Background
Methods
Identification of studies and study selection
Inclusion criteria
Data extraction
Study population | ||||||||
---|---|---|---|---|---|---|---|---|
No. participants | ||||||||
Ref. | First author, year | Country | Cases | Controls | Age range | Setting, control type | Data acquisition (period) | Assessed medical drug(s) |
[28] | Zwink, 2016 | Germany | 158 | 474a | < 18 - ≥30 | population-based, no major birth defects | Data from the German Network for congenital uro-rectal malformations and Malformation Monitoring Centre Saxony-Anhalt of the Otto-von-Guericke University in Magdeburg (2009–2011) | Folic acid, multivitamins |
[52] | Furu, 2015 | Norway | 799 | 2,303,647 | ≤24 - ≥45 | population-based, all births | Data from nationwide Nordic health registers (Denmark, Finland, Iceland, Norway, Sweden) (1996–2010) | Antidepressants (any SSRI, citalopram, sertraline) |
[73] | Garne, 2015 | Denmark | 772 265c | 53,402 | < 25 - ≥40 | population-based, non-chromosomal and chromosol anomalies | Data from the EUROmediCAT registries (1995–2010) | Anti-asthma medication (any asthma medication, inhaled ß2-agonists, inhaled corticosteroids) |
[50] | Wemakor, 2015 | UK | 392 | 2,177,977 | N.A. | registry-based, other congenital malformations | Data from 12 EUROCAT congenital anomalies registries (1995–2009) | Antidepressants (any SSRI, fluoxetine, paroxetine, citalopram, sertraline, escitalopram) |
[53] | Zwink and Choinitzki, 2015 | Germany | 123 | 140 | < 18 - ≥30 | population-based, other congenital malformationsa | Data from the German Network for congenital uro-rectal malformations (2009–2012) and Consortium of Genetic Risk for Esophageal Atresia (2011–2012) | Anti-asthma medication, thyroid hormone supplementations, iron intake, folic acid, multivitamins |
[57] | Gilboa, 2014 | USA | 176 | 4525 | < 20 - ≥35 | population-based, all births | Data from the National Birth Defects Prevention Study (1997–2005) | Vitamin E |
[75] | Källén and Wikner, 2014 | Sweden | 588 | 48,012 | < 20 - ≥45 | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1996–2011) | Thyroxin |
[41] | Wijers, 2014 | The Netherlands | 643b | 714 | < 18 - ≥30 | hospital-based, no major birth defects | Questionnaire (1990–2012) | Folic acid |
[76] | Källén, 2013 | Sweden | 590 | 69,749 | < 20 - ≥45 | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1996–2011) | Opioids, anticonvulsants, neuroleptics other than dixyrazine or prochloperazine, dixyrazine or prochlorperazine, sedatives or hypnotics, antidepressants |
[49] | Pasternak, 2013 | Denmark | 52 | 1,222,503 | N.A. | register-based, all births | Data from the nationwide administrative and health care registries in Denmark (1997–2011) | Metoclopramide |
[54] | Polen, 2013 | USA | 741 | 8002 | < 30 - ≥30 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2007) | Antidepressants, venlafaxine |
[67] | Yau, 2013 | USA | 274 | 7606 | < 25 - ≥34 | population-based, no birth defects | Data from the Slone Epidemiology Center Birth Defects Study (1993–2010) | Decongestants (pseudoephedrine) |
[59] | Lin, 2012 | USA | 285 | 6726 | < 20 - ≥35 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2003) | Anti-asthma medication (bronchodilator use), anti-inflammatory use |
[58] | Hernandez, 2012 | USA | 540 | 5546 | < 20 - ≥35 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2004) | Non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen) |
[60] | van Gelder, 2011 | The Netherlands | 16 | 65,287 | < 20 - ≥40 | population-based, no major birth defects | Data from the Norwegian Mother and Child Cohort Study (1999–2006) | Non-steroidal anti-inflammatory drugs |
[55] | Reefhuis, 2011 | USA | 582 | 6406 | < 25 - ≥40 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2005) | Clomiphene citrate |
[56] | Reis and Källén, 2010 | Sweden | 428 | 1,062,190 | < 20 - ≥45 | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1995–2007) | Antidepressants |
[27] | van Rooij, 2010 | The Netherlands | 85 | 650 | ≥35 | hospital-based, no major birth defects | Questionnaire (cases 1996–2008, controls 1996–2004) | Folic acid, multivitamins |
[61] | Browne, 2009 | USA | 534 | 5875 | 12 - ≥35 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2004) | Anti-thyroid medication |
[63] | Crider, 2009 | USA | 470 | 5008 | < 18–49 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2003) | Antibacterial medication (any antibacterial, penicillins, erythromycins, nitrofurantoins, sulfonamides, cephalosporins) |
[62] | Carter, 2008 | USA | 209 | 4774 | N.A. | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2003) | Antifungal drugs |
[68] | Alwan, 2007 | USA | 418 | 4092 | < 35 - ≥35 | population-based, no birth defects | Data from the National Birth Defects Prevention Study (1997–2002) | Antidepressants |
[42] | Källén and Otterblad Olausson, 2007 | Sweden | 495 | 40,728 | N.A. | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1995–2004) | Anti-asthma medication (ß2-adrenergic agonists, inhaled corticosteroids, anticholinergic drugs, cromoglicic acid, xanthines, leucotrien receptor antagonists) |
[77] | Källén, 2007 | Sweden | 11 | 873,383 | < 20 - ≥45 | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1995–2004) | Folic acid |
[64] | Louik, 2007 | USA | 215 | 5860 | N.A. | population-based, no birth defects | Data from the Slone Epidemiology Center Birth Defects Study (1993–2004) | Antidepressants (any SSRI, fluoxetine, sertraline, paroxetine, citalopram, non-SSRI antidepressant) |
[66] | Czeizel, 2004 | Hungary | 220 | 38,151 | < 25 - > 29 | national-based, no birth defects | Data from the Hungarian Congenital Abnormality Registry (1980–1996) and National Birth Registry of the Central Statistical Office (1996–1992) | Folic acid, multivitamins |
[69] | Czeizel, 2004 | Hungary | 220 | 38,151 | < 25 - > 29 | national-based, no birth defects | Data from the Hungarian Congenital Abnormality Registry (1980–1996) and National Birth Registry of the Central Statistical Office (1996–1992) | Multivitamins |
[6] | Correa, 2003 | USA | 50 | 3029 | < 20 - ≥30 | population-based, no birth defects | Data from the Atlanta Birth Defects Case-Control Study (1968–1980) | Multivitamins |
[65] | Czeizel, 2003 | Hungary | 220 | 38,151 | < 25 - > 29 | national-based, no birth defects | Data from the Hungarian Congenital Abnormality Registry (1980–1996) and National Birth Registry of the Central Statistical Office (1996–1992) | Diazepam |
[78] | Källén and Mottet, 2003 | Sweden | 8 | 504,660 | < 19–45 | population-based, all births | Data from the nationwide Swedish Medical Birth Register (1995–2001) | Meclozine |
[43] | Bonnot, 2001 | France | 6 | 13,703 | N.A. | population-based, all births | Data from the French Central-East Registry of congenital malformations (1976–1998) | Lorazepam |
[70] | Czeizel, 2001 | Hungary | 220 | 38,151 | < 25 - > 29 | national-based, no birth defects | Data from the Hungarian Congenital Abnormality Registry (1980–1996) and National Birth Registry of the Central Statistical Office (1996–1992) | Cephalosporin (cephalexin, cefuroxime) |
[51] | Myers, 2001 | USA | 50 | 222,264 | N.A. | provinces-based, all births | Data from a public health campaign conducted in China (1993–1995) | Folic acid |
[71] | Czeizel, 2000 | Hungary | 220 | 38,151 | < 25 - > 29 | national-based, no birth defects | Data from the Hungarian Congenital Abnormality Registry (1980–1996) and National Birth Registry of the Central Statistical Office (1996–1992) | Acetylsalicylic acid |
[72] | Stoll, 1997 | France | 108, 51
c
| 108 | F: mean age 26.9, M: mean age 29.9 | hospital-based, no birth defects | Interview (1979–1995) | Antibiotics, antispasmodics, estrogens and other miscellaneous medication |
[74] | Angerpointer, 1981 | Germany | 78 78 78 78 | 210d 169e 75f 53g | < 20 - > 40 | hospital-based, other malformed infants | Questionnaire (1970–1974) | Antiemetic, analgetic, laxative and antihypotensive drugs, and iron preparations |
[79] | Heinonen, 1977 | USA | 13 | N.A. | N.A. | population-based, no controls | Data from the Collaborative Perinatal Project (1958–1965) | Aspirin |
Meta-analyses
Results
Literature search result
Studies included in this review
Findings for the reviewed risk factors
Maternal use of dietary supplements | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[28] | Zwink, 2016 | Folic acid | 1.2 [0.54, 2.48] | 1.0 [0.29, 3.40] | Adjusted for gender and birth year of the child, maternal age and BMI |
Multivitamins | 0.5 [0.11, 2.46] | 1.2 [0.21, 7.00] | |||
[53] | Zwink and Choinitzki, 2015 | Folic acid | 0.9 [0.49, 1.55]b | – | – |
0.8 [0.39, 1.83]c | – | ||||
0.9 [0.57, 1.50]a,d | – | ||||
Iron | 0.9 [0.43, 2.05]b | – | |||
2.4 [0.62, 10.72]c | – | ||||
Multivitamins | 1.8 [0.61, 5.60]b | – | |||
0.5 [0.18, 1.46]c | – | ||||
1.1 [0.48, 2.36]a,d | – | ||||
[57] | Gilboa, 2014 | Vitamin E | – | 1.1 [0.65, 1.74]g | Adjusted for study center and maternal total energy intake, folate intake (dietary folate equivalents), race/ethnicity, age, education, pre-pregnancy body mass index, smoking, alcohol use and use of folic acid supplements |
1.7 [1.01, 2.72]h | |||||
1.5 [0.88, 2.51]i | |||||
[41] | Wijers, 2014 | Folic acid | – | 1.1 [0.8, 1.4]j | Adjusted for maternal education |
– | 1.0 [0.7, 1.5]k | ||||
– | 1.1 [0.7, 1.6]l | ||||
[27] | van Rooij, 2010 | Folic acid | 1.0 [0.6, 1.7] | – | – |
Multivitamins | 1.6 [1.0, 2.7] | – | |||
[77] | Källén, 2007 | Folic acid | 0.9 [0.51, 1.69]a | 1.0 [0.55, 1.84] | Year of birth, maternal age, parity, maternal smoking, and number of previous miscarriages |
[66] | Czeizel, 2004 | Folic acid | 0.5 [0.17, 1.23]e | – | – |
0.4 [0.17, 0.88]f | – | ||||
Multivitamins | 0.2 [0.02, 1.69] | – | |||
[69] | Czeizel, 2004 | Multivitamins | 0.3 [0.01, 2.35] | – | – |
[6] | Correa, 2003 | Multivitamins | 0.9 [0.45, 1.67] | – | – |
[51] | Myers, 2001 | Folic acid | 0.5 [0.29, 0.88]m,n | 0.6 [0.33, 1.07]m,n | Maternal age |
0.5 [0.24, 1.04]m,o | 0.7 [0.31, 1.42]m,o | ||||
0.9 [0.28, 2.96]m,p | 0.9 [0.27, 3.06]m,p | ||||
0.3 [0.05, 1.24]m,q | 0.3 [0.05, 1.38]m,q |
Maternal use of asthma medication | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[73] | Garne, 2015 | Any anti-asthma medication | – | 1.6 [1.08, 2.51]b | Registry and maternal age |
– | 2.0 [1.30, 3.20]c | ||||
Beta-2-agonists in general | – | 1.5 [0.84, 2.66]b | Center, maternal age and use of inhaled corticosteroids | ||
– | 1.5 [0.79, 2.93]c | ||||
Inhaled beta-2-agonists | 1.7 [1.08, 2.80] | 1.5 [0.85, 2.68]b | Center, maternal age and use of corticosteroids | ||
2.3 [1.39, 3.75] | 1.8 [0.92, 3.44]c | ||||
– | 1.8 [1.11, 2.87]b | Center, maternal age | |||
– | 2.1 [1.26, 3.54]c | ||||
– | 1.5 [0.85, 2.69]b | Center, maternal age, systemic steroids and use of corticosteroids | |||
– | 1.5 [0.79, 2.94]c | ||||
– | 1.5 [0.83, 2.63]b | Center, maternal age, period (5-year intervals) and use of corticosteroids | |||
– | 1.8 [0.92, 3.45]c | ||||
– | 1.2 [0.35, 3.73]b,f | Center, maternal age, period (5-year intervals) and use of corticosteroids | |||
– | 0.8 [0.23, 2.76]c,f | ||||
Inhaled corticosteroids | 2.0 [1.10, 3.51] | 1.5 [0.74, 3.02]b | Center, maternal age and use of beta-2-agonists | ||
3.3 [1.81, 5.98] | 1.7 [0.73, 3.77]c | ||||
– | 2.0 [1.09, 3.48]b | Center, maternal age | |||
– | 2.8 [1.48, 5.17]c | ||||
– | 1.5 [0.74, 3.03]b | Center, maternal age, systemic steroids and use of beta-2-agonists | |||
– | 2.1 [0.94, 4.51]c | ||||
– | 1.5 [0.75, 3.07]b | Center, maternal age, period (5-year intervals) and use of beta-2-agonists | |||
– | 1.6 [0.72, 3.73]c | ||||
– | 1.2 [0.31, 4.68]b,f | Center, maternal age, period (5-year intervals) and use of beta-2-agonists | |||
– | 2.7 [0.78, 9.58]c,f | ||||
1.3 [0.41, 4.06]a,b,f | – | ||||
Combination treatments | – | 1.0 [0.31, 3.24]
b
| Center, maternal age and use of short-acting beta-2-agonists | ||
– | 1.4 [0.43, 4.28]c | ||||
Salbutamol | – | 1.6 [0.87, 2.88]b | Center, maternal age and use of inhaled corticosteroids | ||
– | 1.5 [0.78, 3.04]c | ||||
[53] | Zwink and Choinitzki, 2015 | Any anti-asthma medication | 0.8 [0.02, 29.50]d | – | – |
0.3 [0.01, 16.63]e | |||||
[67] | Yau, 2013 | Pseudoephedrine | – | 1.3 [0.8, 2.3] | Matched and adjusted for further factors (not specified) |
[59] | Lin, 2012 | Anti-inflammatory use | – | 2.1 [1.09, 4.12] | Age, parity, race/ethnicity, education, alcohol use, smoking, gender, folic acid use, fever in first trimester |
Bronchodilator use | – | 0.9 [0.38, 2.01] | |||
[42] | Källén and Otterblad Olausson, 2007 | Any anti-asthma medication | – | 1.7 [1.11, 2.56] | Year of birth, maternal age, parity, smoking, and number of previous miscarriages |
Inhaled corticosteroids | – | 1.9 [1.00, 3.22] | |||
Salbutamol | – | 1.5 [0.50, 3.60g | |||
Terbutaline | – | 1.5 [0.82, 2.52]g | |||
Salmeterol | – | 2.5 [0.52, 7.37]g | |||
Budesonide | – | 1.9 [0.95, 3.42]g |
Maternal use of thyroid medication | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[53] | Zwink and Choinitzki, 2015 | Thyroid hormone supplementations | 1.0 [0.25, 3.74]b | – | – |
0.4 [0.10, 1.54]c | |||||
[75] | Källén and Wikner, 2014 | Thyroxin | 1.9 [1.00, 1.85]a | – | – |
[61] | Browne, 2009 | Anti-thyroid medication | 8.6 [1.7, 40.2] | – | – |
Maternal use of psychiatric drugs | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[52] | Furu, 2015 | Any SSRI | 1.5 [0.95, 2.37] | 1.4 [0.88, 2.32] | Maternal age, year of birth, birth order, smoking, maternal diabetes, and country, and use of other prescribed drugs (antiepileptics, anxiolytics and hypnotics, and angiotensin converting enzyme inhibitors) |
Sertraline | 2.8 [1.33, 5.92] | 2.5 [1.09, 5.57] | |||
Citalopram | 1.6 [0.70, 3.48] | 1.5 [0.64, 3.25] | |||
[50] | Wemakor, 2015 | Any SSRI | – | 2.5 [1.06, 5.68] | Registry |
Fluoxetine | – | 2.6 [0.60, 10.91] | |||
Paroxetine | – | 2.8 [0.66, 11.96] | |||
Citalopram | – | 2.2 [0.29, 16.63] | |||
Sertraline | – | – | |||
Escitalopram | – | 6.0 [0.73, 49.62] | |||
[76] | Källén, 2013 | Opioids | – | – | – |
Anticonvulsants | 2.9 [0.96, 6.86]a | – | |||
Neurolepticsb | – | – | |||
Dixyrazine or prochlorperazine | – | – | |||
Sedatives or hypnotics | 1.2 [0.33, 3.06]a | – | |||
Antidepressants | 1.2 [0.66, 2.10] | – | |||
[54] | Polen, 2013 | Antidepressantsc | – | – | – |
Venlafaxinec | – | – | |||
[56] | Reis and Källén, 2010 | Antidepressants | 1.1 [0.40, 2.36]a | – | – |
[68] | Alwan, 2007 | Any SSRI | 1.0 [0.4, 2.0] | 0.7 [0.3, 1.8] | Maternal race or ethnic group, presence or absence of maternal obesity, presence or absence of maternal smoking, and family income |
[64] | Louik, 2007 | Any SSRI | – | 1.9 [0.8, 4.3] | Maternal age, maternal race or ethnic group (self-reported), maternal education, year of last menstrual period/study center (a composite variable), parity, first-trimester smoking status, first-trimester alcohol consumption, any family history of a birth defect, history of a cardiac defect in a first-degree relative, prepregnancy body-mass index, seizures, diabetes mellitus, hypertension, infertility, any use of folic acid, and first-trimester use of folic acid |
Fluoxetine | – | 1.4 [0.3, 6.1] | |||
Paroxetine | – | 1.0 [0.1, 7.8] | |||
Citalopram | – | 3.0 [0.3, 28.2] | |||
Sertraline | – | 4.4 [1.2, 16.4] | |||
Non-SSRI antidepressant | – | 2.2 [0.6, 7.8] | |||
[65] | Czeizel, 2003 | Diazepam in entire pregnancy Diazepam in second-third months of gestation | 2.2 [1.2, 3.9] | 1.9 [1.1, 3.3] | – |
10.0 [1.3, 78.1] | 5.2 [1.4, 19.7] | ||||
[43] | Bonnot, 2001 | Lorazepam | – | 6.2 [2.44, 15.74] | Maternal age and parity |
Maternal use of painkiller | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[58] | Hernandez, 2012 | Aspirin | 1.3 [0.79, 2.03] | – | – |
Ibuprofen Naproxen | 1.1 [0.89, 1.42] | – | |||
1.3 [0.84, 2.01] | – | ||||
[60] | van Gelder, 2011 | Non-steroidal anti-inflammatory drugs | 1.4 [0.2, 10.7] | – | – |
[71] | Czeizel, 2000 | Acetylsalicylic acid | – | 2.3 [0.9, 5.6]b | Adjusted for maternal age, birth order, acute and chronic maternal disorders and other drug use |
1.2 [0.7, 2.8]c | |||||
1.3 [0.5, 3.9]d | |||||
[79] | Heinonen, 1977 | Aspirina | – | – | – |
Maternal use of anti-infectives | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[63] | Crider, 2009 | Any antibacterial medication use | – | 1.0 [0.7, 1.3] | Maternal age, race, education, prepregnancy BMI, time from the estimated date of delivery to the interview, use of folic acid or multivitamins, and any periconceptional smoking or alcohol use |
Penicillins | – | 0.8 [0.5, 1.2] | |||
Erythromycins | – | 1.0 [0.4, 2.1] | |||
Nitrofurantoins | – | 1.1 [0.4, 3.0] | |||
Sulfonamides | – | 1.0 [0.4, 2.9] | |||
Cephalosporins | – | 1.6 [0.7, 3.5] | |||
[62] | Carter, 2008 | Antifungal drugs | – | 1.4 [0.66, 3.06] | Pregnancy BMI, maternal education |
[70] | Czeizel, 2001 | Cephalexin | 0.7 [0.1, 3.4] | – | – |
Cefuroxime | 1.0 [0.0, 51.9] | ||||
[72] | Stoll, 1997 | Antibiotics | 0.6 [0.23, 1.47] | – | – |
Maternal use of drugs against nausea and vomiting | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[49] | Pasternak, 2013 | Metoclopramide | 0.7 [0.34, 1.54]c | 0.8 [0.36, 1.66]b | Matched and adjusted for hospitalization for hyperemesis gravidarum or nausea and vomiting, and use of other antiemetics in the first trimester |
[78] | Källén and Mottet, 2003 | Meclozine | 2.3 [0.99, 4.50]a | – | – |
Maternal use of sexual hormones | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[55] | Reefhuis, 2011 | Clomiphene citrate | 1.2 [0.6, 2.3] | 1.2 [0.6, 2.3] | Maternal age, maternal race, parity, previous miscarriages, maternal education, smoking, alcohol use, obesity, and folic acid use |
[72] | Stoll, 1997 | Estrogens | 0.1 [0.03, 0.63] | – | – |
Maternal use of other medical drugs | |||||
---|---|---|---|---|---|
Ref. | First author, year | Exposure | ORcrude [95% CI] | ORadj [95% CI] | Adjustment/matching factors |
[72] | Stoll, 1997 | All assessed medicationsc | 0.04 [0.004, 0.32]a | – | – |
0.03 [0.003, 0.27]b | |||||
Antispasmodics Other miscellaneous medication | 0.4 [0.16, 1.18] | ||||
0.5 [0.19, 1.32] | |||||
[74] | Angerpointer, 1981 | All assessed medicationsd | 0.7 [0.38, 1.43] | – | – |