Endometrial microbiota composition is associated with reproductive outcome in infertile patients.

BACKGROUND: Previous evidence indicates associations between the female reproductive tract microbiome composition and reproductive outcome in infertile patients undergoing assisted reproduction. We aimed to determine whether the endometrial microbiota composition is associated with reproductive outcomes of live birth, biochemical pregnancy, clinical miscarriage or no pregnancy. METHODS: Here, we present a multicentre prospective observational study using 16S rRNA gene sequencing to analyse endometrial fluid and biopsy samples before embryo transfer in a cohort of 342 infertile patients asymptomatic for infection undergoing assisted reproductive treatments. RESULTS: A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was associated with unsuccessful outcomes. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. CONCLUSIONS: Our findings indicate that endometrial microbiota composition before embryo transfer is a useful biomarker to predict reproductive outcome, offering an opportunity to further improve diagnosis and treatment strategies. Video Abstract.

Peak Serum Estradiol Level During Controlled Ovarian Stimulation Is not Associated with Lower Levels of Pregnancy-Associated Plasma Protein-A or Small for Gestational Age Infants: A Cohort Study.

OBJECTIVE: During controlled ovarian stimulation in IVF, supraphysiologic levels of estradiol (E2) have been associated with poor placentation and adverse pregnancy outcomes. This study aimed to investigate whether high peak E2 on the day of human chorionic gonadotropin trigger is associated with low pregnancy-associated plasma protein-A (PAPP-A) and adverse perinatal outcomes. METHODS: We performed a retrospective cohort study at a private, university-affiliated fertility centre in Vancouver, BC. We enrolled 216 patients with a singleton pregnancy after fresh embryo transfer who also underwent first trimester screening. Adverse perinatal outcomes were collected from a local registry and included preterm birth, hypertension in pregnancy, antepartum hemorrhage, intrauterine growth restriction, SGA, stillbirth, admission to the NICU, and neonatal death. RESULTS: High serum E2 (≥13 035 pmol/L) at controlled ovarian stimulation was not correlated with low PAPP-A (<0.4 multiples of the median) at first trimester screening (P = 0.46). When each adverse outcome was analysed separately, there was no association between high E2 and any of the outcomes (P > 0.05 for all). High peak E2 was not associated with a total composite of maternal and neonatal adverse birth outcomes (P = 0.30). CONCLUSION: Our results do not support the theory that high E2 at fresh embryo transfer impedes placentation. We found no association between peak E2 and low PAPP-A levels or adverse pregnancy outcomes.

Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization.

OBJECTIVE: Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. METHODS: We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. RESULTS: A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). CONCLUSION: The administration of growth hormone during the luteal phase before a microdose GnRH agonist flare protocol for in vitro fertilization did not improve outcomes in "poor responder" patients.

Objectif : L'hormone de croissance (GH) agit pendant le développement folliculaire tant précoce que tardif pour stimuler la prolifération et la différenciation des cellules de la granulosa, ainsi que pour accroître la production d'estradiol par les ovaires chez l'animal et l'homme. Les chercheurs se sont donc penchés sur le recours à la supplémentation en GH pour améliorer les issues chez les femmes qui font appel à la fécondation in vitro, tout en portant une attention particulière aux femmes qui présentent une réserve ovarienne amoindrie. De récentes méta-analyses indiquent que la supplémentation en GH peut être bénéfique pour les femmes qui réagissent mal à la FIV. Dans la plupart des études, on administre de la GH de façon concomitante avec des gonadotrophines pendant la phase folliculaire; cette façon de faire pourrait ne pas être optimale, puisque le recrutement folliculaire débute au cours de la phase lutéale qui précède. Nous avons donc souhaité examiner l'effet de la supplémentation en GH pendant la phase lutéale, avant la tenue d'une stimulation ovarienne contrôlée (SOC) au moyen d'un « protocole de poussée ¼ faisant appel à une microdose d'agoniste de la GnRH (MDF), chez des femmes qui font l'objet d'une fécondation in vitro. Méthodes : Nous avons mené une étude cas-témoins appariés rétrospective se penchant sur des patientes qui ont fait l'objet d'un traitement au sein d'un établissement privé de FIV entre juin 2012 et juillet 2013. Les patientes identifiées comme réagissant mal à la SOC se sont vu offrir un traitement adjuvant à la GH dans le cadre de leur schéma thérapeutique de stimulation ovarienne. Les patientes du groupe expérimental ont choisi de recevoir de la GH, à raison de 3,33 mg par jour sous forme d'injection sous-cutanée pendant 14 jours, avant le début de la SOC. Toutes les patientes ont fait l'objet d'un protocole de stimulation MDF faisant appel à 450 UI d'hormone folliculostimulante (FSH) par jour. Résultats : Au total, 42 femmes ont participé à l'étude. Le groupe expérimental (GH) comptait 14 femmes et le groupe témoin (C) comptait 28 femmes appariées en fonction de l'âge, de l'IMC et du taux de FSH au jour 3. Aucune différence n'a été constatée entre les groupes en matière de taux de grossesse clinique (GH = 29 %, C = 32 %, P = 0,99), de nombre d'ovocytes matures récupérés (GH = 2,5, C = 5,0, P = 0,13), de taux d'annulation de cycle (GH = 21 %, C = 14 %, P = 0,88), de durée de la SOC (GH = 10,1, C = 10,1, P = 0,93) ou de niveau moyen du pic d'estradiol (GH = 4 174 pmol/l, C = 5 105 pmol/l, P = 0,44). Conclusion : L'administration d'hormone de croissance pendant la phase lutéale, avant la mise en œuvre d'un « protocole de poussée ¼ faisant appel à une microdose d'agoniste de la GnRH aux fins de la fécondation in vitro, n'a pas permis d'améliorer les issues obtenues par les patientes « réagissant mal ¼ à la SOC.

First-trimester levels of pregnancy-associated plasma protein A2 (PAPP-A2) in the maternal circulation are elevated in pregnancies that subsequently develop preeclampsia.

Recent studies have consistently found pregnancy-associated plasma protein A2 (PAPP-A2) to be upregulated in preeclamptic placentae at term. We tested whether first-trimester circulating PAPP-A2 levels differed between complicated and uncomplicated pregnancies. We measured maternal PAPP-A2 levels at 10 to 14 weeks of gestational age in 17 pregnancies resulting in small-for-gestational-age (SGA) infants, 6 which developed preeclampsia (PE), 1 which developed PE and resulted in an SGA infant, and 37 gestational age-matched controls. The concentration of the PAPP-A2 isoform corresponding to the full-length protein was significantly higher in pregnancies that developed PE (35 ng/mL) compared with those that did not (23 ng/mL; P < .044). In contrast, we found no difference in PAPP-A2 levels between pregnancies that did or did not result in an SGA infant. The upregulation of PAPP-A2 that has previously been observed in PE at term appears to begin early in pregnancy, well before the symptoms develop.