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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., (Copyright © 2022 by The American Association of Immunologists, Inc.)

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.

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.

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., (© 2016 Australasian Society for Ultrasound in Medicine.)

Objective: To evaluate the effect of cerclage, with and without cervical occlusion., Design: Multicentre, stratified, randomised controlled trial., Setting: Hospital-based multicentre study with 18 tertiary centres from nine countries., Population: Women with a history of cervical insufficiency (prophylactic trial) and women with a short cervix (therapeutic trial) were recruited from August 2006 to August 2011., Methods: A centralised telephone randomisation service with a computer system was used to randomise women to cervical cerclage with or without cervical occlusion. Only the analyst performing the interim analyses was blinded., Main Outcome Measures: The take-home baby rate (number of infants discharged alive from the hospital), gestational age at delivery, and the number of days in the neonatal intensive care unit (NICU)., Results: Women (n = 309) were stratified into the prophylactic trial (n = 213) or the therapeutic trial (n = 96). The trial stopped early due to slow recruitment and an interim analysis showing no benefit of occlusion. Final analysis comprised 197 women in the prophylactic trial and 87 women in the therapeutic trial. No added effect of cervical occlusion was found in terms of the take-home baby rate in the prophylactic trial (92 versus 90%, RR 1.03, 95% CI 0.94-1.12) or in the therapeutic trial (81 versus 85%, RR 0.96, 95% CI 0.79-1.16). No effect of cervical occlusion was found in terms of gestational age at delivery and number of days the neonate spent in the NICU. Cervical occlusion was associated with no harm., Conclusions: Cervical occlusion with cerclage had no significant additional effect., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

Objective: To evaluate the effect of double cerclage compared with a single cerclage., Design: Randomised, controlled multicentre trial., Setting: Ten different countries are participating with both secondary and tertiary centres. The countries participating are Denmark, Sweden, Germany, United Kingdom, Spain, South Africa, Australia and India. This gives both a broad spectrum of diversity global and local. We expect a total of 242 women enrolled per year., Population: Prophylactic study: 1. History of cervical incompetence/insufficiency. (Delivery 15 to <36 weeks.) 2. Congenital short cervix (secondary to maternal administration of diethyl stilbestrol) or traumatic/surgical damage rendering the vaginal approach difficult (e.g. conisation). 3. Cervical suture applied in previous pregnancy, successful outcome. 4. Previous failed cerclage. Therapeutic study: 5. Secondary cerclage: Short cervix, without the membranes being exposed to the vagina. 6. Tertiary cerclage: Short cervix, membranes exposed to the vagina. Observational study: Eligible women who refuse to be randomised will participate in an observational study. 7. Repeat/requested cervical occlusion., Methods: The women will be randomised between a single (vaginal or abdominal) and a double cerclage. The cervical cerclage (McDonald or Shirodkar) as well as the abdominal suture will be performed with the same material and technique normally used by the participating department. Those randomised to the double cerclage will have their external os closed with a continuous nylon 2-0/3-0 suture, in addition to the standard single cerclage. Local guidelines concerning antibiotics, Heparin, bed rest, tocolytics etc. are followed and recorded in the follow-up form., Main Outcome Measures: Primary endpoint is take home baby rate. The secondary endpoints are gestational age at delivery, incidence of preterm birth (<34+0 days) and number of days in neonatal unit.