Early Embryonic Compression or Disruption: Tubal Ectopic Pregnancy, Early Amnion Rupture, Limb-Body Wall Complex, and Body Stalk Anomaly

GENESIS

Constraint that occurs during the latter period of gestation can cause molded deformations with good prospects for spontaneous or assisted return to normal form; however, when constraint occurs during early morphogenesis, it can have more severe and lasting impacts on form. The types of defects that can be produced by such compression during this early period of organogenesis (i.e., within the first trimester) fall into three categories: molded deformations, incomplete morphogenesis, and disruptions of morphogenesis ( Table 49.1 ). All three types of defects were produced experimentally by Poswillo after early amniotic sac puncture in rat embryos at 15.5 days’ gestation. At this stage of gestation, the rat embryo is at a period of development equivalent to that of the 6- to 7-week human embryo, and mesenchymal condensations have formed bones within the developing limbs but the fingers are not fully separated ( Fig. 49.1 ). The lip has fused, but the palatal shelves have not yet closed ( Table 49.2 ). Amniotic bands were only present in 19% of the rat fetuses in Poswillo’s study, and there were no defects in control animals. Treated animals showed a small jaw that was caused by compression of the mandible against the sternum. In all but one rat fetus, this caused the tongue to be thrust between the posterior palatal shelves, thereby preventing closure of the palatal shelves (similar to what is seen in Pierre Robin sequence). Poswillo found that 29% of these rat fetuses with Robin sequence defects induced by oligohydramnios and compression also had limb defects. Defects such as cleft palate and syndactyly were also interpreted as incomplete morphogenesis secondary to compression. Limb-reduction defects involving the radius, femur, and other long bones were interpreted as resulting from vascular disruption due to focal hemorrhage and necrosis.

Vascular disruption is the most common cause of limb deficiency. In a hospital-based surveillance program of 161,252 infants born in the years 1972 to 1974 and 1979 to 1994, the overall prevalence of limb-reduction defects was 0.69 per 1000 live births, with 34% of these defects attributed to vascular disruption (a prevalence of 0.22 per 1000 live births). Kennedy and Persaud demonstrated that early amnion puncture, particularly on day 15 in the rat, leads to edema and hemorrhage, thereby causing tissue damage and resorption within the distal limbs, and these researchers showed that lower limbs are more affected than upper limbs ( Figs. 49.2 and 49.3 ). Webster et al. demonstrated that a broad variety of uterine manipulations in pregnant mice during a similar early stage of gestation can result in hemorrhagic disruption of various fetal structures, and this may be mediated through fetal hypoxia. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries, and this could be a consequence of exposure to cocaine, misoprostol, or severe shock. There is evidence that these exposures have resulted in hypoxia-related malformations in humans, and the strongest evidence of hypoxia causing birth defects in humans comes from studies of fetuses lacking hemoglobin F. Such fetuses are hypoxic from the middle of the first trimester and show a range of birth defects, particularly transverse limb-reduction defects. Hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects but also to patterns of anomalies that suggest a more classic teratogenic effect, such as abnormal embryonic neuronal migration and organization resulting in polymicrogyria, cortical dysplasia, or dysgenesis, and some types of focal cortical dysplasia.

The combination of early embryonic compression with vascular disruption that results in extensive extremity and body wall defects in humans has been termed limb-body wall complex (LBWC) ( Fig. 49.4 ). This defect occurs with a birth prevalence of 0.26 per 10,000 births, with half of the cases being stillborn, and there is a strong association with very low birth weight, short gestational age, and younger maternal age. The spectrum of defects can include variable combinations of body wall defects with evisceration of thoracic and/or abdominal organs, limb deficiency, neural tube defects, and facial clefts, with or without amniotic bands and renal agenesis. Lower limbs are more severely and consistently affected than upper limbs, with distal structures more involved than proximal structures, similar to what is seen in rats subjected to early amnion puncture on day 15, which suggests a vascular pathogenesis. Several theories have been suggested to explain this complex: early amnion rupture (operating through uterine pressure and/or disruption by amniotic bands), vascular compromise (primarily hypoperfusion), and an early intrinsic defect of the developing embryo. These associations of malformations originate as early as the embryonic disc stage, since some of the observed associated anomalies are secondary complications of a primary disturbance in embryogenesis.

There are patterns of malformation whose pathogenesis has not been firmly established, such as sirenomelia, vertebral anal cardiac tracheo-esophageal fistula renal limb defects (VACTERL) association, omphalocele exstrophy imperforate anus spinal defects (OEIS) complex, limb-body wall complex (LBWC), urorectal septum malformation (URSM) sequence, and Müllerian duct aplasia renal anomalies cervico-thoracic somite dysplasia (MURCS) association, all of which predominantly affect caudal structures. Based on the overlap of component malformations, Stevenson proposed a common pathogenesis for these early patterns of malformation. A single umbilical artery is present in all cases of sirenomelia and 30% to 50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWC. This single artery arises from the descending aorta high and redirects blood flow from the developing caudal structures of the embryo to the placenta, a phenomenon termed vitelline vascular steal. As more genomic sequencing has been done in patients with caudal malformations such as sirenomelia, persistent cloaca, and imperforate anus with renal, urogenital, vertebral, and limb defects, pathogenic variants in CSX2 , TBXT (sacral agenesis), and CSX1 (anorectal malformations) have been discovered. Recurrent malformation associations affecting the development of the embryo such as LBWC, MURCS, oculo-auricul-vertebral spectrum (OAVS), OEIS, pentalogy of Cantrell (POC), and VACTERL are now termed recurrent constellations of embryonic malformations (RCEM), which are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence.

There have been several attempts to subcategorize infants with amniotic rupture sequence. Among 1,706,639 births reported to the Polish Registry of Congenital Malformations between 1998 and 2006, there were 47 infants with a diagnosis of amniotic rupture sequence (presenting with fibrous bands, possibly as a result of amniotic tear in the first trimester of gestation), 38 infants with only limb involvement, and 9 infants with associated body wall defects. The cases with body wall defects were more frequently affected by other congenital defects, particularly urogenital malformations, suggesting this combination arose at an earlier stage of development. In both groups, limb-reduction defects occurred in approximately 80% of cases; however, minor distal limb defects (phalangeal or digital amputation, pseudosyndactyly, constriction rings) predominated in the group with only limb involvement, which also had a higher frequency of hand and upper limb involvement. Among 50 cases with prenatal diagnosis of amniotic band sequence from 1993 to 2010, the mean maternal age was 25.7 ± 6.9 years, and 54% (27 of 50) were primiparous, compared with 22% (11 of 50) who had three or more previous pregnancies. Craniofacial defects were seen in 78% (39 of 50) of the cases, followed by defects of the extremities 70% (35 of 50), abdominal wall, spine, and/or thorax 52% (26 of 50). The most frequent defects were the following: encephalocele and facial clefts in the craniofacial group; shortening at any level in the limb defects group; and alterations of the spinal column curvature in the group with body wall defects. Among eight fetuses encountered over a 3-year period with limb-body wall defect, 50% of mothers were younger than 25 years and in their first pregnancy (62.5%). Craniofacial defects were verified in three patients (37.5%), thoracic/abdominal abnormalities in six (75%), and limb defects in all eight (100%). Congenital heart defects were observed in five patients (62.5%). Complementary examinations, such as fetal magnetic resonance imaging (MRI) and echocardiography, have been used to better define the observed defects.

Body stalk anomaly is a rare lethal malformation of unknown cause that has been reported with discordant occurrence in four monoamniotic pregnancies. Ultrasound at 10 to 14 weeks' gestation shows a fetus with a large anterior abdominal wall defect, with most of the abdominal contents and almost half of the body in the celomic cavity, in association with severe kyphoscoliosis and a very short umbilical cord. Exteriorized abdominal contents and lower limbs within the extraembryonic celom, with an intact amniotic membrane, have been visualized by fetal MRI at 14 weeks’ gestation. Among 16 Danish infants with body stalk anomaly, representing 3.4% of 469 infants ascertained in a nationwide dataset of live- and stillborn infants born with abdominal wall defects during 1970 to 1989, the prevalence was 0.12 per 10,000 live- and stillborn infants, and all affected infants died at or shortly after birth. The gestational age at birth varied from 33 to 40 weeks. There was an excess of males (M/F ratio: 2.2:1.0), and all infants had associated malformations: severe limb-reduction defects (56%), absence of one kidney associated with malformations of genitalia and/or urinary bladder (62%), scoliosis (82%), and anal atresia (57%). There were two sets of twins; one discordant and one concordant.

Infants with limb-reduction defects resulting from early exposure to misoprostol or chorion villus sampling (CVS) have asymmetric digit loss, constriction rings, and syndactyly owing to vascular disruption in limb structures that had formed normally ( Fig. 49.5 ). These defects can resemble amniotic band disruption. The underlying mechanism of such vascular disruption is embryonic hypotension and hypoxia followed by endothelial cell damage, hemorrhage, and necrosis with tissue loss. Such defects are more likely to involve distal structures in the upper body (hands and tongue) than proximal structures or the lower body, with middle digital rays more affected than medial or lateral rays (see Fig. 49.5 ). The frequency of terminal transverse limb-reduction defects is significantly higher after CVS than in nonexposed pregnancies, with earlier procedures resulting in more severe types of defects. Absence of the distal portion of the third finger, with tapering and stiff joints, appears to be a distinctive feature of exposure to CVS.

Misoprostol, a synthetic analog of prostaglandin E ₁ , increases the amplitude and frequency of uterine contractions and stimulates uterine bleeding. When used illegally to induce abortions during the first trimester, it has been associated with limb-reduction defects and Möbius sequence. Other unsuccessful attempts to induce abortion during the first trimester have resulted in similar defects as well as other vascular disruption defects such as arthrogryposis, amyoplasia, gastroschisis, bowel atresia, and scalp defects. Other types of defects may occur because of incomplete morphogenesis or compression, such as scoliosis, facial clefts, heart defects, cortical gyral abnormalities, camptodactyly, and syndactyly. Similar defects have resulted after severe abdominal trauma in early pregnancy, and also after high maternal fever in early pregnancy. These defects have also been reproduced experimentally through early amnion puncture, uterine manipulations, or hyperthermia in pregnant rats and mice.

Matsunaga and Shiota recognized early spatial limitation as a significant factor in constraint-induced malformations, noting that 11.6% of 43 embryos and fetuses recovered from ectopic tubal pregnancies had structural defects, as did 6.2% of 97 fetuses from myomatous pregnancies, in contrast to a 3.3% incidence of structural defects among 3474 normally implanted therapeutic abortuses from nonmyomatous uteri. Amelia was present in two of the five fetuses with structural defects who implanted in a fallopian tube ( Fig. 49.6 ), which is consistent with the notion that early fetal disruption leads to more severe limb-reduction defects. Ectopic pregnancy , defined as the implantation of a fertilized ovum outside the uterus, occurs most commonly in the fallopian tube (see Fig. 49.6 ), with 70% implanting in the ampulla, 12% in the isthmus, 11% in the fimbrial end, 2% in the interstitial region, and 3% ovarian. The incidence of ectopic pregnancies increased from 4.5 per 1000 pregnancies in 1970 to 19.7 per 1000 pregnancies in 1992, with risk factors including tubal damage or sterilization, use of an intrauterine device, infertility, previous genital infections, multiple sexual partners, and cigarette smoking. Ectopic pregnancy is also associated with previous adnexal surgery, pelvic inflammatory disease, positive serum Chlamydia trachomatis immunoglobulin G antibody, a history of infertility including tubal infertility, and nontubal infertility. In vitro fertilization has also been correlated with the recent increased risk of ectopic pregnancy.