Torie C. Plowden

Subclinical Hypothyroidism and Thyroid Autoimmunity Are Not Associated With Fecundity, Pregnancy Loss, or Live Birth

CONTEXT Prior studies examining associations between subclinical hypothyroidism and antithyroid antibodies with early pregnancy loss and live birth suggest mixed results and time to pregnancy (TTP) has not been studied in this patient population. OBJECTIVE This study sought to examine associations of prepregnancy TSH concentrations and thyroid autoimmunity with TTP, pregnancy loss, and live birth among women with proven fecundity and a history of pregnancy loss. DESIGN AND SETTING This was a prospective cohort study from a large, randomized controlled trial that took place at four medical centers in the United States. PATIENTS OR OTHER PARTICIPANTS Healthy women, ages 18-40 y, who were actively attempting to conceive and had one or two prior pregnancy losses and no history of infertility were eligible for the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURE TTP, pregnancy loss, and live birth. RESULTS Women with TSH ≥ 2.5 mIU/L did not have an increased risk of pregnancy loss (risk ratio, 1.07; 95% confidence interval [CI], 0.81-1.41) or a decrease in live birth rate (risk ratio, 0.97; 95% CI, 0.88-1.07) or TTP (fecundability odds ratio, 1.09; 95% CI, 0.90-1.31) compared with women with TSH <2.5 mIU/L after adjustment for age and body mass index. Similar findings were observed for women with thyroid autoimmunity and after additional adjustment for treatment assignment. CONCLUSIONS Among healthy fecund women with a history pregnancy loss, TSH levels ≥ 2.5 mIU/L or the presence of antithyroid antibodies were not associated with fecundity, pregnancy loss, or live birth. Thus, women with subclinical hypothyroidism or thyroid autoimmunity can be reassured that their chances of conceiving and achieving a live birth are likely unaffected by marginal thyroid dysfunction.

Dietary fat intake and reproductive hormone concentrations and ovulation in regularly menstruating women

BACKGROUND Emerging evidence suggests potential links between some dietary fatty acids and improved fertility, because specific fatty acids may affect prostaglandin synthesis and steroidogenesis. OBJECTIVE The objective of this exploratory study was to evaluate associations between total and specific types of dietary fat intake and 1) hormone concentrations and 2) the risk of sporadic anovulation in a cohort of 259 regularly menstruating women in the BioCycle Study. DESIGN Endogenous reproductive hormones were measured up to 8 times/cycle for up to 2 cycles, with visits scheduled with the use of fertility monitors. Dietary intake was assessed with up to four 24-h recalls/cycle. Linear mixed models and generalized linear models were used to evaluate the associations between dietary fatty acids and both reproductive hormone concentrations and ovulatory status. All models were adjusted for total energy intake, age, body mass index, and race. RESULTS Relative to the lowest levels of percentage of energy from total fat, the highest tertile was associated with increased total and free testosterone concentrations (total: percentage change of 4.0%; 95% CI: 0.7%, 7.3%; free: percentage change of 4.1%; 95% CI: 0.5%, 7.7%). In particular, the percentage of energy from polyunsaturated fatty acids (PUFAs) in the highest tertile was associated with increases in total and free testosterone (total: percentage change of 3.7%; 95% CI: 0.6%, 6.8%; free: percentage change of 4.0%; 95% CI: 0.5%, 7.5%). The PUFA docosapentaenoic acid (22:5n-3) was not significantly associated with testosterone concentrations (P-trend = 0.86 in energy substitution models) but was associated with increased progesterone and a reduced risk of anovulation (highest tertile compared with the lowest tertile: RR: 0.42; 95% CI: 0.18, 0.95). Fat intakes were not associated with other reproductive hormone concentrations. CONCLUSIONS These results indicate that total fat intake, and PUFA intake in particular, is associated with very small increases in testosterone concentrations in healthy women and that increased docosapentaenoic acid was associated with a lower risk of anovulation.

Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women

BACKGROUND Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in womens reproductive health. OBJECTIVE The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. METHODS The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. RESULTS Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). CONCLUSIONS These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.

Biomarkers in uterine leiomyoma

Biomarkers are biologic compounds that are easily accessible and reflect normal physiology or pathology. They are useful in a variety of clinical situations that involve detection of subclinical disease, risk stratification, preoperative planning, and monitoring treatment. A useful intervention needs to exist for a biomarker to be an effective tool. Many compounds have been investigated as potential biomarkers for the diagnosis and surveillance of uterine leiomyomas. Most of these compounds demonstrate subtle differences among patients when leiomyomas are compared with controls. The compounds investigated lack the diagnostic accuracy necessary to add any benefit to the current available modalities used to diagnose and monitor uterine leiomyomas.

Dairy Food Intake Is Associated with Reproductive Hormones and Sporadic Anovulation among Healthy Premenopausal Women

BACKGROUND Dairy food intake has been associated with infertility; however, little is known with regard to associations with reproductive hormones or anovulation. OBJECTIVE We investigated whether intakes of dairy foods and specific nutrients were associated with reproductive hormone concentrations across the cycle and the risk of sporadic anovulation among healthy women. METHODS We prospectively measured serum reproductive hormones ≤8 times/menstrual cycle for 2 cycles from 259 regularly menstruating women (mean age: 27.3 y). Dairy food intake was assessed via 24-h dietary recalls 4 times/cycle. Dairy food intakes were assessed by 1) total and low- and high-fat dairy products; 2) dairy nutrients, including fat, lactose, calcium, and phosphorus; and 3) dairy foods, including milk, cheese, butter, cream, yogurt, and ice cream categories. Weighted linear mixed models were used to evaluate associations between dairy nutrients or food intakes and hormone concentrations. Modified Poisson regression models with robust error variance were used to evaluate anovulation. Models were adjusted for age, body mass index, race, physical activity, Mediterranean diet score, total energy, protein, fiber, caffeine, and other hormones. RESULTS Each serving increase in total and low- and high-fat dairy foods and all increases in amounts of all dairy nutrients tested were associated with an ∼5% reduction in serum estradiol concentrations but were not associated with anovulation. Total and high-fat dairy food intakes were positively associated with serum luteinizing hormone concentrations. We observed associations between intakes of >0 servings of yogurt (RR: 2.1; 95% CI: 1.2, 3.7) and cream (RR: 1.8; 95% CI: 1.0, 3.2) and a higher risk of sporadic anovulation compared with no intake. CONCLUSIONS Our study showed associations between increasing dairy food and nutrient intakes and decreasing estradiol concentrations as well as between cream and yogurt intakes and the risk of sporadic anovulation. These results highlight the potential role of dairy in reproductive function in healthy women.

Does the Presence of Blood in the Catheter or the Degree of Difficulty of Embryo Transfer Affect Live Birth

The technique used for embryo transfer (ET) can affect implantation. Prior research that evaluated the effect of postprocedural blood of the transfer catheter tip have yielded mixed results, and it is unclear whether this is actually a marker of difficulty of the transfer. Our objective was to estimate the effect of blood at the time of ET and the difficulty of ET on live birth rates (LBR). This retrospective cohort study utilized generalized estimating equations (GEEs) with nesting for repeated cycles for all analyses. Univariate modeling was performed and a final multivariate (adjusted) GEE model accounted for all significant confounders. Embryo transfers were subjectively graded (easy, medium, or hard) by a physician at the time of transfer. The presence of blood at ET was associated with more difficult ETs, retained embryos, and presence of mucous in the catheter. In the univariate analysis, ET with blood was not associated with live birth, while the degree of difficulty for ET had a negative impact on LBR. In the final multivariate GEE model, which accounts for repeated cycles from a patient, the only factors associated with an increased LBR were the degree of difficulty of the ET, female age, and blastocyst transfer. After controlling for confounding variables, the presence of blood in the transfer catheter was not associated with the likelihood of pregnancy and thus was not an independent predictor of cycle outcome. This indicates that the difficulty of the transfer itself was a strong negative predictor of pregnancy.The technique used for embryo transfer (ET) can affect implantation. Prior research that evaluated the effect of postprocedural blood of the transfer catheter tip have yielded mixed results, and it is unclear whether this is actually a marker of difficulty of the transfer. Our objective was to estimate the effect of blood at the time of ET and the difficulty of ET on live birth rates (LBR). This retrospective cohort study utilized generalized estimating equations (GEEs) with nesting for repeated cycles for all analyses. Univariate modeling was performed and a final multivariate (adjusted) GEE model accounted for all significant confounders. Embryo transfers were subjectively graded (easy, medium, or hard) by a physician at the time of transfer. The presence of blood at ET was associated with more difficult ETs, retained embryos, and presence of mucous in the catheter. In the univariate analysis, ET with blood was not associated with live birth, while the degree of difficulty for ET had a negative impact on LBR. In the final multivariate GEE model, which accounts for repeated cycles from a patient, the only factors associated with an increased LBR were the degree of difficulty of the ET, female age, and blastocyst transfer. After controlling for confounding variables, the presence of blood in the transfer catheter was not associated with the likelihood of pregnancy and thus was not an independent predictor of cycle outcome. This indicates that the difficulty of the transfer itself was a strong negative predictor of pregnancy.

Thyroid-stimulating hormone, anti–thyroid antibodies, and pregnancy outcomes

Background Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. Objective The purpose of this study was to examine the association between prepregnancy anti–thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. Study Design We conducted a secondary analysis of a prospective cohort of 18‐ to 40‐year‐old women with 1–2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo‐controlled trial of low‐dose aspirin. Prepregnancy levels of thyroid‐stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. Results Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid‐stimulating hormone level (>2.5 vs ≤2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40–1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54–3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71–2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65–2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51–3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54–1.92), compared with women without these antibodies. Conclusion Among women with 1–2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low‐risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.

Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study

BACKGROUND Vitamin D deficiency during pregnancy is associated with adverse pregnancy outcomes, although the association between preconception vitamin D concentrations and livebirth is unknown. We aimed to assess the association between preconception vitamin D and pregnancy outcomes among women with proven fecundity. METHODS We did a secondary analysis of a prospective cohort from the block-randomised, double-blind, placebo-controlled EAGeR trial. Women aged 18-40 years with one to two previous pregnancy losses were recruited from June 15, 2007, to July 15, 2011, at four clinical sites in the USA and followed up for up to six menstrual cycles while attempting pregnancy and throughout pregnancy if they conceived. Serum 25-hydroxyvitamin D was measured at baseline (preconception) and 8 weeks of gestation. Outcomes of interest included clinical pregnancy, time to pregnancy, pregnancy loss, and livebirths. Risk ratios (RRs) and 95% CIs for livebirths, pregnancy, and pregnancy loss were estimated with weighted log-binomial regression. To assess time to pregnancy, we used discrete time Cox proportional hazards models to calculate fecundability odds ratios (FORs) with 95% CIs. EAGeR is registered with ClinicalTrials.gov, number NCT00467363. FINDINGS 1191 women had available data on preconception 25-hydroxyvitamin D concentrations. 555 (47%) women were classified as having sufficient concentrations (≥75 nmol/L) and 636 (53%) as having insufficient concentrations (<75 nmol/L). Women with sufficient preconception 25-hydroxyvitamin D were more likely to achieve clinical pregnancy (adjusted RR 1·10 [1·01-1·20]) and livebirth (1·15 [95% CI 1·02-1·29]) than were women with insufficient concentrations. Among women who achieved pregnancy, sufficient preconception 25-hydroxyvitamin D, but not that at 8 weeks of gestation, was associated with reduced risk of pregnancy loss (preconception RR per 25 nmol/L 0·88 [95% CI 0·77-0·99]; 8 weeks of gestation 0·98 [0·95-1·01]). No association was observed with fecundability in women with sufficient versus those with insufficient preconception 25-hydroxyvitamin D concentrations (adjusted FOR 1·13 [95% CI 0·95-1·34]). INTERPRETATION Sufficient preconception 25-hydroxyvitamin D (≥75 nmol/L) was associated with increased likelihood of pregnancy and livebirth. Increased vitamin D concentrations before conception, but not in early pregnancy, were associated with reduced pregnancy loss. FUNDING National Institutes of Health and Doris Duke Charitable Foundation.

Recent attempted and actual weight change in relation to pregnancy loss: a prospective cohort study

To assess weight change and attempted weight loss during the 12–18 months before spontaneous conception in relation to the risk of pregnancy loss.

Adjusting for abstinence time in semen analyses: some considerations

K. A. Michels, K. Kim, E. H. Yeung, T. C. Plowden, E. N. Chaljub, Y.-L. Lu and S. L. Mumford Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, and Division of Library Services, Office of Research Services, National Institutes of Health Library, National Institutes of Health, Bethesda, MD, USA