To study whether infertility treatments, including IVF and non-IVF fertility treatments, are associated with diseases of placental insufficiency in early gestation. First trimester placental volumes ...by ultrasound and chorionic villi weight during sampling (CVS) were performed to detect differences between pregnancies conceived spontaneously versus with fertility treatments.
Retrospective cohort.
Academic tertiary center.
Women with singleton pregnancies undergoing CVS and first trimester ultrasound from April 2007 to November 2015.
Estimated placental volume (EPV) was calculated from ultrasound images using a validated computation and CVS estimated tissue weight was performed using a validated visual analogue scale.
Adjusted linear regression was used to compare EPV and CVS weight based on mode of conception.
A total of 1,977 spontaneous and 334 conceived with fertility treatments (133 non-IVF and 201 IVF) pregnancies were included. Significant differences in maternal age, gravidity, hypertension, and smoking status were identified. EPV and CVS weight were correlated with maternal age, gestational age, and maternal hypertension. Adjusted linear regression showed no difference in EPV in pregnancies conceived with fertility treatments versus spontaneously. The CVS weight was significantly lower in the IVF conceptions in unadjusted univariate analyses. However, after adjusted regression, this was no longer significant.
Mode of conception does not appear to affect first trimester placental size. As differences in maternal age, hypertension, and smoking status differ among the groups and are correlated to placental size, it may be the underlying patient population leading to abnormal placentation and insufficiency, not the fertility treatments used.
Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually ...dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences. Summary sentence Sex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are 62.5% more female exclusive gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.
To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population.
Secondary analysis of the ...Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial.
Multicenter university-based clinical practices.
Nine hundred couples with unexplained infertility were included. Women were 18-40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed.
None.
The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss.
When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes.
In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment.
NCT 01044862.
Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational ...age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.
Objective: To investigate perinatal outcomes in a cohort of fertile and infertile nulliparous women.
Design: Retrospective cohort study.
Setting: Academic medical center.
Patients: All nulliparous ...women delivering singletons ≥24-week gestation at our center from 1 January 2012 to 31 December 2012 were included. Women were classified into two groups - fertile and infertile - based on a chart review at the time of delivery.
Outcome measure: Perinatal outcomes of interest included mode of delivery, gestational age at delivery, and birth weight.
Results: A total of 3293 mother/infant dyads fulfilled the inclusion criteria. Of these, 277 women (8.4%) were classified as infertile. Infertile women were significantly older than fertile women. In bivariate analyses, infertile women were more likely to undergo cesarean delivery (51.8 versus 36.1%, p < .001) and deliver at an earlier gestational age (38.9 ± 2.3 versus 39.4 ± 1.7 weeks, p < .0001). Infertility was no longer significantly associated with cesarean delivery after adjusting for maternal age. Infertility remained associated with an earlier gestational age at delivery after adjusting for maternal age and maternal race (β coefficient −0.42, 95%CI −0.64, −0.2). There was no difference in infant birth weight. Late preterm deliveries (34-36 completed gestational weeks) accounted for 8.3% of deliveries for infertile women compared to 4.3% for fertile women (p = .032).
Conclusions: We conclude that the increased risk of cesarean section associated with infertility is driven by maternal age. Late preterm infants represent a key cohort for further evaluation in the perinatal outcomes of infertile women.
Abstract
Context
Maternal metabolic status reflects underlying physiological changes in the maternal-placental-fetal unit that may help identify contributors to adverse pregnancy outcomes associated ...with infertility and treatments used.
Objective
To determine if maternal metabolomic profiles differ between spontaneous pregnancies and pregnancies conceived with fertility treatments that may explain the differences in pregnancy outcomes.
Design
Metabolon metabolomic analysis and ELISAs for 17-β-estradiol and progesterone were performed during the late first trimester of pregnancy.
Setting
Academic institution.
Subjects
Women in the Spontaneous/Medically Assisted/Assisted Reproductive Technology cohort (N = 409), 208 of whom conceived spontaneously and 201 with infertility non in vitro fertilization treatments (NIFT), n=90; in vitro fertilization (IVF), n=111.
Intervention
Mode of conception.
Main Outcome Measures
Levels of of 806 metabolites within eight superpathways, 17-β-estradiol, and progesterone in maternal plasma in the late first trimester.
Results
Metabolomic differences in the lipid superpathway (i.e., steroid metabolites, lipids with docosahexaenoyl acyl chains, acyl cholines), and xanthine and benzoate metabolites (P < 0.05) were significant among the spontaneous and two infertility groups, with greatest differences between the spontaneous and IVF groups. 17-β-estradiol and progesterone levels were significantly elevated in the infertility groups, with greatest differences between the spontaneous and IVF groups.
Conclusion
Metabolomic profiles differ between spontaneous and infertility pregnancies, likely driven by IVF. Higher levels of steroids and their metabolites are likely due to increased hormone production from placenta reprogrammed from fertility treatments, which may contribute to adverse outcomes associated with infertility and the treatments used.
Levels of lipid metabolites and xenobiotics differed significantly in maternal plasma from pregnancies conceived spontaneously vs through infertility treatment, largely driven by IVF.
To determine if mosaicism that occurs in infertility and assisted reproductive technologies continues in the late first trimester and if this is unique to infertility or occurs in all pregnancies.
...Retrospective case-controlled study.
University hospital.
5337 consecutive chorionic villus samplings (CVS).
None.
Mosaic karyotypes at CVS.
We confirmed 69 mosaic karyotypes, a rate of 1.29%. Comparing spontaneous pregnancies with pregnancies from infertility treatment, no difference was found in the prevalence of mosaicism: 1.22% versus 1.32%, respectively. Subgroup analysis of infertile couples, comparing in vitro (assisted reproduction) with in vivo fertilization (other treatments) revealed a mosaicism rate of 1.84% and 0.41%, respectively. Confined placental mosaic (CPM) rates for infertility treated pregnancies and spontaneously conceived pregnancies were 0.88% and 0.92%, respectively. Subgroup analysis of infertile patients revealed a CPM rate of 1.15% for in vitro fertilization treatment and 0.41% for in vivo fertilization treatment. These results were not statistically significant.
There was no difference in the prevalence of mosaicism at the end of the first trimester in pregnancies conceived spontaneously compared with those with infertility. There was no difference in the prevalence of mosaicism when in vitro and in vivo treatment were compared.
FOXL2 is expressed in granulosa cells (GC) of small and medium ovarian follicles, functions as a repressor of the human steroidogenic acute regulatory gene, a marker of a GC differentiation, and its ...mutation is associated with premature ovarian failure (POF) in women with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), type I. We now report that FOXL2 also represses the transcription of aromatase, P450scc, and cyclin D2, three other key genes involved in GC proliferation, differentiation, and steroidogenesis, and that a FOXL2 mutation found in patients with BPES type I, also fails to repress aromatase transcription, further supporting a role for FOXL2 in follicle maturation.
The forkhead transcription factor forkhead box L2 (FOXL2) is expressed in granulosa cells of small and medium follicles in the mouse ovary. Foxl2 female knockout mice exhibit primordial follicle ...depletion and primary ovarian failure, but evidence from adult female conditional Foxl2 knockout mice suggests that FOXL2 may also play a significant role in maintenance of ovarian differentiation at stages beyond the primordial follicle and initial wave of folliculogenesis. We previously showed that human FOXL2 functions as a transcriptional repressor of several key genes involved in granulosa cell proliferation and differentiation, including steroidogenic acute regulatory protein (STAR), P450aromatase (CYP19A1 (CYP19)), P450scc (CYP11A1 (CYP11A)), and cyclin D2 (CCND2). To elucidate the role of mouse FOXL2, we determined its role in transcriptional regulation in Chinese hamster ovary (CHO) cells and then confirmed our findings in mouse granulosa cells. We found that mouse FOXL2 represses the activities of the mouse Star, Cyp19a1, Cyp11a1 promoters in CHO cells, but may not repress the Ccnd2 promoter, and identified the minimal mouse Star, Cyp19a1, and Cyp11a1 promoter regions responsive to FOXL2 regulation. We then knocked down Foxl2 in mouse granulosa cells using siRNA, which resulted in significantly increased expression levels of mouse Star, Cyp19a1, and Cyp11a1 but not Ccnd2. To increase Foxl2 expression levels, we generated a mouse Foxl2 lentiviral construct and used it to infect mouse granulosa cells. Following lentiviral infection, the expression levels of mouse Star, Cyp19a1, and Cyp11a1, but not Ccnd2, decreased significantly. These data confirm that mouse FOXL2 functions as a transcriptional repressor of key granulosa cell genes that influence ovarian development.
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