Faculty Bibliography

OBJECTIVE:We examined if thyroid autoimmunity is relevant to the relationship between maternal TSH levels and pregnancy outcomes. DESIGN/METHODS:Retrospective cohort analysis of data from two randomized controlled trials (RCTs). SUBJECTS/METHODS:Participants of the Pregnancy in Polycystic Ovary Syndrome (PPCOS II, n = 746) and the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS, n = 832 with unexplained infertility) RCTs. EXPOSURE/METHODS:Pre-trial intervention levels of thyroid stimulating hormone (TSH) at threshold of ≥2.0 mU/L and thyroid peroxidase antibody (TPO-Ab) at titer threshold of ≥30 U/mL. MAIN OUTCOME/RESULTS:Live birth (primary outcome), pregnancy loss and preterm birth (secondary outcomes). Generalized linear model (GLM) analyses examined the relationship between exposure to TSH and TPO-Ab at specified thresholds with the specified outcomes; covariates adjusted for included age, body mass index, race, ethnicity, education, smoking, duration of infertility, PCOS (versus unexplained infertility) and randomized intervention arm in the respective RCTs. RESULTS:On adjusted analyses, live birth was significantly reduced in the exposed population (those with TSH ≥2.0 mU/L and TPO-Ab ≥30 U/mL, n= 117/1578, 7.4%, adjusted risk ratio [ARR] 0.55, 95% CI 0.35- 0.87) compared to the unexposed (those with TSH <2.0 mU/L and TPO-Ab <30 U/mL, n=865/1578, 54.8%). Furthermore, the risk of pregnancy loss and of early preterm birth (<32 weeks) was significantly higher in the exposed compared to the unexposed (ARR for pregnancy loss was 1.66, 95% CI 1.14- 2.42, and ARR for early preterm birth was 4. 82 (95% CI 1.53- 15.19). CONCLUSIONS:In women with TPO-Ab titers ≥30 U/mL, pregnancy outcomes may be compromised at TSH threshold of ≥2 mU/L. These findings of an interaction between TSH and TPO for pregnancy outcomes merit further investigation in prospective studies.

OBJECTIVE:To evaluate if in pregnancies conceived with the transfer of single genetically tested embryos, maternal race and ethnicity relate to pregnancy outcome. DESIGN/METHODS:Retrospective cohort. SETTING/METHODS:Data available in the Clinical Outcome Reporting System of the Society for Assisted Reproductive Technology (SART-CORS) for years 2016-2018. PATIENT(S)/METHODS:Autologous frozen-thaw embryo transfer (FET) cycles with transfer of single genetically tested embryo in SART-CORS for years 2016-2018; cycles associated with diagnoses of recurrent pregnancy loss, gestational carrier, donor egg and donor embryo were excluded. INTERVENTION(S)/METHODS:Information on race and ethnicity linked with in vitro fertilization and FET cycles available in SART-CORS. MAIN OUTCOME MEASURE(S)/METHODS:Multivariable analyses using generalized estimating equation examined the relationship between categories of race and ethnicity with the following outcomes: Pregnancy positive β hCG (human chorionic gonadotropin), clinical pregnancy, pregnancy loss (early [at gestation <13 weeks] and late [loss between ≥13 and <20 weeks]), preterm (<37 weeks), term (≥37 weeks) and live birth. Covariates adjusted for included age, body mass index, anti-Mullerian hormone, infertility diagnosis and smoking history. RESULT(S)/RESULTS:Seventy-nine thousand four hundred and sixteen FET cycles met the eligibility criteria. Information on race and ethnicity was specified for 50,820 (64.0%) and was not known in 28,723 (36%) of the cycles. The population was predominantly non-Hispanic White (44%); non-Hispanic Black comprised 2.7%, Asian 12.3%, Hispanic 3.4%, and American Indian, Pacific Islander, Hawaiian, and Alaskan comprised 0.2% of the population. Nearly 1.0 % self-identified with more than one race. On multivariable analyses, pregnancies in non-Hispanic Black and in Hispanic women (compared with non-Hispanic Whites') were significantly more likely to result in in preterm birth. Compared with non-Hispanic White women, the likelihood of live birth was significantly lower in non-Hispanic Blacks, Asian, Hispanic, American Indian, Pacific Islander, Hawaiian, and Alaskan women. The likelihood for delivery by Cesarean was also disproportionately higher in the non Hispanic Black and, Hispanic women and in those identifying with more than one race (0.023) compared with non-Hispanic White women. CONCLUSION(S)/CONCLUSIONS:Racial and ethnic differentials are apparent in the outcomes of FET conceived pregnancies resulting from the transfer of single genetically tested embryos.

In this review, we have summarized the evolution in our understanding of a relevance of gonadotropin dosing for cycle outcomes in women attempting to conceive through the utilization of the in vitro fertilization technology.

Objective: To examine if pregnancy outcomes following transfer of thawed single genetically tested (PGT-A) blastocysts differ by race & ethnicity.
Material(s) and Method(s): SARS CORS data on autologous single embryo transfer (ET) PGT-A cycles were analyzed. Recurrent pregnancy loss, gestational carrier, donor egg & donor ET cycles were excluded. Racial categories available in SART CORS are: White (W), Black (B), Asian (As), Pacific Islander (PI) & Unknown (Unk). Ethnic categories are Hispanic (H) & non-Hispanic (nH). SART specified pregnancy outcomes include preterm birth (PTB), stillbirth (SB), ectopic pregnancy (EP) & live birth (LB). Term birth (TB, birth at gestation >=37 weeks), early loss (EL, loss at gestation<13 weeks) & late loss (LL, loss between>=13 and <20 weeks) were computed. Multivariable analysis examined relationship between race & ethnicity with specified outcomes, after adjusting for age, BMI, smoking, endometrial thickness (mm), infertility diagnoses of uterine & tubal factor & AMH (linked with fresh cycle).
Result(s): Of the 79,416 FET single ET cycles meeting eligibility criteria, racial & ethnic representations were: W: 35, 654 (45%), B: 2,255 (2.8%), As: 10.015 (12.6%), PI: 115 (0.14%), Unk (31,378 (39.5%), H: 3,168 (4.0%). Outcomes of pregnancies resulting from single genetically tested ET were significantly compromised in women of non-W race & of H ethnicity compared to W & non-H women (Table). EP & EL were unrelated to race or ethnicity (p>0.05). [Formula presented]
Conclusion(s): Concerning racial & ethnic differentials in pregnancy outcomes of IVF PGT-A cycles utilizing transfer of single thawed blastocysts were noted. Impact Statement: Among women of color achieving pregnancy following transfer of genetically tested single embryos in the US, Black women are at a disproportionately higher risk for concerning obstetric outcomes including late PL, PTB & SB. Systemic racism as underpinning to the observed associations is a plausible consideration that merits attentiveness. Support: None
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Objective: To determine pregnancy outcomes in women with PCOS compared to those with other infertility diagnoses following frozen-thawed embryo transfer (FET) of a single preimplantation genetically tested (PGT-A) blastocyst.
Material(s) and Method(s): Retrospective cohort analysis of the SART CORS database 2016-2018. Autologous single embryo transfer cycles of PGT-A tested blastocysts were included. Exclusion criteria were recurrent pregnancy loss, gestational carrier and cycles using donor oocytes or embryos. We examined pregnancy outcomes in women with PCOS compared to those without PCOS diagnosis for the SART specified outcomes: biochemical pregnancy (BP), pregnancy loss (PL, loss at 5 to <20 weeks), preterm birth (PTB), stillbirth (SB), ectopic pregnancy (EP) and live birth (LB). Term birth (TB) was defined as live birth at >=37 weeks. Univariate and multivariable analysis were performed using STATA V13.0. Covariates adjusted for included age, BMI, race/ethnicity, smoking, endometrial thickness, uterine factor and AMH. The data are presented as odds ratios (OR) and 95% CI.
Result(s): 79,416 FET cycles of single PGT-A tested embryos met eligibility criteria, of these 12,230 (15%) were in women with PCOS. Compared to the other infertility diagnoses, the diagnosis of PCOS was significantly associated with greater likelihood of BP, PL and PTL, and lower likelihood of LB (Table). The outcomes of SB and EP were unrelated to the PCOS diagnosis.
Conclusion(s): We found that compared to other infertility etiologies, the diagnosis of PCOS is associated with adverse outcomes in pregnancies following transfer of a single PGT-A tested blastocyst. Our results suggest that other factors than embryo aneuploidy are contributors to attenuated pregnancy success in women with PCOS. Impact Statement: In women with PCOS, pregnancy outcomes are compromised following transfer of a single genetically tested embryo. Intensified pregnancy surveillance may be warranted in women with PCOS. The future research needs to confirm the observed adverse pregnancy outcomes in women with PCOS and explore the underlying mechanisms. [Formula presented] Support: None.
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OBJECTIVE:To investigate the effect of the selective progesterone receptor modulator, telapristone acetate (CDB-4124), on endometrial biology and reproductive outcomes. Ovariectomized and hormone-treated CD1 female mice, CD1 female mice with xenotransplants of reconstructed human endometrial tissue, mated wildtype female mice, and cultured human endometrial stromal cells (hESCs) were treated with CDB-4124, followed by the assessment of endometrial cell deoxyribonucleic acid (DNA) proliferation, stromal decidual response, and embryo implantation. DESIGN:Experimental study. SETTING:Academic research laboratory. PATIENTS:Healthy volunteer women from the community were recruited for endometrial biopsies. ANIMALS:CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME). INTERVENTION:Treatment of mice and hESCs with CDB-4124. MAIN OUTCOME MEASURE:The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation. RESULTS:CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro. CONCLUSION:CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization.

The human endometrium undergoes extensive morphological, biochemical and molecular changes under the influence of female sex steroid hormones. Besides the fact that estrogen stimulates endometrial cell proliferation and progesterone inhibits this proliferation and induces differentiation, there is limited knowledge about precise molecular mechanisms underlying human endometrial biology. The importance of paracrine signaling in endometrial physiology explains why in vitro culture of endometrial cells has been challenging. Researchers, therefore, have developed alternative experimental in vivo models for the study of endometrial biology. The objective of this review is to summarize the recent developments and work on these in vivo endometrial research models. The in vivo recombinant tissue models in which wild-type endometrial cells are combined with endometrial cells from a gene-targeted mouse strain followed by xenografting to host mice have been critical in confirming the significance of paracrine signaling between the epithelium and stroma in the growth regulation of the endometrium. Additionally, these studies have uncovered differences between the mouse and human, emphasizing the need for the development of experimental models specifically of the human endometrium. Recently, xenotransplants of human endometrial fragments into the subcutaneous space of host mice and endometrial xenografts of dissociated and recombined epithelial and stromal cells beneath the kidney capsule of immunodeficient host mice have proven to be highly promising tools for in vivo research of endometrial functions. For the first time, the latter approach provides an immense opportunity for the application of genome engineering, such as targeted ablation of endometrial genes for example by using CRISPR/CAS9 system. This research will begin to elucidate the functional role of specific genes in this complex tissue. Another advantage of xenotransplantation and xenograft models of the human endometrium is their use to investigate endometrial effects of new compounds and drugs without needing to give them to women. Underpinning the molecular mechanisms underlying endometrial functions is critical to ultimately advance our understanding of endometrial pathophysiology and develop targeted therapies to prevent and cure endometrial pathologies as well as enhance endometrial function when it is desired for fertility.

Receptive endometrium is essential for successful implantation and ongoing pregnancy. Significant health issues and associated therapies, especially oncologic therapies, have potential to negatively impact future fertility in young women. Irradiation and chemotherapeutic alkylating agents are known to cause ovarian failure in most females; however, less well is characterized the impact of irradiation on uterine development and integrity. With an increasing number of cancer survivors, women are seeking infertility treatment after such therapies. Here, we present a young woman who developed ovarian failure after the treatment of acute myeloid leukemia with bone marrow transplant and preceding irradiation and chemotherapy and who was diagnosed with thin endometrial lining while seeking infertility therapy.