Clomiphene

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Banhidy, 2008	case control	Prospectively recorded data concerning exposure to clomiphene citrate were obtained from the log-books of prenatal care, which are mandatory in Hungary.	Cases of congenital abnormalities were selected from the Hungarian Congenital Abnormality Registry, and controls (i.e., newborns without abnormalities) were selected from the National Birth Registry.	Cases matched with 2 controls according to sex, birth week, and district of the parents' residence. Some outcomes: adjusted for birth order, maternal age, maternal marital status, employment status, and whether follicular cysts of the ovary were present.
Benedum, 2016	case control	Mother were interviewed in person or by telephone by trained study nurses within 6 months of delivery, fetal loss, or termination, including questions on medication use at any time from 2 months before pregnancy through the end of pregnancy.	Research staff identified cases by reviewing admission and discharge lists and clinical and surgical logs, and by contacting newborn nurseries and labor and delivery rooms, from participating birth hospitals and tertiary-care centers or from statewide birth-defect registries.	Adjusted for maternal education and study center (variable changed the cOR estimates by more than 10%). Other potential confounders assessed (<10%): maternal race/ethnicity, age, body mass index, previous miscarriages, periconceptional folic acid intake, pregestational diabetes mellitus, history of convulsions or seizures, pregestational hypertension, smoking during the exposure period, parity.
Gorgui, 2022	retrospective cohort (claims database)	Régie de l’Assurance Maladie du Québec (RAMQ), which includes medical services/procedures and pharmaceutical service database (including drug name, start date, dosage, duration, prescribers).	Outcomes were defined according to the MedEcho database validated against measures in patients charts (which includes hospitalization archives data, ICD-9 and 10 diagnostic codes, gestational age, ...) in addition to the statistics database (which includes notably birth weight, and gestational age).	Singletons only. Exclusion of pregnancies exposed to known fetotoxic medications during pregnancy. Adjusted for sociodemographic variables (urban dwelling, welfare recipient) as well as maternal comorbidities measured within 12 months prior to the 1DG (polycystic ovarian syndrome) and during the 1st trimester of pregnancy (hypertension, diabetes).
Lammer, 1995	case control	Mothers were interviewed face to face in their homes, before their infant was 6 months old, with a standard questionnaire included information about maternal and paternal exposures to drugs. Information about the use of ovulation-inducing drugs was elicited by two specific questions.	Malformed stillborn and liveborn infants are ascertained by multiple methods. Obstetric, newborn, and pediatric wards are regularly visited by Metropolitan Atlanta Congenital Defects Program (MACDP) staff to identify and register infants with structural malformations.	None.
Lind, 2013	case control	The National Birth Defects Prevention Study uses computer-assisted telephone interviews to collect information from women 6 weeks to 24 months after their estimated date of delivery.	Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias as isolated.	Adjusted for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, study site, and year of due date.
Malchau, 2014	population based cohort retrospective	All initiated treatment cycles are recorded in the mandatory assisted reproductive technology (ART) register, which includes data notably on the type of medication used during fertility treatment.	Data on perinatal outcomes were extracted from the medical birth register. Diagnoses obtained from the hospital discharge register were: hypertensive disorders of pregnancy, placenta previa, cesarean section, induction of labor, and admittance to a neonatal intensive care unit.	Singletons only. Adjusted for maternal age, parity, child gender, year of birth, smoking, maternal body mass index, elective cesarean section, and induction of labor.
Meijer, 2006	case control	Until 1996, exposure is recorded by the health care provider who was explicitly asked whether the pregnancy resulted from clomiphene treatment. After 1996, exposure was ascertained with clomiphene prescription recorded by the pharmacy and the actual use is verified with the mother.	Information about the anomalies is collected through physicians, midwives, clinical geneticists, and pathologists.	No adjustment.
Mili, 1991	case control	Not specified.	Not specified.	Adjusted for several potentially confounding factors such as subfertility (no other details).
Milunsky, 1990	prospective cohort	Authors interviewed women at around 16 weeks of pregnancy. Among the many questions asked were those directed to the use of clomiphene during the 3 months prior to pregnancy.	Pregnancy outcome was ascertained from a brief questionnaires mailed to the delivering physicians near the expected date of delivery (76.5%), or subsequently to the mothers themselves when physicians did not respond (23.5%),.	None.
Nehard, 2024	prospective cohort	Not specified (prospective records).	The characterisation of the severity of each defect was determined after consideration of the information provided by the healthcare professionals in the follow-up questionnaire and assessed collegially by the CRAT’s medical team who were blinded to the exposure group.	Exclusion of women who were exposed to known teratogens during pregnancy (medication and infections). Controls matched on the calendar year of initial contact. congenital anomalies adjusted for maternal age.
Olshan, 1999	case control	After initial contact, the parents were sent an interview guide (containing notably list of medications) used to facilitate recall and increase interview efficiency. Then, a structured telephone interview was conducted with the mother, and information on fertility medication use was gathered.	Retrospective selection of patients less than 19 years of age newly diagnosed with neuroblastoma at one of the 139 participating hospitals (no other details provided).	Controls were individually matched to cases on date of birth (±6 months for cases <3 years of age and ±1 year for cases >3 years of age). Adjusted for mother's race, mother's education, and household income in the birth year.
Reefhuis, 2011	case control	Detailed information notably about medication use during pregnancy (including over-the-counter (OTC) and prescription medication) was collected from the mothers via computer-assisted telephone interviews conducted between 6 weeks and 24 months after the estimated date of delivery (EDD).	Cases were identified in the The National Birth Defects Prevention Study. The NBDPS clinical data for birth defect cases were abstracted from medical records and classified by clinical experts. Controls were selected from birth certificates or hospital records in the same area.	Adjusted for maternal age, maternal race, parity, previous miscarriages, body mass index, education, maternal smoking or alcohol use from 1 month before pregnancy through the end of the first trimester, and use of folic acid or multivitamin supplements. Mothers who reported a diagnosis of type I or type 2 diabetes before pregnancy were excluded.
Reefhuis, 2003	case control	All 3 locations used the same interview instrument and completed a telephone interview (approximately 1 hour) with mothers of case and control infants, included questions on medication use.	Cases were ascertained using surveillance systems (Birth Defects Monitoring Program, Iowa Birth Defects Registry, and MACDP) or hospitals and genetic clinics in some counties. Control infants were selected from birth hospitals. Case records were reviewed by a clinical geneticist at each site.	No adjustment. Case infants whose mothers reported a first-degree family history of craniosynostosis were excluded. No differences were observed for maternal age, maternal education, smoking, or gravidity.
Shaw, 1995	case control	Interviews were conducted with case and control mothers in English or Spanish, primarily face to face. The average 2-h interview elicited information from each mother notably on medical conditions and their treatment.	Cases were ascertained by reviewing medical records at all hospitals and genetic clinics for those infants/fetuses who were delivered in the area of the study.	Singletons only. Exclusion of women who had a previous Neural tube defect-affected pregnancy.
Sorensen, 2005	nested case control	Prescriptions identified in a research database that aggregates pharmacy electronic systems recording information on the drug, dose, personal identification number, and date of dispensing of the drug.	Cases were identified from the Danish hospital discharge registry, which contains all discharges from hospitals in Denmark, and includes surgical procedures, and up to 20 discharge diagnoses classified according to ICD-8 the ICD-10. Controls identified in the Danish birth registry.	Controls matched for birth month, birth year, and county of residence of the child. Adjusted for maternal age, birth order, maternal pre-eclampsia, maternal epilepsy, and maternal diabetes.
Weller, 2017	retrospective cohort	The exposure data were collected from the Clalit Health Services medication dispense database, which records the drugs dispensed to all registered women, including the dates that the drugs were dispensed before and during pregnancy, the classification codes, the dose schedules and dispensed.	Outcomes (classified according to ICD-9) obtained from the Soroka Medical Center computerised hospitalization database that includes birth defects and illnesses of the newborn and from the Committee for Termination of Pregnancies (for suspected congenital malformations).	Adjusted for maternal age, parity, the year of birth/termination of pregnancy, presence or absence of pre-pregnancy diabetes, self-reported smoking status during pregnancy, ethnic group (i.e. Jewish or Bedouin Muslim), and the use of gonadotropins/progesterone. Exclusion of pregnancies with exposure to folic acid antagonist drugs during pregnancy and multiple pregnancies.
Wu, 2006	nested case control	Prescribed drugs are recorded in an electronic database within Kaiser Permanente Medical Care Program (KPMCP). An electronic search for the following text strings to indicate an infertility drug prescription prior to delivery was performed: clomiphene, clomid, ...	Outcomes searched in Kaiser Permanente Medical Care Program (KPMCP) electronic clinical databases for infants who were given an inpatient or outpatient physician diagnosis of interest. A child neurologist who was blinded to information regarding infertility reviewed the medical records of all cases.	Singletons and term infants only. Infants with spinal neural tube defects did not differ from control infants in gender, maternal age at delivery, maternal race, gestational age, or birth weight.

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