Amniotic band sequence

INTRODUCTION — Amniotic band sequence (ABS) refers to a highly variable spectrum of congenital anomalies that occur in association with amniotic bands [1-6]. We consider it a sequence, rather than a syndrome, because the pattern of congenital anomalies is related to a single type of insult resulting from one or more amniotic bands that can result from a variety of different etiologies (eg, rupture of membranes, vascular insult). By contrast, a syndrome refers to a pattern of congenital anomalies that are known, or at least assumed, to result from a single etiology (eg, Down syndrome is due to trisomy 21).

There is no standard definition of ABS in the literature. Heterogeneity in the clinical manifestations, diagnosis, and recurrence risk of amniotic band-associated anomalies has contributed to confusion regarding nomenclature. Historically, diverse terms have been used to describe these anomalies, including amniotic band sequence [4,5], amniotic band syndrome [7], amniotic band disruption complex [8], limb body wall complex [9,10], body wall complex with limb deficiencies [11]; amniotic deformity, adhesion, mutilation (ADAM) sequence [12]; and others. We consider amniotic band sequence (ABS) the most appropriate term since the pattern of anomalies is secondary to developmental disruption of heterogeneous etiology [6]. However, this nomenclature remains controversial [6,11,13,14].

This topic will discuss clinical manifestations, diagnosis, and management of ABS. The causes, epidemiology, and general approach to evaluation of children with congenital anomalies are reviewed separately:

●(See "Congenital anomalies: Epidemiology, types, and patterns".)

●(See "Congenital anomalies: Causes".)

●(See "Congenital anomalies: Approach to evaluation".)

PREVALENCE AND EPIDEMIOLOGY — The estimated prevalence of ABS ranges from 1:1200 to 1:15,000 live births [2] and 1:70 stillbirths [5]. It affects both males and females equally. The prevalence of ABS including limb body wall abnormalities and body wall abnormalities is estimated to be 1.08 per 10,000 births [15].

Maternal risk factors reported in case studies and reviews include smoking and residence at high altitude, but relatively few cases have been reported and data are inconsistent, in part because definitions of the disorder vary among studies [12,15-18].

PATHOGENESIS — The presence of multiple or severe abnormalities in some ABS cases suggests the occurrence of more than one of the following disruptive factors [13,19].

●Amniotic bands – The primary mechanism for ABS is thought to be rupture of the amnion in early pregnancy resulting in development of multiple loose mesodermic strands (amniotic bands) from the chorionic side of the amnion that adhere to and/or entangle the embryo or germ disc [1-4,9,10,20-22]. Constriction of otherwise normally developing structures by the amniotic band can result in constriction rings, and in severe cases can lead to vascular disruption and subsequent partial autoamputation of the involved structure. Adherence even without constriction can have adverse mechanical effects that result in malformation or deformation (eg, anatomic clefts) [23].

●Vascular disruption – Amniotic bands do not explain all of the findings in ABS (see 'Fetal and neonatal findings' below). Some cases also have internal visceral and other anomalies that are not readily explicable by amniotic bands, while others have the characteristic disruptive abnormalities but a histologically intact normal amniotic lining [20,24,25]. In these cases, disruption of fetal blood flow due to a vascular abnormality unrelated to amniotic bands is thought to be the primary event.

●Pathogenic variant – A small subset of ABS cases cannot be explained by either amniotic bands or primary vascular disruption; these cases may be due to a pathogenic variant of a single gene [4,14]. Pathogenic variants in the human homologue of the mouse gene Ds "disorganization gene" have been proposed as one mechanism for the combination of constriction/duplication abnormalities [26-28]. Rare familial cases and concordance in monozygotic twins have been reported, supporting a genetic etiology in some instances [15,29,30].

POSSIBLE ETIOLOGIES — In cases due to amniotic bands, the cause of the amnion rupture is unknown in most cases. Maternal or fetal disorders have been reported in some of these cases (eg, epidermolysis bullosa [31,32], connective tissue disorders [33]). "Pseudoamniotic band syndrome" has been used to describe cases due to iatrogenic rupture of the amnion from an invasive procedure (eg, failed first trimester curettage, fetoscopy or septostomy for management of twin-twin transfusion syndrome) [34-36].

In cases related to vascular disruption, the disruption can be caused by a variety of etiologies, including first-trimester exposure to misoprostol and chorionic villus sampling before 10 weeks of gestation.

FETAL AND NEONATAL FINDINGS

Overview — The four main categories of findings are [37]:

●Constrictive rings

●Limb abnormalities

●Central nervous system abnormalities (spine, brain)

●Craniofacial abnormalities

Constriction rings and limb or digital amputation are the most common findings, present in at least 80 percent of cases [15,16,38,39]. Constriction rings are congenital depressions of tissue that encircle a portion of the body. Multiple constriction rings that involve multiple digits and limbs may be present. The fibrous bands of amnion may be confined to the skin and soft tissue, but also may extend deep inside the constriction ring, where they can compromise the vascular supply, lymphatic system, bone, and nerves [22,40]. This can result in lymphedema, neuropathy, fracture, and amputation. If constriction occurs sufficiently early in pregnancy, the devitalized body part is often resorbed over time, and thus the constriction ring will not be present at postnatal examination of the amputated limb. Although constriction rings and amputations are common, the clinical spectrum of ABS is highly variable: from a single mild abnormality with an excellent prognosis to multiple severe anomalies affecting cranium, spine, limbs, and trunk that are incompatible with life [15,41-43].

Spectrum of specific findings — Potential specific findings include [44-46]:

●Craniofacial abnormalities, such as:

•Encephalocele, facial clefts, and cleft lip/cleft palate, which are often in atypical (eg, nonmidline, embryologically nonanatomic) locations

•Asymmetric facial structures (asymmetric microphthalmia, severe nasal deformity)

•Exencephaly/anencephaly sequence

●Body wall abnormalities, especially if not in the midline. Abdominal or thoracic contents may herniate through the body wall defect and into the amniotic cavity. Rarely, the abnormalities are close to midline and will mimic a gastroschisis.

●Limb abnormalities, such as:

•Constriction rings on limbs (image 1), sometimes with distal swelling. At times, the actual "band" of tissue will be seen constricting the soft tissues.

•Absence of distal portions of one or more fingers and toes, especially the central digits; hypoplasia of digits with syndactyly, rudimentary digits.

•Hand and foot deformities (eg, club foot). Hands are more commonly involved than feet and the thumb is often spared since it is protected within the palm in utero.

•Multiple joint contractures.

•Fractures.

●Visceral abnormalities, such as lung hypoplasia.

●Umbilical cord abnormalities, such as:

•Short umbilical cord (secondary to restricted fetal movement)

•Constriction

●Spinal abnormalities, scoliosis.

●Amniotic bands entangling, adherent to, or disrupting fetal parts.

●Other abnormalities, such as autotransplanted tissue on skin tags, pterygium, ambiguous genitalia, crusting and fibrous strands of tissue on the tip of one or more fingers, nodules of tissue near the ends of fingers, circumferential constriction ring around the trunk, and oligohydramnios [42,43,47].

DIAGNOSIS — Heterogeneity in the clinical manifestations and etiology of ABS makes diagnosis particularly challenging.

●Prenatal diagnosis

•Ultrasound – Prenatally, the diagnosis may be suspected as early as the late first trimester when ultrasound imaging detects constriction rings, limb amputations, and/or lateralization of body wall or craniofacial abnormalities that are normally midline [16]. Distal limb edema is also suggestive of the diagnosis. An accurate prenatal diagnosis is most likely in cases at the severe end of the disease spectrum, which have multiple abnormalities (both limb and body wall abnormalities), a short umbilical cord, and amniotic bands. The so-called limb body wall complex is a severe consequence of early ABS. These cases typically have large and asymmetric anterior body wall abnormalities, severe kyphoscoliosis, and a dramatically shortened umbilical cord.

In a minority of cases, thin wispy undulating strands of amnion are seen crossing the gestational sac and adherent to the fetus, restricting its movement (image 2A-C) and supporting the presumptive diagnosis. Thus, it is important to closely observe fetal movements over time to see if the fetus is able to move freely. Changing maternal position to roll the fetus away from one uterine margin to the other may reveal a band tethering the fetus at the site of the defect [37]. A high-resolution transducer may also reveal a thin band not seen with a lower resolution transducer. It should be emphasized that visualization of the amnion itself before 16 weeks of gestation without fetal structural abnormalities or restricted movement does not establish the diagnosis because the amnion does not "fuse" to the chorion until about 16 weeks of gestational age. In addition, the amnion can rupture, particularly after invasive procedures such as amniocentesis [48].

•3D ultrasound and MRI – Prenatal three-dimensional (3D) sonography or magnetic resonance (MR) imaging may be performed if the diagnosis or associated abnormalities are uncertain and if prenatal diagnosis will affect pregnancy decision-making. These are adjunctive techniques may provide more detailed information about the abnormalities and thus help to support the diagnosis or establish an alternative diagnosis [49,50].

On T2-weighted MR imaging, amniotic bands can be seen as thin wispy hypointense strands [50]. As previously mentioned, amniotic bands are seen in only a minority of cases; the diagnosis in the majority of cases is based on identification of the classical abnormalities associated with ABS.

●Postnatal diagnosis – Postnatally, the diagnosis of ABS should be suspected in infants with limb amputations, nonmidline body wall abnormalities, or craniofacial abnormalities in unusual locations, as described above (see 'Fetal and neonatal findings' above). If amniotic bands are not visible on a newborn with these types of abnormalities, immediate investigation of the fresh fetal membranes and placenta is important, as identification of amniotic strands supports the diagnosis. The strands can be visualized easily by immersion of fresh membranes and placenta into a tub of water. Care should be taken if there is frayed amnion or complete or partial separation of amnion from the chorion so as not to create the appearance of amniotic bands postpartum.

Differential diagnosis of amniotic bands

●Synechiae and septa – Uterine synechiae are intrauterine adhesions, sometimes called amniotic sheets, that are external to the amniotic sac and have two layers of amnion and two layers of chorion around them [51]. Synechiae often have a wide triangular base along the uterine wall, may extend to the contralateral uterine wall, and look like a shelf rather than a band on cross-section [52]. Since synechiae are a type of scar, patients typically have a history of intrauterine surgery (cesarean, uterine curettage) or infection. These synechiae become increasingly thin over the course of the pregnancy. In twin pregnancies, synechiae can be differentiated from intertwin fetal membranes because they have no relationship to the placenta.

By comparison, uterine septa are congenital malformations seen in the midline of the uterus, best demonstrated in 3D reconstructed coronal plane. The classic appearance of a septate uterus may be distorted by the pregnancy and difficult to diagnose. If the septum is complete (extends to the cervix), the pregnancy will be seen on one side of the uterus and a decidual reaction will be seen on the other side.

Both synechiae and amniotic bands originate from random sites in the uterus, but septa originate from the fundus and have a sagittal orientation. In contrast to amnion bands, synechiae and thin septa do not impinge upon the fetus, do not restrict fetal movement, and are not associated with fetal anomalies of the type that occur in ABS. Synechiae and septa may have blood flow detected on Doppler interrogation, but amniotic bands do not.

Although usually considered to be an incidental benign finding, three series observed an increase in some types of obstetric morbidity (eg, prelabor rupture of membranes, placental abruption, malpresentation) in pregnancies with synechiae [53-55], and two reports described a total of four stillbirths; three of the four were attributed to cord accidents, and one was unexplained [55,56]. Additional studies are needed to determine whether there is a true association between synechiae and adverse pregnancy outcome.

●Residual gestational sac – The residual gestational sac of a demised twin will become smaller and disappear over time whereas amniotic bands persist with uterine enlargement.

●Fibrin strands – Fibrin rather than amniotic strands in the amniotic fluid may occur after in utero bleeding. The clinical history is usually positive for vaginal bleeding or a recent invasive procedure. Like amniotic bands, these strands may be adherent to the fetus, but in contrast to amniotic bands, they typically get smaller over time (as the blood products are resorbed) and are not associated with fetal anomalies.

●Chorioamniotic nonfusion or separation – Chorioamniotic nonfusion or separation may be mistaken for an amniotic band, but the curvature of the amnion is often crescent shaped and mirrors the contour of the chorion. The amnion and chorion typically have a fused appearance by 16 weeks of gestation; however, separation may develop as a result of fluid leak or bleeding related to an invasive procedure (eg, laser procedure for twin-twin transfusion syndrome, early genetic amniocentesis), or less commonly, spontaneously [37,57]. If separation persists, it may be associated with a positional deformity such as club foot, but the other anomalies of ABS do not occur.

●Circumvallate placenta – A circumvallate placenta may have an elevated edge of fetal membrane that can resemble an amniotic sheet (picture 1). When imaged tangentially, it starts within a few centimeters of one placental edge and runs parallel to the surface of the placenta to within a few centimeters of the other placental edge. Unlike an amniotic band, it is related to the placenta rather than the uterine wall, does not impinge on fetal parts, and a thicker band of tissue is visualized rather than a thin wisp of amnion. (See "Gross examination of the placenta", section on 'Circumvallate placenta'.)

Differential diagnosis of causes of limb amputation — As limb and digital amputation are common findings in ABS, it is important to consider other etiologies of limb reduction abnormalities, such as genetic and teratogenic causes. Although terminal transverse limb deficiencies are similar in appearance to ABS, they lack fibrous strands [43].

●Syndromes and teratogens – The most common genetic syndrome associated with congenital transverse limb deficiency is Adams-Oliver syndrome, which is characterized by asymmetric terminal transverse limb abnormalities, aplasia cutis and deficiency of the bony calvarium, and, frequently, congenital heart disease [58] (see "Aplasia cutis congenita", section on 'Associated genetic syndromes or congenital anomalies'). Inheritance can be autosomal dominant or autosomal recessive.

Longitudinal (along the long axis of the limb) limb deficiency may be due to inherited or sporadic mutations or an environmental etiology (eg, poor first trimester glycemic control in diabetes, thalidomide). Thalidomide-induced limb deformities are usually reduction abnormalities, usually symmetrical, and usually affect the upper limbs.

●Acquired limb ischemia in monochorionic twin pregnancies – Acquired limb ischemia is a rare complication of monochorionic twin pregnancies [59]. The etiology is unclear, but, in some cases, it may be related to a vascular accident or interventions for twin-twin transfusion syndrome.

PROGNOSIS — ABS has been associated with an increased risk for miscarriage, preterm birth, and stillbirth, which may be related to cord strangulation [2,3,36,39].

The postnatal prognosis depends upon the severity of the anomalies; involvement of internal organs is generally lethal [60]. Progression in severity of anomalies does not occur following birth, with the exception of cases with marked vascular occlusion due to constrictive bands, which might cause progressive edema distal to the constriction rings.

MANAGEMENT

Prenatal evaluation and counseling

●We suggest referral to a tertiary fetal diagnostic center for ultrasound examination, counseling, and genetic evaluation.

●All patients should receive information about the fetal abnormalities that have been detected and the possibility of additional undetected abnormalities.

●Genetic counseling includes a three-generation pedigree and past and present pregnancy history, including assessment of teratogen exposure, and discussion of other potential etiologies (eg, monosomy X associated with distal extremity edema).

●Amniocentesis to obtain amniocytes for chromosomal microarray is indicated if results will affect pregnancy decision making. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

●Prognosis is discussed, ideally involving relevant pediatric specialists (eg, orthopedics, neurology).

●For patients who choose to terminate the pregnancy, it is useful to try to deliver an intact fetus, so it can be examined to confirm the diagnosis

●Some patients may be candidates for prenatal lysis of a constriction ring. (See 'In utero lysis of constriction rings' below.)

●Postnatal interventions, including palliative care, should be reviewed. (See 'Postnatal' below.)

In utero lysis of constriction rings — Timely in utero lysis of constriction rings before severe progressive downstream vascular compromise occurs can restore normal perfusion and prevent amputation. The efficacy of this investigational approach is unproven, and there is no consensus regarding selection criteria for candidates for in utero intervention. For amniotic bands involving a limb, reasonable criteria are that the limb should have normal Doppler flow above the constriction and abnormal, but present, flow below the constriction [61,62]. One group hypothesized that fetal limb recovery after a severe ischemic injury is more likely than postnatal recovery because of the plasticity of fetal healing [63]. Although fetoscopic release of the band with scissors or laser may restore blood flow and save the limb, plastic surgery may be needed after birth to correct the scar tissue in the skin [64]. (See 'Postnatal' below.)

The potential consequences of nonintervention depend on the specific abnormalities and need to be weighed against the potential morbidity of intervention, which includes preterm prelabor rupture of membranes (PPROM) and preterm birth. One literature review included 27 cases of fetoscopic lysis of amniotic bands using laser (12 cases), scissors (6 cases), or both (5 cases) [65]. The procedures were performed between 21 and 26 weeks of gestation. Outcome was available in 25 cases and included a functional limb in 17 cases (68 percent), limited mobility/malposition in 7 cases (28 percent), and limb amputation in 1 case (4 percent). In addition, 5 pregnancies (20 percent) developed PPROM <32 weeks and 16 pregnancies (64 percent) delivery preterm (<37 weeks). The authors emphasized the importance of dividing the entire band down to the fetal tissues under continuous direct visualization and believed that laser was more effective and safer than scissors.

Pregnancy monitoring and delivery — There are no published guidelines specific for pregnancies complicated by ABS. The frequency of ultrasound examination and choice of mode of birth are tailored to individual needs based on organ involvement. If a vascular constriction is identified, fetal intervention may be considered, as described above. (See 'In utero lysis of constriction rings' above.)

Postnatal — Release of constriction rings can relieve venous congestion and lymphedema, and salvage some limbs [2,66,67]. In a review of one-stage circular incision techniques in 27 patients (average age 11.7 months [range 0 to 72 months]) with limb ring constrictions due to ABS, all limbs, toes, and fingers were saved [67]. The vascular compromise mandates urgent surgical intervention; otherwise, surgery can be delayed for weeks to months [68].

Postnatal treatment options include surgical interventions to enhance function or for cosmetic purposes (eg, Z-plasty) and prostheses and physiotherapy for individuals with limb abnormalities [69]. (See "Surgical reconstruction of the upper extremity".)

RECURRENCE RISK — Most ABS is sporadic; however, a few familial cases have been reported [2,70-72]. Genetic counseling to discuss recurrence risk is recommended.

SUMMARY AND RECOMMENDATIONS

●Diagnosis – Amniotic band sequence (ABS) refers to a highly variable spectrum of congenital anomalies that usually occur in association with amniotic bands. (See 'Introduction' above.)

The diagnosis may be suspected prenatally as early as the late first trimester when limb amputations or lateralization of usually midline body wall or craniofacial abnormalities are seen on ultrasound examination. Distal limb edema is also suggestive of the diagnosis. In a minority of cases, thin wispy undulating strands of amnion are seen crossing the gestational sac and adherent to the fetus, restricting its movement and supporting the presumptive diagnosis. (See 'Diagnosis' above.)

●Pathogenesis and etiology – Most cases of ABS are sporadic. The etiology is heterogeneous and controversial. In most cases, loose strands of amnion adhere to and then entangle the embryo/fetus or germ disc, resulting in mechanical or vascular disruption of developing structures. However, in some cases, amniotic bands may not be involved, and the primary etiology may be vascular disruption or a pathogenic variant in a developmental gene. Rare familial cases and concordance in monozygotic twins have been reported. (See 'Pathogenesis' above and 'Possible etiologies' above.)

●Clinical findings – The four main categories of findings are constriction rings, central nervous system abnormalities (spinal, brain), craniofacial abnormalities, and limb abnormalities. (See 'Fetal and neonatal findings' above.)

●Prognosis – The prognosis depends on the severity of the anomalies, especially involvement of internal organs. (See 'Prognosis' above.)

●Pregnancy management

•We suggest referral to a tertiary fetal diagnostic center for ultrasound, counseling, and genetic evaluation. Patients should receive information about the fetal abnormalities that have been detected and the possibility of additional undetected abnormalities.

•If a vascular constriction is identified, fetal intervention may be considered. Timely in utero lysis of constriction rings before severe progressive downstream vascular compromise occurs can restore normal perfusion and prevent amputation. The efficacy of this investigational approach is unproven and selection criteria for candidates for in utero intervention have not been defined. Although fetoscopic release of the band may restore blood flow and save the limb, plastic surgery may needed after birth to correct the scar tissue in the skin, and the pregnancy may be complicated by preterm birth or in utero demise. (See 'In utero lysis of constriction rings' above.)