Asthma in 9-year-old children of subfertile couples is not associated with in vitro fertilization procedures.

Asthma is a chronic reversible obstructive airway disease, which is common among children and leads to respiratory impairment. Studies showed that asthma is more common among children born after in vitro fertilization (IVF) than among spontaneously conceived children. However, it is unknown which component of the IVF procedure contributes to this putative link. Therefore, the aim of this prospective follow-up study was to differentiate the possible effect of ovarian hyperstimulation from that of the in vitro culture procedure on asthma and rhinitis in 9-year-old children conceived with IVF. The study comprised three groups of singletons: (I) conceived with ovarian hyperstimulation-IVF (COH-IVF, n = 95); (II) conceived with modified natural cycle-IVF (MNC-IVF, n = 48); and (III) naturally conceived to subfertile couples (Sub-NC, n = 68). Parents filled out the validated Dutch version of the asthma questionnaire of the International Study of Asthma and Allergies. Asthma prevalence in the groups did not differ: COH-IVF n = 8 (8%); MNC-IVF n = 0 (0%); and Sub-NC n = 4 (6%). Adjustment for confounders did not alter the results.Conclusion: Neither ovarian hyperstimulation nor the in vitro culture procedure was associated with asthma and rhinitis at 9 years. IVF children had a similar prevalence of asthma compared with children conceived naturally by subfertile couples.Trial registration: ISRCTN76355836 What is Known: • An increased risk for asthma has been observed in children born after in vitro fertilization at preschool and school age. • The association between IVF and asthma may be partly explained by parental subfertility. What is New: • IVF children do not have a higher prevalence of asthma than children of subfertile couples conceived naturally. • Ovarian hyperstimulation used in IVF is not associated with asthma in 9-year-old children of subfertile couples.

Follicle pool, ovarian surgery and the risk for a subsequent trisomic pregnancy.

STUDY QUESTION: Is there an association between trisomic pregnancy, a marker for decreased oocyte quality, and the reduced oocyte quantity that follows ovarian surgery? SUMMARY ANSWER: Previous ovarian surgery is not associated with an increased risk for a subsequent trisomic pregnancy. WHAT IS KNOWN ALREADY: Ovarian surgery diminishes the number of oocytes. The risk for a trisomic pregnancy is suggested to be higher in women with fewer oocytes, independent of their chronological age. STUDY DESIGN, SIZE, DURATION: This is a matched case-control study. Cases are women with a confirmed trisomic pregnancy occurring between 1 January 2000 and 31 December 2010 regardless of pregnancy outcome and controls are women that had a live born child without a trisomy. In total, there were 8573 participants in the study; 1723 cases and 6850 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from Danish medical registries. Matching criteria were maternal age and year of conception. Number of controls matched per case ranged from one to four. Among cases and controls with a trisomic pregnancy, 2.7% (46/1723) versus 2.5% (172/6850) had undergone ovarian surgery before pregnancy. MAIN RESULTS AND ROLE OF CHANCE: History of ovarian surgery is not associated with a higher risk for a subsequent trisomic pregnancy (odds ratio = 1.00, 95% confidence interval 0.99-1.01). Subgroup analyses by indication of surgery and interval between ovarian surgery and pregnancy do not show an effect on trisomic pregnancy risk. LIMITATIONS, REASONS FOR CAUTION: The medical registries used to select cases and controls did not contain information on surgical technique nor volume of ovarian tissue resected, previous trisomic pregnancy prior to the ovarian surgery or long-term use of oral contraceptives. Therefore, correction for these factors was not performed. WIDER IMPLICATIONS OF THE FINDINGS: We did not confirm the hypothesis that ovarian surgery, a marker for decreased oocyte quantity, is related to trisomic pregnancy, a marker for decreased oocyte quality. This suggests that ovarian surgery, which has a direct reductive effect on the size of the follicle pool, may affect oocyte quality differently when compared with the reduction in follicle pool size due to ageing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Gratama Stichting, University of Groningen and the University Medical Center Groningen, The Netherlands. Ø.L. has within the last 3 years received honoraria for speeches in pharmacoepidemiological issues, not related to this study. The Department of Obstetrics and Gynaecology receives unrestricted educational grants from Ferring Pharmaceuticals. A.H. received a grant from ZonMW (i.e. National Dutch Scientific funding) for a RCT not related to this publication. Dr A.H. received speakers fee from MSD for an educational presentation. All other authors have no conflict of interest.

Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: a randomized controlled trial.

Modified natural-cycle IVF has a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation due to, for example, premature ovulation. Indometacin administered before ovulation prevents follicle rupture. Therefore, addition of indometacin may improve the effectiveness of modified natural-cycle IVF. This double-blind, randomized, placebo-controlled trial with indometacin or placebo in 120 women aged 27-36 years compared the number of patients without premature ovulation as compared with the number of patients with one or more ovulations in a maximum of six cycles. Indometacin had no significant influence on the probability of a premature ovulation in patients during the six cycles (OR 2.38, 95% CI 0.94-6.04). A subgroup analysis showed a significant influence of indometacin in decreasing the probability of a premature ovulation in cycles without LH surge at the day of human chorionic gonadotrophin administration (OR 8.29, 95% CI 1.63-42.3, P=0.009). Although this study could not detect a significantly lower ovulation rate in the indometacin group versus the placebo group, the data suggest that a subgroup of patients without LH surge prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.

The impact of IVF/ICSI on parental well-being and anxiety 1 year after childbirth.

BACKGROUND: More couples are delaying childbirth resulting in an increase of age-related subfertility in women. Subfertility and assisted reproductive technology (ART) treatments may affect couples' psychological well-being. The aim of the present study was to investigate whether factors related to IVF/ICSI affect anxiety and mental health in couples 1 year after childbirth. METHOD: In this cohort study, we included couples with a singleton pregnancy following IVF/ICSI treatment (n=113) and subfertile couples who naturally conceived (NC; n=83). Parental trait anxiety (Dutch version of the Spielberger State-Trait Anxiety Inventory) and mental health (Dutch version of General Health Questionnaire) were assessed 1 year after childbirth. The influence of fertility-related factors was analyzed with logistic regression analyses. RESULTS: One hundred and ninety-six couples participated, 93% of those eligible. Trait anxiety and mental health were similar in IVF/ICSI and NC groups. However, NC fathers had more often mental health scores in the clinical range (21%) than fathers in the IVF/ICSI group (9%). The risk of having a trait anxiety or mental health score in the clinical range was reduced by the presence of one of the following factors: for females a higher number of IVF/ICSI treatment cycles, and a maternal cause of subfertility, for males having been treated by IVF/ICSI and a longer time to pregnancy. CONCLUSIONS: The present study indicates (i) that IVF/ICSI treatment is not associated with an increase in clinically relevant Spielberger State-Trait Anxiety Inventory and General Health Questionnaire scores in parents 1 year after childbirth and (ii) a higher number of IVF/ICSI treatment cycles and a longer time to pregnancy were associated with less trait anxiety and better mental health. A limitation of the study is the absence of mental health and trait anxiety data at baseline.

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 woman's 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 woman's trisomy risk. Since a questionnaire was used, we cannot fully exclude the possibility of selection bias in this study.

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.

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.

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.

Congenital adrenal hyperplasia as a cause of adrenal incidentaloma.

Congenital adrenal hyperplasia (CAH) can present as a benign adrenal tumour, which should be treated medically. The diagnosis of CAH must be considered in a patient presenting with adrenal incidentaloma in order to avoid unnecessary adrenalectomy. Urinary steroid profiling is a useful diagnostic tool to identify the presence of CAH.

The number of small antral follicles (2-6 mm) determines the outcome of endocrine ovarian reserve tests in a subfertile population.

BACKGROUND: Ovarian reserve is related to age and can be estimated by ovarian reserve tests (ORTs), such as antral follicle count (AFC) and various endocrine parameters. The endocrine function of a follicle is related to its size. The aim of this study is to evaluate which sizes of antral follicles are most closely correlated with age and the outcome of endocrine ORTs. METHODS: In total 474 subfertile, ovulatory patients, recruited from two fertility centers in The Netherlands, participated in this prospective cohort study. The following ORTs were performed: AFC (follicles from 2 to 10 mm), basal FSH, basal inhibin B (bInhB), clomiphene citrate challenge test and inhibin B after stimulation with clomiphene citrate. RESULTS: The number of small follicles (2-6 mm) declined with age; the number of larger follicles (7-10 mm) remained constant. Independent of age, the number of small follicles was significantly related to all ORTs (P<0.001, except bInhB P=0.005). The number of larger follicles was only significantly related to bInhB (P=0.009). CONCLUSIONS: The number of small antral follicles (2-6 mm) is significantly related to age and also, independent of age, to all endocrine ORTs tested, suggesting the number of small antral follicles represents the functional ovarian reserve.