The Long-term Safety Of Luteal-phase Ovarian Stimulation:A Three-year Follow-up Study

OBJECTIVES: To investigate the long-term safety of the luteal-phase stimulation(LPS)protocol in terms of the neonatal outcomes,the physical growth and health status before the age of three and the prevalence of congenital anomalies(CAs).At the same time,to explore the independent risk factors of CAs and to summarize the characteristics and relevant factors of the occurrences of CAs or severe disease in different organ systems.METHODS: It is a retrospective cohort study conducted in a tertiary-care academic medical center between March 2013 and September 2014.664 couples and their children born after the LPS and 1308 couples and their children born after the standard gonadotropin releasing hormone(Gn RH)agonist short protocol were recruited.In the LPS group,patients with antral follicles <8 mm in diameter on the day after ovulation were given 225 IU of human menopausal gonadotropin(HMG)and simultaneously 2.5 mg of letrozole daily.In the short protocol group,ovarian stimulation was initiated with a daily injection of triptorelin 0.1mg and HMG 150 IU or 225 IU,from menstrual cycle day 3(MC3)to the trigger day.Preparations before follow-up were completed during the last three outpatient visits.The patients finished a total of four telephone interviews in the first-stage follow-up: during three stages of pregnancy and during the first month after delivery.They received another telephone interview in the second-stage follow-up when their children were at the age of three.The primary outcome measure was the incidence of congenital anomalies(CAs)observed by the age of three.The secondary measures were composed of three parts.The maternal characteristics and neonatal outcomes,in which the gestational age,birth weight and birth length were selected as indicators;The physical growth and motor development of the infants,in which the height and weight at 24/30/36 months and the first time when the infants can stand alone,walk alone or speak consciously were chosen to make assessment;The health status of infants before 36 months of age,estimating by admission rate,duration of hospital stay,main discharge diagnosis,times of outpatient visit,operation and hospitalization.RESULTS: The maternal characteristics were comparable between the LPS group and the short protocol group.With regard to the neonatal outcomes,lower birth weight and shorter birth length were found in the LPS group for the mul tiplets(2482.21±457.80 vs.2570.59±451.84,p=0.004;47.57±2.69 vs.47.97±2.39,p=0.021;respectively),while no apparent differences for the singletons.In the evaluation of physical growth and health status,no significant differences were discovered between the two groups in any aspect.As for the main discharge diagnosis,the proportion of skin and subcutaneous tissue category was higher and the proportion of diseases belonging to the others category was lower in the LPS group for the singletons(3.82% vs.0%,p=0.005;3.82% vs.15.20%,p=0.001;respectively).The total prevalence of CAs did not differ between groups.The detailed classification showed a higher percentage of musculoskeletal system CAs in singletons and a lower percentage of digestive system CAs in multiplets,both in the short protocol group(0% vs.1.30%,p=0.020;1.78% vs.0.33%,p=0.028;respectively).The following multiple binary logistic regression analysis was in support of this result.The low birth weight was proven an risk factor for CAs(OR: 0.440,95%CI: 0.330-0.585,P<0.001 both for the unadjusted model and for the adjusted model).CONCLUSIONS: This cohort study manifested that the offspring born after the LPS protocol did not exhibit an elevated rate of total CAs up to the age of three,a finding waiting to be confirmed by further study with larger populations.In addition,the indicators regarding physical growth and health status were discovered broadly similar between the two groups.Furthermore,the occurrence of CAs was found to be dramatically correlated with low birth weight.This result might favor the adoption of elective,single embryo transfer to avoid multiple pregnancy.Meanwhile,patients undergoing IVF should be reminded of the increased risk of the CAs associated with low birth weight,usually accompanying with twin birth.Subsequent Long-term follow-up is to be carried out for more convincing evidence and more accurate conclusions.