The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

OBJECTIVE: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. DESIGN: Observational cohort study. SETTING: A total of 49 hospitals across the United Kingdom between 2011 and 2016. PARTICIPANTS: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. METHODS: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. INTERVENTION: None. MAIN OUTCOME MEASURE: Rates of thyroid dysfunction. RESULTS: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). CONCLUSIONS: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism.

BACKGROUND: Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction. OBJECTIVES: To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist. SELECTION CRITERIA: We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri-iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage. MAIN RESULTS: The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies.In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%.In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I2 = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I2 = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%.Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. AUTHORS' CONCLUSIONS: We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Minimizing the Risk of Infection and Bleeding at Trans-Vaginal Ultrasound-Guided Ovum Pick-up: Results of a Prospective Web-Based World-Wide Survey.

OBJECTIVE: The objective of this study was to identify clinical practices worldwide, which would help in recognizing women at risk of excessive bleeding or of developing pelvic infection following trans-vaginal ovum pick-up (TV-OPU), measures taken to minimize risks and their management. METHOD: A prospective, web-based questionnaire with distinct questions related to the practice of TV-OPU. RESULTS: A total of 155 units from 55 countries performing 97,200 IVF cycles annually responded to this web-based survey. A majority (65 %) responded that they would routinely carry out full blood count, while 35 % performed coagulation profile. Less than a third agreed screening women for vaginal infections. About a third used both sterile water and antiseptic to minimize ascending infection, and 52 % used antibiotics for prophylaxis. Doppler ultrasound was routinely used by 20 % of clinicians. 73 % of the clinicians preferred conservative management as their first line management for patients diagnosed with intra-abdominal bleeding. CONCLUSION: The study has identified a wide variation in the practices of minimizing infection and bleeding complications. The dearth of good quality evidence may be responsible for the lack of published guidelines, and therefore a lack of consensus on the optimum practice for minimizing the risk of infection and bleeding during TV-OPU.

Time-Line in HFEA Developments and Regulatory Challenges: 20 Years of Overseeing Fertility Practices and Research in the UK.

In the wake of political upheaval, the Human Fertilisation and Embryo Authority (HFEA) has faced increasing insecurity over its future as a pivotal regulatory body of fertility practices in the UK. HFEA regulates activities by means of licensing, audit, and inspection of fertility centers and maintaining the Code of Practice, which ensures the optimum undertaking of licensed activities by fertility centers. In 2009, amendments to the 1990 Act came into force representing an amalgamation of cumulative proposals, debates, and changes in legislation, which have shaped the world of reproductive medicine. The medical world has, in many cases, adapted to righteous political and social demands, and continues to evolve at a rapid rate. The HFEA has faced many regulatory challenges and changes, and through this study, we aim to provide an overview of some of these changes, particularly those during the last 10 years and the implications that they may have had to fertility practices.

Prospective randomized trial of multiple micronutrients in subfertile women undergoing ovulation induction: a pilot study.

This study investigated whether subfertile women undergoing ovulation induction using standard treatment regimens with clomiphene citrate/gonadotrophins have higher pregnancy rates when on an adjuvant multiple micronutrient (MMN) nutritional supplement compared with folic acid alone. A prospective randomized controlled trial was conducted in a teaching-hospital fertility clinic on 58 subfertile women, of which 56 women completed the study. Women undergoing ovulation induction were allocated to either receive adjuvant MMN supplementation or folic acid. Clinical pregnancy rates and blood nutrient concentrations were assessed after the third treatment attempt or as soon as the women achieved pregnancy. Using intention-to-treat analysis, it was observed that women on adjuvant MMN supplementation had a significantly higher cumulative clinical pregnancy rate (66.7%) compared with those on folic acid (39.3%; P = 0.013). The ongoing pregnancy rate in women on MMN supplementation was 60.0% versus 25.0% (P < 0.02) in the folic-acid group. Further, women who were on MMN supplementation had significantly fewer attempts to achieve pregnancy compared with women on folic acid (P < 0.001). The results of this pilot study suggest that women who take adjuvant MMN supplementation during ovulation induction have a higher chance of pregnancy compared with women on folic acid.

Role of vascular endothelial growth factor in women with PCO and PCOS: a systematic review.

The aim of this study was to investigate the strategic role of vascular endothelial growth factor (VEGF) in the pathophysiology of polycystic ovary syndrome (PCOS) and to critically review the published trials that have evaluated VEGF in women with PCOS. An electronic database search of Medline, Embase, Cinahl and Cochrane library was conducted. Studies were included if they evaluated VEGF either in the circulation or in granulosa lutein cell culture media in in-vitro laboratory studies of women with a polycystic ovary (PCO) or PCOS. Studies analysing immunohistochemical expression of VEGF in PCO were also included. This review concluded that VEGF may have a strategic role in the pathophysiology of PCOS and is the key mediator in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) in women undergoing assisted reproductive procedures. Its role is perhaps not singular and several other factors such as the bioavailability of its soluble receptor sFlt-1 and a multidisciplinary orchestration of other cytokines and growth factors may be involved in the pathophysiology of PCOS and OHSS.

Prevalence of polycystic ovaries and polycystic ovary syndrome in lesbian women compared with heterosexual women.

OBJECTIVE: To determine the prevalence of polycystic ovaries (PCO) and polycystic ovarian syndrome (PCOS) in lesbian women compared with heterosexual women undergoing fertility treatment. DESIGN: A prospective observational study. SETTING: The London Women's clinic and The Hallam Medical Center. Tertiary referral fertility setup. PATIENT(S): Six hundred eighteen women undergoing ovarian stimulation with or without IUI treatment between November 2001 and January 2003. Of these, 254 were self-identified as lesbians and 364 were heterosexual women. INTERVENTION(S): Baseline pelvic ultrasound examination and blood tests conducted to measure biochemical parameters such as FSH, LH, E(2), PRL, T, androstenedione (A), sex hormone-binding globulin (SHBG), and DHEAS were performed between day 2 and 3 of each woman's menstrual cycle. Tubal patency tests were performed by hysterosalpingography or laparoscopy. MAIN OUTCOME MEASURE(S): Biochemical parameters. RESULT(S): Eighty percent of lesbian women, compared with 32% of the heterosexual women, had PCO on pelvic ultrasound examination. Thirty-eight percent of lesbian women, compared with 14% of heterosexual women, had PCOS. There were no significant differences in the androgen concentrations between lesbian and heterosexual women with normal ovaries. However, lesbian women with PCO and PCOS had significantly higher androgen concentrations compared with heterosexual women with PCO and PCOS. Tubal disease was as common in lesbian women as in heterosexual women. CONCLUSION(S): There is a significantly higher prevalence of PCO and PCOS in lesbian compared with heterosexual women. Lesbian women with either PCO or PCOS had more pronounced hyperandrogenism than did heterosexual women with either PCO or PCOS.

Concentration of vascular endothelial growth factor released by cultured human luteinized granulosa cells is higher in women with polycystic ovaries than in women with normal ovaries.

To test the hypothesis that increased serum levels of vascular endothelial growth factor (VEGF) in women with polycystic ovaries or the polycystic ovary syndrome (PCOS) result from excess release by ovarian granulosa cells. Prospective study. Academic research setting. Twenty women undergoing IVF treatment, of whom 10 had normal ovaries and 10 had polycystic ovaries. Human granulosa lutein cells were isolated from follicular fluid obtained on the day of oocyte retrieval. Release of VEGF was assessed after co-incubation of granulosa lutein cells with gonadotropins and insulin. Serum and follicular fluid concentrations of VEGF were measured. Release of VEGF from granulosa lutein cells and serum levels of VEGF. Incubation with human hCG, and luteinizing hormone increased release of VEGF into the culture medium. Insulin alone did not increase release of VEGF, but addition of insulin increased hCG-stimulated release of VEGF. Serum and follicular fluid VEGF concentrations and the amount VEGF released from granulosa lutein cells obtained from women with polycystic ovaries or PCOS and those who developed the ovarian hyperstimulation syndrome were greater than those from granulosa lutein cells obtained from women with normal ovaries and those who did not develop the ovarian hyperstimulation syndrome. The amount of VEGF released by granulosa lutein cells is gonadotropin dependent and is augmented by insulin. The increased circulating concentrations of VEGF in women with PCOS may not only be due to an increased number of actively secreting granulosa lutein cells but also due to increased secretory capacity of each granulosa cell.

What's new in the pathogenesis and prevention of ovarian hyperstimulation syndrome?

Several pathophysiological mechanisms have been proposed for the development of ovarian hyperstimulation syndrome (OHSS), such as activation of the ovarian renin--prorenin--angiotensin system, release of ovarian cytokines and nitric oxide, but numerous reports now attest to the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen, as an important mediator of the syndrome. Luteinizing hormone (LH) or human chorionic gonadotrophin (hCG) regulates VEGF production by the ovary. Formation of multiple follicles, as seen in regimens of ovarian stimulation used for in vitro fertilization (IVF), and intensified sensitivity towards human menopausal gonadotrophin (hMG) and hCG, as seen in women with polycystic ovaries (PCO) or polycystic ovary syndrome (PCOS), result in increased serum VEGF concentrations, probably due to enhanced VEGF production by the ovaries. It is possible that the hypersecretion of VEGF in women with PCO is due to an increase in the number of VEGF secreting cells or that the cells individually hypersecrete VEGF. This hypothesis was tested by in vitro studies on granulosa lutein cells. After the cells were stimulated with gonadotrophins and hCG, VEGF production was higher in granulosa cells obtained from women with PCO compared with those obtained from women with normal ovaries under similar culture conditions. The studies performed in vivo and in vitro were consistent with increased VEGF expression as a constitutive feature of PCO. Increased VEGF may be responsible for the fluid shift from the vascular bed to the extravascular space, which characterizes OHSS. Prevention of OHSS focuses on predicting the possibility of developing OHSS. Markers such as serum oestradiol concentrations and number of follicles on the day of hCG administration, the presence of PCO and the number of oocytes retrieved may be subject to inter-observer and inter-operator variations. As individual markers of OHSS, each of these factors predicts less than a quarter of cases of the syndrome. It has been shown that a combination of pretreatment diagnosis of PCO along with number of follicles on the day of hCG administration and 'VEGF rise' gives the highest prediction rates for the risk of developing OHSS. Neither pathogenesis nor prevention and treatment of OHSS are specific. Therefore, at present, OHSS remains a condition that cannot be avoided altogether.