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Table. Characteristics and Results of Studies Included for Key Questions 1 and 2

Study, Year (Reference) Design and Methods Participants Interventions
Czeizel et al, 20044 Cohort Hungary, 1 May 1993 to 30 April 1996. Supplementation group: 3056 offspring of women considering pregnancy, recruited from Hungarian Periconceptional Service. Originally created for the RCT of folate and NTD. Exclusions: unable to receive multivitamins (7), declined multivitamins (186), had induced abortion (15), had ectopic pregnancy (15), had early miscarriage (488), did not take supplement (147), outcomes could not be clarified (54), had late abortion (4), were lost to follow-up (9). Nonsupplementation group: 3056 women who had not received supplements, recruited in their 8th-12th gestational week from regional antenatal care clinics. Matched to supplementation group by age, quality of schools, employment status, and residence. Multivitamin tablets, containing 0.8 mg of folic acid, 1 month before planned conception and supplied every third month for up to 12 months. Nonsupplementation group received routine care.
Goh et al, 20067 Meta-analysis. Searched up to July 2005 in MEDLINE®, PubMed, EMBASE, Toxline, HealthSTAR, and Cochrane Central Register of Controlled Trials in all languages, using the search terms multivitamin, pregnancy, and malformation. Reviewed reference lists of all collected articles for potential studies. Two reviewers assessed articles for possible inclusion. 41 studies eligible on the basis of inclusion criteria: 27 case-control studies, 4 RCTs, and 10 cohort studies. Inclusion criteria: RCT, case-control, or cohort study; reported pre- and periconceptional multivitamin intake; had a control group; and reported raw data of rates of congenital malformation outcomes. Exclusion criteria: studies on specific vitamins; exposure to known teratogens; or review article, letter, or abstract. Multivitamin use before or in first trimester of pregnancy.
Shaw et al, 19955 Study Pregnant women and their offspring in California counties (except Los Angeles, Riverside, and Ventura counties). NTD cases: 538 diagnosed prenatally and electively aborted from February 1989-January 1991 or born from June 1989-May 1991, ascertained from all hospitals and genetic clinics. Control participants: 539 births without major structural malformations from June 1989-May 1991, selected in proportion to hospital's contribution to total births. Exclusions: not English- or Spanish-speaking (29 case patients, 32 control participants), previous NTD (11 case patients and 1 control participant), and interview data not available (75 case patients, 72 control participants), of 665 case patients and 644 control participants who were originally eligible. Case-patient mothers were more likely to be Hispanic and <25 years of age and have completed fewer years of school. Folic acid from supplements or multivitamins in the 3 months before and the 3 months after conception. Amount of folic acid was estimated from personal interview on type, brand, and frequency of use.
Thompson et al, 20036 Study that explored multivitamin folic acid use, dietary folate intake, and risk for NTDs Pregnant women residing in South Carolina who gave birth between October 1992 and September 1997. Investigators obtained 170 cases by monitoring amniocentesis programs, perinatal centers, all medical practitioners providing care to pregnant women, medical records from hospitals with delivery or newborn units, and vital records. Investigators randomly selected 269 control participants from hospital, in proportion to the hospital's estimated contribution to the total population of infants born, concurrently with case patients. Case patients and control participants were similar with respect to age, education, gravidity, month that prenatal care began, previous NTD, body mass index, smoking, alcohol use, drug use, chronic conditions, and multivitamin use. A higher proportion of case patients were white (79.3% vs. 69.1%) and reported having been exposed to environmental tobacco smoke (51.4% vs. 26.1%). Average daily folic acid supplement intake in periconceptional period (3 months before and 3 months after conception) was assessed by maternal interview conducted within 2 weeks of discharge (live baby born to control participant or baby with NTD) or 4 weeks of termination; 77% of women with NTD-affected pregnancies and 86% of control participants were interviewed within 6 months of delivery (means not given).
Vollset et al, 20058 Retrospective cohort All women giving birth in Norway between December 1998 and December 2001 (n = 176 042). Information on IVF obtained from Norway registry and by contacting fertility clinics in Denmark and Sweden. Folic acid tablets containing either 0.2 mg or 0.4 mg; multivitamins containing 0-0.2 mg of folic acid per tablet. Folic acid use assessed by birth attendant, who checked off use of multivitamin or folic acid before or during pregnancy. Preconceptional folate use in 6% (24% among IVF pregnancies).


Table. Characteristics and Results of Studies Included for Key Questions 1 and 2 (continued)

Study, Year (Reference) Outcomes Results Notes
Czeizel et al, 20044 NTDs, abnormalities of urinary tract, cardiovascular, and orofacial clefts NTDs: 1 NTD in supplementation group and 9 NTDs in nonsupplementation group; adjusted OR, 0.11 (CI, 0.01-0.91)

Urinary tract congenital abnormalities: adjusted OR, 0.71 (CI, 0.33-1.50)

Cardiovascular congenital abnormalities: adjusted OR, 0.60 (CI, 0.38-0.96)

Orofacial clefts: adjusted OR, 1.63 (CI, 0.31-28.8)

All ORs adjusted for birth order, chronic maternal disorder, and history of previous fetal death or congenital abnormalities
Fair quality: adherence was assessed for supplementation group by personal interview at 4 separate visits, "tick-off" form for basal body temperature before conception, and counting unused tablets; measurement of exposure to supplements differed in the 2 groups; potential self-selection; no adjustment for important potential confounders.
Goh et al, 20067 Congenital malformations, including NTDs, associated with multivitamin use before and in first trimester of pregnancy NTD: OR in case-control studies, 0.67 (CI, 0.58-0.77); OR in RCTs and cohorts studies, 0.52 (CI, 0.39-0.69)

Cleft palate: OR in case-control studies, 0.76 (CI, 0.62-0.93); OR in RCTs and cohort studies, 0.42 (CI, 0.06-2.84)

Urinary tract anomalies: OR in case-control studies, 0.48 (CI, 0.30-0.76); OR in RCTs and cohort studies, 0.68 (CI, 0.35-1.31)

Cardiovascular defects: OR in case-control studies, 0.78 (CI, 0.67-0.92); OR in RCTs and cohort studies, 0.61 (CI, 0.40-0.92)

Limb defects: OR in case-control studies, 0.48 (CI, 0.30-0.76); OR in RCTs and cohort studies, 0.57 (CI, 0.38-0.85)

Congenital hydrocephalus: OR in case-control studies, 0.37 (CI, 0.24-0.56); OR in RCTs and cohort studies, 1.54 (CI, 0.53-4.50)
Fair quality: searched multiple databases and reference lists but did not include experts, no standard appraisal of included studies explicitly stated, studies on folate-only supplementation were excluded, included several studies published before 1995 or performed in special populations.
Shaw et al, 19955 Risk for NTDs associated with folic acid-containing supplement NTD risk and any use of folic acid in 3 months before conception: OR, 0.65 (CI, 0.45-0.94)

Any use of folic acid in 3 months after conception: OR, 0.60 (CI, 0.46-0.79)
Good quality: accurate ascertainment of cases; selection of case patients and control participants seems nonbiased, with exclusion criteria applied equally to both; response rates >80%; exposure measurement applied equally to each group; attention to appropriate covariates and confounding variables.
Thompson et al, 20036 Risk for NTDs associated with folic acid-containing supplement Regular use (3 times/week): 16 case patients and 43 control participants; adjusted OR, 0.55 (CI, 0.25-1.22)

Some use: 123 case patients and 188 control participants; adjusted OR, 0.92 (CI, 0.55-1.55)

No use: 40 case patients and 57 control participants (reference)

Adjusted for age, race, body mass index, environmental tobacco smoke exposure, and dietary folate
Fair quality: potential for selection bias (25 of 71 women with NTD pregnancies chose not to participate, but participation rate in the NTD group was similar to that of the control group); measurement of exposure assessed by interview at different times for case patients with terminated pregnancies versus control participants or patients who had babies with NTDs; small sample size; few received multivitamins regularly in 6 months periconceptionally.
Vollset et al, 20058 Risk for twin gestation after preconceptional folate use OR, 1.59 (CI, 1.41-1.78)

OR in subset of women who did not report IVF, 1.13 (CI, 0.97-1.33) after adjustment for the underreporting (12.7% unidentified IVF; 45% unidentified folate use)

OR for twin delivery, 1.02 (CI, 0.85-1.24), adjusted for age and parity
Fair quality: exposure measured at delivery, possible recall and potential differential recall problems for twin gestations compared with singletons, authors modeled for underreporting of folate use and unidentified IVF pregnancies.

Abbreviations: IVF = in vitro fertilization; NTD = neural tube defect; OR = odds ratio; RCT = randomized, controlled trial.

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