insulin resistance affect T cell responses to suppress generation of Treg cells, summarize data that implicate a role for altered glucose metabolism in impaired maternal-fetal tolerance, and explore the prospect of targeting dysregulated metabolism to rebalance the adaptive immune response in women experiencing reproductive disorders.

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.

Do raised two-hour pre-pregnancy insulin levels confer the same risks of developing GDM, as raised fasting levels, in recurrent miscarriage patients?

This study questioned whether raised pre-pregnancy two-hour (2 h) insulin levels, measured in recurrent embryonic miscarriage (RM) patients via a 75 g Oral Glucose Tolerance Test (OGTT), are associated with an increased risk of gestational diabetes mellitus (GDM) in a subsequent pregnancy. Patients had a 75 g OGTT and insulin levels evaluated (n = 170). 54.1% had normal glucose and insulin levels, 45.9% had levels indicating hyperinsulinism (HI). In the 98 patients who achieved a pregnancy, the prevalence of GDM was 3.7% in those without HI, and 35.7% in the patients who only had raised 2 h insulin levels. While HI has been described as a risk factor for miscarriages only in relation to raised fasting (basal) insulin levels, this study demonstrated that raised 2 h insulin levels predict an increased risk of GDM in a subsequent pregnancy. Thus raised 2 h insulin levels likely confer a similar risk to raised fasting insulin levels in RM patients.Impact statementWhat is already known on this subject? Fasting hyperinsulinism is known to be associated with an increased risk of gestational diabetes mellitus (GDM) in pregnancy. Hyperinsulinism, as reflected by the fasting (basal) insulin levels >20mU/L, has been recognized as a risk factor for recurrent miscarriages, particularly in patients with polycystic ovarian syndrome (PCOS), in the World literature. Raised two-hour insulin levels have not been considered as a risk factor in the literature before.What do the results of the study add? We have demonstrated a 10-fold increase in the development of GDM in patients with fasting insulin resistance, and/or raised 2h insulin levels, and an almost 10-fold increase in patients with only raised 2h levels. 58.8% of the patients who subsequently developed GDM only had raised 2h levels and would have been missed with routine testing.What are the implications of these findings for clinical practice and/or further research? Our study has demonstrated that GDM was three times more prevalent in the patients with only raised 2h levels, than in those only with raised fasting levels, reflecting insulin resistance/hyperinsulinism. Insulin studies including 2h insulin levels are therefore an important factor to consider when working up these patients. Insulin studies pre-pregnancy may be useful in identifying women at risk of suffering miscarriages or of developing GDM in a subsequent pregnancy.

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.

Association between vitamin D status and hyperinsulinism.

Aims: Some studies have suggested that vitamin D deficiency is associated with an increased risk of first trimester miscarriages, others have suggested that it is associated with an increased risk of hyperinsulinism/insulin resistance and the development of gestational diabetes. Hyperinsulinism is also thought to increase miscarriages. We investigated the association between vitamin D levels and hyperinsulinism in a cohort of recurrent miscarriage patients. Methods: Patients undergoing miscarriage investigations had insulin and vitamin D levels tested. Vitamin D levels were classified as: sufficient (≥75 nmol/L), insufficient (50-74.9 nmol/L) or deficient (<50 nmol/L). Hyperinsulinism was assessed via a 75 g oral glucose tolerance test (OGTT) with insulin studies. Results: One hundred and fifty-five patients underwent the testing. Hyperinsulinism was detected in 58.3% of the vitamin D deficient group, 38.7% of the insufficient group, and 33.3% of the sufficient group (chi-square p = .034). There were no significant associations between BMI and vitamin D levels, or BMI and hyperinsulinism. Caucasians comprised 82% of the clinic, and 67% of these women had vitamin D insufficiency/deficiency. Noncaucasians comprised 18% of the clinic but 89% of these patients had vitamin D insufficiency/deficiency. Discussion: We found that insufficient or deficient vitamin D levels were significantly associated with hyperinsulinism in these patients. Vitamin D deficiency is also thought to contribute to an increased risk of adverse pregnancy outcomes including preeclampsia, preterm birth, small-for-gestational-age gestational diabetes mellitus, and miscarriages. Larger level one trials are needed to establish if increasing serum vitamin D levels prior to conception or in early pregnancy improves adverse pregnancy outcomes.

Triggering of acute myocardial infarction by respiratory infection.

BACKGROUND: Respiratory infection has been associated with an increased short-term risk of myocardial infarction (MI). However, previous studies have predominantly been conducted without angiographic confirmation of MI. The possibility can therefore not be excluded that raised troponin levels or electrocardiogram abnormalities that may be seen with respiratory infections are due to non-ischaemic causes. AIMS: To investigate the association between respiratory infection and angiographically confirmed MI. METHODS: Interviews were conducted within 4 days of hospitalisation in 578 patients with angiographically confirmed MI, to assess for recent exposure to respiratory infection symptoms and the usual annual frequency of these symptoms. Using case-crossover methodology, exposure to respiratory infection prior to the onset of MI was compared against the usual frequency of exposure in the past year. RESULTS: Symptoms of respiratory infection were reported by 100 (17%) and 123 (21%) within 7 and 35 days, respectively, prior to MI. The relative risk (RR) for MI occurring within 1-7 days after respiratory infection symptoms was 17.0 (95% confidence interval (CI) 13.2-21.8), and declined with subsequent time periods. In a subgroup analysis, the RR tended to be lower in groups taking regular cardiac medications. For those who reported milder, upper respiratory tract infection symptoms, the RR for the 1-7-day time period was 13.5 (95% CI 10.2-17.7). CONCLUSION: These findings confirm that respiratory infection can trigger MI. Further study is indicated to identify treatment strategies to decrease this risk, particularly in individuals who may have increased susceptibility.

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.