The impact of thyroid function and thyroid autoimmunity on embryo quality in women with low functional ovarian reserve: a case-control study.

BACKGROUND: Women with hyper-and hypothyroidism are at increased risk for infertility and adverse pregnancy outcomes. Whether in women considered euthyroid thyroid function (TSH values) and thyroid autoimmunity (thyroid antibodies) influence in vitro fertilization (IVF) cycle outcome has, however, remained controversial. Any such effect should be easily visible in women with low functional ovarian reserve (LFOR) and thus small oocyte and embryo numbers. METHODS: We evaluated the relationship between TSH levels and embryo quality in euthyroid women with LFOR undergoing IVF. Mean age for the study population was 39.9±4.6 years. Embryo quality was assessed in 431 embryos from 98 first IVF cycles according to TSH levels (with cut-off 2.5µIU/mL), and to presence versus absence of thyroid autoantibodies. RESULTS: Mean Anti Mullerian hormone (AMH) was 0.8±0.8 ng/mL and mean TSH was 1.8±0.9 µIU/mL. Comparable embryo quality was observed in women with TSH≤ and >2.5µIU/mL. TPO antibodies significantly affected embryo quality in women with low-normal TSH levels (P=0.045). In women with high-normal TSH levels, increasing TSH had a negative impact on embryo quality (P=0.027). A trend towards impaired embryo quality with TPO antibodies was also observed in these patients (p=0.057). CONCLUSIONS: TPO antibodies affect embryo quality in euthyroid women with low-normal TSH≤2.5 µIU/mL. In women with high-normal TSH levels, increasing TSH levels, and possibly TPO antibodies, appear to impair embryo quality. These results suggest that the negative impact of thyroid autoimmunity becomes apparent, once thyroid hormone function is optimized.

Some aspects of interactivity between endocrine and immune systems required for successful reproduction.

BACKGROUND: In successful reproduction, endocrine and immune systems closely interact. We here attempt to further elucidate the relationship between androgen levels, systemic activation of the immune system and reproductive success in infertile women, utilizing 2 distinct infertile patient cohorts. METHODS: In Group 1, we investigated 322 women (ages 38.6+/-5.4 years) at initial presentation; in Group 2 125 women undergoing in vitro fertilization (169 IVF cycles, ages 38.9+/-5.5 years). In Group 1, we assessed androgens and an immune panel, previously demonstrated to discriminate between activated quiescent immune systems; in Group 2, utilizing the same immune panel, we investigated whether immune system activation relates to embryo quality in IVF cycles. RESULTS: No individual immune test within the immune panel was associated with androgen levels. The total/free testosterone ratio (TT/FT) was, however, significantly associated with presence of gammopathies (in IgG, IgM, IgA, IgE; P=0.026). Surprisingly, immune system activation was associated with significantly improved embryo quality (P=0.008), a finding persistent after adjustment for age and repeat IVF cycles (P=0.006). CONCLUSIONS: Association of immune system activation with improved embryo quality concurs with previously reported immune activation in association with normal functional ovarian reserve (FOR) and normal androgen levels, while, counter intuitively, hypoandrogenism and low FOR are associated with lack of immune system activation. Mild immune system activation, therefore, likely appears essential for establishment of pregnancy, and may be regulated by androgens.

Utilizing FMR1 gene mutations as predictors of treatment success in human in vitro fertilization.

CONTEXT: Mutations of the fragile X mental retardation 1 (FMR1) gene are associated with distinct ovarian aging patterns. OBJECTIVE: To confirm in human in vitro fertilization (IVF) that FMR1 affects outcomes, and to determine whether this reflects differences in ovarian aging between FMR1 mutations, egg/embryo quality or an effect on implantation. DESIGN, SETTING, PATIENTS: IVF outcomes were investigated in a private infertility center in reference to patients' FMR1 mutations based on a normal range of CGG(n = 26-34) and sub-genotypes high (CGG(n>34)) and low (CGG(<26)). The study included 3 distinct sections and study populations: (i) A generalized mixed-effects model of morphology (777 embryos, 168 IVF cycles, 125 infertile women at all ages) investigated whether embryo quality is associated with FMR1; (ii) 1041 embryos in 149 IVF cycles in presumed fertile women assessed whether the FMR1 gene is associated with aneuploidy; (iii) 352 infertile patients (< age 38; in 1st IVF cycles) and 179 donor-recipient cycles, assessed whether the FMR1 gene affects IVF pregnancy chances via oocyte/embryo quality or non-oocyte maternal factors. INTERVENTIONS: Standardized IVF protocols. MAIN OUTCOME MEASURES: Morphologic embryo quality, ploidy and pregnancy rates. RESULTS: (i) Embryo morphology was reduced in presence of a low FMR1 allele (P = 0.032). In absence of a low allele, the odds ratio (OR) of chance of good (vs. fair/poor) embryos was 1.637. (ii) FMR1 was not associated with aneuploidy, though aneuploidy increased with female age. (iii) Recipient pregnancy rates were neither associated with donor age or donor FMR1. In absence of a low FMR1 allele, OR of clinical pregnancy (vs. chemical or no pregnancy) was 2.244 in middle-aged infertility patients. CONCLUSIONS: A low FMR1 allele (CGG(<26)) is associated with significantly poorer morphologic embryo quality and pregnancy chance. As women age, low FMR1 alleles affect IVF pregnancy chances by reducing egg/embryo quality by mechanisms other than embryo aneuploidy.

Monozygotic multiple pregnancies following IVF: a case report series of rare experience.

Monozygotic multiple pregnancies are three times more common after assisted reproduction (with or without IVF) than after spontaneous conception (1.2% versus 0.4%). These pregnancies are associated with multiple maternal and fetal risks. This article is a description of nine cases of monozygotic pregnancies following IVF at the OVO Clinic (Montreal) between January 2007 and August 2011 and a scientific review of the literature on monozygotic multiple pregnancies after assisted reproductive treatment found in the MEDLINE and Cochrane Databases. In this retrospective series, 3522 embryos were transferred and 1033 pregnancies were obtained, of which there were nine monozygotics (0.87%). The exact mechanism behind this increased frequency remains uncertain. Possible explanations associated with fertility treatments include alterations of the zona pellucida, transfers at the blastocyst stage, prolonged culture, preimplantation genetic diagnosis, ovarian stimulation and maternal age. Assisted reproduction treatment appears to increase monozygotic pregnancies; however, the rate is still low and therefore it is difficult to exactly conclude the real mechanism. There are two types of multiple pregnancy: the dizygotic (two different embryos) and the monozygotic (one embryo which splits to make two identical genetic embryos). We know the risk factors for dizygotic pregnancies, but the mechanism of monozygotic pregnancies remains unclear. Assisted reproduction treatment seems to increase the multiple monozygotic pregnancy rate to 3-times more than that in nature. Several possibilities could be suspected as responsible for these monozygotic multiple pregnancies - advanced maternal age, alterations of the zona pellucida, transfers at the blastocyst stage, prolonged culture and ovarian stimulation - but a absolute explanation is not yet defined. This article is a scientific review of the literature on monozygotic multiple pregnancies after IVF treatment and a description of nine cases following IVF treatment at the OVO Clinic in Montreal between January 2007 and August 2011. The bibliographic references were found in the Medline and Cochrane Database.

Midtrimester intra-amniotic sludge and the risk of spontaneous preterm birth.

We examined the association between midtrimester intra-amniotic sludge and spontaneous preterm birth (PTB) in asymptomatic women undergoing amniocentesis. We performed a prospective cohort study of women having an amniocentesis for fetal karyotyping between 14 and 24 weeks' gestation. Cervical length and the presence of amniotic sludge were assessed by transvaginal ultrasound. Amniotic fluid concentrations of matrix metalloproteinase-8, glucose and lactate were measured. Early (<32 weeks) and late (32 to 36 weeks) preterm premature rupture of membranes (PPROM) and spontaneous PTB constituted primary outcomes. Nonparametric analyses were conducted. Three hundred ten women, including 94 (30%) with free-floating echogenic particles and 16 (5%) with dense amniotic sludge, were recruited. Dense amniotic sludge was linked with early (13%) but not with late (0%) primary outcome ( P < 0.01). Two women with combined dense amniotic sludge and short cervix delivered 4 and 10 weeks later (at 20 and 25 weeks, respectively) and had a higher median amniotic lactate concentration than controls ( P < 0.05). A third woman with dense amniotic sludge at 15 weeks was diagnosed with a short cervix and an intra-amniotic infection at 22 weeks that was eradicated with intravenous antibiotics. Midtrimester dense amniotic sludge is associated with early PPROM and spontaneous PTB.

The origin of Fusobacterium nucleatum involved in intra-amniotic infection and preterm birth.

OBJECTIVE: To evaluate the potential oral origin of Fusobacterium nucleatum found in amniotic fluid of women at high risk of preterm birth. METHODS: A transversal study nested into a cohort study of women with preterm labor and/or preterm premature rupture of membranes was undergone. Women with the presence of F. nucleatum in the amniotic fluid and their respective partners were invited to be examined for their periodontal health after delivery, and samples of saliva and subgingival plaque were collected. For each couple, specific PCR detection of Fusobacterium species was performed on each oral sample, and the DNA sequences were compared with the one obtained from amniotic fluid. RESULTS: Three women, all in preterm labor with intact membranes, were included. Intra-amniotic sludge was observed in all of them. A strain of F. nucleatum with 100% sequence identity with the strain detected in the amniotic fluid was found in the oral samples of one of them and of two partners. CONCLUSION: This study suggests that intra-amniotic F. nucleatum could originate from the patient's or the partner's oral microflora.