The addition of FSH to clomiphene citrate for ovarian stimulation does not affect offspring stature but may alter body composition in childhood.

Clomiphene citrate (a nonsteroidal oestrogen antagonist) has been used for ovarian stimulation since its discovery in the late 1950s and continues to have an important role in fertility treatment. Currently, follicle-stimulating hormone (FSH) is used in mild ovarian stimulation either by itself or in combination with clomiphene citrate. Required doses of FSH vary considerably, depending on whether it is used in ovarian stimulation alone or associated with assisted reproductive technology. While exogenous FSH administration does not lead to the marked anti-oestrogenic effects of clomiphene, it has been shown to have several effects other than stimulation of ovaries. We have previously shown that children conceived following mild ovarian stimulation (clomiphene citrate with/without FSH, and without undergoing IVF treatment) were 0 53 SDS shorter than naturally conceived controls. However, it is unclear whether those findings were affected by the administration of additional FSH injections. Therefore, we aimed to assess whether the observed shorter stature was due to maternal treatment with clomiphene citrate alone or due to additional FSH injection(s). Ethics approval for this study was provided by the Northern Y Regional Ethics Committee (Ministry of Health, New Zealand). Participants were healthy prepubertal children of New Zealand European ethnicity, born at term (37–41 weeks of gestation) after singleton pregnancies, and of higher socio-economic status. Fertility treatment methods were as previously described. In brief, mothers of participants received a standard stimulation regimen of clomiphene citrate for days 3–7, followed by 50–150 IU FSH on alternate days from day 9 if the oestradiol level on this day was <2000 pmol/l. The starting dose of clomiphene was 50 mg/day, subsequently increased to 100 mg/day if response was low in the first cycle or reduced to 25 mg/day if the initial response was high. For patients who received FSH, the mean total dose was 360 IU. All children were conceived using sperm from the mother’s partner, so that the offspring of donor sperm were not included. Clinical assessments were performed at the Paykel Clinical Research Unit as per Savage et al. Each child’s birthweight, height and BMI were transformed into standard deviation scores (SDS); mid-parental height SDS (MPHSDS) and mean parental BMISDS (MPBMISDS) were calculated. Children’s heights SDS were then individually adjusted for their genetic potential (parents’ heights), using the formula: child’s height SDS minus MPHSDS. Fasting blood samples were drawn for the assessment of lipid profile, growth factors, glucose and insulin (with assays as previously described). Study participants were allocated into three groups, according to the drug treatment received by the mother for ovarian stimulation: CC (clomiphene citrate alone), CCFSHSING (clomiphene citrate with a single FSH injection) and CCFSHMULT (clomiphene citrate with two or more FSH injections). Two sets of comparisons were carried out: CCFSHSING vs CCFSHMULT, and combined CCFSH vs CC. Groups were compared using linear mixed models with maternal code as random factor, and important confounders adjusted for (e.g. sex, birthweight SDS, gestational age, birth order and maternal age).