The current pathogenic concept of BEEC is based on the assumption of underlying polygenic gene-gene and multifactorial gene-environment interactions leading to a spectrum of anomalies in which part or all of the distal urinary tract fail to close and are exposed on the outer abdominal wall. Due to its low prevalence, epidemiological data on non-genetic risk factors are limited.6
The present survey represents one of the largest to be conducted among BEEC families to date.
As described previously,6
we also found a male predominance in all subgroups, significant for the CBE group and consecutively for the entire sample (p
0.001) (). However, we were unable to reproduce earlier findings describing a sex ratio close to unity among CE patients,6
but consistent with these also found some patients with an intermediate phenotype between the clinical entities of CBE and CE. In support of the assumption that all BEEC phenotypes (E, CBE and CE) share the same developmental defect, we failed to detect differences regarding the co-occurrence of congenital anomalies or health problems outside the BEEC spectrum.
Comparison of parental age in our BEEC families with the distribution in the general population was not performed since our families originated from 14 different countries. Contrary to previous findings describing an overrepresentation of very young mothers of BEEC children2
but consistent with Boyadjiev et al.,6
we only found two mothers younger than 20 years. Furthermore, we detected no differences in parental age among the different phenotypes. The two multiplex families observed suggest genetic components causally related to BEEC. However, pedigree structures are not compatible with Mendelian transmission, pointing towards polygenetic and/or environmental factors contributing to the risk.
Severe congenital anomalies occur in 5% of all live births among central Europeans, but the underlying causes of 65–75% of these defects remain unknown.9
Multifactorial and polygenic malformations, e.g. cleft lip and/or cleft palate (CLP), spina bifida and congenital heart defects, generally carry an increased risk of recurrence for siblings (λs) of 1 in 20 to 1 in 30.10
Regarding BEEC, Shapiro et al. having surveyed 2,500 CBE families in North America, found CBE to reoccur roughly in one of every 275 families.4
Using these data for isolated CBE, a λs of 108 can be estimated based on an overall prevalence of CBE among Europeans with 1 in 20,000 to 1 in 30,000 live births,.4
Therefore, the risk is 108-times higher compared to the general population (risk comparison λs: 1/275 divided 1/30,000 = 108). Furthermore, in their series, Shapiro et al. described a 400-fold increased risk in offspring of affected individuals (λo) compared to the general population.4
These data were confirmed by concordance rates among mono- and dizygotic BEEC twins.7
Ascertainment of possible teratogenic exposures was limited by sample size and lack of an available control group. Looking at our complete sample, we noticed the same frequency (15%) of first trimester fetal exposure to maternal smoking as recently observed.6
However, comparing the different subgroups, first trimester exposure to maternal smoking was found to be associated with formation of the more severe BEEC phenotype (p
0.009) possibly indicating gene-environment interactions as described by Maestri et al. who reported that the risk of non-syndromic oral clefts was significantly influenced by an interaction involving genetic variants of the TGFB3
-gene and first trimester exposure to maternal smoking.11
Exposure to alcohol (any amount) was reported by 14% of mothers, almost always limited to a few drinks before confirmation of pregnancy. A detailed study by the CDC found an alcohol exposure rate in the general population of 12.8% among women who delivered in 1999, parallel to our present survey.12
Also, in our study report of exposure to periconceptional or first trimester receipt of drugs or medications these were limited to few occasions. It has been scientifically proven that under regular use, none of the substances reported possesses teratogenic effects.13
Exposure to medical radiation (x-rays or CT-scans) was reported in 6% of mothers, all cases limited to a single application. The Israel Teratogen Information Service reported a value of 10.9% of X-ray exposures during early pregnancy in a ten year prospective study which comprises almost twice the rate compared to our cohort.14
However, they did not observe any increased prevalence of birth defects in the outcome follow-up. Other studies concluded that nuclear medicine and radiological diagnostic procedures, if not repeated during pregnancy, do not exceed 100 mSv, the threshold dose for deterministic effects on the fetus.15
A previous report suggested a possible association between in vitro fertilization and BEEC.16
In our study, assisted reproduction, such as IVF and ICSI had been applied in 1.4% (twice ICSI and once IVF) of mothers resulting in the birth of two children with CBE and one child with CE. In 2000, the combined rate of newborns resulting from IVF or ICSI procedures in Germany was 1.3%, suggesting that IVF and ICSI do not carry a major risk of BEEC formation.17
Forty-four of the 214 (21%) mothers reported a history of, in all cases unique, spontaneous abortion reflecting the observation by Buss et al. who, during follow-up of pregnancies in a large Danish cohort, found a value of 20.9%.18
Unlike previous observations of a significantly greater rate of miscarriages among mothers of E patients (n=10; 34%), we found the highest rate in the CBE group (n=37; 18.6%).6
Periconceptional folic acid supplementation implemented according to the current recommendations has been beneficial in the prevention of neural tube defects (NTDs), and it has been assumed to be preventative in the occurrence of non-syndromic omphalocele.19
Both these congenital anomalies are part of the BEEC spectrum. In our survey, only 16.8% of mothers had supplemented folic acid starting before conception and only 17.6% of all mothers started before the 10th
week of gestation. Interestingly, mothers of children with CE were significantly (p
0.037) more compliant in their supplementation starting before the 10th
week of gestation than mothers of the combined group of E/CBE patients. This contradicting finding might either be due to the fact that NTDs and omphalocele are only in part receptive to the preventive effects of periconceptional folic acid and/or that beneficial effects only display if supplementation has been started before conception according to the current recommendations. On the other hand NTDs and omphalocele associated with BEEC might underlie a completely different pathogenic concept compared to their isolated occurrence.
Further comparisons of patients and/or mothers of the combined E/CBE group with patients and/or mothers of the CE group revealed that mothers of CE patients underwent prenatal diagnostic amniocentesis significantly (p
0.021) more often and prenatally, were significantly (p
< 0.0001) more often aware of their child being affected by major congenital malformation than mothers of E/CBE patients (). In general, due to better prenatal ultrasound techniques, BEEC has been diagnosed prenatally more frequently than in the past. However, most prenatal reports describe detection of fetuses with CE, due to the severity and the high frequency of NTDs associated with this phenotype.20
The disproportion of barely diagnosed milder but much more prevalent BEEC phenotypes could be due to the fact that prenatal ultrasound focuses more on imaging of NTDs than on the full urinary bladder.