Clomiphene

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Gorgui
2022 		Canada
2010 - 2014
retrospective cohort (claims database) 		The Quebec Pregnancy Cohort, built through the linkage of three Quebec databases: Régie de l’Assurance Maladie du Québec (RAMQ), the MED-ECHO and the Institut de la Statistique du Québec (ISQ). Pregnancies with at least one prescription filling for clomiphene only occurring within 2 months prior to and 1 month after the first day of gestation. unexposed (general population or NOS)
Pregnancies with spontaneous conception 		preconceptional for kinetic reason 302 / 55569
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).
Malchau
2014 		Denmark
2007 - 2012
population based cohort retrospective 		A national cohort of children born after intrauterine insemination (IUI) based on Danish national registries (the medical birth register and hospital discharge register). Singletons born after intrauterine insemination (IUI) of women who used clomiphene citrate (CC) as ovarian stimulation in the cycle leading to birth. unexposed, sick
Singletons born after intrauterine insemination (IUI) of women with natural cycle, defined as those who received no treatment with clomiphene citrate (CC) or follicle-stimulating hormone (FSH)–containing preparations. 		preconceptional for kinetic reason 1357 / 1744 Children born after oocyte donation, preimplantation genetic diagnosis, percutaneous epididymal/testicular sperm aspiration, and frozen embryo transfer were excluded.
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.
Milunsky
1990 		USA
1984 - 1987
prospective cohort 		Center for Human Genetics and the Boston Collaborative Drug Surveillance Program, Boston, USA. Women who reported use of clomiphene during the 3 months prior to pregnancy. unexposed (general population or NOS)
Women who did not reporte use of clomiphene during the 3 months prior to pregnancy. 		preconceptional for kinetic reason 438 / 22317 Material and methods completed with Milunsky 1989
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.
Nehard
2024 		France
? - 2022
prospective cohort 		A retrospective cohort study, based on prospectively ascertained clinical data from the French Teratology Information Service, Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Pregnant women with an inadvertent post-conceptional exposure to Clomiphene citrate, at any time between 2 and 12 weeks after last menstrual period, at any dosage and for any duration. unexposed (general population or NOS)
Pregnant women unexposed to Clomiphene citrate in the 3 months before conception or during pregnancy, matched on the year of referral. 		1st trimester 309 / 1236 Exclusion of foetuses or children with chromosomal abnormalities.
Not specified (prospective records).
Weller
2017 		Israel
1998 - 2009
retrospective cohort 		The Clalit Health Services maintenance organisation at Soroka Medical Center, in southern Israel. Singleton pregnancies where clomifene citrate was dispensed from 2 months before conception through the first month of pregnancy. unexposed (general population or NOS)
All singleton pregnancies in which clomifene citrate was not taken over the course of the study period. 		preconceptional for kinetic reason 1861 / 98728 Conditions for exclusion included newborns/fetuses with chromosomal/genetic malformations, birth before 20 weeks of pregnancy, exposure to folic acid antagonist drugs during pregnancy, in vitro fertilization (IVF) treatments, and multiple pregnancies.
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.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Banhidy
2008 		Hungary
1980 - 1996
case control 		The Hungarian Case–Control Surveillance of Congenital Abnormalities. Newborns with abnormalities. Newborns without abnormalities, matched to cases according to sex, birth week, and district of the parents' residence. Prospectively recorded data concerning exposure to clomiphene citrate were obtained from the log-books of prenatal care, which are mandatory in Hungary. early pregnancy 22843 / 38151 Overlapping: Banhidy 2008 included totally studies published by Czeizel 1989 (based on a lower study period) and Medveczky 2004 (that only studied neural tube defects). => The MA only included Banhidy 2008.
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.
Benedum
2016 		USA
1993 - 2012
case control 		The Boston University Slone Epidemiology Center Birth Defects Study. Infants live born, stillborn or therapeutic abortions with anencephaly, encephalocele, or spina bifida, excluding those with an accompanying conjoined twin, a chromosomal anomaly. Nonmalformed liveborn infants ascertained from the same birth population. 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. preconceptional for kinetic reason 219 / 4262 Very low risk of overlapping between the 2 studies using the Slone epidemiology center birth defects: Benedum 2016 (1993-2002) and Werler 1994 (study period not specified but before 1994).
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.
Lammer
1995 		USA
1970 - 1979
case control 		The Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry, USA. Mothers of infants with neural tube defects (spina bifida aperta or anencephaly). mothers of infants who had one (or several) of the other major malformations (except chromosomal abnormalities other than trisomy 21). 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. preconceptional for kinetic reason 289 / 802 The reported OR was this one with control group excluding malformations also potentially associated with clomiphene (numbers in control group not available).
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.
Lind
2013 		USA
1997 - 2007
case control 		The National Birth Defects Prevention Study (NBDPS). Male infants with isolated second- or third-degree hypospadias, defined as the urethral opening at the penile shaft, scrotum, or perineum. Male infants with no major birth defects selected randomly from vital records or birth logs. 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. preconceptional for kinetic reason 1537 / 4314 For hypospadias: Overlapping between Lind 2013 (1997 - 2007) and Reefhuis 2011 (1997 - 2005) with more cases in Lind 2103 => The MA only included hypospadias data of Lind 2013.
Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias as isolated.
Meijer
2006 		The Netherlands
1981 - 2003
case control 		The European Registration of Congenital Anomalies and Twins (EUROCAT) Northern Netherlands. Male subjects with hypospadias (either glandular/coronary, penile, penoscrotal, or perineal), isolated or in combination with other defects. All male subjects without hypospadias but with other malformations. 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. preconceptional for kinetic reason 392 / 4538 Subjects with hypospadias recognized as part of a syndrome (n=30) were excluded from this study, as well as subjects with epispadias (n=12).
Information about the anomalies is collected through physicians, midwives, clinical geneticists, and pathologists.
Mili
1991 		USA
1968 - 1980
case control 		The population-based Atlanta Birth Defects Case-Control Study, USA. Mothers of infants with birth defects (no other details). Mothers of infants without birth defects (no other details). Not specified. preconceptional for kinetic reason 4904 / 3027 Outcomes of subgroups of malformations cannot be reported because authors provided only OR (without confidence interval) and insufficient raw data.
Not specified.
Olshan
1999 		USA and Canada
1992 - 1996
case control 		Hospitals members of either of two pediatric collaborative clinical trials groups, the Children's Cancer Group and the Pediatric Oncology Group (139 participating hospitals). Patients less than 19 years of age who were newly diagnosed with neuroblastoma at one of the participating hospitals. Patients without neuroblastoma identified by using a random digit dialing procedure, based on adding two random digits to the first eight digits of the home telephone number of the case. 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. preconceptional for kinetic reason 504 / 504 Results of clomiphene use 1 month before pregnancy was reported here rather 'clomiphene 2-12 months before pregnancy', or 'ever used clomiphene' to maximize level of exposure embryo.
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).
Reefhuis
2011 		USA
1997 - 2005
case control 		The National Birth Defects Prevention Study (NBDPS), a large population-based multicenter case–control study of major birth defects. Live bom, stillborn, or induced terminations with at least one of the 30 different birth defects (excluding chromosomal or monogenic disorders) diagnosed prenatally, at birth, or during the first year of life. Liveborn infants without major birth defects randomly selected from the same geographical area and time period. 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). preconceptional for kinetic reason 19059 / 6807 Total number of cases not provided by authors (number of cases provided for each kind of malformations or group of malformations). For hypospadias: Overlapping: data of Lind 2013 (longer study period) was used because more cases than in Reefhuis 2011.
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.
Reefhuis
2003 		USA
1993 - 1997
case control 		Birth Defect Risk Factor Surveillance, in California, Georgia, and Iowa. Infants who had nonfamilial, nonsyndromic craniosynostosis. Liveborn infants without birth defects, randomly selected from the same regions and time period. 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. preconceptional for kinetic reason 99 / 777 Case infants whose mothers reported a first-degree family history of craniosynostosis were excluded. Mothers who used Ovulation stimulation (OV) in combination with artificial insemination (AI) or assisted reproductive techniques (ART) were excluded.
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.
Shaw
1995 		USA
1989 - 1991
case control 		The California Birth Defects Monitoring Program, USA. Singleton fetuses and liveborn or stillborn infants diagnosed with a Neural tube defect (anencephaly, spina bifida cystica, craniorachischisis, or iniencephaly). Singleton without reportable birth defect, born alive during the same period, randomly selected from area hospitals in proportion to each hospital’s estimated contribution. 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. preconceptional for kinetic reason 538 / 539 Only the pre-conceptional data reported here, because there are also 2 use reported into the postconceptional period (in one case and one control) but it is not known if it is during organogenesis.
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.
Sorensen
2005 		Denmark
1989 - 2003
nested case control 		The Danish birth registry and Danish hospital discharge registry of 4 counties: North Jutland, Aarhus, Viborg, and Ringkjoebing. Male births with a diagnosis of hypospadias and with a full prescription history. Male births without a diagnosis of hypospadias and with a full prescription history, selected and matched for birth month, birth year, and county of residence of the child. 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. preconceptional for kinetic reason 319 / 3190 Restricting the exposure to clomifene to the first trimester and up to 30 days before the time of conception did not change the risk estimate substantially (data not shown).
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.
Wu
2006 		USA
1994 - 1997
nested case control 		A nested case-control study within the Kaiser Permanente Medical Care Program (KPMCP) in Northern California. Infants with spinal neural tube defects (NTDs). Random sample of infants who did not have a diagnosis of spinal cord abnormalities, cerebral palsy, genetic disease, chromosomal abnormalities, arthrogryposis, or muscle disease. 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, ... preconceptional for kinetic reason 18 / 1608 Kaiser covered all costs related to evaluation, diagnoses, monitoring, and pharmacologic treatment of infertility, excluding in vitro fertilization.
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.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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