Maaike L. Haadsma

A reduced size of the ovarian follicle pool is associated with an increased risk of a trisomic pregnancy in IVF-treated women

BACKGROUND The increased risk of a trisomic pregnancy with a womans age arises from an increased rate of meiotic non-disjunction in the oocytes. It has been hypothesized that the increase in meiotic errors is related to the decreasing number of oocytes with age. Our aim was to assess the relation between trisomic pregnancy and three parameters of oocyte quantity. METHODS In a Dutch nationwide database on in vitro fertilization (IVF) treatment from 1983 to 1995, we identified 28 women with a trisomic pregnancy conceived via or within 1 year from IVF treatment. We selected five age-matched controls with a healthy child for each trisomy case. We performed a case-control study to examine whether trisomy cases more often had a history of ovarian surgery and a lower response to ovarian hyperstimulation than controls. Subsequently, cases and controls were followed to compare the incidence of signs of menopause at the end of the study period as self-reported by questionnaire. RESULTS Logistic regression analysis showed an association between trisomic pregnancy and a history of ovarian surgery [odds ratio (OR) 3.3; 95% confidence interval (CI): 1.0-10.5; P = 0.04] and between trisomic pregnancy and retrieval of < or = 4 oocytes during IVF treatment (OR 4.0; 95% CI: 1.4-11.5; P = 0.01). The adjusted OR for signs of menopause associated with trisomic pregnancy was 5.7 (95% CI: 1.1-29.9; P = 0.04). CONCLUSIONS Our results suggest that IVF-treated women with a reduced ovarian follicle pool are at increased risk of a trisomic pregnancy, independent of their age. Our findings support the hypothesis that follicle pool size and not chronological age determines a womans trisomy risk. Since a questionnaire was used, we cannot fully exclude the possibility of selection bias in this study.

Ovarian hyperstimulation and the in vitro fertilization procedure do not influence early neuromotor development; a history of subfertility does

OBJECTIVE To evaluate specific effects of ovarian hyperstimulation, the in vitro procedure, and a history of subfertility on neuromotor development at 3 months of age. DESIGN Prospective, cohort study. SETTING University Medical Center Groningen, The Netherlands. PATIENT(S) Singletons conceived after controlled ovarian hyperstimulation-IVF/intracytoplasmic sperm injection (COH-IVF; n = 68) or modified natural cycle-IVF/intracytoplasmic sperm injection (MNC-IVF; n = 57), and naturally conceived singletons of subfertile couples (NC; n = 90). Data from a reference population were available (n = 450). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Quality of general movements (GMs), classified as normal-optimal, normal-suboptimal, mildly abnormal, or definitely abnormal. Definitely abnormal GMs indicate brain dysfunction, mildly abnormal GMs normal but non-optimal brain function. RESULT(S) Mildly abnormal and definitely abnormal GMs were observed equally frequently in COH-IVF, MNC-IVF, and NC singletons. The three subfertile groups showed a reduction in GM quality, in particular more mildly abnormal GMs, in comparison with the reference population. CONCLUSION(S) Singletons born after IVF (with or without ovarian hyperstimulation) are not at increased risk for abnormal GMs compared with naturally conceived peers of subfertile parents. Mildly abnormal GMs occur more often in infants of subfertile parents than in the general population, suggesting that factors associated with subfertility rather than those related to IVF procedures may be associated with less-optimal early neurodevelopmental outcome. These results need confirmation through replication and follow-up at older ages.

The predictive value of ovarian reserve tests for spontaneous pregnancy in subfertile ovulatory women

BACKGROUND The predictive value of ovarian reserve tests (ORTs) for spontaneous pregnancy is unclear. Our study aimed to determine whether ORTs have added value to previously identified prognostic factors for spontaneous pregnancy in subfertile ovulatory couples. METHODS A prospective cohort study was performed on 474 subfertile ovulatory couples in two hospitals in Groningen, The Netherlands. The ORTs performed were: antral follicle count (AFC), follicle-stimulating hormone (FSH), inhibin B (basal levels and after stimulation with clomiphene citrate) and the clomiphene citrate challenge test. For each couple, the probability of spontaneous pregnancy was retrospectively calculated using the validated Hunault prediction model which includes the main known prognostic factors for spontaneous pregnancy. Outcome measure was time to spontaneous pregnancy resulting in a live birth. RESULTS When added to the Hunault model, only basal FSH and AFC significantly improved the prediction of spontaneous pregnancy (P-values of 0.05 and 0.04). Absolute changes in predicted probabilities after adding basal FSH or AFC were small: the predicted probability of spontaneous pregnancy shifted >or=10% in only 3.8% and 7.9% of the couples, respectively. CONCLUSIONS Although basal FSH and AFC significantly improved the validated prediction model for spontaneous pregnancy, the clinical relevance of this finding is limited. We recommend that none of the ORTs studied should be used routinely in the subfertility evaluation of ovulatory couples to predict spontaneous pregnancy chances.

Miscarriage risk for IVF pregnancies in poor responders to ovarian hyperstimulation

The increasing miscarriage rate with advancing female age is attributed to a decline in oocyte quality. A poor response to ovarian hyperstimulation is often an expression of a decrease in oocyte quantity. Although oocyte quality and quantity both decrease as a result of ovarian ageing, it is unclear whether these two processes are related to each other. To investigate the relationship between oocyte quantity and quality, we compared miscarriage rates between IVF treated women with a poor and normal response, respectively. Data were studied from a retrospective nationwide cohort of Dutch women undergoing IVF treatment from 1983 to 1995. Women achieving an ongoing pregnancy after their first complete IVF cycle (n=1468) were compared with those experiencing miscarriage (n=357) with respect to their ovarian response. Logistic regression analysis showed a statistically significant association between poor response (fewer than four retrieved oocytes) and miscarriage (P=0.001). Due to interaction, this association became stronger with increasing female age. Among women < 36 years, miscarriage rates between poor and normal responders did not differ, whereas among women 36 years poor responders had a statistically significant increased miscarriage rate compared with normal responders (P=0.001). These results support the hypothesis of a relationship between quantitative ovarian reserve and oocyte quality.

Is the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures

Singletons born after IVF are at risk of adverse pregnancy outcome, the cause of which is unknown. The present study investigated the influence of ovarian stimulation and IVF laboratory procedure on birthweight. Birthweight of singleton pregnancies resulting from IVF treatment with (n=161) and without ovarian stimulation (using a modified natural cycle (MNC) protocol; n=158), and spontaneous conceptions in subfertile patients (n=132) were compared. Mean+/-SD birthweight of singletons after conventional IVF with ovarian stimulation, MNC-IVF and natural conception were 3271+/-655, 3472+/-548 and 3527+/-582 g (P=0.001). After adjustment for biological and social confounders, the difference in birthweight between conventional IVF and MNC-IVF was reduced to 88 g and the differences between conventional IVF and MNC-IVF versus spontaneous conceptions to 123 and 23 g, respectively. The results lead to three conclusions. First, a major part of the crude differences in birthweight between the three groups is related to patient and pregnancy characteristics. Second, the IVF laboratory procedure has no influence on birthweight. Third, although a trend towards lower birthweight after ovarian stimulation was found, an adverse effect of ovarian stimulation on birthweight was not substantiated.

Congenital anomalies in offspring of subfertile couples : a registry-based study in the northern Netherlands

OBJECTIVE To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN Case-only analyses. SETTING Not applicable. PATIENT(S) We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n = 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder. RESULT(S) We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05-5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58-27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06-2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93-62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39-16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43-17.65). CONCLUSION(S) In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands.

The predictive value of ovarian reserve tests for miscarriage in a population of subfertile ovulatory women

BACKGROUND The increase in miscarriage rate with female age is attributed to a decline in oocyte quality. This age-related decrease of oocyte quality is accompanied by a decrease in oocyte quantity. Assessment of the number of oocytes by ovarian reserve tests (ORTs) may therefore also represent their quality. The objective of our study was to assess the predictive value of ORTs for miscarriage in subfertile women. METHODS This study was a subanalysis within a prospective cohort study of 474 subfertile ovulatory couples in two hospitals in Groningen, The Netherlands. The ORTs performed were: antral follicle count (AFC), basal and stimulated levels of follicle-stimulating hormone (FSH) and inhibin B, and the clomiphene citrate challenge test (CCCT). Women who achieved an ongoing pregnancy (n = 233) were compared with women experiencing miscarriage (n = 72) on the results of their ORTs and patient characteristics. RESULTS In univariate analysis, the outcome of the ORTs did not differ between the groups. Logistic regression analysis including patient characteristics such as female age did not reveal an association between the ORT results and miscarriage either. CONCLUSIONS Neither AFC, basal and stimulated levels of FSH and inhibin B, nor the CCCT have a statistically significant predictive value for miscarriage in subfertile ovulatory women.

Early menopause in mothers of children with Down syndrome

OBJECTIVE To investigate whether having a Down syndrome pregnancy at a relatively young age is associated with lower ovarian reserve as reflected by lower antimüllerian hormone (AMH) levels and the occurrence of earlier menopause. DESIGN Retrospective, case control study. SETTING Not applicable. PATIENT(S) Two hundred twenty mothers (118 trisomy cases, 102 controls). INTERVENTION(S) Questionnaire and serum AMH measurement. MAIN OUTCOME MEASURE(S) Serum AMH levels and menopause, defined as not having a menstrual cycle for at least 1 year. RESULT(S) The participant response rate was 93%. After applying the exclusion criteria, 144 women were evaluable (73 trisomy cases, and 71 controls). The baseline characteristics of the women were not statistically significantly different. More women with a Down syndrome pregnancy had an AMH level below 0.5 μg/L, a difference that was statistically significant. Eleven women (15.1%) in the Down syndrome group had reached menopause compared with 9 (12.7%) of the controls. CONCLUSION(S) Women who have had a Down syndrome pregnancy at a younger age show signs of limited ovarian reserve, as evidenced by their frequently having lower AMH levels. The study has found no obvious signs of early menopause thus far. Whether their age at menopause is within the normal range remains to be determined.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach

STUDY QUESTION What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children? SUMMARY ANSWER Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness. WHAT IS KNOWN ALREADY Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown. STUDY DESIGN, SIZE, DURATION In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS We measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. MAIN RESULTS AND THE ROLE OF CHANCE Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. LIMITATIONS, REASONS FOR CAUTION Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies. STUDY FUNDING/COMPETING INTEREST(S) The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Blood pressure and anthropometrics of 4-y-old children born after preimplantation genetic screening: follow-up of a unique, moderately sized, randomized controlled trial

Background:Recent studies suggest that in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are associated with suboptimal cardiometabolic outcome in offspring. It is unknown whether preimplantation genetic screening (PGS), which involves embryo biopsy, affects blood pressure (BP), anthropometrics, and the frequency of received medical care.Methods:In this prospective multicenter follow-up study, we assessed BP, anthropometrics, and received medical care of 4-y-old children born to women who were randomly assigned to IVF/ICSI with PGS (n = 49) or without PGS (controls; n = 64). We applied linear and generalized linear mixed-effects models to investigate possible effects of PGS.Results:BP in the PGS and control groups was similar: 102/64 and 100/64 mm Hg, respectively. Main anthropometric outcomes in the PGS vs. control group were: BMI: 16.1 vs. 15.8; triceps skinfold: 108 vs. 98 mm; and subscapular skinfold: 54 vs. 53 mm (all P values > 0.05). More PGS children than controls had received paramedical care (speech, physical, or occupational therapy: 14 (29%) vs. 9 (14%); P = 0.03 in multivariable analysis). The frequency of medicial treatment was comparable.Conclusion:PGS does not seem to affect BP or anthropometrics in 4-y-old children. The higher frequency of received paramedical care after PGS may suggest an effect of PGS on subtle developmental parameters.