Comparison of environmental risk factors for esophageal atresia, anorectal malformations, and the combined phenotype in 263 German families

Abstract

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.

Esophageal Atresia with or without Tracheoesophageal Fistula (EA/TEF): Association of Different EA/TEF Subtypes with Specific Co-occurring Congenital Anomalies and Implications for Diagnostic Workup

“…The correlation between gastrointestinal anomalies and EA/TEF might be explained by the nonrandom co-occurrence of these two anomalies within the context of VACTERL association. [17][18][19][20] Although this observation has to be confirmed by future studies, it might lead to a higher awareness of co-occurring gastrointestinal anomalies in newborns with subtype 3b.…”

Maternal drug use and the risk of anorectal malformations: systematic review and meta-analysis

“…Case numbers ranged from six ARM cases [ 43 ] to 799 ARM cases [ 52 ]. Children with known chromosomal anomalies were excluded in 20 studies [ 27 , 28 , 41 , 42 , 49 , 50 , 53 – 66 ]. Twenty-one studies used infants with no (major) birth defects as control group [ 6 , 27 , 28 , 41 , 54 , 55 , 58 – 72 ] and four studies used malformed infants with other anomalies than ARM [ 50 , 53 , 73 , 74 ].…”

“…Children with known chromosomal anomalies were excluded in 20 studies [ 27 , 28 , 41 , 42 , 49 , 50 , 53 – 66 ]. Twenty-one studies used infants with no (major) birth defects as control group [ 6 , 27 , 28 , 41 , 54 , 55 , 58 – 72 ] and four studies used malformed infants with other anomalies than ARM [ 50 , 53 , 73 , 74 ]. Controls of the remaining 11 studies were all infants born in the same settings during the respective study period [ 42 , 43 , 49 , 51 , 52 , 56 , 57 , 75 – 78 ].…”

“…One study only reported on prevalences and did not use a control group [ 79 ]. Only nine studies examined the association between maternal medical drug intake and ARM infants with isolated anomalies [ 41 , 53 , 57 , 59 , 65 , 69 – 71 , 73 ].…”

“… First author, year Country Cases Controls Age range Setting, control type Data acquisition (period) Assessed medical drug(s) [ 28 ] Zwink, 2016 Germany 158 474 a < 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 772 265 c 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 ß 2 -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 malformations a 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 [ ...…”