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BIRTH DEFECT RISK FACTOR SERIES: Craniosynostosis

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Introduction

Definition

Craniosynostosis is premature closure of any of the cranial sutures. That is, the bones of the fetal skull fuse together before delivery. This syndrome can affect one suture or multiple sutures (sagittal, metopic, coronal, or lambdoid), and often results in an abnormally shaped head [1].

Craniosynostosis cases are categorized in several ways. Cases involving one suture are classified as simple; multiple suture cases are classified as complex [2]. Unlike secondary craniosynostosis, which results from disorders like hyperthyroidism and brain growth anomalies, primary craniosynostosis is not secondary to other underlying problems [2, 3]. Studies frequently distinguish between nonsyndromic (isolated) craniosynostosis, which occurs without other major defects, and syndromic craniosynostosis, which may have multiple associated defects, particularly of the limbs and face [2, 4]. Nonsyndromic cases account for about 85% of all craniosynostoses.

Craniosynostosis is associated with more than 180 syndromes [2]. Some of the more common ones include Crouzon syndrome, Muenke syndrome, Apert syndrome (Acrocephalosyndactyly Type I), Carpenter syndrome (Acrocephalosyndactyly Type II), Saethre-Chotzen syndrome (Acrocephalosyndactyly Type III), and Pfeiffer syndrome (Acrocephalosyndactyly Type IV).  Because many of these syndromes have known genetic causes, many studies focus on elucidating risk factors for nonsyndromic cases of craniosynostosis.

About one half of children with nonsyndromic craniosynostosis demonstrate speech, cognitive, or behavioral abnormalities [5]. Syndromic craniosynostosis may be associated with more severe deficits [2, 6].

Prevalence

The birth prevalence in Texas for 1999-2008 deliveries was 4.53 cases per 10,000 live births [7]. Birth prevalence in the United States for craniosynostosis is not currently known.

Many craniosynostosis studies report that sagittal synostosis is most common [1, 8-16]. The lambdoid suture is rarely affected [9-14]. A few studies have reported a larger proportion of lambdoidal craniosynostosis cases than expected [1, 15, 17], but this has been found to be due to regional differences in case ascertainment [15, 18].

Genetic Factors

Although the etiology for most nonsyndromic craniosynostoses is unknown, many syndromic cases are caused by single-gene mutations or chromosomal abnormalities [2, 19]. Mutations in fibroblast growth factor receptor (FGFR) and TWIST1 genes are responsible for common forms of syndromic craniosynostosis [2]. FGFR2 mutations can cause Apert, Crouzon, Jackson-Weiss, and Beare-Stevenson syndromes. Pfeiffer syndrome results from mutations in FGFR1 or FGFR2, and a specific mutation in FGFR3 (P250R) causes Muenke syndrome. Mutations in TWIST1 cause most cases of Saethre-Chotzen syndrome. FGFRs 1-3 and TWIST1 are involved in bone and tissue formation in the head and limbs during embryonic development [20]. Other syndromic forms of craniosynostosis have been linked to mutations in EFNB1 (craniofrontonasal dysplasia), RAB23 (Carpenter syndrome), RECQL4 (Baller-Gerold syndrome), POR (Antley-Bixler syndrome) and MSX2 (Boston-type craniosynostosis) [2]. Genetically identical mutations may result in a wide variety of phenotypes.

Autosomal dominant inheritance with variable expression is seen with most common syndromic forms of craniosynostosis. A small percentage of nonsyndromic craniosynostoses have been found to be inherited, especially those with coronal suture involvement [21, 22]. Because genetic mutations are found more frequently in cases of coronal synostosis, genetic testing is suggested for syndromic craniosynostosis cases and nonsyndromic coronal synostosis cases [2, 19, 23].

Demographic and Reproductive Factors

Trends

Craniofacial centers in Europe and the United States have reported recent increases in metopic synostosis [10, 14, 16, 24], although one population-based study did not share this finding [8]. Although changes in lambdoidal craniosynostosis prevalence have also been reported [8, 15], these trends warrant careful interpretation because acquired plagiocephaly is easily misdiagnosed as lambdoidal craniosynostosis [25]. 

Ethnicity

No clear association has been seen between ethnicity and craniosynostosis risk. Non-Hispanic white maternal ethnicity has been associated with an increased risk for having a child with craniosynostosis [1, 9, 12, 13]. Studies have also found a lower risk for black or non-white mothers [8, 26]. However, one investigation found no significant effect of ethnicity on craniosynostosis risk [15]. Foreign-born Hispanic mothers may have a decreased risk of having a child with craniosynostosis compared to Hispanic mothers born in the United States [27]; however, this association may be limited to recent immigrants [28].

Parental Age

Craniosynostosis risk appears to increase with increasing maternal age [8, 9, 12, 26, 29, 30]; however, some studies did not find a significant relationship between maternal age and craniosynostosis risk [1, 15]. The relationship between father’s age and craniosynostosis risk is less clear. One study identified older age of the father as a risk factor [15], but other studies did not [26, 31]. Increased age of the father has been linked to some craniosynostosis syndromes [32, 33].

The risk of craniosynostosis associated with parental age may vary by the suture involved. For example, two studies found older maternal or paternal age to be a risk factor for coronal synostosis [22, 34]. Other studies found no association between increased parental age and sagittal or metopic synostosis [35-37]; however, one study contradicts these findings [8].

Parental Education

Studies of parental education have yielded inconsistent results. A higher level of maternal education has been linked to craniosynostosis [9, 12], but other studies have not found an association between maternal or paternal education and the risk of craniosynostosis [1, 26, 34].

Infant Sex

Most studies have reported higher craniosynostosis rates or ratios among male infants, particularly for sagittal and metopic synostosis [1, 8, 11-15, 24, 26, 34-39]. Coronal craniosynostosis seems to be more common in female infants [8, 11, 14, 22]; however, not all studies have observed this association [15, 34].

Fetal Constraint-Related Factors

It has been hypothesized that some cases of craniosynostosis may be related to fetal head constraint in the womb [13, 40, 41]. Possible constraint-related factors like gestational age, birth weight, parity, plurality, and certain obstetric factors have been studied for associations with craniosynostosis risk.

Gestational age as a risk factor for craniosynostosis has mixed results. Some studies have found an increased risk of craniosynostosis associated with preterm birth [12, 13, 15], but others have not found gestational age to be a risk factor [8, 26]. Both high and low infant birth weights have been associated with increased risk of craniosynostosis [8, 12, 13, 26], although in one study birth weight was no longer a significant risk factor after consideration of gestational age in the analysis [15]. Craniosynostosis risk related to birth weight varies by the suture involved, although not consistently [8, 13, 15, 36, 37].

Several studies have not found parity to be a risk factor overall for craniosynostosis [8, 9, 13, 26]. Other studies have reported associations between parity and craniosynostosis risk that have been inconsistent [13, 30, 34]. Evaluation of the impact of plurality on craniosynostosis risk has produced mixed results, with some studies reporting increased risk of the defect for multiple births [8, 9, 12, 26] while others found no association [1, 13, 15, 42]. Gravidity and previous pregnancy termination have not been found to be risk factors [1, 12, 26].

Certain obstetric factors, like birth presentation, may be linked with increased craniosynostosis risk [15]. Delivery method has not been linked to craniosynostosis risk [15].

Factors In Lifestyle or Environment

Parental Occupation

Occupation of the father in the agriculture and forestry or mechanics and repairman fields has been suggested as a risk factor for craniosynostosis [43]. While one study found an increased risk of having a child with craniosynostosis for women employed as administrative support personnel [44], another found no association of maternal occupation with craniosynostosis risk [43]. Maternal or paternal military service since 1990 does not appear to be a risk factor for craniosynostosis [45].  

Place of Residence

Place of residence has not been found to affect craniosynostosis risk, except for a decreased risk for lambdoid synostosis in rural areas [15, 26]. Overall, altitude exposure has not been associated with an increased risk of craniosynostosis [26, 42]. However, mothers who live or work at high altitudes and smoke may have an increased risk for having a child with craniosynostosis, especially for coronal and metopic synostosis [42].

Maternal Health

Mothers who are overweight may be at an increased risk for delivering a child with isolated craniosynostosis [46], but another study failed to confirm this finding [47]. Although maternal pre-gestational diabetes mellitus has not been found to be a risk factor for craniosynostosis, gestational diabetes mellitus may confer an increased risk for having a child with craniosynostosis and multiple additional defects [48]. Maternal thyroid disease has been reported as a risk factor for craniosynostosis [12]. No associations have been found for maternal genital tract infections or dietary glycemic intake and craniosynostosis risk [49, 50].

Smoking

Studies have found that maternal smoking is associated with an increased risk of infant craniosynostosis [17, 34, 51]. One study found this association only for heavy smokers who continued smoking after the first trimester and had delayed or no folic acid supplement use [52]. Another study did not report smoking as a risk factor [30].

Drugs and Medication

Studies of maternal alcohol consumption have had mixed results. One study found no relationship between maternal alcohol consumption and craniosynostosis risk [17]. However, one study found risk to be inversely related to alcohol consumption after the first trimester, and another found an inverse relationship between alcohol consumption and risk of sagittal synostosis [37, 53]. High levels of caffeine consumption may confer an increased risk for craniosynostosis, although lower amounts showed no association [54].

There may be a connection between nitrosatable drugs (chlordiazepoxide, nitrofurantoin, and chlorpheniramine) and increased risk of craniosynostosis [30]. However, one study found an increased risk only for cases of sagittal and lambdoidal synostosis [55], and another failed to find an association between nitrofurantoins and craniosynostosis [56].

Evidence is also inconclusive as to whether selective serotonin reuptake inhibitors (SSRIs)—typically used to treat depression—are associated with an increased risk for this defect. One study found an increased risk of craniosynostosis with SSRI use, particularly among obese women; when examining specific SSRIs, fluoxetine was associated with increased craniosynostosis risk [57]. However, two other studies did not support these findings [58, 59].

Use of antihistamines during early pregnancy, specifically diphenhydramine, may be a risk factor for craniosynostosis [60]. Although treatment for maternal thyroid disease may be linked to an increased risk of infant craniosynostosis [12], one study found no association between maternal use of thyroxine and craniosynostosis risk [30].

Valproic acid and other anticonvulsants have been linked to increased craniosynostosis risk [30, 61]. Specifically, a relationship has been suggested between valproic acid exposure and metopic synostosis [62]. However, one study reported no association between valproic acid use and craniosynostosis risk [55].

No associations have been found between craniosynostosis risk and use of the following substances:

  • analgesics, including acetaminophen, codeine, and hydrocodone [30, 63, 64]
  • antibacterial drugs, including penicillins, erythromycins, sulfonamides, and cephalosporins [30, 56]
  • antifungal drugs [65]
  • oral contraceptives [66]
  • illicit drugs, including cannabis, cocaine, and stimulants [55, 67]
  • weight loss products, including ephedra [68]
  • spermicides [69]

Fertility Treatments

Some evidence exists for a link between specific fertility treatments and greater risk of craniosynostosis. Clomiphene citrate, a drug used for ovulation stimulation, was associated with an increased craniosynostosis risk in two studies [1, 70]. However, one study found no association between craniosynostosis risk and infertility treatment or ovulation stimulation [30]. No studies have found a statistically significant association of craniosynostosis with assisted reproductive technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), or with surgical fertility treatments [1, 71, 72].

Vitamins and Nutrients

Vitamins and dietary nutrients have been studied for their associations with craniosynostosis risk. In one study, higher maternal intake of riboflavin, vitamin B6, vitamin E, and vitamin C before and during pregnancy was associated with a decreased risk for sagittal synostosis, and higher intake of methionine and vitamin C was associated with a decreased risk for coronal synostosis [9]. In the same study, an increased risk of metopic synostosis was reported with higher intake of choline and vitamin B12. Previous studies of multivitamin usage have not demonstrated a link to craniosynostosis risk [30, 55]. There does not appear to be a protective effect from folic acid supplementation [9]; in fact, one unusual finding indicated an increased risk of craniosynostosis with folic acid taken in the first trimester [30]. However, small numbers limit the strength of this finding.

References

1.       Reefhuis J, Honein MA, Shaw GM, Romitti PA: Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993-1997. Pediatrics 2003, 111(5 Part 2):1163-1166.

2.       Kimonis V, Gold J-A, Hoffman TL, Panchal J, Boyadjiev SA: Genetics of craniosynostosis. Seminars In Pediatric Neurology 2007, 14(3):150-161.

3.       Rasmussen SA, Yazdy MM, Frías JL, Honein MA: Priorities for public health research on craniosynostosis: summary and recommendations from a Centers for Disease Control and Prevention-sponsored meeting. American Journal Of Medical Genetics Part A 2008, 146A(2):149-158.

4.       Boyadjiev SA: Genetic analysis of non-syndromic craniosynostosis. Orthodontics & Craniofacial Research 2007, 10(3):129-137.

5.       Becker DB, Petersen JD, Kane AA, Cradock MM, Pilgram TK, Marsh JL: Speech, cognitive, and behavioral outcomes in nonsyndromic craniosynostosis. Plastic And Reconstructive Surgery 2005, 116(2):400-407.

6.       Da Costa AC, Walters I, Savarirayan R, Anderson VA, Wrennall JA, Meara JG: Intellectual outcomes in children and adolescents with syndromic and nonsyndromic craniosynostosis. Plastic And Reconstructive Surgery 2006, 118(1):175.

7.       Texas Birth Defects Registry, Report of Defects Among 1999-2008 Deliveries. In Prevalence of Selected Birth Defects, Texas, 1999-2008. Texas Department of State Health Services; 2010.

8.       Boulet SL, Rasmussen SA, Honein MA: A population-based study of craniosynostosis in metropolitan Atlanta, 1989-2003. American Journal Of Medical Genetics Part A 2008, 146A(8):984-991.

9.       Carmichael SL, Rasmussen SA, Lammer EJ, Ma C, Shaw GM: Craniosynostosis and nutrient intake during pregnancy. Birth Defects Research Part A, Clinical And Molecular Teratology 2010, 88(12):1032-1039.

10.     Di Rocco F, Arnaud E, Renier D: Evolution in the frequency of nonsyndromic craniosynostosis. Journal Of Neurosurgery Pediatrics 2009, 4(1):21-25.

11.     Kolar JC: An epidemiological study of nonsyndromal craniosynostoses. The Journal Of Craniofacial Surgery 2011, 22(1):47-49.

12.     Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA, Honein MA: Maternal thyroid disease as a risk factor for craniosynostosis. Obstetrics And Gynecology 2007, 110(2 Pt 1):369-377.

13.     Sanchez-Lara PA, Carmichael SL, Graham JM, Jr., Lammer EJ, Shaw GM, Ma C, Rasmussen SA: Fetal constraint as a potential risk factor for craniosynostosis. American Journal Of Medical Genetics Part A 2010, 152A(2):394-400.

14.     Selber J, Reid RR, Chike-Obi CJ, Sutton LN, Zackai EH, McDonald-McGinn D, Sonnad SS, Whitaker LA, Bartlett SP: The changing epidemiologic spectrum of single-suture synostoses. Plastic And Reconstructive Surgery 2008, 122(2):527-533.

15.     Singer S, Bower C, Southall P, Goldblatt J: Craniosynostosis in Western Australia, 1980-1994: a population-based study. American Journal Of Medical Genetics 1999, 83(5):382-387.

16.     van der Meulen J, van der Hulst R, van Adrichem L, Arnaud E, Chin-Shong D, Duncan C, Habets E, Hinojosa J, Mathijssen I, May P et al: The increase of metopic synostosis: a pan-European observation. The Journal Of Craniofacial Surgery 2009, 20(2):283-286.

17.      Alderman BW, Bradley CM, Greene C, Fernbach SK, Barón AE: Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy. Teratology 1994, 50(1):13-18.

18.     Root S: Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy. Teratology 1995, 51(5):289-291.

19.     Wilkie AOM, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJL, Lester T, Richards PG, Twigg SRF, Wall SA: Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 2010, 126(2):e391-e400.

20.     Genetics Home Reference: Your Guide to Understanding Genetic Conditions [http://ghr.nlm.nih.gov/BrowseGenes]

21.     Kabbani H, Raghuveer TS: Craniosynostosis. American Family Physician 2004, 69(12):2863-2870.

22.     Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D: Genetic study of nonsyndromic coronal craniosynostosis. American Journal Of Medical Genetics 1995, 55(4):500-504.

23.     Wilkie AOM, Bochukova EG, Hansen RMS, Taylor IB, Rannan-Eliya SV, Byren JC, Wall SA, Ramos L, Venâncio M, Hurst JA et al: Clinical dividends from the molecular genetic diagnosis of craniosynostosis. American Journal Of Medical Genetics Part A 2007, 143A(16):1941-1949.

24.     Kweldam CF, van der Vlugt JJ, van der Meulen JJNM: The incidence of craniosynostosis in the Netherlands, 1997-2007. Journal Of Plastic, Reconstructive & Aesthetic Surgery: JPRAS 2011, 64(5):583-588.

25.     Wilkie AO: Epidemiology and genetics of craniosynostosis. American Journal Of Medical Genetics 2000, 90(1):82-84.

26.     Alderman BW, Lammer EJ, Joshua SC, Cordero JF, Ouimette DR, Wilson MJ, Ferguson SW: An epidemiologic study of craniosynostosis: risk indicators for the occurrence of craniosynostosis in Colorado. American Journal Of Epidemiology 1988, 128(2):431-438.

27.      Zhu M, Druschel C, Lin S: Maternal birthplace and major congenital malformations among New York Hispanics. Birth Defects Research Part A, Clinical And Molecular Teratology 2006, 76(6):467-473.

28.     Ramadhani T, Short V, Canfield MA, Waller DK, Correa A, Royle M, Scheuerle A: Are birth defects among Hispanics related to maternal nativity or number of years lived in the United States? Birth Defects Research Part A, Clinical And Molecular Teratology 2009, 85(9):755-763.

29.     Reefhuis J, Honein MA: Maternal age and non-chromosomal birth defects, Atlanta--1968-2000: teenager or thirty-something, who is at risk? Birth Defects Research Part A, Clinical And Molecular Teratology 2004, 70(9):572-579.

30.     Källén B, Robert-Gnansia E: Maternal drug use, fertility problems, and infant craniostenosis. The Cleft Palate-Craniofacial Journal: Official Publication Of The American Cleft Palate-Craniofacial Association 2005, 42(6):589-593.

31.     Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK: Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004. Annals Of Epidemiology 2010, 20(3):241-249.

32.     Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, Johnson D, Walsh S, Oldridge M, Wall SA et al: Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. American Journal Of Human Genetics 2000, 66(3):768-777.

33.     Tolarova MM, Harris JA, Ordway DE, Vargervik K: Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome. American Journal Of Medical Genetics 1997, 72(4):394-398.

34.     Källén K: Maternal smoking and craniosynostosis. Teratology 1999, 60(3):146-150.

35.     Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D: Genetic study of scaphocephaly. American Journal Of Medical Genetics 1996, 62(3):282-285.

36.     Lajeunie E, Le Merrer M, Marchac D, Renier D: Syndromal and nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. American Journal Of Medical Genetics 1998, 75(2):211-215.

37.      Zeiger JS, Beaty TH, Hetmanski JB, Wang H, Scott AF, Kasch L, Raymond G, Jabs EW, VanderKolk C: Genetic and environmental risk factors for sagittal craniosynostosis. The Journal Of Craniofacial Surgery 2002, 13(5):602-606.

38.     Lajeunie E, Crimmins DW, Arnaud E, Renier D: Genetic considerations in nonsyndromic midline craniosynostoses: a study of twins and their families. Journal Of Neurosurgery 2005, 103(4 Suppl):353-356.

39.     Singh RP, Dhariwal D, Bhujel N, Shaikh Z, Davies P, Nishikawa H, Solanki G, Dover MS: Role of parental risk factors in the aetiology of isolated non-syndromic metopic craniosynostosis. The British Journal Of Oral & Maxillofacial Surgery 2010, 48(6):438-442.

40.     Graham JM, Jr., deSaxe M, Smith DW: Sagittal craniostenosis: fetal head constraint as one possible cause. The Journal Of Pediatrics 1979, 95(5 Pt 1):747-750.

41.     Graham JM, Jr., Badura RJ, Smith DW: Coronal craniostenosis: fetal head constraint as one possible cause. Pediatrics 1980, 65(5):995-999.

42.     Alderman BW, Zamudio S, Barón AE, Joshua SC, Fernbach SK, Greene C, Mangione EJ: Increased risk of craniosynostosis with higher antenatal maternal altitude. International Journal Of Epidemiology 1995, 24(2):420-426.

43.     Bradley CM, Alderman BW, Williams MA, Checkoway H, Fernbach SK, Greene C, Bigelow PL, Reif JS: Parental occupations as risk factors for craniosynostosis in offspring. Epidemiology (Cambridge, Mass) 1995, 6(3):306-310.

44.     Herdt-Losavio ML, Lin S, Chapman BR, Hooiveld M, Olshan A, Liu X, DePersis RD, Zhu J, Druschel CM: Maternal occupation and the risk of birth defects: an overview from the National Birth Defects Prevention Study. Occupational And Environmental Medicine 2010, 67(1):58-66.

45.     Langlois PH, Ramadhani TA, Royle MH, Robbins JM, Scheuerle AE, Wyszynski DF: Birth defects and military service since 1990. Military Medicine 2009, 174(2):170-176.

46.     Waller DK, Shaw GM, Rasmussen SA, Hobbs CA, Canfield MA, Siega-Riz A-M, Gallaway MS, Correa A: Prepregnancy obesity as a risk factor for structural birth defects. Archives Of Pediatrics & Adolescent Medicine 2007, 161(8):745-750.

47.      Boulet SL, Rasmussen SA, Honein MA: Maternal body mass index as a risk factor for craniosynostosis. American Journal Of Medical Genetics Part A 2010, 152A(11):2895-2897.

48.     Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves MA, Riehle-Colarusso TJ, Waller DK, Reece EA: Diabetes mellitus and birth defects. American Journal Of Obstetrics And Gynecology 2008, 199(3):237.e231-239.

49.     Carter TC, Olney RS, Mitchell AA, Romitti PA, Bell EM, Druschel CM: Maternal self-reported genital tract infections during pregnancy and the risk of selected birth defects. Birth Defects Research Part A, Clinical And Molecular Teratology 2011, 91(2):108-116.

50.     Yazdy MM, Mitchell AA, Liu S, Werler MM: Maternal dietary glycaemic intake during pregnancy and the risk of birth defects. Paediatric And Perinatal Epidemiology 2011, 25(4):340-346.

51.     Honein MA, Rasmussen SA: Further evidence for an association between maternal smoking and craniosynostosis. Teratology 2000, 62(3):145-146.

52.     Carmichael SL, Ma C, Rasmussen SA, Honein MA, Lammer EJ, Shaw GM: Craniosynostosis and maternal smoking. Birth Defects Research Part A, Clinical And Molecular Teratology 2008, 82(2):78-85.

53.     Richardson S, Browne ML, Rasmussen SA, Druschel CM, Sun L, Jabs EW, Romitti PA, the National Birth Defects Prevention S: Associations between periconceptional alcohol consumption and craniosynostosis, omphalocele, and gastroschisis. Birth Defects Research Part A: Clinical and Molecular Teratology 2011, 91(7):623-630.

54.     Browne ML, Hoyt AT, Feldkamp ML, Rasmussen SA, Marshall EG, Druschel CM, Romitti PA: Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention Study. Birth Defects Research Part A, Clinical And Molecular Teratology 2011, 91(2):93-101.

55.     Gardner JS, Guyard-Boileau B, Alderman BW, Fernbach SK, Greene C, Mangione EJ: Maternal exposure to prescription and non-prescription pharmaceuticals or drugs of abuse and risk of craniosynostosis. International Journal Of Epidemiology 1998, 27(1):64-67.

56.     Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ: Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Archives Of Pediatrics & Adolescent Medicine 2009, 163(11):978-985.

57.      Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM: Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. The New England Journal Of Medicine 2007, 356(26):2684-2692.

58.     Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA: First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. The New England Journal Of Medicine 2007, 356(26):2675-2683.

59.     Källén BAJ, Otterblad Olausson P: Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Research Part A, Clinical And Molecular Teratology 2007, 79(4):301-308.

60.     Gilboa SM, Strickland MJ, Olshan AF, Werler MM, Correa A: Use of antihistamine medications during early pregnancy and isolated major malformations. Birth Defects Research Part A, Clinical And Molecular Teratology 2009, 85(2):137-150.

61.     Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, de Jong-van den Berg LTW: Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations. New England Journal of Medicine 2010, 362(23):2185-2193.

62.     Lajeunie E, Barcik U, Thorne JA, El Ghouzzi V, Bourgeois M, Renier D: Craniosynostosis and fetal exposure to sodium valproate. Journal Of Neurosurgery 2001, 95(5):778-782.

63.     Feldkamp ML, Meyer RE, Krikov S, Botto LD: Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstetrics And Gynecology 2010, 115(1):109-115.

64.     Broussard CS, Rasmussen SA, Reefhuis J, Friedman JM, Jann MW, Riehle-Colarusso T, Honein MA: Maternal treatment with opioid analgesics and risk for birth defects. American Journal Of Obstetrics And Gynecology 2011, 204(4):314.e311-311.

65.     Carter TC, Druschel CM, Romitti PA, Bell EM, Werler MM, Mitchell AA: Antifungal drugs and the risk of selected birth defects. American Journal Of Obstetrics And Gynecology 2008, 198(2):191.e191-197.

66.     Waller DK, Gallaway MS, Taylor LG, Ramadhani TA, Canfield MA, Scheuerle A, Hernández-Diaz S, Louik C, Correa A: Use of oral contraceptives in pregnancy and major structural birth defects in offspring. Epidemiology (Cambridge, Mass) 2010, 21(2):232-239.

67.      van Gelder MMHJ, Reefhuis J, Caton AR, Werler MM, Druschel CM, Roeleveld N: Maternal periconceptional illicit drug use and the risk of congenital malformations. Epidemiology (Cambridge, Mass) 2009, 20(1):60-66.

68.     Bitsko RH, Reefhuis J, Louik C, Werler M, Feldkamp ML, Waller DK, Frias J, Honein MA: Periconceptional use of weight loss products including ephedra and the association with birth defects. Birth Defects Research Part A, Clinical And Molecular Teratology 2008, 82(8):553-562.

69.     Gallaway MS, Waller DK, Canfield MA, Scheuerle A: The association between use of spermicides or male condoms and major structural birth defects. Contraception 2009, 80(5):422-429.

70.     Reefhuis J, Honein MA, Schieve LA, Rasmussen SA: Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Human Reproduction (Oxford, England) 2011, 26(2):451-457.

71.     Källén B, Finnström O, Nygren KG, Olausson PO: In vitro fertilization (IVF) in Sweden: risk for congenital malformations after different IVF methods. Birth Defects Research Part A, Clinical And Molecular Teratology 2005, 73(3):162-169.

72.     Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA: Assisted reproductive technology and major structural birth defects in the United States. Human Reproduction (Oxford, England) 2009, 24(2):360-366.

Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.

For more information:

Birth Defects Epidemiology and Surveillance
Texas Department of State Health Services
1100 W. 49th Street, Austin, Texas 78756
512-458-7232 Fax 512-458-7330

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Document E58-10957B                    Revised July 2011

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Last updated August 25, 2011