Comprehensive Developmental Mechanisms in Gastroschisis

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Original Paper

Fetal Diagn Ther 2014;36:223–230 DOI: 10.1159/000360080

Comprehensive Developmental Mechanisms in Gastroschisis

Frédéric Bargy a Sylvie Beaudoin a–c

a Department of Anatomy and Morphogenesis, Institut d’Anatomie des Saints Pères, Université Paris Descartes, b Department of Pediatric Surgery, Hôpital Saint-Vincent de Paul and c Department of Pediatric Surgery, Hôpital Universitaire Necker Enfants Malades, APHP, Paris , France

considering it as merely a misdiagnosed ruptured om-phalocele [7, 8] . We decided to compare our clinical ex-perience in gastroschisis with observations of normal em-bryos and fetuses, in order to assess normal and abnormal abdominal wall development focused on the umbilical cord.

Material and Methods

Material A total of 50 human embryos ranging from 3 to 11 weeks of

development (WD, weeks from fertilization) were studied ( ta-ble 1 ); 38 were part of institutional collections and were already prepared in serial sections 8 μm thin and stained with hematoxy-lin and eosin (Prof. Barbet, Laboratoire d’Histo-Embryologie de l’UFR Cochin and Prof. Delmas, Institut d’Anatomie des Saints-Pères, Université Paris Descartes). The remaining 12 had been col-lected after miscarriage.

Overall, 71 fetuses ranging from 13 to 32 WD underwent post-mortem examination after fetal demise or termination of preg-nancy according to French law ( table 1 ). None of them was af-fected by gastroschisis. All subjects were studied according to French ethical rules as they existed at the time.

In addition, 143 rabbit embryos harvested from 6.5 to 19.5 days of gestation, matching early stages of human development as pre-viously reported [9] , were included to provide additional sections and pictures when needed ( table 2 ).

In total, 139 cases of gastroschisis were managed between 1982 and 2010 by one of the authors in Hôpital Saint-Vincent de Paul. Medical records, including operative pictures, were reviewed, and in 2 cases the whole edge of the defect had been resected at the time of primary closure, allowing for further histological study. The consent of the parents was obtained in all cases.

Key Words

Gastroschisis · Umbilical cord · Abdominal wall defect · Development

Abstract

Introduction: The development of gastroschisis remains an area of controversy. Various theories have been proposed, but none has ever been supported by a thorough embryo-logical study. Material and Methods: We herein report ana-tomical and microscopic observations of the developing ab-dominal wall and cord of embryos and fetuses, along with clinical features of gastroschisis. Results: It appears that the developing cord normally has two parts, a firm left-sided part formed by the vessels and urachus, and a thin right-sid-ed pouch covering the intestinal loops (the ‘physiological umbilical hernia’), which could rupture, giving the basis of gastroschisis. Discussion: Gastroschisis could be the result of amniotic damage, possibly from some as yet unidentified toxin. Further bowel damage can be explained by the subse-quent mesenteric injury. © 2014 S. Karger AG, Basel

Introduction

Numerous theories have been presented to explain the development of gastroschisis [1–6] . Some authors have even challenged the very existence of such an anomaly,

Received: November 1, 2013 Accepted after revision: January 23, 2014 Published online: August 19, 2014

Dr. Sylvie Beaudoin Service de Chirurgie Pédiatrique Hôpital Universitaire Necker Enfants Malades 149 rue de Sèvres, FR–75015 Paris (France) E-Mail sylvie.beaudoin @ nck.aphp.fr

© 2014 S. Karger AG, Basel1015–3837/14/0363–0223$39.50/0

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Fetal Diagn Ther 2014;36:223–230DOI: 10.1159/000360080

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Methods Microdissection was performed in 10 embryos after 8 WD us-

ing a 16× binocular microscope or 8× magnifying glasses. Addi-tional sagittal or axial sections at the umbilical cord level were carried out on 16 fetuses and 12 embryos (previously fixed in formalin) between 8 and 12 WD. Serial semithin sections (8 μm) in either sagittal or transversal planes were made on 41 embryos embedded in paraffin and then stained with hematoxylin and eo-sin.

All these sections and dissections were photographed with a microscope-connected Zeiss camera when necessary. Newborns were photographed in the operating room before surgery. The pic-tures focused on the defect, its relationship to the umbilical cord and mesenteric and bowel features.

The first pictures were obtained as slides. More recently, nu-meric cameras have been used with high-resolution focus. All the slides were then scanned in high resolution (7,200 pixels per inch) and incorporated into computed files. Adobe Photoshop CS5 ® software was used to create a complete database. The anatomic figures are provided with matching drawings to give a better com-prehension. Stages of development are given according to O’Rahilly and Müller [10] .

In each case we focused on the following: – The amniotic continuity around the embryo and its relation-

ship with both the umbilical cord and the epidermal covering of the embryo

– The anatomy of the peritoneum and its continuity during the development of the midgut

In embryos, special attention was given to the evolution of um-bilical and vitelline veins. In neonates, we studied the relationship between the peritoneum and the margin of the defect, including along the umbilical cord. We also assessed the mesenteric features, with nervous and vascular involvement.

Results

Amniotic Continuity The amniotic membrane arises at 7 days of gestation

(stage 5) surrounded by extra embryonic mesenchyme. The early extension of the amniotic cavity (stages 10–18, 21–44 days) is well seen ( fig. 1 ). The epidermis, proceed-ing from ectoderm, is a single-layer epithelium, continu-ous with the amniotic epithelium at 4 WD. At 7 WD a more superficial layer of periderm appears, which is still in continuity with the amnion until 13 WD ( fig. 2 a).

During the second trimester of gestation (after 20 WD), this periderm desquamates and a real skin epithe-lium appears. The amniotic epithelium remains around the implantation of the umbilical cord and covers the cord itself. The rectus abdominis muscles join in the mid-line along the umbilical vessels and urachus, only parted by the Wharton jelly enclosed within the amniotic epithe-lium. In normal development, the amnion was thus al-ways found continuous with the abdominal wall covering ( fig. 2 b).

In newborns affected by gastroschisis, the defect was always found on the right side of the cord, often with a

Table 1. Distribution of human embryos and fetuses

Period WD Days Stage n

Embryogenesis 3 21 – 28 9 – 13 3Embryogenesis 4 28 – 35 14 – 16 5

Organogenesis 5 36 – 42 17 5Organogenesis 6 43 – 49 18 – 20 5Organogenesis 7 50 – 56 21 – 23 5

Organogenesis and fetal period 8 57 – 63 6Organogenesis and fetal period 9 64 – 70 8Organogenesis and fetal period 10 7Organogenesis and fetal period 11 3

Fetal growth 12 3Fetal growth 13 3Fetal growth 14 4Fetal growth 15 1Fetal growth 16 3Fetal growth 22 5Fetal growth 24 4Fetal growth 26 6Fetal growth 28 18Fetal growth 30 12Fetal growth 32 15

Stages are provided according to O’Rahilly and Müller [10].

Table 2. Distribution of rabbit embryos

Days Stage n

6.5 6 77.5 7 78.5 10 89.5 12 10

10.5 13 1211.5 14 812.5 15 1213.5 16 1814.5 19 815.5 20 1516.5 22 917.5 23 1118.5 23 1119.5 Fetus 7

According to Beaudoin et al. [9].

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Developmental Mechanisms in Gastroschisis


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a b c

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Fig. 1. Amniotic cavity and body stalk. a Human embryo at 5 WD. b Lateral view of a rabbit embryo at stage 10. c Lateral view of a rab-bit embryo at stage 13.

Fig. 2. Continuity of the amnion and em-bryonic covering. a Sagittal section of a hu-man embryo at the beginning of 12th WD. b Parasagittal section of a human fetus at 20 WD. 1: Wharton’s jelly; 2: allantoid; 3: umbilical vessel; 4: stratum germinativum; 5: periderm; 6: amniotic epithelium; 7: in-testinal loops; 8: umbilical cord; 9: fetal skin; 10: urachus; 11: bladder; 12: pubic bone; 13: bowel; 14: peritoneal margin; 15: liver.

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sort of cord split ( fig. 3 ). Neither skin nor skin remnants were ever seen on this left side of the defect. Furthermore, we were able to demonstrate in microscopic sections that the amniotic epithelium on the right side of the cord was also missing and was replaced by fibrinous coating ( fig. 4 ).

Peritoneal Continuity during the Development of the Midgut From 4 to 6 WD the body stalk (future implantation of

the umbilical cord) is large and quite short, with a still unclosed abdominal cavity ( fig. 1 ). The lateral mesoblast progresses mainly between 6 and 8 WD, so that the rectus abdominis muscular pattern is clear at the end of the 8th week. During the same period, the right umbilical and vitelline veins combine and fuse to build the portal and hepatic venous system. The left umbilical vein thus re-mains with the umbilical arteries, disposed in a left-sided tight pars vasculosa of the cord, whereas the midgut de-velops on their right side in a pouched pars flaccida of the cord ( fig. 5 ). The pars flaccida is at that point very thin, made of amnion and peritoneum and barely parted by Wharton’s jelly.

The midgut is covered by the peritoneum as well as the other abdominal organs. This serous membrane derives from the mesoblast and continuously lines the dorsal, lat-eral and eventually ventral abdominal wall. Visceral bulg-ing along with vascular strings then causes the serous membrane to fold in various recesses and layers ( fig. 6 ). Between 8 and 10 WD the increasing growth of the loops leads them to elongate within the pars flaccida of the cord. The cord later stretches, so that the intestine has reen-tered the abdominal cavity by 12 WD.

After 12 WD the Wharton’s jelly totally fills the um-bilical cord, and the peritoneal recesses along the umbili-cal vessels and urachus become enclosed in the abdomi-nal cavity ( fig. 7 ). This disposition is seen until birth.

In neonates with gastroschisis, the ventral peritoneal recess was found to be open on the right side of the cord, with the peritoneum covering the right side of the um-bilical vein. On the left side the implantation of the liga-mentum teres was always normal. The herniated bowel was in all cases the midgut and ascending colon, which is the intestinal part depending solely on the cranial mes-enteric artery. Neither foregut nor hindgut vessels were ever passing through the defect, even when the descend-ing colon was outside the cavity. Moreover, when the stomach was herniated its surface was remarkably nor-mal in all cases; the gonads, though, when exposed, were as covered with peels as the bowel ( fig. 8 ). All cases had universal mesentery and none presented with omphalo-mesenteric duct. The mesentery was more or less con-stricted in the defect. Lymphatic swelling and mesenter-ic lymph nodes were noted in all cases presenting intes-tinal peels, even in mild intestinal congestion cases. Mesenteric torsion was variously observed, as shown in figure 8 . In only 11/139 cases had the bowel suffered ische-mic lesions (atresia, complete necrosis, volvulus with partial necrosis; fig. 9 ).

Discussion

Diagnosis of abdominal wall defects in humans is con-sidered only after 12 WD because the physiological um-bilical hernia (the herniation of the bowel within the body stalk) may be late in resolving [11] . Most authors con-sider that omphalocele is an abnormally persistent her-nia, whereas gastroschisis arises from a different defect either before or after its closure [2, 4, 12] . It is well admit-ted that newborns affected by gastroschisis seldom dis-play the same malformations as in omphalocele [4, 13, 14] .This fact led some authors to think of a later onset of this anomaly, when the main structures are developed [8] . Byrne and Feldkamp [15] reported a case of early malfor-mative complex associated with gastroschisis, but this ob-servation is not consistent with other clinical series and therefore does not rule out the likelihood of a mere coin-cidence.

The abdominal defect in gastroschisis is almost always right-sided, except for very few cases reported [16, 17, 18] . It is, however, very intriguing to note that left-sided cases are more often associated with extra digestive malforma-

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Fig. 3. Gastroschisis. Note the split on the right side of the nor-mally tight cord.

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tions than the classical type [18] . Furthermore, at least the case reported by Shi et al. [17] is clearly different from a gastroschisis, considering the defect was laterally located far from the absolutely normal base of the cord and left rectus muscle. Since gastroschisis is usually not associated with chromosomal anomalies or other malformations

apart from intestinal atresia, hypotheses regarding its de-velopment sometimes focused on vascular causes. Inad-equate obliteration of the right umbilical vein [2] , or of the right omphalomesenteric artery [3] , would lead to ei-ther weakness or necrosis of the forming abdominal wall. Epidemiological support has been given to such views

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Fig. 4. Microscopic features of the cord in gastroschisis. a Section at a distance from the defect, with normal amniotic epitheli-um. b Section at the margin of the defect. The epithelium is replaced by fibrinous coating. Note the peritoneal layer on the right side of both sections.

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Fig. 5. Physiological umbilical hernia. a Right view of a human embryo at 10 WD. The pars flaccida appears clearly, crowded by the developing loops, which hide the left-sided umbilical vessels. b Details in a rabbit embryo at stage 22. The cecum is vis-ible; the pars flaccida is as thin as a veil.

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[19] . However, the right rectus muscle is always well de-veloped in gastroschisis, and the cord itself appears split on the right as we described in figure 3 . We therefore think that vascular causes should be ruled out because the amnion has no blood supply to be interrupted. A possible anomaly of the yolk sac was advocated for by Stevenson

et al. [5] in 2009 and Komuro et al. in 2010 [20] , but these theses were not supported by any morphological study. It is, moreover, not so surprising to find some yolk sac rem-nants in the umbilical cord, as the normal development involves its absorption to form the cord. Abnormal early folding of the embryo between 3 and 4 WD has been pro-

Fig. 6. Peritoneum. Sagittal section of a hu-man embryo at stage 17. 1: Wharton’s jelly; 2: peritoneal serosa; 3: primitive midgut; 4: liver; 5: amniotic epithelium.

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Fig. 7. Peritoneal recess. Sagittal section of a human fetus at 20 WD. 1: Umbilical cord; 2: ventral peritoneal recess; 3: urachus; 4: umbilical artery; 5: liver.

Fig. 8. Gastroschisis. a , b Partial torsion of the mesentery with intestinal congestion and peels, unlike the case shown in figure 3. c The loops are covered with peels, where-as the stomach appears normal. d The right fallopian tube and ovary are equally cov-ered with peels.

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posed to explain gastroschisis, along with ectopia cordis and bladder exstrophies [11, 21] . Besides the unlikelihood of such an early developmental disruption giving an iso-lated anomaly, this timing is not consistent with the cord appearance in gastroschisis because it would then never tighten. Clinical observations [12, 22] support the thesis of an early rupture of the umbilical ring previously pro-posed by Thomas and Atwell [1] , but no embryological evidence was given in their work.

Our observations in embryos demonstrate that the umbilical hernia is physiologically located on the right side of the cord because after 6 WD (stage 17) the left um-bilical vein becomes predominant [2, 10] . We thus divide the normal cord in two parts, a left pars vasculosa and a pars flaccida, wherein the developing midgut appears on the right side of the left umbilical vein. This part is very thin and more likely to rupture than the left one contain-ing firm vessels. A rupture of the cord in this place would allow the bowel to keep growing outside the hernia, with-out mesenchymal edge on the left side of the defect or amniotic remnants on the loops: these are the typical fea-tures of gastroschisis [23] . Moreover, this description highlights the inconsistency of the common view that omphalocele is a mere persistent physiological hernia; in order to persist, the hernia has probably to be not physi-ological in the first place.

Although the embryonic period is classically achieved at 8 WD, the organogenesis is not yet complete and con-tinues until 12 WD [10] . The umbilical cord elongates and induces a mechanical process that allows the intestine to return within the abdominal cavity. The amnion re-mains in continuity with the periderm throughout the embryonic period. During the 11th WD, an intermediate layer forms from the cells of the stratum germinativum,

including collagenous and elastic fibers [24] . The peri-derm keratinizes and desquamates [10] . Between 13 and 17 WD the stratum germinativum produces epidermal ridges. The skin with its three layers is present at 22 WD [24] .

The timing of such an accident can thus be pointed between 8 and 11 WD because the midgut has to be her-niated while the periderm stays in continuity with the am-nion. Moreover, the cord has to be completely formed, especially in its pars vasculosa, which does not yet exist in the primitive body stalk. Such a period is consistent with the absence of associated anomalies reported in the clini-cal series [25, 26] . On the other hand, this event occurs before the end of organogenesis (before 12 WD) because the mesenteric placement (the so-called rotation) is never completely achieved in gastroschisis. Intestinal atresia or perforations, if associated, are to be considered as a con-sequence of the mesenteric ischemia and a part of gastros-chisis disease [13, 23, 27] . Further bowel injury, in our view, arises mainly from vascular mesenteric impair-ment, considering that we have never found any peel on the viscera, the blood supply of which remains within the abdomen. We did not find any support for the thesis ac-cording to which the bowel would be damaged by the am-niotic fluid and fetal urine [28, 29] . One can expect the amniotic fluid to bathe even the intra-abdominal viscera when the abdominal wall is open, especially if the defect is large-sized. Interestingly, bowel damage seems to be greater in small abdominal defects [13] . Deans et al. [30] gave evidence of nondamaging prolonged exposure of the bowel. Moreover, almost all gastroschisis cases are nowa-days prenatally diagnosed in the first trimester of preg-nancy; yet not all babies present with intestinal peels. In-flammatory factors found in amniotic fluid in gastroschi-sis are, in our opinion, a mere consequence of the venous and lymphatic mesenteric obstruction.

The cause of the primary rupture is not yet clear and we do not offer any explanation in this morphological study. Epidemiological surveys have been made world-wide, giving support to a possible effect of various exog-enous factors. Toxins, viruses and radiation have been equally incriminated [31–35] . Moreover, it is well admit-ted that gastroschisis occurs more often in mothers using drugs [36, 37] . Some genetic predisposition is not to be neglected, as some cases of gastroschisis in siblings have been reported [38, 39] . A primitive amniotic failure in-volving teratogenic effect is consistent with the peculiar vacuolar changes of the amniotic epithelium in gastros-chisis [40] , and further studies should be carried out in this direction.

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Fig. 9. Prenatal ischemia in gastroschisis.

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Conclusion

Gastroschisis is probably due to an amniotic rupture along the umbilical cord in its pars flaccida between 8 and 11 WD. As a consequence, the midgut elongates freely out of the abdominal cavity, stretching outside its mesentery. With subsequent fetal growth the intestine might suffer

vascular compression, especially of venous and lymphat-ic flows, both by a small-sized defect and mainly consis-tent with chronic intestinal volvulus. Such findings may guide the prenatal management of fetuses affected by gas-troschisis, with particular regard to the mesenteric ap-pearance as a prognostic factor.

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Comprehensive Developmental Mechanisms in Gastroschisis