Clomiphene - Medication and Pregnancy KB

Clomiphene

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Gorgui, 2022	Canada 2010 - 2014	Pregnancies of women resulted in a singleton liveborn, occurring during the study period and covered by the Quebec public prescription drug insurance plan	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	302 / 55569
Malchau, 2014	Denmark 2007 - 2012	All children born after intrauterine insemination in Denmark from 2007 to 2012 and all spontaneous conception singletons, 2008–2011.	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.	1357 / 1744	Children born after oocyte donation, preimplantation genetic diagnosis, percutaneous epididymal/testicular sperm aspiration, and frozen embryo transfer were excluded.
Milunsky, 1990	USA 1984 - 1987	Women recruited when they had either a maternal serum a-fetoprotein screen or an amniocentesis.	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.	438 / 22317	Material and methods completed with Milunsky 1989
Nehard, 2024	France ? - 2022	Pregnant women that called the Teratology information service with a gestational age at initial contact < 22 weeks after last menstrual period.	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.	309 / 1236	Exclusion of foetuses or children with chromosomal abnormalities.
Weller, 2017	Israel 1998 - 2009	All women aged 15–49 years registered to the Clalit Health Services maintenance organisation in southern Israel who gave birth or underwent termination of pregnancy (for suspected congenital malformations) at Soroka Medical Center.	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.	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.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Banhidy, 2008	Hungary 1980 - 1996	Newborns with abnormalities.	Newborns without abnormalities, matched to cases according to sex, birth week, and district of the parents' residence.	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.
Benedum, 2016	USA 1993 - 2012	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.	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).
Lammer, 1995	USA 1970 - 1979	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).	289 / 802	The reported OR was this one with control group excluding malformations also potentially associated with clomiphene (numbers in control group not available).
Lind, 2013	USA 1997 - 2007	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.	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.
Meijer, 2006	The Netherlands 1981 - 2003	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.	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).
Mili, 1991	USA 1968 - 1980	Mothers of infants with birth defects (no other details).	Mothers of infants without birth defects (no other details).	4904 / 3027	Outcomes of subgroups of malformations cannot be reported because authors provided only OR (without confidence interval) and insufficient raw data.
Olshan, 1999	USA and Canada 1992 - 1996	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.	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.
Reefhuis, 2011	USA 1997 - 2005	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.	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.
Reefhuis, 2003	USA 1993 - 1997	Infants who had nonfamilial, nonsyndromic craniosynostosis.	Liveborn infants without birth defects, randomly selected from the same regions and time period.	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.
Shaw, 1995	USA 1989 - 1991	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.	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.
Sorensen, 2005	Denmark 1989 - 2003	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.	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).
Wu, 2006	USA 1994 - 1997	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.	18 / 1608	Kaiser covered all costs related to evaluation, diagnoses, monitoring, and pharmacologic treatment of infertility, excluding in vitro fertilization.

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