El tabaquismo materno durante el embarazo y las malformaciones congénitas en niños: una revisión sistemática y meta-análisis

Nicoletti, Dilvania; Appel, Leilane Droppa; Siedersberger Neto, Pedro; Guimarães, Gabriel Waihrich; Zhang, Linjie

doi:10.1590/0102-311X00115813

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Review • Cad. Saúde Pública 30 (12) • Dic 2014 • https://doi.org/10.1590/0102-311X00115813 copiar

El tabaquismo materno durante el embarazo y las malformaciones congénitas en niños: una revisión sistemática y meta-análisis

Autoría SCIMAGO INSTITUTIONS RANKINGS

Esta revisión sistemática se encargó de investigar la asociación entre el tabaquismo materno durante el embarazo y las malformaciones congénitas en los niños. Se realizó una búsqueda electrónica de los estudios de observación en las bases de datos de ovid MEDLINE (1950 hasta abril de 2010), LILACS y SciELO. 188 estudios con 13.564.914 participantes se incluyeron en esta revisión. Se encontraron asociaciones positivas significativas entre el tabaquismo materno y malformaciones de los sistemas: cardiovascular (OR: 1,11; IC95%: 1.03-1.19), digestivo (OR: 1,18; IC95%: 1,07-1,30), musculoesqueléticos (OR: 1,27; IC95%: 1,16-1,39) y de cara y cuello (OR: 1,28; IC95%: 1,19-1,37). La fuerza de la asociación entre el tabaquismo materno y los defectos de nacimiento, medidos por el OR (IC95%) está significativamente relacionada con la cantidad de cigarrillos fumados diariamente (χ² = 12,1; p = 0,002). Llegamos a la conclusión de que el tabaquismo materno durante el embarazo se asocia con un mayor riesgo de malformaciones congénitas en los niños y esta asociación es dosis-dependiente.

Hábito de Fumar; Embarazo; Anomalías Congénitas

Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Adams et	Case-	Five	Conotruncal heart	Interview	First quarter	83	1,303	Matching: race, month
al. ¹⁸ (1989)	control	metropolitan	defect					of birth, place of birth
		areas of Atlanta
		(United States)
Akre et al.	Nested	Medical birth	Cryptorchidism;	Interview	Unspecified	2,576 (cryptor-	12,910	Adjusted: maternal
¹⁹ (1999)	case-	record and	hypospadias			chidism);	(cryptor-	factors (age, height,
	control	admission				1,137 (hypos-	chidism);	parity, preeclampsia)
		records (Sweden)				padias)	5,687	and perinatal factors
							(hypos-	(plurality, Apgar, other
							padias)	defects); Matching:
								sex, month and place
								of birth
Alderman	Case-	Birth defects	Crooked foot at	Birth	Unspecified	124	1,438	Adjusted or stratified:
et al. ²⁰	control	registry,	birth	certificate				sex of the child,
(1991)		Washington		data				stillborn, plurality,
		State (United						marital status
		States)
Alderman	Case-	Colorado	Craniosynostosis	Phone	Any period	212	291	Adjusted or stratified:
et al. ²¹	control	Craniosynostosis		interview				maternal age, race,
(1994)		Registry (United						multiparity, sex of
		States)						the child, type of
								craniosynostosis period
								of exposure
Ananijevic-	Case-	Belgrade Study	General	Interview	Unspecified	113	195	Matching: sex,
Pandey et	control	(Serbia)	malformations					gestational age,
al. ²² (1992)								maternal age, place of
								birth
Aro et al. ²³	Case-	The Finnish	Limb reduction	Structured	Unspecified	453	453	Adjusted: maternal
(1983)	control	registry of		question-				age, alcohol intake;
		congenital		naire				Matching: month/year
		malformations						and place of birth
Bailey et al.	Cohort	Christchurch	Birth defects	Interview	Unspecified	58	1,116	-
²⁴ (1970)		Women’s
		Hospital (New
		Zealand)
Batra et	Case-	Comprehensive	Ventricular septal	Birth	Unspecified	2,898	11,186	Matching: year of birth
al. ²⁵ (2007)	control	Hospital Abstract	defect	certificate
		Reporting		data
		System,
		Washington
		State (United
		States)
Beard et	Case-	Rochester Study,	Cryptorchidism	-	Unspecified	113	226	Adjusted: maternal age,
al. ²⁶ (1984)	control	Minnesota						birth weight, parity, year
		(United States)						of birth
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Beaty	Case-	Maryland State	Oral fissures	Interview	Unspecified	121	86	-
et al. ²⁷	control	Birth Defects
(2008)		Reporting and
		Information
		System (United
		States)
Beaty	Case-	Maryland State	Oral fissures	Interview	Conception	135	152	Adjusted: maternal
et al. ²⁸	control	Birth Defects			and first			age, maternal/paternal
(2001)		Reporting and			quarter			schooling
		Information
		System (United
		States)
Bell &	Cross-	Statistics of	Birth defects	Interview	Second half of	7	5,550	-
Lumley ²⁹	sectional	perinatal		or medical	pregnancy
(1989)		morbidity.		records
		Victoria
		(Austrália)
Berkowitz	Case-	Study of the	Cryptorchidism	-	Unspecified	63	219	Matching: month/year
& Lapinski	control	city of New York						of birth, sex, place of
³⁰ (1996)		(United States)						birth
Biggs et	Case-	Birth certificate	Cryptorchidism	Birth	Unspecified	2,395	9,580	Matching: month/year
al. ³¹	control	data,		certificate				of birth, sex
(2002)		Washington		data
		State (United
		States)
Bille et	Nested	Danish National	Oral fissures	Question-	First quarter	189	836	Adjusted: maternal age,
al. ³²	case-	Birth Cohort		naire and				social class
(2007)	control	Data		phone
				interview
Bird et al. ⁶	Case-	National	Musculoskeletal	Interview	Pre-	653	4,967	Adjusted: place
(2009)	control	Birth Defects			conception			of birth, folic acid
		Prevention Study			exposure and			supplementation, BMI,
		(United States)			in the first			maternal diabetes
					quarter
Bitsko	Case-	Birth Defects	Birth defects	-	Unspecified	142	243	Matching: month/year
et al. ³³	control	Risk Factor						of birth, place of birth
(2007)		Surveillance,
		Iowa (United
		States)
Blatter	Case-	Hospitals of the	CNS defects	Question-	Unspecified	274	314	Matching: place of birth
et al. ³⁴	control	Netherlands		naire and
(1996)				phone
				interview
Botto et	Case-	Atlanta	Heart defects	Phone	Pre-	905	3,029	Matching: month/year
al. ³⁵	control	Congenital		interview	conception			of birth, place of birth,
(2001)		Defects Program			exposure and			race
		(United States)			in the first
					quarter
Bracken et	Case-	Hospitals of	Birth defects	Interview	First quarter	1,369	2,967	-
al. ⁷ (1978)	control	Connecticut
		(United States)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Brouwers	Case-	Pediatric	Hypospadias	Question-	Pre-	583	251	Adjusted: maternal/
et al. ³⁶	control	urology center		naire	conception			paternal schooling,
(2007)		(Netherlands)			exposure and			place of birth, paternal
					in the first			hypospadias, infertility
					quarter			treatment, exposure
								to DES, multiparity,
								vitamin supplements
								prior to conception,
								exposure to pesticides,
								use of medication by
								the father; Matching:
								month/year of birth,
								place of birth, sex
Brouwers	Case-	University	Hypospadias	Question-	Unspecified	305	629	Adjusted: year of birth
et al. ³⁷	control	Hospital,		naire
(2010)		Netherlands
Browne	Case-	National	Heart defects	Phone	Pre-	403	131	Adjusted: race, place
et al. ³⁸	control	Birth Defects		interview	conception			of birth
(2007)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Carbone	Case-	Ragusa Study	Cryptorchidism;	-	Unspecified	91	203	Matching: month/place
et al. ³⁹	control	(Italy)	hypospadias					of birth, place of birth,
(2007)								sex
Cardy	Case-	Talipes Study	Congenital	Interview	Unspecified	194	60	Adjusted: year of birth,
et al. ⁴⁰	control	(United	equinovarus					sex
(2007)		Kingdom)
Carmi-	Case-	California	Anencephaly	Phone	Pre-	122	464	-
chael &	control	Birth Defects		interview	conception
Shaw ⁴¹		Monitoring			exposure and
(2000)		Program (United			in the first
		States)			quarter
Carmi-	Case-	California	Malformations	Phone	Pre-	696	734	-
chael et	control	Birth Defects	(cardiovascular	interview	conception
al. ⁴²		Monitoring	defects and facial		exposure and
(2003)		Program (United	cleft)		in the first
		States)			quarter
Carmi	Case-	National	Hypospadias	Interview	Any period	437	1,225	Adjusted: maternal
chael et	control	Birth Defects						age, race, maternal
al. ⁴³		Prevention Study						schooling, parity, history
(2005)		(United States)						of subfertility
Carmi	Case-	National	Craniosynostosis	Interview	Any period	531	5,008	Adjusted: maternal age,
chael et	control	Birth Defects						race, maternal/paternal
al. ⁴⁴		Prevention Study						schooling, parity, history
(2008)		(United States)						of subfertility, folic acid
								intake, Maternal BMI,
								place of the study
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Caton	Case-	National	Hypospadias	Phone	Pre-	755	2,044	-
et al. ⁴⁵	control	Birth Defects		interview	conception
(2008)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Cedergren	Case-	Southeastern	Heart defects	Medical	Beginning of	264	515	-
et al. ⁸	control	region of		records	pregnancy
(2002)		Sweden
Chambers	Case-	Southern region	Gastroschisis	Medical	First quarter	102	117	-
et al. ⁴⁶	control	of California		records
(2007)		(United States)
Chevrier	Case-	Hospitals of	Oral fissures	Question-	First quarter	240	236	Adjusted: place of birth,
et al. ⁴⁷	control	France		naire				sex, race
(2008)
Chew	Cohort	Collaborative	Eye defects	Interview	Unspecified	1,658	37,133	Adjusted: maternal age,
et al. ⁴⁸		perinatal project						race, birth weight, place
(1994)		(United States)						of birth
Christen-	Case-	Danish national	Oral fissures	Interview	First quarter	296	551	Adjusted: maternal
sen et al. ⁹	control	study						alcohol intake,
(1999)								periconcepcional
								vitamin
								supplementation, place
								of birth, month/year of
								birth
Christian-	Cohort	Kaiser	Anomalies in all	Interview	First quarter	2,547	12,138	-
son ⁴⁹		Foundation	systems
(1980)		health plan
		(United States)
Chung &	Cohort	Collaborative	Inguinal hernia	-	Unspecified	713	51,482	-
Myriantho-		perinatal project
poulos ⁵⁰		(United States)
(1975)
Chung	Case-	Natality	Cleft lip; cleft	Interview	The entire	2,207	4,414	Adjusted: maternal
et al. ⁵¹	control	database (United	palate	and	pregnancy			age, race, maternal/
(2000)		States)		database				paternal schooling,
								maternal hypertension,
								birth weight , maternal
								diabetes, sex
Cordier	Case-	Study in	Major defects	Interview	Unspecified	325	325	Adjusted: place of birth
et al. ⁵²	control	hospitals of
(1992)		Marseille and
		Paris (France)
Correy	Cohort	Cigarette	Malformations in	Interview	First quarter	1,095	54,942	-
et al. ⁵³		smoking, alcohol	general
(1991)		consumption
		and fetal outcome in Tasmania (Australia)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Croen	Case-	California	Holoprosen-	Phone	Pre-	48	106	Matching: month/year
et al. ⁵⁴	control	Birth Defects	cephaly	interview	conception			of birth, place of birth,
(2000)		Monitoring			exposure and			sex
		Program (United			in the first
		States)			quarter
Czeizel &	Case-	Hungarian	Omphalocele	Interview	Unspecified	134	134	Matching: month/year
Vitez ⁵⁵	control	congenital						of birth, place of birth,
(1981)		abnormalities						sex, pregnancy outcome
		registry
Czeizel &	Case-	Hungarian	Cleft lip; cleft	Interview	The entire	1,088	752	Adjusted: maternal/
Nagy ⁵⁶	control	congenital	palate		pregnancy			paternal schooling,
(1986)		abnormalities						parity; Matching:
		registry						month/year of birth,
								place of birth, sex
Czeizel	Case-	Hungarian	Limb reduction	Question-	Pre-	537	537	Matching: month/year
et al. ⁵⁷	control	congenital		naire	conception			of birth, place of birth,
(1994)		abnormalities			exposure and			sex
		registry			the entire
					pregnancy
Czeizel	Case-	Hungarian	Orofacial	Interview	The entire	1,346	1,346	Matching: month/year
et al. ⁵⁸	control	congenital	clefts; limb		pregnancy			of birth, place of birth,
(2004)		abnormalities	malformations					sex
		registry
Costa	Case-	Rio de Janeiro	Birth defects	Question-	Unspecified	149	9,223	-
et al. ⁵⁹	control	hospital study		naires
(2006)		(Brazil)
Damgaard	Cohort	University	Cryptorchidism	Question-	The entire	127	2,368	Adjusted: place of birth,
et al. ⁶⁰		hospitals of		naire and	pregnancy			classe social; Matching:
(2008)		Denmark and		interview				sex
		Finland
Davies	Case-	Addenbrookes	Cryptorchidism	Medical	Unspecified	83	129	Matching: month/year
et al. ⁶¹	control	Hospital		records				of birth, place of birth,
(1986)		Study (United						sex
		Kingdom)
De Roo	Cohort	Washington	Oral fissures	Birth	The entire	608	297,530	Adjusted: race, maternal
et al. ¹⁰		State Birth		certificate	pregnancy			age, marital status, sex
(2003)		Defects Registry		data
		(United States)
Dickinson	Case-	North Carolina	Crooked foot at	Birth	The entire	443	4,492	Adjusted: maternal
et al. ¹¹	control	Birth Defects	birth	certificate	pregnancy			age, race, sex, time
(2008)		Monitoring		data				until commencement of
		Program (United						antenatal care
		States)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Draper	Case-	Birth defects	Gastroschisis	Interview	First quarter	144	432	Adjusted: use of illicit
et al. ⁶²	control	registry in three						drugs by the mother,
(2008)		regions of the						use of vasoconstrictive
		United Kingdom						drugs, maternal BMI,
								marital status, maternal
								use of aspirin, parental
								home ownership,
								maternal diseases;
								Matching: maternal age,
								place of birth
Erickson ⁶³	Case-	Atlanta Birth	General	Interview	Unspecified	4,908	3,024	Adjusted: race, place
(1991)	control	Defects	malformations					of birth, month/year of
		Risk Factor						birth
		Surveillance
		(United States)
Ericson	Case-	Swedish National	CNS defects;	Hospital	First quarter	132	261	Matching: month/year
et al. ⁶⁴	control	Board of Health	orofacial clefts	records				of birth, place of birth,
(1979)								maternal age, parity
Evans	Retrospec-	Cardiff Births	All birth defects	Birth	Any period	2,266	653,443	-
et al. ⁶⁵	tive cohort	Survey (United		records
(1979)		Kingdom)
Fredrick	Case-	Assessment	Congenital heart	Question-	Second and	290	15,719	-
et al. ⁶⁶	control	of perinatal	diseases	naire	third quarter
(1971)		mortality (United
		Kingdom)
Feldkamp	Case-	Utah Birth Defect	Gastroschisis	Birth certi-	First quarter	189	423,588	-
et al. ¹²	control	Network (United		ficate
(2008)		States)
Felix et	Case-	Pediatric surgery	Esophageal	Question-	Pre-	105	192	Adjusted: maternal age;
al. ⁶⁷	control	reference center,	atresia;	naire	conception			Matching: month/year
(2008)		Netherlands	diaphragmatic		exposure and			of birth, sex
			hernia		in the first
					quarter
Ferencz	Case-	Baltimore-	Cardiovascular	Question-	Unspecified	1,541	3,572	-
et al. ⁶⁸	control	Washington	defects	naire
(2008)		Infant Study
		(United States)
Garcia	Case-	Data from 8	Birth defects	Phone	Pre-	261	161	Matching: month/year
et al. ⁶⁹	control	public hospitals		interview	conception			of birth, place of birth
(1999)		of a community			exposure and
		in Valencia			in the first
		(Spain)			quarter
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Goldbaum	Case-	Birth records,	Gastroschisis	Birth	Unspecified	62	617	Adjusted: month/year
et al. ⁷⁰	control	Washington		records				of birth, sex, maternal
(1990)		State (United						age, race, marital status,
		States)						maternal occupation,
								rural/urban, pre-
								natal care, previous
								miscarriage, previous
								induction of abortion,
								paternal occupation;
								Matching: month/year
								of birth
Golding &	Case-	Assessment	Anencephaly	Birth	Beginning of	483	19,172	-
Butler ⁷¹	control	of perinatal		records	pregnancy
(1983)		mortality (United
		Kingdom)
Grewal	Case-	Hospitals of	All birth defects	Interview	Pre-	1,351	620	-
et al. ⁷²	control	California			conception
(2008)		(United States)			exposure and
					in the first two
					months
Haddow	Cohort	Maternal serum	Gastroschisis	Interview	Second	21	59,919	Adjusted: maternal age,
et al. ⁷³		alpha-fetoprotein			quarter			month/year of birth
(1983)		screening
		programs
		(United States)
Hakin &	Case-	Pediatric	Esotropia;	Interview	The entire	377	377	Adjusted: maternal age,
Tielsch ⁷⁴	control	Ophthalmology	exotropia	and medical	pregnancy			paternal age, maternal
(1992)		Centers in		data				schooling, alcohol
		Baltimore						intake, marital status,
		(United States)						race, birth weight,
								Apgar, gestational age
Hearey	Case-	Antioch-	CNS defects	Medical	Unspecified	9	27	-
et al. ⁷⁵	control	Pittsburg,		records
(1984)		California
		(United States)
Heinonen	Case-	Collaborative	Malformations	Medical	Unspecified	1,393	4,889	Matching: month/year
⁷⁶ (1977)	control	perinatal project		records				of birth, place of birth,
		(United States)						sex
Hemminki	Case-	The Finnish	CNS defects	Interview	Unspecified	3,300	3,300	Matching: sex
et al. ⁷⁷	control	registry of
(1981)		congenital
		malformations
Himmel-	Case-	Survey of	Defects	Interview	First quarter	1,369	9,724	Adjusted: age, parity,
berger	control	American						exposures to anesthetic
et al. ⁷⁸		Healthcare						gases
(1978)		Workers (United
		States)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Honein	Case-	Data from the	Craniosynostosis	Interview	Pre-	44	3,029	Adjusted: race, month/
et al. ⁸⁰	control	Atlanta Birth			conception			year of birth, place of
(2000)		Defects Study			exposure and			birth
		(United States)			in the first
					quarter
Honein &	Case-	Data from the	Crooked foot at	Interview	Pre-	346	3,029	Adjusted: sex, parity
Rasmussen	control	Atlanta Birth	birth		conception
⁸¹ (2000)		Defects Study			exposure and
		(United States)			in the first
					quarter
Honein	Case-	National Vital	17 defects:	Birth	Unspecified	24,014	6,134,773	Adjusted: maternal age,
et al. ⁸²	control	Statistics (United	CNS; digestive;	certificate		(CNS: 4,352;		race, maternal schooling
(2001)		States)	musculoskeletal;	data		digestive:
			urogenital; face			1.312;
			and neck			musculo-
						skeletals:
						12,293;
						urogenital:
						819; face and
						neck: 5,238)
Honein	Case-	National	Oral fissures	Phone	Pre-	1,461	3,390	Adjusted: maternal age,
et al. ⁸³	control	Birth Defects		interview	conception			race, parity, alcohol
(2007)		Prevention Study			exposure and			intake in the first
		(United States)			in the first			quarter, birth control
					quarter			with folic acid, sex
Hoobs	Case-	Arkansas	Heart defects	Interview	Pre-	275	118	-
et al. ⁷⁹	control	Reproductive			conception
(2006)		Health			exposure
		Monitoring			and in the
		System (United			first primeiro
		States)			month of
					pregnancy
Hougland	Cross-	Children’s	Gastroschisis	Medical	Unspecified	82	47,146	-
et al. ⁸⁴	sectional	Medical Center		records
(2006)		(United States)
Jensen	Cohort	Birth cohort,	Cryptorchidism	Question-	The entire	270	5,716	Adjusted: maternal age,
et al. ⁸⁵		1984-1987		naire and	pregnancy			paternal age, infertility
(2007)		(Denmark)		medical				treatment, parity, social
				records				class, maternal alcohol
								intake, birth weight,
								gestational age, weight
								of the placenta
Johansen	Case-	Norway medical	Cleft lip; cleft	Question-	First quarter	573	763	-
et al. ⁸⁶	control	birth records	palate	naire
(2009)
Jones	Case-	Oxford study	Cryptorchidism	Medical	Beginning of	1,499	10,811	Matching: month/year
et al. ⁸⁷	control	(United		records	pregnancy			of birth, place of birth,
(1998)		Kingdom)						sex
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Kallen ⁸⁸	Cohort	Swedish birth	Craniosynostosis	Interview	First quarter	303	1,413,585	Stratified: place of birth,
(1999)		defects registry						maternal age, parity,
								maternal schooling
Kallen ⁸⁹	Cohort	Swedish birth	44 defects:	Interview	First quarter	27,670 (CNS:	1,413,811	Adjusted: month/
(2000)		defects registry	CNS; heart;			856; heart:		year of birth, maternal
		and birth	face and neck;			13,266;		age, parity, maternal
		medical records	musculoskeletal;			face and		schooling
		(1983-1996)	digestive;			neck: 3,345;
			urogenital; other			musculo-
						skeletal:
						4,342; diges-
						tive: 1,241;
						urogenital:
						4,502;
						other:
						118)
Kelsey	Case-	Birth data from	Malformations	Interview	First quarter	1,370	2,968	-
et al. ⁹⁰	control	5 Connecticut
(1978)		hospitals (United
		States)
Khoury	Case-	Atlanta Birth	Cleft lip; cleft	Phone	Pre-	345	2,809	Adjusted: maternal
et al. ⁹¹	control	Defects Case-	palate	interview	conception			age, schooling,
(1989)		Control Study			and first			alcohol intake, use
		(United States)			quarter			of tranquilizers, use
					exposure			of contraceptives,
								pregnancy planning,
								race
Krapels	Case-	Dutch university	Cleft lip with	Interview	Pre-	349	222	-
et al. ⁹²	control	medical centers	or without cleft		conception
(2006)			palate		exposure e
					first quarter
Krauss	Case-	Missouri Birth	Microcephaly	Interview	Unspecified	360	3,600	-
et al. ⁹³	control	Defects Registry
(2003)		(United States)
Kricker	Case-	Two states of	Limb reduction	Interview	First quarter	155	2,274	Matching: data of birth,
et al. ⁹³	control	Australia						place of residency
(1986)
Kuciene &	Case-	Medical records	Heart defects	Interview	Unspecified	187	643	-
Dulskiene	control	of hospitals and
⁹⁵ (2009)		clinics of the
		city of Kaunas
		(Lithuania)
Kullander	Cohort	Study in the	Defects	Question-	First quarter	192	5,548	-
& Kallen ⁹⁶		Malmö hospital		naire
(1971)		(Sweden)
Kurahashi	Case-	Hokkaido	Hypospadias	Question-	Unspecified	31	64	-
et al. ⁹⁷	control	University		naire
(2005)		Hospital and
		Chukyo Hospital
		(Japan)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Kurahashi	Case-	Hokkaido	Cryptorchidism	Question-	Unspecified	96	116	Adjusted: maternal age,
et al. ⁹⁸	control	University		naire				maternal schooling, year
(2005)		Hospital and						of birth
		Chukyo Hospital
		(Japan)
Lam &	Case-	California	Gastroschisis	Interview	Pre-	55	94	-
Torfs ⁹⁹	control	Birth Defects			conception
(2006)		Monitoring			exposure and
		Program (United			in the first
		States)			quarter
Leite &	Case-	Hospitals of	Oral fissures	Interview	Pre-	274	548	-
Koifman	control	Rio de Janeiro			conception
¹⁰⁰ (2009)		(Brazil)			exposure and
					in the first
					quarter
Li et al. ¹⁰¹	Case-	Birth Defects	Urinary tract	Interview	The entire	118	369	Adjusted: family income,
(1996)	control	Registry,	defects		pregnancy			paternal schooling,
		Washington						periconceptional vitamin
		State (United						supplementation,
		States)						maternal use of illicit
								drugs, parity, place and
								year of birth
Li et al. ¹⁰²	Case-	Birth difects	Neural tube	Interview	Pre-	158	226	-
(2006)	control	surveillance	defects		conception
		system in the			exposure and
		province of			in the first
		Shanxi (China)			quarter
Lie et al.	Case-	Birth records of	Oral fissures	Question-	First quarter	573	763	-
¹⁰³ (2008)	control	Norway		naire
Lieff et	Case-	Birth defects	Oral fissures	Interviews	The entire	1,479	2,295	-
al. ¹⁰⁴	control	study, Boston			pregnancy
(1999)		University
		(United States)
Linn et	Case-	Women’s	Defects	Interview	Unspecified	579	11,861	Adjusted: parity, use
al. 105	control	hospital, Boston						of oral contraceptive,
(1983)		(United States)						previous miscarriage,
								social class, maternal/
								paternal age/, race,
								maternal/paternal
								schooling, maternal
								religion
Little et	Case-	Scotland,	Oral fissures	Interview	First quarter	190	248	Adjusted: sex, race,
al. ¹⁰⁶	control	Manchester						month of birth, maternal
(2004)		and Merseyside						schooling
		(United
		Kingdom)
Liu et	Case-	City hospitals	Heart defects	Interview	Pre-	164	328	-
al. ¹⁰⁷	control	in the province			conception
(2009)		of Shandong			exposure and
		(China)			in the first
					quarter
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Lorente	Case-	European	Oral fissures	Interview	First quarter	161	1,134	Adjusted: place of birth,
et al. ¹⁰⁸	control	registry of						maternal age, maternal
(2000)		congenital						alcohol intake, social
		anomalies						class; Matching: month/
		(France, Italy,						year of birth, place of
		Netherlands and						birth
		United Kingdom)
Lowe ¹⁰⁹	Cohort	Maternity,	Malformations	Question-	Any period	23	1,800	-
(1959)		Birmingham		naire
		Hospital (United
		Kingdom)
Lubs ¹¹⁰	Retrospec-	Yale Hospital	Major anomalies	Interview	Unspecified	102	4,067	-
(1973)	tive cohort	Study, New
		Haven (United
		States)
Lumley	Cohort	Cigarette	Malformations	Interview	Unspecified	251	10,112	Adjusted: maternal age,
et al. ¹¹¹		smoking, alcohol						maternal alcohol intake,
(1985)		consumption						parity, social class
		study in
		Tasmania
		(Australia)
MacBird	Case-	National	Omphalocele	Interview	Any period	168	4,967	Adjusted: place of birth,
et al. ¹¹²	control	Birth Defects						maternal diabetes,
(2009)		Prevention Study						maternal BMI, folic acid
		(United States)						intake materna
Malik et al.	Case-	National	Heart defects	Interview	Any period	3,067	3,947	Adjusted: sex, race,
¹¹³ (2008)	control	Birth Defects						maternal age, maternal
		Prevention Study						BMI, folic acid and
		(United States)						periconceptional
								vitamines intake, alcohol
								and caffeine maternal
								intake, family history
								of malformation, place
								of birth
Malloy	Case-	Missouri Birth	Malformations	Birth	Unspecified	10,223	277,844	Adjusted: maternal
et al. ¹¹⁴	control	Defects Registry		certificate				age, race, marital
(1989)		(United States)						status, parity, maternal
								schooling
Man &	Case-	Natality	Digital anomaly	Interview	Unspecified	5,171	10,342	Adjusted: marital status,
Chang ¹¹⁵	control	database (United						maternal diseases,
(2006)		States)						maternal diabetes,
								maternal hypertension,
								previous premature
								delivery, maternal
								chronic disease, Rh
								sensitivity
Mandira-	Case-	Study in Izmir	Neural tube	Interview	Unspecified	44	88	Matching: place of birth,
cioglu	control	hospital (Turkey)	defects					month/year of birth
et al. ¹¹⁶
(2004)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Martinez-	Case-	Birth defects	Gastroschisis	Phone	Pre-	45	690	Matching: month/year
Frias et	control	study in Spain		interview	conception			of birth, sex
al. ¹¹⁷					exposure and
(2008)					in the first
					quarter
McBride	Case-	Birth Defects	Cryptorchidism	Phone	Pre-	244	488	Adjusted: maternal
et al. ¹¹⁸	control	Registry		interview	conception			age, maternal/paternal
(1991)		(Canada)			exposure and			schooling, race,
					in the first			maternal alcohol intake,
					quarter			caffeine
McDonald	Case-	Assessment of	Birth defects	Interview	First quarter	1,928	87,389	Matching: sex
et al. ¹¹⁹	control	occupational
(1992)		factors in
		pregnancy
		in Montreal
		(Canada)
McGlynn	Nested	Collaborative	Cryptorchidism	Interview	Unspecified	424	23,994	-
et al. ¹²⁰	case-	perinatal project
(2006)	control	(United States)
Miller et	Case-	National	Anorectal atresia	Phone	Pre-	464	4,940	-
al. ¹²¹	control	Birth Defects		interview	conception
(2009)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Miller et	Case-	National	Holoprosen-	Phone	Pre-	59	4,999	-
al. 122	control	Birth Defects	cephaly	interview	conception
(2010)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Mitchell	Case-	Danish case-	Oral fissures	Interview	First quarter	296	559	Matching: month/year
et al. ¹²³	control	control study						of birth, place of birth
(2001)
Morales-	Cohort	Danish national	Birth defects	Interview	First quarter	3,767	73,001	Adjusted: maternal age,
Suarez-		birth cohort						maternal alcohol intake
Varela		Denmark
et al. ¹²⁴
(2006)
Morgana	Case-	Child Health and	Cryptorchidism	Interview	Unspecified	84	250	Matching: race, month/
et al. ¹²⁵	control	Development						year of birth, sex
(2008)	aninhado	Studies of
		California
		(United States)
Mori et	Case-	University	Cryptorchidism	Interview	Beginning of	104	104	Matching: age, sex
al. 126	control	Hospital of			pregnancy
(1992)		Sapporo (Japan)
Mossey	Case-	Regions of	Oral fissures	Phone	First quarter	191	247	-
et al. ¹²⁷	control	England		interview
(2007)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Munoz	Case-	Neural tube	Anencephaly	Interview	Pre-	151	151	Matching: month/year
et al. ¹²⁸	control	defects			conception			of birth, place of birth
(2006)		epidemiological			exposure
		surveillance			and in the
		system (Mexico)			first month of
					pregnancy
Mygind	Cross-	Denmark	Birth defects	Interview	First quarter	342	9,284	Adjusted: maternal age,
et al. ¹²⁹	sectional							gestational age
(2002)
Niebyl	Case-	Children’s	Cleft lip; cleft	Interview	Unspecified	59	59	Matching: race,
et al. ¹³⁰	control	Hospital,	palate					maternal age
(1985)		Baltimore
		(United States)
Noorgaard	Case-	National Patient	Hypospadias	Database	Pre-	1,591	14,900	-
et al. ¹³¹	control	Regsitry of			conception
(2009)		Denmark			exposure and
					in the first
					quarter
Oddsberg	Case-	Swedish Registry	Esophagus atresia	Prenatal	First quarter	722	3,610
et al. ¹³²	control	of Birth Defects		data
(2008)
Ormond	Case-	Southeastern	Hypospadias	Phone	First quarter	468	485	Adjusted: family income
et al. ¹³³	control	England		interview				gestational age, birth
(2009)		Study (United						weight, folic acid intake;
		Kingdom)						Matching: month/year
								of birth, place of birth,
								sex
Parikh	Case-	Birth records	Renal agenesis	Birth	Unspecified	188	940	Matching: month/year
et al. ¹³⁴	control	of the State of		certificate				of birth
(2002)		Colorado (United		data
		States)
Parker	Case-	Birth Defects	Crooked foot at	Birth	Unspecified	6,139	61,390	Adjusted: race, maternal
et al. ¹³⁵	control	Surveillance	birth	certificate				age, parity, maternal/
(2009)		Program (United		data				paternal schooling;
		States)						Matching: month/year
								of birth, place of birth
Pierik et	Nested	Cohorte of	Cryptorchidism;	Interview	Unspecified	134	313	-
al. 136	case-	infants in the city	hypospadias
(2004)	control	of Rotterdam
		(Netherlands)
Porter	Case-	Hospitais,	Hypospadias	Birth	Unspecified	2,006	10,084	Matching: month/year
et al. ¹³⁷	control	Washington		certificate				of birth, sex
(2006)		State (United		data
		States)
Preiksaet	Cohort	Hospital-based	Cryptorchidism	Question-	Unspecified	69	1,135	Matching: sex
al. ¹³⁸		study in the city		naire
(2006)		of Panevežys
		(Lithuania)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Queissur-	Cohort	Birth defects	Major birth	Interview	Unspecified	2,144	28,796	-
Luft et		monitoring	defects
al. ¹³⁹		system of Mainz
(2002)		(Germany)
Ramirez	Case-	Population-	Oral fissures	Phone	Pre-	431	299	-
et al. ¹³	control	based study		interview	conception
(2007)		in California			exposure and
		(United States)			in the first
					quarter
Rantakallio	Nested	Birth cohort,	Malformations	Interview	Unspecified	95	3,549	Matching: parity,
¹⁴⁰ (1978)	case-	Northern Finland						marital status, maternal
	control							age, place of birth,
								multiparity
Reefhuis	Case-	EUROCAT Study	Crooked foot at	Interview	Any period	2,905	7,829	Adjusted: maternal age,
et al. ¹⁴¹	control	(Europe)	birth	and hospital				place of birth, parity,
(1998)				records				month/year of birth
Robitaille	Case-	National	Limb reduction	Phone	Unspecified	527	4, 956	-
et al. ¹⁴²	control	Birth Defects		interview
(2009)		Prevention Study
		(United States)
Rodriguez-	Case-	Collaborative	Hypospadias	Interview	Unspecified	2,393	12,465	Adjusted: maternal
Pinilla	control	birth defects						age, maternal/paternal
et al. ¹⁴³		study (Spain)						schooling, maternal
(2008)								epilepsy, maternal
								chronic disease,
								race, family history of
								malformations, fever
								during pregnancy,
								maternal alcohol
								intake mother,
								periconceptional vitamin
								supplementation,
								maternal use of
								medication; Matching:
								month/year of birth,
								place of birth, sex
Romitti	Case-	National	Cleft lip with	Phone	Pre-	1,748	4,094	-
et al. ¹⁴⁴	control	Birth Defects	or without cleft	interview	conception
(2007)		Prevention Study	palate		exposure and
		(United States)			in the first
					quarter
Salemi	Retrospe-	Florida Registry	Gastroschisis	Birth	Unspecified	394	117,8147	Adjusted: maternal
et al. ¹⁴⁵	ctive cohort	of Birth Defects		records				age, marital status,
(2009)		(United States)						race, maternal/paternal
								schooling, parity, place
								of birth
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Saxen ¹⁴⁶	Case-	The Finnish	Cleft lip with	Interview	The entire	599	590	Matching: month/year
(1974)	control	registry of	or without cleft		pregnancy			of birth, place of birth
		congenital	palate
		malformations
Schmidt	Case-	National	CNS defects	Phone	Pre-	768	4,143	-
et al. ¹⁴⁷	control	Birth Defects		interview	conception
(2009)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Seidman	Cross-	Hospitals of	Malformations	Interview	The entire	1,296	15,856	-
et al. ¹⁴⁸	sectional	Jerusalem (Israel)			pregnancy
(1990)
Shaw et al.	Case-	California	Cardiovascular	Phone	Pre-	141	176	Adjusted: race,
¹⁴⁹ (1992)	control	Birth Defects	defects	interview	conception			maternal age, maternal/
		Monitoring			exposure and			paternal schooling,
		Program (United			in the first			maternal alcohol intake;
		States)			quarter			Matching: month/year
								of birth, place of birth
Shaw et	Case-	California	Neural tube	Phone	Pre-	538	539	Adjusted:
al. ¹⁵⁰	control	Birth Defects	defects	interview	conception			periconceptional vitamin
(1996)		Monitoring			exposure and			supplementation, race,
		Program (United			in the first			maternal schooling,
		States)			quarter			maternal age, maternal
								alcohol intake
Shaw et	Case-	California	Cleft lip with	Phone	Pre-	728	731	Matching: month/year
al. ¹⁵¹	control	Birth Defects	or without cleft	interview	conception			of birth, place of birth
(1996)		Monitoring	palate		exposure and
		Program (United			in the first
		States)			quarter
Shaw et	Case-	California	Malformations	Phone	Pre-	1,299	734	Matching: month/year
al. ¹⁵²	control	Birth Defects		interview	conception			of birth, place of birth
(1999)		Monitoring			exposure and
		Program (United			in the first
		States)			quarter
Shaw et	Case-	California	Multiple	Phone	Pre-	112	194	Matching: month/year
al. 153	control	Birth Defects	congenital	interview	conception			of birth, place of birth
(2000)		Monitoring	anomalies		exposure and
		Program (United			in the first
		States)			quarter
Shi et al.	Case-	Case-control	Orofacial cleft	Interview	The entire	1,378	1,435	-
¹⁵⁴ (2007)	control	study (United			pregnancy
		States and
		Denmark)
Shiono	Cohort	Kaiser	Major	Interview	Unspecified	592	28,810	Adjusted: maternal age,
et al. ¹⁵⁵		Permanente	malformations					race, maternal alcohol
(1986)		Birth Defects						intake
		Study (United
		States)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Skelly	Case-	Hospitais,	Crooked foot at	Interview	Unspecified	239	356	Adjusted: maternal age,
et al. ¹⁵⁶	control	Washington	birth					race, family history of
(2002)		State (United						birth defects
		States)
Slickers	Case-	National	Renal agenesis or	Interview	Pre-	73	859	-
et al. ¹⁵⁷	control	Birth Defects	hypoplasia		conception
(2008)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Smedts	Case-	HAVEN Study	Congenital heart	Question-	Pre-	276	324	-
et al. ¹⁵⁸	control	(Netherlands)	defects	naire	conception
(2009)					exposure and
					in the first
					quarter
Sorensen	Case-	North Justland,	Hypertrophic	Birth certifi-	Unspecified	78	57,918	-
et al. ¹⁵⁹	control	Denmark	pyloric stenosis	cate data
(2002)
Stein-	Case-	Baltimore-	Heart defects	Interview	Unspecified	48	3,572	Matching: month/year
berger	control	Washington						of birth, place of birth,
et al. ¹⁶⁰		Infant Study						sex
(2002)		(United States)
Stoll et al.	Case-	Strasbourg Study	Anal atresia	Hospital	Unspecified	108	225,644	Matching: sex,
¹⁶¹ (1997)	control	(France)		records				gestational age
Stoll et al.	Case-	Strasbourg Study	Musculoskeletal	Hospital	Unspecified	105	105	Matching: sex,
¹⁶² (2001)	control	(France)		records				gestational age
Suarez	Case-	Texas neural	Neural tube	Interview	Pre-	175	221	Adjusted: maternal age,
et al. ¹⁶³	control	tube defects	defects		conception			schooling, maternal
(2008)		project (United			exposure and			BMI, use of folic acid
		States)			in the first
					quarter
Szendrey	Case-	Hungarian Birth	Esophageal	Interview	Unspecified	160	160	Matching: month/year
et al. ¹⁶⁴	control	Defects Registry	atresia					of birth, place of birth,
(1985)								sex
Tamura	Case-	Study in the	Facial clefts	Interview	Unspecified	74	283	-
et al. ¹⁶⁵	control	Province of Cebu
(2006)		(Philippines)
Targett	Cohort	Maternity of the	Major defects	Interview	Unspecified	122	2,878	-
et al. ¹⁶⁶		Mercy hospital
(1977)		(Australia)
Tata et al.	Case-	Health network	Birth defects	Birth	The entire	3,995	23,156	Matching: month/year
¹⁶⁷ (2008)	control	database (United		records	pregnancy			of birth, place of birth,
		Kingdom)						multiparity
The et	Case-	National	Biliary atresia	Phone	Unspecified	62	4,094	-
al. 168	control	Birth Defects		interview
(2007)		Prevention Study
		(United States)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Tikkanen &	Case-	The Finnish	Cardiovascular	Interview	First quarter	573	1,055	-
Heinonen	control	registry of	defects
¹⁶⁹ (1991)		congenital
		malformations/
		children’s cardiac
		registry (Finland)
To & Tang	Case-	Department of	Birth defects	Prenatal	Pre-	1,678	57,714	-
¹⁷⁰ (1999)	control	Gynecology and		records	conception
		Obstetrics of			exposure until
		a Hong Kong			the second
		hospital (China)			quarter of
					pregnancy
Torfs et	Case-	California	Gastroschisis	Interview	First quarter	110	220	Matching: maternal age
al. ¹⁷¹	control	Birth Defects
(1994)		Monitoring
		Program (United
		States)
Tornquist	Case-	Registry of	Optic nerve	Interview	Beginning of	125	2,109,316	Matching: maternal age,
et al. ¹⁷²	control	visual impaired	hypoplasia		pregnancy			race
(2002)		children
		(Sweden)
Torp-	Cohort	Danish national	Strabismus	Interview	The entire	1,299	95,543	Adjusted: month/year
Pedersen		birth cohort			pregnancy			of birth, social class,
et al. ¹⁷³								maternal age, caffeine
(2010)
Tuohy	Retrospec-	Plunket National	Birth defects	Medical	Unspecified	169	3,759	-
et al. ¹⁷⁴	tive cohort	Child Health		records
(1993)		Study (New
		Zealand)
Under-	Retrospec-	Hospitals of	Major	Hospital	Unspecified	68	16,090	-
wood et	tive cohort	South Carolina	malformations	records
al. ¹⁷⁵		(United States)
(1965)
van den	Case-	Study of cleft	Cleft lip with	Question-	Pre-	181	132	-
Boogaard	control	palate defects	or without cleft	naire	conception
et al. ¹⁷⁶		(Netherlands)	palate		exposure and
(2008)					in the first
					quarter
van den	Case-	Birth records,	General	Medical	Unspecified	3,163	4,323	Adjusted: maternal age,
Eeden	control	Washington	malformations	records				parity. Matching: month/
et al. ¹⁷⁷		State (United						year of birth, sex
(1990)		States)
van Rooij	Case-	Population-	Cleft lip with	Question-	Pre-	113	104	-
et al. ¹⁷⁸	control	based study	or without cleft	naire	conception
(2001)		in Nijimegen	palate		exposure and
		(Netherlands)			in the first
					quarter
van Rooij	Case-	Population-	Malformations	Phone	Unspecified	84	72	-
et al. ¹⁷⁹	control	based study		interview
(2002)		in Nijimegen
		(Netherlands)
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Verkerk	Case-	Dutch	Birth defects	Medical	First quarter	40	2,320	-
et al. ¹⁸⁰	control	obstectrics study		records
(1994)		(Netherlands)
Virtanen	Case-	Central	Cryptorchidism	Interview	Unspecified	125	1,159	Matching: sex
et al. ¹⁸¹	control	University		and medical
(2006)		Hospital of Turku		records
		(Finland)
Wang	Case-	Study in the city	Cleft lip with	Interview	Pre-	586	1,172	-
et al. ¹⁸²	control	of Shenyang	or without cleft		conception
(2009)		(China)	palate		exposure
					and in the
					beginning of
					pregnancy
Wasser-	Case-	California	Limb reduction	Phone	First quarter	178	481	Matching: month/year
man et	control	Birth Defects		interview				of birth, place of birth
al. ¹⁸³		Monitoring
(1996)		Program (United
		States)
Watkins	Case-	Study of birth	Spina bifida;	Interview	Pre-	307	2,755	Matching: month/year
et al. ¹⁸⁴	control	defects in	Anencephaly		conception			of birth, place of birth,
(1996)		Atlanta (United			exposure and			race
		States)			in the first
					quarter
Watkins	Case-	Atlanta Birth	Malformations	Interview	Unspecified	644	330	-
et al. ¹⁸⁵	control	Defects
(2003)		Risk Factor
		Surveillance
		(United States)
Werler	Case-	29 hospitals in	Malformations	Phone	First quarter	332	416	Adjusted: use of
et al. ¹⁸⁶	control	the United States	(Gastroschisis and	interview				vasoconstrictor drugs,
(2003)		and Canada	intestinal atresia)					maternal/paternal
								schooling, family
								income maternal use of
								medication, maternal
								alcohol intake, use
								of illicit drugs by the
								mother, maternal age;
								Matching: month/year
								of birth, place of birth
Werler	Case-	26 cities in the	Hemifacial	Phone	First quarter	230	678	Adjusted: maternal age,
et al. ¹⁸⁷	control	United States	microsomia	interview				maternal schooling,
(2009)		and Canada						family income,
								parity, race, maternal
								use of medication,
								maternal diabetes and
								hypertension
Werler	Case-	National	Transverse limb	Phone	Pre-	367	5,886	-
et al. ¹⁸⁸	control	Birth Defects	reduction	interview	conception
(2009)		Prevention Study			exposure and
		(United States)			in the first
					quarter
Reference	Type of	Site/Source	Type of defect	Exposure (maternal		Case	Controls	Control of confounders
(year)	study	of data		smoking)				(adjustment/
				Data	Stage of			matching)
				collection	pregnancy

Werler	Case-	National	Gastroschisis	Phone	Pre-	514	3,277	Adjusted: maternal age,
et al. ¹⁸⁹	control	Birth Defects		interview	conception			maternal schooling,
(2009)		Prevention Study			exposure and			family income, parity,
		(United States)			in the first			race, maternal use of
					quarter			medication, place of
								birth, maternal BMI,
								maternal alcohol intake,
								folic acid intake, use of
								oral contraceptives
Williams	Case-	Atlanta Birth	Ventricular septal	Phone	Pre-	122	3,029	-
et al. ¹⁴	control	Defects Case-	defects	interview	conception
(2004)		Control Study			exposure and
		(United States)			in the first
					quarter
Wong-	Case-	National	Esophageal	Phone	Pre-	334	4,967	Adjusted: multiparity,
Gibbons	control	Birth Defects	atresia with or	interview	conception			maternal age, race,
et al. ¹⁹⁰		Prevention Study	without tracheoe-		exposure and			maternal/paternal
(2008)		(United States)	sophageal fistula		in the first			schooling, maternal
					quarter			diabetes, infertility
								treatment, maternal
								alcohol intake, duration
								of maternal smoking,
								place of birth
Woods &	Cohort	Data of the	Malformations	Interview	Unspecified	2,066	15,950	Adjusted: maternal age,
Raju ¹⁹¹		TriHealth health						race, maternal diabetes
(2001)		system (United
		States)
Wyszynski	Case-	Birth database	Oral fissures	Database	First quarter	2,029	4,050	Adjusted: maternal age;
& Wu ¹⁹²	control	(United States)						Matching: month/year
(2002)								of birth, place of birth,
								sex, race
Yerush-	Cohort	Child Health and	Malformations	Question-	Unspecified	1,329	11,754	-
almy ¹⁹³		Development		naire
(1971)		Studies (United
		States)
Yerush-	Cohort	Child Health and	Congenital heart	Question-	Unspecified	115	14,616	-
almy ¹⁹⁴		Development	disease	naire
(1973)		Studies (United
		States)
Yuan et	Case-	Kanagawa	Anal atresia	Interview	Unspecified	84	176	Matching: maternal age,
al. ¹⁹⁵	control	Birth Defects						sex, parity, month/year
(1995)		Monitoring						of birth
		Program (Japan)
Zeiger	Case-	Metropolitan	Craniosynos-	Phone	Unspecified	42	182	Adjusted: race, sex;
et al. ¹⁹⁶	control	area of	tosis	interview				Matching: sex
(2002)		Baltimore-
		Washington
		(United States)

Reference (year)	Type of defect	OR	95%CI	Weight (%) *

Adams et al. ¹⁸ (1989)	Conotruncal heart defect	1.13	0.71-1.81	0.35
Akre et al. ¹⁹ (1999)	Cryptorchidism	1.19	1.06-1.33	0.99
Alderman et al. ²⁰ (1991)	Crooked foot at birth	1.92	1.31-2.81	0.46
Alderman et al. ²¹ (1994)	Craniosynostosis	1.70	1.11-2.60	0.40
Ananijevic-Pandey et al. ²² (1992)	General malformations	1.58	0.96-2.60	0.32
Aro et al. ²³ (1983)	Limb reduction	1.30	0.89-1.90	0.46
Bailey et al. ²⁴ (1970)	Birth defects	0.75	0.43-1.32	0.27
Batra et al. ²⁵ (2007)	Ventricular septal defect	0.93	0.83-1.04	0.98
Beard et al. ²⁶ (1984)	Genitourinary defect	1.00	0.50-2.00	0.19
Beaty et al. ²⁷ (2008)	Oral fissures	1.04	0.51-2.12	0.19
Beaty et al. ²⁸ (2001)	Oral fissures	1.77	0.86-3.65	0.18
Bell & Lumley ²⁹ (1989)	Birth defects	0.80	0.44-1.46	0.24
Berkowitz & Lapinski ³⁰ (1996)	Cryptorchidism	1.24	0.59-2.61	0.17
Biggs et al. ³¹ (2002)	Cryptorchidism	1.24	1.11-1.38	1.00
Bille et al. ³² (2007)	Oral fissures	1.50	1.05-2.14	0.50
Bird et al. ⁶ (2009)	Musculoskeletal	1.44	1.04-2.00	0.54
Bitsko et al. ³³ (2007)	Birth defects	1.61	1.00-2.60	0.33
Blatter et al. ³⁴ (1996)	Central nervous system defects	0.95	0.68-1.32	0.54
Botto et al. ³⁵ (2001)	Heart defects	1.11	0.95-1.30	0.90
Bracken et al. ⁷ (1978)	Birth defects	1.09	0.96-1.25	0.95
Brouwers et al. ³⁶ (2007)	Hypospadias	0.90	0.61-1.32	0.45
Brouwers et al. ³⁷ (2010)	Hypospadias	1.50	0.97-2.32	0.39
Browne et al. ³⁸ (2007)	Heart defects	1.16	1.03-1.31	0.98
Carbone et al. ³⁹ (2007)	Cryptorchidism; hypospadias	1.33	0.55-3.18	0.13
Cardy et al. ⁴⁰ (2007)	Congenital equinovarus	1.37	0.72-2.61	0.22
Carmichael et al. ⁴² (2003)	Cardiovascular defects and facial cleft	1.70	1.35-2.14	0.73
Carmichael & Shaw ⁴¹ (2000)	Anencephaly	0.81	0.49-1.33	0.32
Carmichael et al. ⁴⁴ (2008)	Craniosynostosis	1.03	0.80-1.33	0.68
Carmichael et al. ⁴³ (2005)	Hypospadias	1.00	0.76-1.31	0.64
Caton et al. ⁴⁵ (2008)	Hypospadias	0.88	0.72-1.10	0.77
Cedergren et al. ⁸ (2002)	Heart defects	1.19	0.86-1.66	0.54
Chambers et al. ⁴⁶ (2007)	Gastroschisis	1.37	0.63-2.96	0.16
Chevrier et al. ⁴⁷ (2008)	Oral fissures	1.00	0.62-1.61	0.55
Chew et al. ⁴⁸ (1994)	Eye defects	1.27	1.22-1.32	1.10
Christensen et al. ⁹ (1999)	Oral fissures	1.16	0.73-1.83	0.37
Christianson ⁴⁹ (1980)	Anomalies in all systems	1.05	0.96-1.15	1.03
Chung & Myrianthopoulos ⁵⁰ (1975)	Inguinal hernia	1.45	1.25-1.68	0.95
Chung et al. ⁵¹ (2000)	Cleft lip; cleft palate	1.35	1.18-1.54	0.92
Cordier et al. ⁵² (1992)	Major defects	0.80	0.53-1.20	0.42
Correy et al. ⁵³ (1991)	Defects	0.94	0.82-1.08	0.94
Croen et al. ⁵⁴ (2000)	Holoprosencephaly	4.08	1.54-10.80	0.11
Czeizel et al. ⁵⁸ (2004)	Orofacial clefts; Congenital limb defects	1.27	1.11-1.45	0.95
Czeizel et al. ⁵⁷ (1994)	Limb reduction	1.68	1.26-2.24	0.61
Czeizel & Nagy ⁵⁶ (1986)	Cleft lip; cleft palate	1.08	0.86-1.36	0.73
Czeizel & Vitez ⁵⁵ (1981)	Omphalocele	1.14	0.64-2.01	0.26
Costa et al. et al. ⁵⁹ (2006)	Birth defects	1.15	0.73-1.81	0.36
Damgaard et al. ⁶⁰ (2008)	Cryptorchidism	0.88	0.53-1.47	0.31
Davies et al. ⁶¹ (1986)	Cryptorchidism	1.38	0.73-2.61	0.22
De Roo et al. ¹⁰ (2003)	Oral fissures	1.10	0.73-1.66	0.41
Reference (year)	Type of defect	OR	95%CI	Weight (%) *

Dickinson et al. ¹¹ (2008)	Crooked foot at birth	1.39	1.06-1.82	0.65
Draper et al. ⁶² (2008)	Gastroschisis	1.70	1.11-2.61	0.39
Erickson ⁶³ (1991)	General malformations	1.12	1.05-1.20	1.07
Ericson et al. ⁶⁴ (1979)	Central nervous system defects; orofacial clefts	1.88	1.22-2.90	0.39
Evans et al. ⁶⁵ (1979)	All birth defects	0.96	0.88-1.04	1.04
Fredrick et al. ⁶⁶ (1971)	Congenital heart diseases	1.54	1.22-1.95	0.72
Feldkamp et al. ¹² (2008)	Gastroschisis	2.56	1.75-3.75	0.46
Felix et al. ⁶⁷ (2008)	Esophageal atresia; diaphragmatic hernia	0.58	0.30-1.13	0.21
Ferencz et al. ⁶⁸ (2008)	Cardiovascular defects	1.02	0.92-1.13	1.01
Garcia et al. ⁶⁹ (1999)	Birth defects	4.25	1.57-11.50	0.10
Goldbaum et al. ⁷⁰ (1990)	Gastroschisis	2.00	1.05-3.80	0.22
Golding & Butler ⁷¹ (1983)	Anencephaly	1.34	1.12-1.60	0.85
Grewal et al. ⁷² (2008)	Defects	0.81	0.57-1.17	0.49
Haddow et al. ⁷³ (1983)	Gastroschisis	2.10	0.92-4.80	0.14
Hakin & Tielsch ⁷⁴ (1992)	Esotropia; exotropia	1.56	1.15-2.12	0.58
Hearey et al. ⁷⁵ (1984)	Central nervous system defects	4.00	0.64-24.99	0.03
Heinonen ⁷⁶ (1977)	Defects	0.94	0.8-1.054	0.99
Hemminki et al. ⁷⁷ (1981)	Central nervous system defects	1.61	1.27-2.04	0.72
Himmelberger et al. ⁷⁸ (1978)	Defects	1.32	1.14-1.53	0.92
Honein et al. ⁸² (2001)	Defects	1.25	1.13-1.38	1.01
Honein et al. ⁸³ (2007)	Oral fissures	1.20	0.98-1.47	0.79
Honein et al. ⁸⁰ (2000)	Craniosynostosis	1.92	1.01-3.65	0.22
Honein & Rasmussen ⁸¹ (2000)	Crooked foot at birth	1.41	1.10-1.81	0.69
Hoobs et al. ⁷⁹ (2006)	Heart defects	1.72	0.95-3.13	0.25
Hougland et al. ⁸⁴ (2006)	Gastroschisis	2.61	1.49-4.57	0.27
Jensen et al. ⁸⁵ (2007)	Cryptorchidism	1.08	0.84-1.39	0.68
Johansen et al. ⁸⁶ (2009)	Cleft lip; cleft palate	1.52	1.21-1.91	0.74
Jones et al. ⁸⁷ (1998)	Cryptorchidism	1.04	0.85-1.27	0.80
Kallen ⁸⁸ (1999)	Craniosynostosis	1.45	1.12-1.87	0.68
Kallen ⁸⁹ (2000)	Defects	1.03	1.00-1.06	1.11
Kelsey e tal. ⁹⁰ (1978)	Defects	1.09	0.96-1.25	0.70
Khoury et al. ⁹¹ (1989)	Cleft lip; cleft palate	1.48	1.16-1.89	0.43
Krapels et al. ⁹² (2006)	Cleft lip; cleft palate	1.12	0.75-1.67	0.41
Krauss et al. ⁹³ (2003)	Microcephaly	1.90	1.00-3.60	0.22
Kricker et al. ⁹³ (1986)	Limb reduction	1.10	0.67-1.81	0.32
Kuciene & Dulskiene ⁹⁵ (2009)	Heart defects	1.48	0.82-2.67	0.25
Kullander & Kallen ⁹⁶ (1971)	Defects	1.14	0.85-1.52	0.61
Kurahashi et al. ⁹⁷ (2005)	Cryptorchidism	1.04	0.50-2.12	0.19
Kurahashi et al. ⁹⁸ (2005)	Hypospadias	1.04	0.24-4.45	0.05
Lam & Torfs ⁹⁹ (2006)	Gastroschisis	1.96	0.98-3.92	0.20
Leite & Koifman ¹⁰⁰ (2009)	Oral fissures	1.19	0.82-1.75	0.43
Li et al. ¹⁰² (2006)	Neural tube defects	1.44	0.35-5.85	0.05
Li et al. ¹⁰¹ (1996)	Urinary tract defects	2.30	1.18-4.49	0.21
Lie et al. ¹⁰³ (2008)	Oral fissures	1.60	1.15-2.23	0.53
Lieff et al. ¹⁰⁴ (1999)	Defects	1.27	1.10-1.46	0.94
Linn et al. ¹⁰⁵ (1983)	All defects	0.93	0.71-1.21	0.66
Little et al. ¹⁰⁶ (2004)	Oral fissures	2.00	1.29-3.10	0.38
Liu et al. ¹⁰⁷ (2009)	Heart defects	5.13	0.98-26.71	0.04
Lorente et al. ¹⁰⁸ (2000)	Oral fissures	1.42	0.92-2.20	0.39
Lowe ¹⁰⁹ (1959)	All defects	1.30	0.57-2.99	0.14
Lubs ¹¹⁰ (1973)	Major defects	0.75	0.50-1.12	0.43
Reference (year)	Type of defect	OR	95%CI	Weight (%) *

Lumley et al. ¹¹¹ (1985)	All defects	1.04	0.80-1.35	0.67
MacBird et al. ¹¹² (2009)	Omphalocele	1.20	0.79-1.82	0.41
Malik et al. ¹¹³ (2008)	Heart defects	1.22	1.10-1.35	1.01
Malloy et al. ¹¹⁴ (1989)	Defects	0.98	0.94-1.03	1.09
Man & Chang ¹¹⁵ (2006)	Congenital digital anomaly	1.31	1.18-1.45	1.01
Mandiracioglu et al. ¹¹⁶ (2004)	Neural tube defects	1.25	0.50-3.13	0.12
Martinez-Frias et al. ¹¹⁷ (2008)	Gastroschisis	1.81	0.96-3.41	0.23
McBride et al. ¹¹⁸ (1991)	Cryptorchidism	1.69	1.21-2.36	0.53
McDonald et al. ¹¹⁹ (1992)	Birth defects	1.07	0.98-1.17	1.04
McGlynn et al. ¹²⁰ (2006)	Cryptorchidism	1.05	0.87-1.27	0.82
Miller et al. ¹²¹ (2009)	Anorectal atresia	1.15	0.91-1.45	0.73
Miller et al. ¹²² (2010)	Holoprosencephaly	0.90	0.47-1.71	0.22
Mitchell et al. ¹²³ (2001)	Oral fissures	1.21	0.91-1.60	0.62
Morales-Suarez-Varela et al. ¹²⁴	Birth defects	1.10	1.00-1.20	1.03
(2006)
Morgana et al. ¹²⁵ (2008)	Cryptorchidism	0.71	0.46-1.10	0.38
Mori et al. ¹²⁶ (1992)	Cryptorchidism	1.00	0.49-2.05	0.18
Mossey et al. ¹²⁷ (2007)	Oral fissures	2.40	1.59-3.62	0.42
Munoz et al. ¹²⁸ (2006)	Anencephaly	0.65	0.23-1.88	0.09
Mygind et al. ¹²⁹ (2002)	Birth defects	1.19	0.94-1.51	0.72
Niebyl et al. ¹³⁰ (1985)	Cleft lip; cleft palate	0.64	0.30-1.36	0.17
Noorgaard et al. ¹³¹ (2009)	Hypospadias	0.87	0.77-0.99	0.96
Oddsberg et al. ¹³² (2008)	Esophageal atresia	0.89	0.70-1.13	0.71
Ormond et al. ¹³³ (2009)	Hypospadias	1.22	0.85-1.76	0.48
Parikh et al. ¹³⁴ (2002)	Renal agenesis	1.49	0.99-2.25	0.42
Parker et al. ¹³⁵ (2009)	Crooked foot at birth	1.53	1.18-1.99	0.67
Pierik et al. ¹³⁶ (2004)	Cryptorchidism; hypospadias	1.45	0.92-2.29	0.37
Porter et al. ¹³⁷ (2006)	Hypospadias	0.93	0.82-1.05	0.97
Preiksa et al. ¹³⁸ (2006)	Hypospadias	1.58	0.94-2.65	0.31
Queissur-Luft et al. ¹³⁹ (2002)	Major birth defects	1.00	0.83-1.20	0.84
Ramirez et al. ¹³ (2007)	Oral fissures	0.76	0.56-1.03	0.58
Rantakallio ¹⁴⁰ (1978)	All defects	0.86	0.55-1.33	0.38
Reefhuis et al. ¹⁴¹ (1998)	Crooked foot at birth	1.21	1.13-1.29	1.07
Robitaille et al. ¹⁴² (2009)	Limb reduction	1.11	0.89-1.38	0.76
Rodriguez-Pinilla et al. ¹⁴³ (2008)	Hypospadias	0.86	0.77-0.96	1.00
Romitti et al. ¹⁴⁴ (2007)	Cleft lip; cleft palate	1.37	1.20-1.57	0.95
Salemi et al. ¹⁴⁵ (2009)	Gastroschisis	0.97	0.74-1.28	0.64
Saxen ¹⁴⁶ (1974)	Cleft lip; cleft palate	2.32	1.46-3.68	0.36
Schmidt et al. ¹⁴⁷ (2009)	Central nervous system defects	0.90	0.73-1.10	0.80
Seidman et al. ¹⁴⁸ (1990)	Malformations	1.04	0.89-1.21	0.90
Shaw et al. ¹⁴⁹ (1992)	Cardiovascular defects	1.13	0.61-2.09	0.24
Shaw et al. ¹⁵⁰ (1996)	Neural tube defects	0.85	0.61-1.18	0.53
Shaw et al. ¹⁵¹ (1996)	Cleft lip with or without cleft palate	1.55	1.12-2.14	0.55
Shaw et al. ¹⁵² (1999)	Neural tube defects	1.31	1.06-1.62	0.78
Shaw et al. ¹⁵³ (2000)	Multiple defects	0.98	0.48-2.01	0.18
Shi et al. ¹⁵⁴ (2007)	Cleft lip; cleft palate	1.28	1.09-1.51	0.89
Shiono et al. ¹⁵⁵ (1986)	Malformations	0.90	0.83-0.98	1.04
Skelly et al. ¹⁵⁶ (2002)	Crooked foot at birth	2.21	1.51-3.23	0.46
Slickers et al. ¹⁵⁷ (2008)	Renal agenesis or hypoplasia	2.12	1.27-3.51	0.32
Smedts et al. ¹⁵⁸ (2009)	Heart defects	0.81	0.54-1.21	0.43
Sorensen et al. ¹⁵⁹ (2002)	Hypertrophic pyloric stenosis	2.00	1.29-3.10	0.38
Reference (year)	Type of defect	OR	95%CI	Weight (%) *

Steinberger et al. ¹⁶⁰ (2002)	Heart defects	2.49	1.23-5.03	0.19
Stoll et al. ¹⁶¹ (1997)	Musculoskeletal	1.18	0.61-2.26	0.22
Stoll et al. ¹⁶² (2001)	Anal atresia	1.36	0.72-2.56	0.23
Suarez et al. ¹⁶³ (2008)	Neural tube defects	2.65	1.40-5.00	0.22
Szendrey et al. ¹⁶⁴ (1985)	Esophageal atresia	0.82	0.49-1.36	0.31
Tamura et al. ¹⁶⁵ (2006)	Oral fissures	0.84	0.28-2.56	0.08
Targett et al. ¹⁶⁶ (1977)	Major malformations	1.33	0.92-1.92	0.48
Tata et al. ¹⁶⁷ (2008)	Birth defects	0.99	0.92-1.06	1.06
The et al. ¹⁶⁸ (2007)	Biliary atresia	0.70	0.34-1.43	0.19
Tikkanen & Heinonen ¹⁶⁹ (1991)	Cardiovascular defects	1.00	0.78-1.27	0.70
To & Tang ¹⁷⁰ (1999)	Birth defects	1.32	0.94-1.85	0.53
Torfs et al. ¹⁷¹ (1994)	Gastroschisis	1.51	0.93-2.46	0.33
Tornquist et al. ¹⁷² (2002)	Optic nerve hypoplasia	1.61	1.08-2.40	0.43
Torp-Pedersen et al. ¹⁷³ (2010)	Strabismus	1.26	1.11-1.42	0.97
Tuohy et al. ¹⁷⁴ (1993)	Birth defects	1.18	0.85-1.63	0.54
Underwood et al. ¹⁷⁵ (1965)	Major malformations	0.78	0.46-1.33	0.29
van den Boogaard et al. ¹⁷⁶ (2008)	Cleft lip	1.57	0.92-2.67	0.29
van den Eeden et al. ¹⁷⁷ (1990)	General malformations	1.00	0.91-1.10	1.02
van Rooij et al. ¹⁷⁹ (2002)	Spina bifida/facial cleft	1.92	0.90-4.12	0.17
van Rooij et al. ¹⁷⁸ (2001)	Cleft lip; cleft palate	1.12	0.58-2.16	0.21
Verkerk et al. ¹⁸⁰ (1994)	Birth defects	1.12	0.59-2.11	0.22
Virtanen et al. ¹⁸¹ (2006)	Cryptorchidism	0.41	0.23-0.72	0.26
Wang et al. ¹⁸² (2009)	Cleft lip; cleft palate	1.50	0.52-4.34	0.09
Wasserman et al. ¹⁸³ (1996)	Limb reduction	1.14	0.77-1.69	0.44
Watkins et al. ¹⁸⁴ (1996)	Spina bifida; anencephaly	1.09	0.85-1.39	0.69
Watkins et al. ¹⁸⁵ (2003)	Birth defects	1.36	0.96-1.93	0.50
Werler et al. ¹⁸⁷ (2009)	Hemifacial microsomia	1.62	0.86-3.06	0.22
Werler et al. ¹⁸⁹ (2009)	Gastroschisis	1.50	1.18-1.90	0.71
Werler et al. ¹⁸⁶ (2003)	Gastroschisis; intestinal atresia	1.31	0.96-1.78	0.57
Werler et al. ¹⁸⁸ (2009)	Transverse limb reduction	1.10	0.85-1.42	0.68
Williams et al. ¹⁴ (2004)	Ventricular septal defects	1.26	0.86-1.84	0.46
Wong-Gibbons et al. ¹⁹⁰ (2008)	Esophageal atresia; tracheoesophageal fistula	1.68	0.99-2.86	0.29
Woods & Raju ¹⁹¹ (2001)	Birth defects	1.16	1.02-1.32	0.95
Wyszynski & Wu ¹⁹² (2002)	Oral fissures	1.12	0.96-1.30	0.91
Yerushalmy ¹⁹³ (1971)	Birth defects	0.51	0.45-0.58	0.96
Yerushalmy ¹⁹⁴ (1973)	Heart defects	0.90	0.61-1.34	0.45
Yuan et al. ¹⁹⁵ (1995)	Anal atresia	1.32	0.59-2.95	0.15
Zeiger et al. ¹⁹⁶ (2002)	Craniosynostosis	0.75	0.29-1.95	0.11
Meta-analysis		1.18	1.14-1.22	100.00

		OR	95%CI	I² (%) *	Difference among subgroups
1.	Study design				χ² = 21.2; p < 0.00001
	Restrospective studies (n = 159)	1.21	1.17-1.26	69.70
	Prospective studies (n = 29)	1.08	1.01-1.17	90.20
2.	Adjustment/matching according to the age of the mother				χ² = 0.06; p = 0.81
	No (n = 127)	1.19	1.13-1.25	76.50
	Yes (n = 61)	1.18	1.13-1.24	78.80
3.	Sample size (cases)				χ² = 16.5; p = 0.0009
	≤ 200 (n = 81)	1.31	1.20-1.43	49.60
	> 200-1,000 (n = 61)	1.23	1.16-1.31	60.90
	> 1,000-5,000 (n = 40)	1.09	1.03-1.15	89.00
	> 5,000 (n = 6)	1.11	1.01-1.22	91.30

		1-9 cigarettes/day	10-19 cigarettes/day	≥ 20 cigarettes/day	Difference among the
		OR (95%CI)	OR (95%CI)	OR (95%CI)	3 dose groups *

1.	Study design
	Retrospective studies (n = 49)	1.25 (1.18-1.33)	1.31 (1.22-1.39)	1.47 (1.33-1.61)	χ² = 7.95; p = 0.002
	Prospective studies (n = 11)	1.05 (0.98-1.14)	1.19 (0.96-1.48)	1.28 (1.10-1.50)	χ² = 5.63; p = 0.06
2.	Adjustment/matching according to
the age of the mother
	No (n = 32)	1.15 (1.05-1.26)	1.22 (1.12-1.33)	1.34 (1.18-1.53)	χ² = 0.89; p = 0.64
	Yes (n = 28)	1.22 (1.15-1.30)	1.35 (1.24-1.48)	1.49 (1.31-1.68)	χ² = 9.37; p = 0.009
3.	Sample size (cases)
	≤ 200 (n = 14)	1.60 (1.34-1.91)	1.66 (1.09-2.51)	1.76 (1.41-2.21)	χ² = 0.43; p = 0.81
	> 200-1,000 (n = 28)	1.21 (1.10-1.34)	1.39 (1.26-1.54)	1.45 (1.24-1.69)	χ² = 5.42; p = 0.07
	> 1,000-5,000 (n = 14)	1.10 (0.93-1.30)	1.19 (1.09-1.31)	1.42 (1.25-1.61)	χ² = 7.14; p = 0.03
	> 5,000 (n = 4)	1.22 (1.00-1.25)	1.28 (1.17-1.41)	1.20 (0.98-1.46)	χ² = 3.25; p = 0.20

Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz Rua Leopoldo Bulhões, 1480 , 21041-210 Rio de Janeiro RJ Brazil, Tel.:+55 21 2598-2511, Fax: +55 21 2598-2737 / +55 21 2598-2514 - Rio de Janeiro - RJ - Brazil
E-mail: cadernos@ensp.fiocruz.br

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[1] Correspondence L. Zhang Faculdade de Medicina, Universidade Federal do Rio Grande. Rua Visconde de Paranaguá 102, Rio Grande, RS 96200-190, Brasil. zhanglinjie63@yahoo.com.br