©1991 S. Karger AG. Basel 1015-3837/91/0062-0014$2.75/0
Fetal Diagn Thor 1991:6:14-27
Contribution of Demographic and Environmental Factors to the Etiology of Gastroschisis: A Hypothesis Robert A. Drongowski, R. Kendall Smith. Jr.. Arnold G. Coran. Michael D. Klein Section of Pediatric Surgery. C.S. Mott Children’s Hospital, and University of Michigan Medical School, Ann Arbor, Mich.. USA
Key Words. Abdominal wall defect • Gastroschisis • Teratology
Introduction We wish to present the hypothesis that gastroschisis may be caused by environmen tal teratogens. Two events lead us to form this hypothesis. First, the clinical impression of pediatric surgeons is that gastroschisis is becoming more common, and second, there are a large number of studies in experimental teratology which demonstrate that many ex ternal influences on a pregnant animal can produce gastroschisis in its offspring.
Congenital abdominal wall defects are di vided into three categories [1], Omphalocele is a large abdominal wall defect with hernia tion of midgut, liver and other abdominal organs into a translucent sac at the umbilical ring. Children with omphalocele frequently have associated congenital anomalies and generally are not premature. Gastroschisis is a small abdominal w'all defect occurring just to the right of the umbilical cord. There is no sac. and midgut alone appears outside the abdominal wall. Children with gastroschisis
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Abstract. We examined the clinical literature on congenital abdominal wall defects to confirm our impression that gastroschisis had become more common than omphalocele. We then examined the teratology literature and noted that congenital abdominal wall defects were frequently induced by teratogens. This lead us to review the antenatal history of 19 infants with gastroschisis and 54 control infants born with a congenital anomaly unrelated to gastroschisis. When compared to controls, mothers of infants with gastroschisis were more likely to have used aspirin during pregnancy and to have been taking oral contraceptives at the time of conception. Additionally, an increased incidence of illegal drug use (particularly cocaine) was noted among the study mothers. We conclude that gastroschisis is becoming the more common congenital abdominal w'all defect, and that it could be related to exposure to an environmental teratogen.
15
Gastroschisis: Environmental Factors
Table 1. Clinical series distinguishing gastroschisis from omphalocele Series
Last year
Gastroschisis
Omphalocele
n
%
n
07
26 22 31 15 23 13 15 39 33 13 43 12 54
Reference
%
Before 1972 England Michigan Ohio South Africa Australia British Columbia Japan Northern Europe Scandinavia Southern Europe United States California Kentucky
1951 1963 1965 1968 1971 1971 1971 1971 1971 1971 1971 1972 1972
13 07 05 10 02 15 37 01 03 52 20
Average (all areas)
20 29 47 17 70 11 23 75 07 04 379 17
74 78 69 87 77 87 85 61 67 87 57 88 46
(63] [1] [5] [64] [25] [15] [25] [25] [25] [25] [25] [14] [24]
74
26
After 1972
Average (all areas)
1977 1977 1977 1977 1977 1977 1977 1977 1978 1979 1979 1979 1981 1981 1985 1986
12 1 14 12 18 33 59 03 03 19
47 23 36 27
46 25 40 58 57 61 33 33 26 42 45 63 49 23 63 56 44
14 340 18 13 25 38 06 06 54
28 24 21 21
54 75 60 42 43 39 67 67 74 58 55 37 51 77 37 44
[25] [14] [25] [25] [25] [25] [25] [25] [15] [10] [01] [19] [65] [13] [27] [66]
56
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Australia California Japan Mexico Northern Europe Scandinavia Southern Europe United States British Columbia Finland Michigan Utah Austria Spain South Carolina Great Britain
Drongowski/Smith/Coran/Klein
16
are often premature and have associated malformations less frequently than children with omphalocele. Umbilical cord hernia is relatively unusual and consists of a small abdominal wall defect with herniation of midgut into a translucent umbilical cord. While familial cases of these defects have been reported [2. 3] no clear pattern of inher itance exists, and the etiology is considered to be multifactorial. The three defects are distinct enough clinically that different causes are suspected, but the cmbrvological explanations for the defects are speculative [1,4-9],
Prior to 1970, omphalocele was the most frequently reported abdominal wall defect. Since 1970, gastroschisis has become the more common lesion (table 1). The absolute incidence of gastroschisis is reported to be increasing in Finland. Norway, Sweden, Spain and California [10-14] though not in British Columbia and Denmark [15, 16], In experimental teratology, congenital ab dominal wall defects are commonly pro duced; however, they are often simply called umbilical hernia, which is also how they are classified in the Index Medicus. Very few photographs of the abdominal wall defects
Defect
Animal
Teratogen
Author
Ref.
Gastroschisis
Chick
Scopalaminc hydrobromide Triamcinolone acctonidc
McBride et al.. 1982
[67]
Fisher. Sawyer. 1980
[68]
Dog
Estrogen antagonists
Schardein el al„ 1973
[69]
Hamster
6-Mcrcaptopurine Nitrous oxide
Shah. Burdett. 1979 Shah et al„ 1979
[70] [71]
Mallard
Methyl mercury
Hoffman, Moore. 1979
[72]
Mouse
Benzo(a)pyrene Hydroxyurea Pyrabital
Barbiéri et al., 1986 Seller. Perkins. 1983 Nomura et al.. 1981
[73] [74] [75]
Pheasant
Methyl-parathion
Deli. Varnagy. 1985
[76]
Rabbit
Aurothiomalate Concanavalin A Gold thioglucose
Szabo et al.. 1978 Desesso, 1979 Szabo et al.. 1978
[77] [78] [77]
Rat
BCNU Cadmium cis-Platinum Methyl salicylate Mevinolin Nitrous oxide Pteroylglutamic acid Streptonigrin
Thompson et al.. 1975 Samarawickrama, Webb, 1981 Beaudoin. 1982 Warkany. Takacs. 1959 Minsker et al., 1983 Fujinaga et al.. 1989 Nelson et al., 1955 Warkany. Takacs. 1965
[79] [80] [81] [62] [82] [83] [84] [85]
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Table 2. Teratogens causing abdominal wall defects in animal models
Gastroschisis: Environmental Factors
17
Table 2 (continued) Defect
Animal
Teratogen
Author
Ref.
Omphalocele
Guinea pig
Hyperthermia
Edwards. 1969
[86]
Mouse
Aminopyrine Bovine albumin Anaphylaxis Carbamates Cytochalasin D Diacetoxyscirpcnol Flubendazole Hypoxia Rhodamine dyes Triton WR
Nomura et al.. 1981 Takayama. 1981
[87] [88]
DiPaola. Elis. 1967 Shepard. Greenway. 1977 Mayura cl al.. 1987 Yoshimura. 1987 Ingalls et al., 1953 Hood, et al.. 1973 Roussel. Tuchmann-Duplessis 1968
[89] [90] [91] [92] [93] [94] [95]
Rabbit
Amenantrone acetate Dillorasone Diflucortolone valerate Hydrocortisone Prednisolone
Kim et al.. 1984 Narama. 1984 Gunzel et al.. 1976 Yamada et al., 1981 Koga et al.. 1980
[55] [56] [57] [58] [59]
Rat
CCNU Clobetasonc Cyclophosphamide Nitrazepam Ochratoxin A Pyridoxine deficiency Streptonigrin Hypogiycin A Uterine vascular clamping
Thompson et al.. 1975 Shinpo et al.. 1980 Slott. Haies. 1986 Saito et al., 1984 Mayura et al., 1982 Davis et al., 1970 Warkany. Takacs. 1965 Persaud. 1972 Brent. Franklin. I960
[79] [60] [96] [97] [98] [99] [85] [100] [101]
Cat
Ethylene thiourea
Khera, Iverson. 1978
[102]
Hamster
Aflatoxin B| Methyl mercuric chloride
Elis, Dipaolo. 1967 Harris et al.. 1969
[103] [104]
Mouse
Microwave radiation Sodium barbital
Tachibana. 1977 Persaud. Henderson. 1969
[105] [106]
Rabbit
Aurothiomalate Hydrocortisone
Szabo et al.. 1978 Yamada et al.. 1981
VI]
Acetylsalicylic acid Cadmium N-N-Diethylbenzene sulfonamide Triamcinolone acetonide
Khera, 1976 Samarawickrama. Webb, 1981 Lcland et al.. 1972
[611 [80] [107]
Rowland. Hendries. 1983
[108]
Rat
[58]
BCNU - N.N,-bis(2-chloroethyl)-N-nitrosourea: CCNU - l-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Umbilical hernia
18
Drongowski/Smith/Coran/KJcin
are available in the teratology literature. When they are available it is apparent that teratologists use terms differently from clini cians. Anomalies which are clearly gastroschisis to a pediatric surgeon can be called omphalocele by a leratologist. Some of the anomalies produced in animals by terato gens bear little resemblance to anomalies seen in humans born alive, such as a large defect with no sac and no rectus muscles and the liver included in the defect. We have tried to classify the defects reported in ani mals by current clinical terms in table 2, although it is our impression that most of the abdominal wall defects produced in animals are gastrosehisis. These epidemiological and teratological observations prompted us to investigate the effect of demographic and environmental conditions on the development of gastroschisis.
demographic questions, as well as questions related to maternal and reproductive history and maternal exposure to suspected environmental toxins related to the pregnancy. All questions were related to first trimester exposures, since that is the postulated time period when the embryologie events responsible for gastrosehisis occur. After thorough follow-up of ini tial nonresponders. 19 questionnaires were returned by case mothers and 54 by control mothers. There was no difference in response rate. Hospital charts of all case and control patients who responded were reviewed. The mother’s hospital chart was reviewed when available. On the questionnaires, mothers were given three choices: 'yes', ‘no- and ‘don't know’. Therefore, some of the items do have missing data, and the negative responses are definite answers, not simply an assumption based on the lack of informa tion. Statistical analysis was performed using Student's t test and Fisher’s exact test, p values less than 0.05 were considered significant.
Materials and Methods Thirty-three infants with a confirmed diagnosis of gastrosehisis were treated at C.S. Mott Children's Hospital between January 1978 and April 1983. Dur ing the same period. 19 newborns with omphalocele were treated. Mothers of 19 infants with gastrosehisis responded to a questionnaire distributed in 1983 and comprised the study group. A control group of infants was derived from children treated at the same hospi tal during the same time period, who had a congenital anomaly and were born within 3 months of a study group infant. The control group was drawn from 105 children and excluded infants with intestinal atresia because of the reported increased incidence of this anomaly in children with gastrosehisis [17, 18]. A group with congenital malformations was chosen to control for the potential reporting bias which may occur with normal healthy controls. The distribution of anomalies in the control group is presented in table 3. The questionnaire was sent to mothers of control and case infants, and included social and
Anomaly
Cases
Congenital heart disease Down's syndrome Respiratory system Diaphragmatic hernia Spleen Tracheoesophageal fistula Hirschsprung’s disease Anal atresia Renal agenesis Undescended testicle Bladder exstrophy Orthopedic Neural tube Microcephaly Hydrocephalus Coloboma Greater than two anomalies Unknown
16 4 3 1 1 3 2 2 i i i 3 2 2 i 7 7 2
Total cases
54
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Table 3. Congenital anomalies in the control group
19
Results Social and demographic data on the gas troschisis study group and control infants are presented in table 4. The average age of mothers of infants with gastroschisis was sig nificantly less (23.2 ± 4.8 years) than the average age of mothers of control infants (26.7 ± 5.8 years) (p < 0.022 by Student’s t
Table 4. Distribution of social and demographic factors in the gastroschisis and control groups Variable
Study patients
Control patients
n
%
n
%
08 11
42 58
31 23
57 43
18 01
94 05
51 03
94 07
10 09
53 47
11 43
20* 80
03 12 04 00
16 63 21 00
04 26 16 08
07 48 30 15
Infant .sex Male Female
Infant race White Black
Maternal age 2 2 Years
Maternal education 9 Years 12 Years Vocaiional/eollege Graduate school
Income level o f household, S/year 32 < 12.000 06 12.000-30,000 > 30.000
13 00
68 00
17 23 10
35 45 20
10 09
54 46
16 33
33 67
Size of community Population < 10.000 Population > 10.000
* p < 0.05 vs. the study patients. Fisher's exact test.
test). A greater proportion of control moth ers (30%) had post-secondary education compared to study group mothers (21%). Similarly, control mothers were more likely to have household incomes greater than $30,000 per year (20 vs. 0%) and to live in towns with populations greater than 30.000 (67 vs. 44%). Both groups were 94% white and 6%black, and there was no difference in the sex ratios between the two groups. The mean birth weight of the gastroschisis pa tients (2.49 ± 0.38 kg) was less (p < 0.001 by Student's t test) than that of the control infants (3.23 ± 0.61 kg). The maternal medical history of study group and control group mothers was unre markable. No differences were evident in parity, gravidity, menstrual history nor in the history of diabetes, hypertension, anemia or liver disease. Maternal medical problems during preg nancy were also not remarkable. There were no differences in vaginal bleeding, hyperten sion, anemia, toxemia, or edema between control and study groups. There were no differences between study group mothers in the use of cigarettes, cof fee, tea. cola or alcohol. There were also no differences in exposure to environmental substances at the work place during the first trimester of pregnancy between the study group and control mothers. There was no difference in infections dur ing pregnancy, with an incidence of 44% among study group mothers as compared to 43% in the control group mothers. Control group mothers, however, had more influenza (44%) and fewer urinary tract infections (25%) than mothers in the study group (0 and 62%, respectively). There were no dif ferences in pneumonia, vaginal infections or genital herpes (table 5).
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Gastroschisis: Environmental Factors
Drongowski/Smilh/Coran/KIcin
20
Sixty-seven percent of the mothers of in fants with gastroschisis had planned their pregnancy while only 52% of the control mothers had planned their pregnancy. There were no differences between study group and control group mothers in the use of dia phragms. spermicides (foam), intrauterine devices or condoms. Study group mothers were 2.6 times more likely to have used oral contraceptives during early pregnancy than controls (table 6). The difference (68 vs. 26%) is statistically significant (p < 0.0014 by Fisher’s exact test).
Maternal medications during the first tri mester of pregnancy are presented in table 7. The only statistically significant difference was in aspirin use between the study group (62%) and control group (20%) mothers (p < 0.0033 by Fisher's exact test). There was a positive correlation between illegal drug use and gastroschisis in this study. Forty-seven percent of study group mothers used illegal drugs compared to 21 % of the control mothers (p < 0.05 by Fisher’s exact test). These data are further presented in table 8.
Table 5. Maternal infections during pregnancy in the gastroschisis and control groups
Table6. Birth control methods employed prior to pregnancy in gastroschisis and control groups
Variable
Variable
Study group
Control group
n
%
n
%
08 10
44 56
23 30
43 57
05 03
62 38
06 18
25 75
00 08
00 100
03 20
13 87
00 08
00 100
10 13
44* 56
03 05
38 62
10 13
44 56
00 08
00 100
01 22
04 96
Infections
*
Planned Unplanned
12 06
67 33
27 25
52 48
Positive Negative
13 06
68 32
14 40
26* 74
Positive Negative
01 18
05 95
07 46
13 87
Positive Negative
05 95
04 49
08 92
00 19
00 100
06 47
11 89
02 17
10 90
11 42
21 79
01 18
Intrauterine device Positive Negative
Condom
Genital herpes Positive Negative
%
Spermicide (foam)
Vaginal infections Positive Negative
n
Diaphragm
Influenza Positive Negative
%
Oral contraceptives
Pneumonia Positive Negative
n
Pregnancy
Urinary tract Positive Negative
Control group
p < 0.05 vs. the study group. Fisher's exact test.
Positive Negative
* p < 0.0014 vs. the study group. Fisher’s exact test.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Positive Negative
Study group
Gastroschisis: Environmental Factors
21
Discussion Lower birth weight, younger maternal age and lower household income among infants with gastroschisis have been noted in other studies [1, 19-21]. Whether these are di-
'I'ablc 7. Maternal medications during the first tri mester of pregnancy in the gastroschisis and control groups Variable
Study group
Control group
n
%
n
%
00 100
01 40
02 98
Prescribed medications
rectly related to the anomaly or simply re flect the known social and demographic fac tors of prematurity is unclear. The relation ship of gastroschisis to prematurity is also unclear. The presence of uncovered abdomi nal contents in the amniotic fluid may be a stimulus for uterine contraction, but if it is, one would not expect the other factors re lated to prematurity to be so predominant. Moore and Stokes [22] are credited with creating, in 1953. the first standardized clas sification of gastroschisis and omphalocele.
Table 8. Illegal drug ingestion during the first tri mester of pregnancy in gastroschisis and control groups
Insulin 00 16
Variable
Morning sickness medication Positive Negative
03 13
19 81
10 30
25 75
Illegal drug use
04 12
25 75
07 34
17 83
Marijuana
06 94
02 38
05 95
Antibiotics Positive Negative
Allergy medication Positive Negative
01 15
Non-prescribed medications
Tylenol Positive Negative
50 50
18 22
45 55
02 14
12 88
08 32
20 80
n
%
n
%
08 09
47 53
11 41
21* 79
07 01
88 12
09 02
83 17
00 08
00 too
01 10
09 91
03 05
38 62
00 11
00** 100
01 07
12 88
00 11
00 100
00 08
00 100
01 10
09 91
Hashish Positive Negative
10 06
62 38
08 32
20* 80
Positive Negative
LSD
Aspirin Positive Negative
Positive Negative
Control group
Cocaine 08 08
Antacids Positive Negative
Positive Negative
Study group
Positive Negative
Amphetamines
* p < 0.0033 vs. the study group. Fisher'si exact test.
Positive Negative
* p < 0.05. ** p < 0.057. vs. the study group. Fisher’s exact test.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Negative Positive
There are very few earlier reports of gastroschisis, although Bernstein [23] used the word in 1940. Since that time, many authors have noted an apparent increase in the inci dence of gastroschisis [1, 11-14. 24-26], In table 1, several representative series are given in which the current clinical defini tion could be determined even if it was not specifically stated. In reports prior to 1973, gastroschisis represented 26% of abdominal wall defects, while after 1974 it represented 44% of such defects. In some centers (British Columbia), gastroschisis still represents a minority of defects (26%). while in others (South Carolina and Utah), it has become the most common defect (63%) [15, 19. 27], In our recent experience reported here, gastroschisis accounted for 65% of the new born abdominal wall defects. There is some question as to whether this increase in the proportion of patients with congenital abdominal wall defects who have gastroschisis reflects an increase in the abso lute incidence of congenital abdominal wall defects, with most of the increase being re presented by gastroschisis, or whether it is due to a concomitant decrease in the inci dence of omphalocele and umbilical cord hernia [12]. Several hypotheses might ex plain this increase in the number of patients with gastroschisis. Gastroschisis is known to occur in smaller and more premature babies, so it may be that children with this defect in the past did not live long enough to be seen by pediatric surgeons. Clementi et al. [28] sug gested that gastroschisis may be underre ported, since nearly half of the children in their group with omphalocele or gastroschi sis were either stillborn or died immediately after birth. With the advent of neonatal in tensive care units in the 1970s, more very ill
Drongowski/Smith/Coran/KIein
infants are surviving to be examined by pe diatric surgeons. This explanation seems un likely since, while it is true that the outcome in general has been better for premature infants in recent years, this increased sur vival is mainly in the very low birth weight category in which gastroschisis is not very common [29], Also, the number of serious congenital malformations in all infants may actually be decreasing [30-32]. A second explanation is that the defects of omphalocele and gastroschisis were not clearly distinguished from each other in all centers until recently. Yet this also appears an unlikely explanation. It is clear from var ious reports, such as those of Bernstein [23] in 1940, Massabuau and Guibal [33] in 1933. Reed [34] in 1913, and even Pare [35] in 1634. that gastroschisis was clearly iden tifiable prior to 1970, even though it was most often called an antenatal rupture of an omphalocele. We took this into account when compiling table 1. and still found a greater proportion of omphaloceles before 1970. A third explanation for the increased inci dence of gastroschisis is the introduction of a new environmental teratogen. Others have speculated that such a factor, having a high exposure rate but a low efficiency, might be responsible [19], and our data support this hypothesis. The use of oral contraceptives, aspirin and illegal drugs as well as occupational ex posure to toxins have been suggested as pos sible candidates. In 1979. Gicrup and Lundkvist [36], compared prenatal histories of mothers of infants born with gastroschisis and omphalocele, concluding that mothers of infants born with gastroschisis or ompha locele were more likely to have been exposed to drugs or chemicals in a work environ-
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
22
Gaslroschisis: Environmental Factors
result of numerous factors acting together, perhaps in this case, numerous drugs. Additional evidence that gastroschisis may result from teratogen exposure during pregnancy comes from the wide variety of compounds which have been used to create the condition in animal models (table 2). Numerous animal studies have demon strated the production of abdominal wall defects by steroids (ametantrone. diflorasonc. diflucortolone, hydrocortisone, pred nisolone and clobetasone) [55-60], and two studies have demonstrated that they can be caused by salicylates [61. 62]. We conclude that gastroschisis has be come the more common congenital abdomi nal wall defect, and that gastroschisis in ani mals is frequently caused by chemical terato gens. In addition, environmental teratogens including birth control pills, illegal drugs (particularly cocaine) and aspirin may be contributory factors in the increase in the relative incidence of gastroschisis.
References 1 Klein MD. Hertzler JH: Congenital defects of the abdominal wall. JAMA 1981:245:1543-1546. 2 Havalad S. Noblett H. Speidel BD: Familial oc currence of omphalocele suggesting sex-linked in heritance. Arch Dis Child 1979:54:142-149. 3 Hershey DW. Haesslevn HC. Adkins JC: Familial abdominal wall defects. Am J Med Genet 1989; 34:174-176. 4 Duhamel B: Embryology of exomphalos and al lied malformations. Arch Dis Child 1963:38:142147. 5 l/.ant RJ. Brown F, Rothman BE: Current em bryology and treatment of gastroschisis and om phalocele. Arch Surg 1966:93:49-53. 6 Shaw A: The myth of gastroschisis. .1 Pediatr Surg 1975:10:235-244. 7 deVries PA: the pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 1980:15:245-251.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
ment. Hoyne et al. [8] have suggested that intrauterine interruption of blood How in the omphalomesenterie artery may be responsi ble for the development of gastroschisis as compared to omphalocele. Sarda and Bard [37] presented a case of gastroschisis in which they believe that maternal alcohol consumption may have been responsible for decreasing blood flow in the fetus, subse quently resulting in gastroschisis. If the vas cular etiology of gastroschisis is in fact cor rect, cocaine might be expected to cause gas troschisis as it too is a vasoconstrictor. While our series suggests that oral contra ceptives, aspirin and illegal drugs might be implicated in the etiology of gastroschisis, the numbers of patients arc certainly too small to do anything but suggest that this might be a fruitful area for further investiga tion. In addition, many clinical studies have failed to show an increase in congenital mal formations among the children of mothers who used sex hormones [38-45] or aspirin [46, 47], Until recently, there was also little evi dence relating congenital anomalies to the use of illegal drugs during pregnancy [48. 49]. It is not biologically plausible that illegal drugs as a class are responsible for a single anomaly. They may, however, serve as a marker for some teratogenic agent, perhaps cocaine. Cocaine use during pregnancy has been associated with increased incidences of skull defects, urinary tract and genital mal formations as well as intestinal obstruction or atresia [50-54], Still, while looking for a single agent it must be remembered that most authorities feel teratogenicity in gen eral is multifactorial. It is unlikely that a sin gle factor will reach a threshold necessary for development of an anomaly, rather the out come of a pregnancy is more probably the
23
Drongowski/Smith/Coran/Klein
8 Hoyme HE. Higginbotlom MC, Jones KL: The vascular pathogenesis of gastroschisis: Intrauter ine interruption of the omphalomesenteric artery. J Pediatr 1981:98:228-231. 9 Glick PL. Harrison MR. Adzick NS. ct al: The missing link in the pathogenesis of gastroschisis. J Pediatr Surg 1985:20:406-409. 10 Gierup J, Lundkvist K: Gastroschisis: A pilot study of its incidence and the influence of terato genic factors. Z Kinderchir 1979:1:39-42. 11 Egcnaes J, Bjerkedal T: Forekomst av gastroschi sis og omfalocele i Norge 1967-1979. Tidsskr Nor Lacgcforen 1982:102:172-176. 12 Lindham S: Omphalocele and gastroschisis in Sweden 1965-1976. Acta Paediatr Scand 1981; 70:55-60. 13 Martinez-Frias ML. Salvador J. Prieto L. Zaplana J: Epidemiological study of gastroschisis and om phalocele in Spain. Teratology 1984:295:377382. 14 Roeper PJ. Harris J. Lee G. et al: Secular rates and correlates for gastroschisis in California (19681977). Teratology 1987;35:203-210. 15 Baird PA. MacDonald F.C: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million con secutive live births. Am J Hum Genet 1981:33: 470-478. 16 Bugge M, Haugc M: Gastroschisis og omphalocele i Danmark. Ugcskr Laeger 1983:145:1323-1327. 17 Hrabovsky EE. Boyd JB. Savrin RA: Advances in the management of gastroschisis. Ann Surg 1980; 192:244-248. 18 Pokorny WJ. Harberg FJ. McGill GW: Gastro schisis complicated by intestinal atresia. J Pediatr Surg 1981:16:261-263. 19 Lindham S: Long-term results in children with omphalocele and gastroschisis - A follow up study. Z Kinderchir 1984:39:164—167. 20 Colombani PM. Cunningham MD: Perinatal as pects of omphalocele and gastroschisis. Am J Dis Child 1977:131:1386-1388. 2 1 Mayer T. Black R. Matlak M E. et al: Gastroschisis and omphalocele. An eight year review. Ann Surg 1980:192:783-787. 22 Moore TC. Stokes CE: Gastroschisis: Report of two cases treated by a modification of the Gross operation for omphalocele. Surgery 1953:33:112120.
23 Bernstein P: Gastroschisis. A rare teratological condition in the newborn. Arch Pediatr 1940:57: 505-513. 24 Hollabaugh RS, Boles ET: The management of gastroschisis. J Pediatr Surg 1973:8:263—270. 25 Moore TC. Khalid N: An international survey of gastroschisis and omphalocele (490 cases). Pediatr Surg Int 1986;1:46-50. 26 International Clearinghouse for Birth Defects. Annual Report. 1981. Stockholm: Swedish Na tional Board of Health and Welfare. 1983. p 39. 27 Otherson HB. Smith CD: Pneumatic reduction bag for treatment of gastroschisis and omphalo cele - A 10-year experience. Ann Surg 1986:203: 512-516. 28 Clementi M. Tcnconi R. Turolla L: Further inves tigations when abdominal wall defects are diag nosed in utero. Lancet 1983:ii: 1083—1084. 29 Cole CH: Prevention of prematurity: Can we do it in America? Pediatrics 1985:76:310-312. 30 Hack M. Fanaroff AA. Merkatz 1R: Current con cepts: The low birth weight infant - Evolution of a changing outlook. N Engl J Med 1979:30:255— 256. 31 Carr-Hill RA. Hall MH: The repetition of sponta neous pre-term labor. Br J Obstet Gynaecol 1985: 313:666-669. 32 Alberman E: Why are stillbirth and neonatal mor tality rates continuing to fall? Br J Obstet Gynae col 1985:92:559-564. 33 Massabuau G. Guibal A: L'éviscération ombili cale congénitale. Arch Fr Mal Appar Dig 19.33:23: 129-150. 34 Reed EN: Infant disemboweled at birth - Appen dectomy successful. JAMA 1913:61:199. 35 Pare A: The Works of That Famous Chirurgeon. London, Cotes & Young. 1634. book 24. p 59. 36 Gierup .1. Lundkvist K: Gastroschisis: A pilot study of its incidence and the influence of terato genic factors. Z Kinderchir 1981:1:39-42. 37 Sarda P. Bard H: Gastroschisis in a case of dizy gotic twins: The possible role of maternal alcohol consumption. Pediatrics 1981:74:94-96. 38 Kasan PN. Andrew's J: The effects of recent oral contraceptive use on the outcome of pregnancy. Fur J Obstet Gynecol Reprod Biol 1986:22:77— 83. 39 Oakley GP. Flint JW: Hormonal pregnancy test and congenital malformations. Lancet I973:ii: 256-257.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
24
40 Harlap S. Shiono PH. Ramcharan S: Congenital abnormalities in the offspring of women who used oral and other contraceptives around the time of conception. Int J F'ertil 1985;30:39-47. 41 Resseguie IJ: Congenital malformations among offspring exposed in utero to progestins. Olmstead County. Minnesota. 1936-1974. Fertil Steril 1985:43:514-519. 42 Bracken MB: Oral contraception and congenital malformations in offspring: A review and meta analysis of the prospective studies. Obstet Gyne col 1990:76:552-557. 43 Katz Z: Teratogenicity of progcstogcns given dur ing the first trimester of pregnancy. Obstet Gyne col 1985:65:775-780. 44 Mulvihill JJ: Congenital heart defects and prena tal sex hormones (letter). Lancet 1974;i:l 168. 45 Wilson JG, Brent RL: Are female sex hormones teratogenic? Am J Obstet Gynecol 1981:141:567580. 46 Slone D, Siskind V. Heinonen OP. et al: Aspirin and congenital malformations. Lancet 1976:i: 1373-1375. 47 Wcrelcr MM, et al: The relation of aspirin use during the first trimester of pregnancy to congeni tal cardiac defects. N Engl J Med 1989:321:16391642. 48 Chasnoff 1.1. Hatcher R. Burns WJ: Polydrug and methadone addicted newborns: A continuum of impairment? Pediatrics 1982;5:1083-1084. 49 Ostrca EM. Chavez CJ: Perinatal problems (ex cluding neonatal wilhdrawl) in maternal drug ad diction: A study of 830 cases. J Pediatr 1979:94: 292-295. 50 Chasnoff IJ. Burns WJ. Schnoll SH. et al: Cocaine use in pregnancy. N Engl J Med 1985:313:666— 669. 51 Bingol N: Teratogenicity of cocaine in humans. J Pediatr 1987:110:93-96. 52 Ora AS. Dixon SD: Perinatal cocaine and methamphetamine exposure: Maternal and neonatal correlates. .1 Pediatr 1987; 11 1:571-578. 53 Hoyme HE: Maternal cocaine use and fetal vascu lar disruption. Am J Hum Genet I988:43:A56. 54 Chavez GF: Maternal cocaine use and the risk for genitourinary tract defects: An epidemiologic ap proach. Ann J Hum Genet I988;43:A43. 55 Kim SN. Octrcrc JA. Fitzgerald JE. el al: Teratol ogy studies of amenantronc acetate in pregnant rats and rabbits. Teratology 1984:29:41 A.
25
56 Narama I: Reproduction studies of dillorasone diacetate (DDA). teratogenicity. Studies in rabbits by percutaneous admininstration. Oyo Yakuri 1984:28:241-250. 57 Gunzel P. El Etreby ME. Bhargava AS. et al: Tierexperimentelle Vcrtraglichkeitspriifung von Diflucocortolonvalerianat als reincr Wirkstoff und als Salbe. Fettsalbe und Creme. Arzneiniittelforschung 1976:26:1476-1479. 58 Yamada T, Nogariya R, Ichikawa A, el al: Repro ductive studies of hydrocortisone 17-bulyrate 21propionate in rats and rabbits. Oyo Yakuri 1981: 21:477-482. 59 Koga T. Ota T. Aoki Y. et al: Reproductive stud ies of prednisolone 17-valerate 21-acetate terato logic studies in rabbits. Oyo Yakuri 1980:20:87— 98. 60 Shinpo D. Mori N. Takahashi M. et al: Reproduc tive studies of clobetasone 17-butyrate (SN-203). Kiso to Rinsho 1980:14:333-379. 61 Khera KS: Teratogenicity studies with methotrex ate. aminopterin. and acetylsal¡cyclic acid in domestic cats. Teratology 1976:14:21-28. 62 Warkany J. Takacs E: Experimental production of congenital malformations in rats by salicylate poi soning. Am .1 Pathol 1959:35:315-331. 63 McKeown T. MacMahon B. Record RG: An in vestigation of 69 cases of exomphalos. Am J Hum Genet 1953:5:168-175. 64 Firor HV: Omphalocele - An appraisal of thera peutic approaches. Surgery 1971:69:208-214. 65 Miholic J. Wurnig P. Hopfgartner L: Prognostisch bedeutsame Faktoren bei Gastroschisis und Omphalozelc. Z Kindcrchir 1981:34:235-241. 66 l.afferty PM. Fmmerson AJ. Fleming PJ. et al: Anterior abdominal wall defects. Arch Dis Child 1989:64:1029-1031. 67 McBride WG. Vardy PH. French J: Effects of sco polamine hydrobromide on the development of the chick and rabbit embryo. Aust .1 Biol Sci 1982: 35:173-178. 68 Fisher CJ. Sawyer RH: The effect of triamcino lone on the bursa of Fabricius in chick embryos. Teratology 1980:22:7-12. 69 Schardein JL, Rcutncr TF, Fitgeral JF. et al: Ca nine teratogencsis with an estrogen antagonist. Teratology 1973;7:199-204. 70 Shah RM. Burdett DN: Developmental abnormal ities induced by 6-mcrcaptopurine in the hamster. Can J Physiol Pharmacol 1979:57:1229-1232.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Gastroschisis: Environmental Factors
71 Shah RM, Burden DN, Donaldson D: The effect of nitrous oxide on the developing hamster em bryo. Can J Pharmacol 1979;57:1229-1232. 72 Hoffman DJ. Moore JM: Teratogenic effects of external egg application of methyl mercury in the mallard. Anasplatyrhynchos. Teratology 1979:20: 453-461. 73 Barbiéri O. Ognio F„ Rossi O. ct al: Embryotoxicity of bcnzo(a)pyrenc and some of its synthetic derivatives in Swiss mice. Cancer Res 1986:46: 94-98. 74 Seller MJ. Perkins KJ: Effect of hydroxyurea on neural tube defects in the curly tail mouse. J Craniofac Genet Dev Biol 1983:3:11-17. 75 Nomura T, Isa Y, Sakammoto Y: Teratogenicity of aminopvrine and its molecular compound with barbital. Toxicology 1981:29:281-291. 76 Deli E, Varnagy L: Tcratological examination of Wofatox 50 EC (50% methylparathion) on pheas ant embryos. Anal Anz 1985:158:237-240. 77 Szabo KT. DeEebbo ME. Phelan DG: The effects of gold-containing compounds on pregnant rab bits and their fetuses. Vet Pathol 1978: 15(suppl 5):97—102. 78 Dessesso JM: Lectin teratogenesis: Defects pro duced by concanavalin A in fetal rabbits. Teratol ogy 1979:19:15-26. 79 Thompson DJ. Molello JA. Strobing RJ, ct al: Reproduction and tcratological studies with !-(2chloroethyl)-3-cyclohexyl-l-nitrosurea (CCNU) in the rat and rabbit. Toxicol Appl Pharm 1975:34: 456-466. 80 Samarawickrama GP. Webb M: The acute toxic ity and teratogenicity of cadmium in the pregnant rat. J Appl Toxicol 1981:1:246-269. 81 Beaudoin AR: Teratogenic action of platinum thymine blue. Life Sci 1982:31:757-762. 82 Minskcr DH. MacDonald JS. Robertson RT. ct al: Mcvalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic Acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzvmeA reductase. Teratology 1983:28:449-456. 83 Fujinaga M. Boden SM: Reproductive and terato genic effects of nitrous oxide, isoflurane and their combinations in Sprague-Dawley rats. Anesthesi ology 1989:67:690-694. 84 Nelson MM. Wright HW. Asling CW. et al: Mul tiple congenital abnormalities resulting from tran sitory deficiency of ptcroylglutamine acid during gestation in the rat. J Nutr 1955:56:349-369.
Drongowski/Smilh/Coran/Klein
85 Warkany J. Takacs E: Congenital malformations in rats from streptonigrin. Arch Pathol 1959:35: 315-331. 86 Edwards MJ: Congenital defects in guinea pigs: Fetal resorptions, abortions and malformations following induced hyperthermia during early gestation. Teratology 1969:2:313-328. 87 Nomura T. Isa Y. Sakamoto Y: Teratogenicity of aminopyrine and its molecular compound with barbital. Toxicology 1981:29:281-291. 88 Takayama Y: Teratogenic effects of anaphylactic immune reaction in mice. Cong Anom 1981:21: 175-186. 89 DiPaola JA. Elis J: The comparison of teratogenic and carcinogenic effects of some carbamate com pounds. Cancer Res 1967:27:1696-1701. 90 Shepard TH, Greenway JC: Teratogenicity of cytochalasin D in the mouse. Teratology 1977: 16:131-136. 91 Mayura K. Smith EE. Clement BA. ct al: Devel opmental toxicity of diacetoxyscirpenol in the mouse. Toxicology 1987:45:245—255. 92 Yoshimura H: Teratogenicity of fiubendazole in rats. Toxicology 1987:43:133-138. 93 Ingalls TH. Avis FR. Curley FJ. et al: Genetic determinants of hypoxia-induced congenital anomalies. J Hcred 1953:44:185-194. 94 Hood RD. I nnes J E. I laves AW: Effects of rubratoxin B on prenatal development in mice. Bull Environ Contam Toxicol 1973:10:200—207. 95 Roussel C. Tuchmann-Duplessis H: Dissociation des actions embryotoxique et tératogène du Tri ton WR 1339 chez les souris. CR Acad Sci 1968; 266:2171-2174. 96 Slott VL. Hales BF: Sodium 2-mercaptoethan sulfonate protection against cyclophosphamideinduced teratogenicity in rats. Toxicol Appl Pharmacol 1986:82:80-86. 97 Sailo H. Kobayashi H, Takcmo S. ct al: Fetal tox icity of benzodiazepines in rats. Res Commun Chem Pathol Pharmacol 1984:46:437-447. 98 Mayura K. Reddy RV, Hayes AW, et al: Embryocidal, fctotoxic and teratogenic effects of ochratoxin A in rats. Toxicology 1982:25:175-185. 99 Davis SD. Nelson T, Shepard TH: Teratogenic ity ofvitamin B* deficiency: Omphalocele, skele tal and neural defects, and splenic hypoplasia. Science 1970:169:1329-1330. 100 Persaud TV: Teratogenic effect of hypoglycin-A. Adv Tcratol 1972:5:77-92.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
26
27
Gastroschisis: Environmental Factors
108 Rowland JM. HendricsAG: Comparative terato genicity of triamcinolone acetonidc. triamcino lone. and cortisol in the rat. Terato Carcinog Muta 1983:3:313-319.
Received: May 27. 1991 Accepted: July 10. 1991 Michael D. Klein, MD Department of Surgery Children's Hospital of Michigan 3901 Beaubien Blvd. Detroit. MI 48201 (USA)
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
101 Brent RL. Franklin JB: Uterine vascular clamp ing: New procedure for the study of congenital malformations. Science 1960:132:89-91. 102 Khera K.S. iverson F: Toxicity of ethylenethiourea in pregnant cats. Teratology 1976; 18:311313. 103 Elis J, DiPaola JA: Aflatoxin B1 induction of malformations. Arch Pathol 1976;83:53-57. 104 Harris SB. Wilson JG. Print/ RH: Embryotoxicily of methyl mercuric chloride in golden ham sters. Teratology 1969:6:139-142. 105 Tachibana M: Effects of irradiation on prenatal development of two in-bred mouse strains. Tera tology 1975:12:227-232. 106 Persaud TVN. Henderson WM: The teratoge nicity of barbital sodium in mice. Arzneimittclforschung 1969:19:1309-1310. 107 Leland TM. Mendelson GF. Steinberg M, et al: Studies on prenatal toxicity and teratology of NN-diethylbenzene sulfonamide. Toxicol Appl Pharmacol 1972:22:315.
Fetal Diagn Thor 1991:6:14-27
Contribution of Demographic and Environmental Factors to the Etiology of Gastroschisis: A Hypothesis Robert A. Drongowski, R. Kendall Smith. Jr.. Arnold G. Coran. Michael D. Klein Section of Pediatric Surgery. C.S. Mott Children’s Hospital, and University of Michigan Medical School, Ann Arbor, Mich.. USA
Key Words. Abdominal wall defect • Gastroschisis • Teratology
Introduction We wish to present the hypothesis that gastroschisis may be caused by environmen tal teratogens. Two events lead us to form this hypothesis. First, the clinical impression of pediatric surgeons is that gastroschisis is becoming more common, and second, there are a large number of studies in experimental teratology which demonstrate that many ex ternal influences on a pregnant animal can produce gastroschisis in its offspring.
Congenital abdominal wall defects are di vided into three categories [1], Omphalocele is a large abdominal wall defect with hernia tion of midgut, liver and other abdominal organs into a translucent sac at the umbilical ring. Children with omphalocele frequently have associated congenital anomalies and generally are not premature. Gastroschisis is a small abdominal w'all defect occurring just to the right of the umbilical cord. There is no sac. and midgut alone appears outside the abdominal wall. Children with gastroschisis
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Abstract. We examined the clinical literature on congenital abdominal wall defects to confirm our impression that gastroschisis had become more common than omphalocele. We then examined the teratology literature and noted that congenital abdominal wall defects were frequently induced by teratogens. This lead us to review the antenatal history of 19 infants with gastroschisis and 54 control infants born with a congenital anomaly unrelated to gastroschisis. When compared to controls, mothers of infants with gastroschisis were more likely to have used aspirin during pregnancy and to have been taking oral contraceptives at the time of conception. Additionally, an increased incidence of illegal drug use (particularly cocaine) was noted among the study mothers. We conclude that gastroschisis is becoming the more common congenital abdominal w'all defect, and that it could be related to exposure to an environmental teratogen.
15
Gastroschisis: Environmental Factors
Table 1. Clinical series distinguishing gastroschisis from omphalocele Series
Last year
Gastroschisis
Omphalocele
n
%
n
07
26 22 31 15 23 13 15 39 33 13 43 12 54
Reference
%
Before 1972 England Michigan Ohio South Africa Australia British Columbia Japan Northern Europe Scandinavia Southern Europe United States California Kentucky
1951 1963 1965 1968 1971 1971 1971 1971 1971 1971 1971 1972 1972
13 07 05 10 02 15 37 01 03 52 20
Average (all areas)
20 29 47 17 70 11 23 75 07 04 379 17
74 78 69 87 77 87 85 61 67 87 57 88 46
(63] [1] [5] [64] [25] [15] [25] [25] [25] [25] [25] [14] [24]
74
26
After 1972
Average (all areas)
1977 1977 1977 1977 1977 1977 1977 1977 1978 1979 1979 1979 1981 1981 1985 1986
12 1 14 12 18 33 59 03 03 19
47 23 36 27
46 25 40 58 57 61 33 33 26 42 45 63 49 23 63 56 44
14 340 18 13 25 38 06 06 54
28 24 21 21
54 75 60 42 43 39 67 67 74 58 55 37 51 77 37 44
[25] [14] [25] [25] [25] [25] [25] [25] [15] [10] [01] [19] [65] [13] [27] [66]
56
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Australia California Japan Mexico Northern Europe Scandinavia Southern Europe United States British Columbia Finland Michigan Utah Austria Spain South Carolina Great Britain
Drongowski/Smith/Coran/Klein
16
are often premature and have associated malformations less frequently than children with omphalocele. Umbilical cord hernia is relatively unusual and consists of a small abdominal wall defect with herniation of midgut into a translucent umbilical cord. While familial cases of these defects have been reported [2. 3] no clear pattern of inher itance exists, and the etiology is considered to be multifactorial. The three defects are distinct enough clinically that different causes are suspected, but the cmbrvological explanations for the defects are speculative [1,4-9],
Prior to 1970, omphalocele was the most frequently reported abdominal wall defect. Since 1970, gastroschisis has become the more common lesion (table 1). The absolute incidence of gastroschisis is reported to be increasing in Finland. Norway, Sweden, Spain and California [10-14] though not in British Columbia and Denmark [15, 16], In experimental teratology, congenital ab dominal wall defects are commonly pro duced; however, they are often simply called umbilical hernia, which is also how they are classified in the Index Medicus. Very few photographs of the abdominal wall defects
Defect
Animal
Teratogen
Author
Ref.
Gastroschisis
Chick
Scopalaminc hydrobromide Triamcinolone acctonidc
McBride et al.. 1982
[67]
Fisher. Sawyer. 1980
[68]
Dog
Estrogen antagonists
Schardein el al„ 1973
[69]
Hamster
6-Mcrcaptopurine Nitrous oxide
Shah. Burdett. 1979 Shah et al„ 1979
[70] [71]
Mallard
Methyl mercury
Hoffman, Moore. 1979
[72]
Mouse
Benzo(a)pyrene Hydroxyurea Pyrabital
Barbiéri et al., 1986 Seller. Perkins. 1983 Nomura et al.. 1981
[73] [74] [75]
Pheasant
Methyl-parathion
Deli. Varnagy. 1985
[76]
Rabbit
Aurothiomalate Concanavalin A Gold thioglucose
Szabo et al.. 1978 Desesso, 1979 Szabo et al.. 1978
[77] [78] [77]
Rat
BCNU Cadmium cis-Platinum Methyl salicylate Mevinolin Nitrous oxide Pteroylglutamic acid Streptonigrin
Thompson et al.. 1975 Samarawickrama, Webb, 1981 Beaudoin. 1982 Warkany. Takacs. 1959 Minsker et al., 1983 Fujinaga et al.. 1989 Nelson et al., 1955 Warkany. Takacs. 1965
[79] [80] [81] [62] [82] [83] [84] [85]
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Table 2. Teratogens causing abdominal wall defects in animal models
Gastroschisis: Environmental Factors
17
Table 2 (continued) Defect
Animal
Teratogen
Author
Ref.
Omphalocele
Guinea pig
Hyperthermia
Edwards. 1969
[86]
Mouse
Aminopyrine Bovine albumin Anaphylaxis Carbamates Cytochalasin D Diacetoxyscirpcnol Flubendazole Hypoxia Rhodamine dyes Triton WR
Nomura et al.. 1981 Takayama. 1981
[87] [88]
DiPaola. Elis. 1967 Shepard. Greenway. 1977 Mayura cl al.. 1987 Yoshimura. 1987 Ingalls et al., 1953 Hood, et al.. 1973 Roussel. Tuchmann-Duplessis 1968
[89] [90] [91] [92] [93] [94] [95]
Rabbit
Amenantrone acetate Dillorasone Diflucortolone valerate Hydrocortisone Prednisolone
Kim et al.. 1984 Narama. 1984 Gunzel et al.. 1976 Yamada et al., 1981 Koga et al.. 1980
[55] [56] [57] [58] [59]
Rat
CCNU Clobetasonc Cyclophosphamide Nitrazepam Ochratoxin A Pyridoxine deficiency Streptonigrin Hypogiycin A Uterine vascular clamping
Thompson et al.. 1975 Shinpo et al.. 1980 Slott. Haies. 1986 Saito et al., 1984 Mayura et al., 1982 Davis et al., 1970 Warkany. Takacs. 1965 Persaud. 1972 Brent. Franklin. I960
[79] [60] [96] [97] [98] [99] [85] [100] [101]
Cat
Ethylene thiourea
Khera, Iverson. 1978
[102]
Hamster
Aflatoxin B| Methyl mercuric chloride
Elis, Dipaolo. 1967 Harris et al.. 1969
[103] [104]
Mouse
Microwave radiation Sodium barbital
Tachibana. 1977 Persaud. Henderson. 1969
[105] [106]
Rabbit
Aurothiomalate Hydrocortisone
Szabo et al.. 1978 Yamada et al.. 1981
VI]
Acetylsalicylic acid Cadmium N-N-Diethylbenzene sulfonamide Triamcinolone acetonide
Khera, 1976 Samarawickrama. Webb, 1981 Lcland et al.. 1972
[611 [80] [107]
Rowland. Hendries. 1983
[108]
Rat
[58]
BCNU - N.N,-bis(2-chloroethyl)-N-nitrosourea: CCNU - l-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Umbilical hernia
18
Drongowski/Smith/Coran/KJcin
are available in the teratology literature. When they are available it is apparent that teratologists use terms differently from clini cians. Anomalies which are clearly gastroschisis to a pediatric surgeon can be called omphalocele by a leratologist. Some of the anomalies produced in animals by terato gens bear little resemblance to anomalies seen in humans born alive, such as a large defect with no sac and no rectus muscles and the liver included in the defect. We have tried to classify the defects reported in ani mals by current clinical terms in table 2, although it is our impression that most of the abdominal wall defects produced in animals are gastrosehisis. These epidemiological and teratological observations prompted us to investigate the effect of demographic and environmental conditions on the development of gastroschisis.
demographic questions, as well as questions related to maternal and reproductive history and maternal exposure to suspected environmental toxins related to the pregnancy. All questions were related to first trimester exposures, since that is the postulated time period when the embryologie events responsible for gastrosehisis occur. After thorough follow-up of ini tial nonresponders. 19 questionnaires were returned by case mothers and 54 by control mothers. There was no difference in response rate. Hospital charts of all case and control patients who responded were reviewed. The mother’s hospital chart was reviewed when available. On the questionnaires, mothers were given three choices: 'yes', ‘no- and ‘don't know’. Therefore, some of the items do have missing data, and the negative responses are definite answers, not simply an assumption based on the lack of informa tion. Statistical analysis was performed using Student's t test and Fisher’s exact test, p values less than 0.05 were considered significant.
Materials and Methods Thirty-three infants with a confirmed diagnosis of gastrosehisis were treated at C.S. Mott Children's Hospital between January 1978 and April 1983. Dur ing the same period. 19 newborns with omphalocele were treated. Mothers of 19 infants with gastrosehisis responded to a questionnaire distributed in 1983 and comprised the study group. A control group of infants was derived from children treated at the same hospi tal during the same time period, who had a congenital anomaly and were born within 3 months of a study group infant. The control group was drawn from 105 children and excluded infants with intestinal atresia because of the reported increased incidence of this anomaly in children with gastrosehisis [17, 18]. A group with congenital malformations was chosen to control for the potential reporting bias which may occur with normal healthy controls. The distribution of anomalies in the control group is presented in table 3. The questionnaire was sent to mothers of control and case infants, and included social and
Anomaly
Cases
Congenital heart disease Down's syndrome Respiratory system Diaphragmatic hernia Spleen Tracheoesophageal fistula Hirschsprung’s disease Anal atresia Renal agenesis Undescended testicle Bladder exstrophy Orthopedic Neural tube Microcephaly Hydrocephalus Coloboma Greater than two anomalies Unknown
16 4 3 1 1 3 2 2 i i i 3 2 2 i 7 7 2
Total cases
54
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Table 3. Congenital anomalies in the control group
19
Results Social and demographic data on the gas troschisis study group and control infants are presented in table 4. The average age of mothers of infants with gastroschisis was sig nificantly less (23.2 ± 4.8 years) than the average age of mothers of control infants (26.7 ± 5.8 years) (p < 0.022 by Student’s t
Table 4. Distribution of social and demographic factors in the gastroschisis and control groups Variable
Study patients
Control patients
n
%
n
%
08 11
42 58
31 23
57 43
18 01
94 05
51 03
94 07
10 09
53 47
11 43
20* 80
03 12 04 00
16 63 21 00
04 26 16 08
07 48 30 15
Infant .sex Male Female
Infant race White Black
Maternal age 2 2 Years
Maternal education 9 Years 12 Years Vocaiional/eollege Graduate school
Income level o f household, S/year 32 < 12.000 06 12.000-30,000 > 30.000
13 00
68 00
17 23 10
35 45 20
10 09
54 46
16 33
33 67
Size of community Population < 10.000 Population > 10.000
* p < 0.05 vs. the study patients. Fisher's exact test.
test). A greater proportion of control moth ers (30%) had post-secondary education compared to study group mothers (21%). Similarly, control mothers were more likely to have household incomes greater than $30,000 per year (20 vs. 0%) and to live in towns with populations greater than 30.000 (67 vs. 44%). Both groups were 94% white and 6%black, and there was no difference in the sex ratios between the two groups. The mean birth weight of the gastroschisis pa tients (2.49 ± 0.38 kg) was less (p < 0.001 by Student's t test) than that of the control infants (3.23 ± 0.61 kg). The maternal medical history of study group and control group mothers was unre markable. No differences were evident in parity, gravidity, menstrual history nor in the history of diabetes, hypertension, anemia or liver disease. Maternal medical problems during preg nancy were also not remarkable. There were no differences in vaginal bleeding, hyperten sion, anemia, toxemia, or edema between control and study groups. There were no differences between study group mothers in the use of cigarettes, cof fee, tea. cola or alcohol. There were also no differences in exposure to environmental substances at the work place during the first trimester of pregnancy between the study group and control mothers. There was no difference in infections dur ing pregnancy, with an incidence of 44% among study group mothers as compared to 43% in the control group mothers. Control group mothers, however, had more influenza (44%) and fewer urinary tract infections (25%) than mothers in the study group (0 and 62%, respectively). There were no dif ferences in pneumonia, vaginal infections or genital herpes (table 5).
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Gastroschisis: Environmental Factors
Drongowski/Smilh/Coran/KIcin
20
Sixty-seven percent of the mothers of in fants with gastroschisis had planned their pregnancy while only 52% of the control mothers had planned their pregnancy. There were no differences between study group and control group mothers in the use of dia phragms. spermicides (foam), intrauterine devices or condoms. Study group mothers were 2.6 times more likely to have used oral contraceptives during early pregnancy than controls (table 6). The difference (68 vs. 26%) is statistically significant (p < 0.0014 by Fisher’s exact test).
Maternal medications during the first tri mester of pregnancy are presented in table 7. The only statistically significant difference was in aspirin use between the study group (62%) and control group (20%) mothers (p < 0.0033 by Fisher's exact test). There was a positive correlation between illegal drug use and gastroschisis in this study. Forty-seven percent of study group mothers used illegal drugs compared to 21 % of the control mothers (p < 0.05 by Fisher’s exact test). These data are further presented in table 8.
Table 5. Maternal infections during pregnancy in the gastroschisis and control groups
Table6. Birth control methods employed prior to pregnancy in gastroschisis and control groups
Variable
Variable
Study group
Control group
n
%
n
%
08 10
44 56
23 30
43 57
05 03
62 38
06 18
25 75
00 08
00 100
03 20
13 87
00 08
00 100
10 13
44* 56
03 05
38 62
10 13
44 56
00 08
00 100
01 22
04 96
Infections
*
Planned Unplanned
12 06
67 33
27 25
52 48
Positive Negative
13 06
68 32
14 40
26* 74
Positive Negative
01 18
05 95
07 46
13 87
Positive Negative
05 95
04 49
08 92
00 19
00 100
06 47
11 89
02 17
10 90
11 42
21 79
01 18
Intrauterine device Positive Negative
Condom
Genital herpes Positive Negative
%
Spermicide (foam)
Vaginal infections Positive Negative
n
Diaphragm
Influenza Positive Negative
%
Oral contraceptives
Pneumonia Positive Negative
n
Pregnancy
Urinary tract Positive Negative
Control group
p < 0.05 vs. the study group. Fisher's exact test.
Positive Negative
* p < 0.0014 vs. the study group. Fisher’s exact test.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Positive Negative
Study group
Gastroschisis: Environmental Factors
21
Discussion Lower birth weight, younger maternal age and lower household income among infants with gastroschisis have been noted in other studies [1, 19-21]. Whether these are di-
'I'ablc 7. Maternal medications during the first tri mester of pregnancy in the gastroschisis and control groups Variable
Study group
Control group
n
%
n
%
00 100
01 40
02 98
Prescribed medications
rectly related to the anomaly or simply re flect the known social and demographic fac tors of prematurity is unclear. The relation ship of gastroschisis to prematurity is also unclear. The presence of uncovered abdomi nal contents in the amniotic fluid may be a stimulus for uterine contraction, but if it is, one would not expect the other factors re lated to prematurity to be so predominant. Moore and Stokes [22] are credited with creating, in 1953. the first standardized clas sification of gastroschisis and omphalocele.
Table 8. Illegal drug ingestion during the first tri mester of pregnancy in gastroschisis and control groups
Insulin 00 16
Variable
Morning sickness medication Positive Negative
03 13
19 81
10 30
25 75
Illegal drug use
04 12
25 75
07 34
17 83
Marijuana
06 94
02 38
05 95
Antibiotics Positive Negative
Allergy medication Positive Negative
01 15
Non-prescribed medications
Tylenol Positive Negative
50 50
18 22
45 55
02 14
12 88
08 32
20 80
n
%
n
%
08 09
47 53
11 41
21* 79
07 01
88 12
09 02
83 17
00 08
00 too
01 10
09 91
03 05
38 62
00 11
00** 100
01 07
12 88
00 11
00 100
00 08
00 100
01 10
09 91
Hashish Positive Negative
10 06
62 38
08 32
20* 80
Positive Negative
LSD
Aspirin Positive Negative
Positive Negative
Control group
Cocaine 08 08
Antacids Positive Negative
Positive Negative
Study group
Positive Negative
Amphetamines
* p < 0.0033 vs. the study group. Fisher'si exact test.
Positive Negative
* p < 0.05. ** p < 0.057. vs. the study group. Fisher’s exact test.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Negative Positive
There are very few earlier reports of gastroschisis, although Bernstein [23] used the word in 1940. Since that time, many authors have noted an apparent increase in the inci dence of gastroschisis [1, 11-14. 24-26], In table 1, several representative series are given in which the current clinical defini tion could be determined even if it was not specifically stated. In reports prior to 1973, gastroschisis represented 26% of abdominal wall defects, while after 1974 it represented 44% of such defects. In some centers (British Columbia), gastroschisis still represents a minority of defects (26%). while in others (South Carolina and Utah), it has become the most common defect (63%) [15, 19. 27], In our recent experience reported here, gastroschisis accounted for 65% of the new born abdominal wall defects. There is some question as to whether this increase in the proportion of patients with congenital abdominal wall defects who have gastroschisis reflects an increase in the abso lute incidence of congenital abdominal wall defects, with most of the increase being re presented by gastroschisis, or whether it is due to a concomitant decrease in the inci dence of omphalocele and umbilical cord hernia [12]. Several hypotheses might ex plain this increase in the number of patients with gastroschisis. Gastroschisis is known to occur in smaller and more premature babies, so it may be that children with this defect in the past did not live long enough to be seen by pediatric surgeons. Clementi et al. [28] sug gested that gastroschisis may be underre ported, since nearly half of the children in their group with omphalocele or gastroschi sis were either stillborn or died immediately after birth. With the advent of neonatal in tensive care units in the 1970s, more very ill
Drongowski/Smith/Coran/KIein
infants are surviving to be examined by pe diatric surgeons. This explanation seems un likely since, while it is true that the outcome in general has been better for premature infants in recent years, this increased sur vival is mainly in the very low birth weight category in which gastroschisis is not very common [29], Also, the number of serious congenital malformations in all infants may actually be decreasing [30-32]. A second explanation is that the defects of omphalocele and gastroschisis were not clearly distinguished from each other in all centers until recently. Yet this also appears an unlikely explanation. It is clear from var ious reports, such as those of Bernstein [23] in 1940, Massabuau and Guibal [33] in 1933. Reed [34] in 1913, and even Pare [35] in 1634. that gastroschisis was clearly iden tifiable prior to 1970, even though it was most often called an antenatal rupture of an omphalocele. We took this into account when compiling table 1. and still found a greater proportion of omphaloceles before 1970. A third explanation for the increased inci dence of gastroschisis is the introduction of a new environmental teratogen. Others have speculated that such a factor, having a high exposure rate but a low efficiency, might be responsible [19], and our data support this hypothesis. The use of oral contraceptives, aspirin and illegal drugs as well as occupational ex posure to toxins have been suggested as pos sible candidates. In 1979. Gicrup and Lundkvist [36], compared prenatal histories of mothers of infants born with gastroschisis and omphalocele, concluding that mothers of infants born with gastroschisis or ompha locele were more likely to have been exposed to drugs or chemicals in a work environ-
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
22
Gaslroschisis: Environmental Factors
result of numerous factors acting together, perhaps in this case, numerous drugs. Additional evidence that gastroschisis may result from teratogen exposure during pregnancy comes from the wide variety of compounds which have been used to create the condition in animal models (table 2). Numerous animal studies have demon strated the production of abdominal wall defects by steroids (ametantrone. diflorasonc. diflucortolone, hydrocortisone, pred nisolone and clobetasone) [55-60], and two studies have demonstrated that they can be caused by salicylates [61. 62]. We conclude that gastroschisis has be come the more common congenital abdomi nal wall defect, and that gastroschisis in ani mals is frequently caused by chemical terato gens. In addition, environmental teratogens including birth control pills, illegal drugs (particularly cocaine) and aspirin may be contributory factors in the increase in the relative incidence of gastroschisis.
References 1 Klein MD. Hertzler JH: Congenital defects of the abdominal wall. JAMA 1981:245:1543-1546. 2 Havalad S. Noblett H. Speidel BD: Familial oc currence of omphalocele suggesting sex-linked in heritance. Arch Dis Child 1979:54:142-149. 3 Hershey DW. Haesslevn HC. Adkins JC: Familial abdominal wall defects. Am J Med Genet 1989; 34:174-176. 4 Duhamel B: Embryology of exomphalos and al lied malformations. Arch Dis Child 1963:38:142147. 5 l/.ant RJ. Brown F, Rothman BE: Current em bryology and treatment of gastroschisis and om phalocele. Arch Surg 1966:93:49-53. 6 Shaw A: The myth of gastroschisis. .1 Pediatr Surg 1975:10:235-244. 7 deVries PA: the pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 1980:15:245-251.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
ment. Hoyne et al. [8] have suggested that intrauterine interruption of blood How in the omphalomesenterie artery may be responsi ble for the development of gastroschisis as compared to omphalocele. Sarda and Bard [37] presented a case of gastroschisis in which they believe that maternal alcohol consumption may have been responsible for decreasing blood flow in the fetus, subse quently resulting in gastroschisis. If the vas cular etiology of gastroschisis is in fact cor rect, cocaine might be expected to cause gas troschisis as it too is a vasoconstrictor. While our series suggests that oral contra ceptives, aspirin and illegal drugs might be implicated in the etiology of gastroschisis, the numbers of patients arc certainly too small to do anything but suggest that this might be a fruitful area for further investiga tion. In addition, many clinical studies have failed to show an increase in congenital mal formations among the children of mothers who used sex hormones [38-45] or aspirin [46, 47], Until recently, there was also little evi dence relating congenital anomalies to the use of illegal drugs during pregnancy [48. 49]. It is not biologically plausible that illegal drugs as a class are responsible for a single anomaly. They may, however, serve as a marker for some teratogenic agent, perhaps cocaine. Cocaine use during pregnancy has been associated with increased incidences of skull defects, urinary tract and genital mal formations as well as intestinal obstruction or atresia [50-54], Still, while looking for a single agent it must be remembered that most authorities feel teratogenicity in gen eral is multifactorial. It is unlikely that a sin gle factor will reach a threshold necessary for development of an anomaly, rather the out come of a pregnancy is more probably the
23
Drongowski/Smith/Coran/Klein
8 Hoyme HE. Higginbotlom MC, Jones KL: The vascular pathogenesis of gastroschisis: Intrauter ine interruption of the omphalomesenteric artery. J Pediatr 1981:98:228-231. 9 Glick PL. Harrison MR. Adzick NS. ct al: The missing link in the pathogenesis of gastroschisis. J Pediatr Surg 1985:20:406-409. 10 Gierup J, Lundkvist K: Gastroschisis: A pilot study of its incidence and the influence of terato genic factors. Z Kinderchir 1979:1:39-42. 11 Egcnaes J, Bjerkedal T: Forekomst av gastroschi sis og omfalocele i Norge 1967-1979. Tidsskr Nor Lacgcforen 1982:102:172-176. 12 Lindham S: Omphalocele and gastroschisis in Sweden 1965-1976. Acta Paediatr Scand 1981; 70:55-60. 13 Martinez-Frias ML. Salvador J. Prieto L. Zaplana J: Epidemiological study of gastroschisis and om phalocele in Spain. Teratology 1984:295:377382. 14 Roeper PJ. Harris J. Lee G. et al: Secular rates and correlates for gastroschisis in California (19681977). Teratology 1987;35:203-210. 15 Baird PA. MacDonald F.C: An epidemiologic study of congenital malformations of the anterior abdominal wall in more than half a million con secutive live births. Am J Hum Genet 1981:33: 470-478. 16 Bugge M, Haugc M: Gastroschisis og omphalocele i Danmark. Ugcskr Laeger 1983:145:1323-1327. 17 Hrabovsky EE. Boyd JB. Savrin RA: Advances in the management of gastroschisis. Ann Surg 1980; 192:244-248. 18 Pokorny WJ. Harberg FJ. McGill GW: Gastro schisis complicated by intestinal atresia. J Pediatr Surg 1981:16:261-263. 19 Lindham S: Long-term results in children with omphalocele and gastroschisis - A follow up study. Z Kinderchir 1984:39:164—167. 20 Colombani PM. Cunningham MD: Perinatal as pects of omphalocele and gastroschisis. Am J Dis Child 1977:131:1386-1388. 2 1 Mayer T. Black R. Matlak M E. et al: Gastroschisis and omphalocele. An eight year review. Ann Surg 1980:192:783-787. 22 Moore TC. Stokes CE: Gastroschisis: Report of two cases treated by a modification of the Gross operation for omphalocele. Surgery 1953:33:112120.
23 Bernstein P: Gastroschisis. A rare teratological condition in the newborn. Arch Pediatr 1940:57: 505-513. 24 Hollabaugh RS, Boles ET: The management of gastroschisis. J Pediatr Surg 1973:8:263—270. 25 Moore TC. Khalid N: An international survey of gastroschisis and omphalocele (490 cases). Pediatr Surg Int 1986;1:46-50. 26 International Clearinghouse for Birth Defects. Annual Report. 1981. Stockholm: Swedish Na tional Board of Health and Welfare. 1983. p 39. 27 Otherson HB. Smith CD: Pneumatic reduction bag for treatment of gastroschisis and omphalo cele - A 10-year experience. Ann Surg 1986:203: 512-516. 28 Clementi M. Tcnconi R. Turolla L: Further inves tigations when abdominal wall defects are diag nosed in utero. Lancet 1983:ii: 1083—1084. 29 Cole CH: Prevention of prematurity: Can we do it in America? Pediatrics 1985:76:310-312. 30 Hack M. Fanaroff AA. Merkatz 1R: Current con cepts: The low birth weight infant - Evolution of a changing outlook. N Engl J Med 1979:30:255— 256. 31 Carr-Hill RA. Hall MH: The repetition of sponta neous pre-term labor. Br J Obstet Gynaecol 1985: 313:666-669. 32 Alberman E: Why are stillbirth and neonatal mor tality rates continuing to fall? Br J Obstet Gynae col 1985:92:559-564. 33 Massabuau G. Guibal A: L'éviscération ombili cale congénitale. Arch Fr Mal Appar Dig 19.33:23: 129-150. 34 Reed EN: Infant disemboweled at birth - Appen dectomy successful. JAMA 1913:61:199. 35 Pare A: The Works of That Famous Chirurgeon. London, Cotes & Young. 1634. book 24. p 59. 36 Gierup .1. Lundkvist K: Gastroschisis: A pilot study of its incidence and the influence of terato genic factors. Z Kinderchir 1981:1:39-42. 37 Sarda P. Bard H: Gastroschisis in a case of dizy gotic twins: The possible role of maternal alcohol consumption. Pediatrics 1981:74:94-96. 38 Kasan PN. Andrew's J: The effects of recent oral contraceptive use on the outcome of pregnancy. Fur J Obstet Gynecol Reprod Biol 1986:22:77— 83. 39 Oakley GP. Flint JW: Hormonal pregnancy test and congenital malformations. Lancet I973:ii: 256-257.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
24
40 Harlap S. Shiono PH. Ramcharan S: Congenital abnormalities in the offspring of women who used oral and other contraceptives around the time of conception. Int J F'ertil 1985;30:39-47. 41 Resseguie IJ: Congenital malformations among offspring exposed in utero to progestins. Olmstead County. Minnesota. 1936-1974. Fertil Steril 1985:43:514-519. 42 Bracken MB: Oral contraception and congenital malformations in offspring: A review and meta analysis of the prospective studies. Obstet Gyne col 1990:76:552-557. 43 Katz Z: Teratogenicity of progcstogcns given dur ing the first trimester of pregnancy. Obstet Gyne col 1985:65:775-780. 44 Mulvihill JJ: Congenital heart defects and prena tal sex hormones (letter). Lancet 1974;i:l 168. 45 Wilson JG, Brent RL: Are female sex hormones teratogenic? Am J Obstet Gynecol 1981:141:567580. 46 Slone D, Siskind V. Heinonen OP. et al: Aspirin and congenital malformations. Lancet 1976:i: 1373-1375. 47 Wcrelcr MM, et al: The relation of aspirin use during the first trimester of pregnancy to congeni tal cardiac defects. N Engl J Med 1989:321:16391642. 48 Chasnoff 1.1. Hatcher R. Burns WJ: Polydrug and methadone addicted newborns: A continuum of impairment? Pediatrics 1982;5:1083-1084. 49 Ostrca EM. Chavez CJ: Perinatal problems (ex cluding neonatal wilhdrawl) in maternal drug ad diction: A study of 830 cases. J Pediatr 1979:94: 292-295. 50 Chasnoff IJ. Burns WJ. Schnoll SH. et al: Cocaine use in pregnancy. N Engl J Med 1985:313:666— 669. 51 Bingol N: Teratogenicity of cocaine in humans. J Pediatr 1987:110:93-96. 52 Ora AS. Dixon SD: Perinatal cocaine and methamphetamine exposure: Maternal and neonatal correlates. .1 Pediatr 1987; 11 1:571-578. 53 Hoyme HE: Maternal cocaine use and fetal vascu lar disruption. Am J Hum Genet I988:43:A56. 54 Chavez GF: Maternal cocaine use and the risk for genitourinary tract defects: An epidemiologic ap proach. Ann J Hum Genet I988;43:A43. 55 Kim SN. Octrcrc JA. Fitzgerald JE. el al: Teratol ogy studies of amenantronc acetate in pregnant rats and rabbits. Teratology 1984:29:41 A.
25
56 Narama I: Reproduction studies of dillorasone diacetate (DDA). teratogenicity. Studies in rabbits by percutaneous admininstration. Oyo Yakuri 1984:28:241-250. 57 Gunzel P. El Etreby ME. Bhargava AS. et al: Tierexperimentelle Vcrtraglichkeitspriifung von Diflucocortolonvalerianat als reincr Wirkstoff und als Salbe. Fettsalbe und Creme. Arzneiniittelforschung 1976:26:1476-1479. 58 Yamada T, Nogariya R, Ichikawa A, el al: Repro ductive studies of hydrocortisone 17-bulyrate 21propionate in rats and rabbits. Oyo Yakuri 1981: 21:477-482. 59 Koga T. Ota T. Aoki Y. et al: Reproductive stud ies of prednisolone 17-valerate 21-acetate terato logic studies in rabbits. Oyo Yakuri 1980:20:87— 98. 60 Shinpo D. Mori N. Takahashi M. et al: Reproduc tive studies of clobetasone 17-butyrate (SN-203). Kiso to Rinsho 1980:14:333-379. 61 Khera KS: Teratogenicity studies with methotrex ate. aminopterin. and acetylsal¡cyclic acid in domestic cats. Teratology 1976:14:21-28. 62 Warkany J. Takacs E: Experimental production of congenital malformations in rats by salicylate poi soning. Am .1 Pathol 1959:35:315-331. 63 McKeown T. MacMahon B. Record RG: An in vestigation of 69 cases of exomphalos. Am J Hum Genet 1953:5:168-175. 64 Firor HV: Omphalocele - An appraisal of thera peutic approaches. Surgery 1971:69:208-214. 65 Miholic J. Wurnig P. Hopfgartner L: Prognostisch bedeutsame Faktoren bei Gastroschisis und Omphalozelc. Z Kindcrchir 1981:34:235-241. 66 l.afferty PM. Fmmerson AJ. Fleming PJ. et al: Anterior abdominal wall defects. Arch Dis Child 1989:64:1029-1031. 67 McBride WG. Vardy PH. French J: Effects of sco polamine hydrobromide on the development of the chick and rabbit embryo. Aust .1 Biol Sci 1982: 35:173-178. 68 Fisher CJ. Sawyer RH: The effect of triamcino lone on the bursa of Fabricius in chick embryos. Teratology 1980:22:7-12. 69 Schardein JL, Rcutncr TF, Fitgeral JF. et al: Ca nine teratogencsis with an estrogen antagonist. Teratology 1973;7:199-204. 70 Shah RM. Burdett DN: Developmental abnormal ities induced by 6-mcrcaptopurine in the hamster. Can J Physiol Pharmacol 1979:57:1229-1232.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
Gastroschisis: Environmental Factors
71 Shah RM, Burden DN, Donaldson D: The effect of nitrous oxide on the developing hamster em bryo. Can J Pharmacol 1979;57:1229-1232. 72 Hoffman DJ. Moore JM: Teratogenic effects of external egg application of methyl mercury in the mallard. Anasplatyrhynchos. Teratology 1979:20: 453-461. 73 Barbiéri O. Ognio F„ Rossi O. ct al: Embryotoxicity of bcnzo(a)pyrenc and some of its synthetic derivatives in Swiss mice. Cancer Res 1986:46: 94-98. 74 Seller MJ. Perkins KJ: Effect of hydroxyurea on neural tube defects in the curly tail mouse. J Craniofac Genet Dev Biol 1983:3:11-17. 75 Nomura T, Isa Y, Sakammoto Y: Teratogenicity of aminopvrine and its molecular compound with barbital. Toxicology 1981:29:281-291. 76 Deli E, Varnagy L: Tcratological examination of Wofatox 50 EC (50% methylparathion) on pheas ant embryos. Anal Anz 1985:158:237-240. 77 Szabo KT. DeEebbo ME. Phelan DG: The effects of gold-containing compounds on pregnant rab bits and their fetuses. Vet Pathol 1978: 15(suppl 5):97—102. 78 Dessesso JM: Lectin teratogenesis: Defects pro duced by concanavalin A in fetal rabbits. Teratol ogy 1979:19:15-26. 79 Thompson DJ. Molello JA. Strobing RJ, ct al: Reproduction and tcratological studies with !-(2chloroethyl)-3-cyclohexyl-l-nitrosurea (CCNU) in the rat and rabbit. Toxicol Appl Pharm 1975:34: 456-466. 80 Samarawickrama GP. Webb M: The acute toxic ity and teratogenicity of cadmium in the pregnant rat. J Appl Toxicol 1981:1:246-269. 81 Beaudoin AR: Teratogenic action of platinum thymine blue. Life Sci 1982:31:757-762. 82 Minskcr DH. MacDonald JS. Robertson RT. ct al: Mcvalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic Acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzvmeA reductase. Teratology 1983:28:449-456. 83 Fujinaga M. Boden SM: Reproductive and terato genic effects of nitrous oxide, isoflurane and their combinations in Sprague-Dawley rats. Anesthesi ology 1989:67:690-694. 84 Nelson MM. Wright HW. Asling CW. et al: Mul tiple congenital abnormalities resulting from tran sitory deficiency of ptcroylglutamine acid during gestation in the rat. J Nutr 1955:56:349-369.
Drongowski/Smilh/Coran/Klein
85 Warkany J. Takacs E: Congenital malformations in rats from streptonigrin. Arch Pathol 1959:35: 315-331. 86 Edwards MJ: Congenital defects in guinea pigs: Fetal resorptions, abortions and malformations following induced hyperthermia during early gestation. Teratology 1969:2:313-328. 87 Nomura T. Isa Y. Sakamoto Y: Teratogenicity of aminopyrine and its molecular compound with barbital. Toxicology 1981:29:281-291. 88 Takayama Y: Teratogenic effects of anaphylactic immune reaction in mice. Cong Anom 1981:21: 175-186. 89 DiPaola JA. Elis J: The comparison of teratogenic and carcinogenic effects of some carbamate com pounds. Cancer Res 1967:27:1696-1701. 90 Shepard TH, Greenway JC: Teratogenicity of cytochalasin D in the mouse. Teratology 1977: 16:131-136. 91 Mayura K. Smith EE. Clement BA. ct al: Devel opmental toxicity of diacetoxyscirpenol in the mouse. Toxicology 1987:45:245—255. 92 Yoshimura H: Teratogenicity of fiubendazole in rats. Toxicology 1987:43:133-138. 93 Ingalls TH. Avis FR. Curley FJ. et al: Genetic determinants of hypoxia-induced congenital anomalies. J Hcred 1953:44:185-194. 94 Hood RD. I nnes J E. I laves AW: Effects of rubratoxin B on prenatal development in mice. Bull Environ Contam Toxicol 1973:10:200—207. 95 Roussel C. Tuchmann-Duplessis H: Dissociation des actions embryotoxique et tératogène du Tri ton WR 1339 chez les souris. CR Acad Sci 1968; 266:2171-2174. 96 Slott VL. Hales BF: Sodium 2-mercaptoethan sulfonate protection against cyclophosphamideinduced teratogenicity in rats. Toxicol Appl Pharmacol 1986:82:80-86. 97 Sailo H. Kobayashi H, Takcmo S. ct al: Fetal tox icity of benzodiazepines in rats. Res Commun Chem Pathol Pharmacol 1984:46:437-447. 98 Mayura K. Reddy RV, Hayes AW, et al: Embryocidal, fctotoxic and teratogenic effects of ochratoxin A in rats. Toxicology 1982:25:175-185. 99 Davis SD. Nelson T, Shepard TH: Teratogenic ity ofvitamin B* deficiency: Omphalocele, skele tal and neural defects, and splenic hypoplasia. Science 1970:169:1329-1330. 100 Persaud TV: Teratogenic effect of hypoglycin-A. Adv Tcratol 1972:5:77-92.
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
26
27
Gastroschisis: Environmental Factors
108 Rowland JM. HendricsAG: Comparative terato genicity of triamcinolone acetonidc. triamcino lone. and cortisol in the rat. Terato Carcinog Muta 1983:3:313-319.
Received: May 27. 1991 Accepted: July 10. 1991 Michael D. Klein, MD Department of Surgery Children's Hospital of Michigan 3901 Beaubien Blvd. Detroit. MI 48201 (USA)
Downloaded by: University of Chicago Library 205.208.116.24 - 9/18/2017 3:53:23 AM
101 Brent RL. Franklin JB: Uterine vascular clamp ing: New procedure for the study of congenital malformations. Science 1960:132:89-91. 102 Khera K.S. iverson F: Toxicity of ethylenethiourea in pregnant cats. Teratology 1976; 18:311313. 103 Elis J, DiPaola JA: Aflatoxin B1 induction of malformations. Arch Pathol 1976;83:53-57. 104 Harris SB. Wilson JG. Print/ RH: Embryotoxicily of methyl mercuric chloride in golden ham sters. Teratology 1969:6:139-142. 105 Tachibana M: Effects of irradiation on prenatal development of two in-bred mouse strains. Tera tology 1975:12:227-232. 106 Persaud TVN. Henderson WM: The teratoge nicity of barbital sodium in mice. Arzneimittclforschung 1969:19:1309-1310. 107 Leland TM. Mendelson GF. Steinberg M, et al: Studies on prenatal toxicity and teratology of NN-diethylbenzene sulfonamide. Toxicol Appl Pharmacol 1972:22:315.
