Limb Deficiencies in Newborn Infants Caroline K. McGuirk, MPH*; Marie-Noel Westgate, MEd‡; and Lewis B. Holmes, MD*‡§ ABSTRACT. Objective. The prevalence rate of all imb deficiencies are a widely known outcome types of limb reduction defects in general and those that associated with teratogenic exposures during potentially are caused by vascular disruption in particu- pregnancy, such as thalidomide,1 misoprostol lar is needed to provide a baseline for the evaluation of L 2 (prostaglandin E1 analog), and the prenatal diagno- infants who are exposed in utero to teratogens that cause sis procedure chorionic villus sampling (CVS).3–5 vascular disruption. The objective of this study was to Each of these teratogens produces a distinctive pat- determine this prevalence rate. tern of limb defects. Specifically, infants who are Methods. All infants with any limb deficiency among damaged in utero by thalidomide have a symmetri- 161 252 liveborn and stillborn infants and elective termi- cal pattern of deficiency (or polydactyly) on the pre- nations were identified in a hospital-based Active Mal- axial side of both arms and legs.1 By contrast, infants formations Surveillance Program in Boston in the years 1972 to 1974 and 1979 to 1994. An extensive search was who are exposed early in pregnancy to misoprostol made to identify infants who were missed by the Sur- and CVS have asymmetrical digit loss, constriction veillance Program; an additional 8 infants (7.3% of total) rings, and syndactyly. These abnormalities are attrib- were identified. The limb reduction defects were classi- uted to the process of vascular disruption in limb fied in 3 ways: 1) by the anatomic location of the defect, structures that had formed normally and include that is longitudinal, terminal, intercalary, etc; 2) for in- defects referred to as the amniotic band syndrome. fants with absence/hypoplasia of fingers or toes, a tabu- The recognized causes of vascular disruption in lation of which digit or digits were affected; and 3) by the fetus, in addition to the prostaglandin misopros- apparent cause. tol administered in the second month of pregnancy2 Results. The prevalence rate for all types of limb and CVS, especially before 10 weeks’ gestation,3–5 deficiency was 0.69/1000. The apparent causes included include exposure to ergotamine,6 dilation and curet- single mutant genes, familial occurrence, and known tage,7 and trauma to the abdomen (and placenta).8 syndromes (24%); chromosome abnormalities (6%); ter- This means that limb reduction defects that are la- atogens (4%); vascular disruption (35%); and unknown beled as amniotic band syndrome can have 1 of cause (32%). several different underlying causes. Experimental Conclusions. A hospital-based surveillance program studies9 suggest that the sequence of events that can be used to establish the prevalence of limb reduction leads to these similar deformities is hypoxia, fol- defects, if ascertainment is extended to include elective lowed by endothelial cell damage, hemorrhage, tis- terminations for fetal abnormalities. An apparent cause can be established for most limb defects when the clin- sue loss, and reperfusion. In addition to digit defects, the phenotypic effects of these exposures may in- ical findings are used rather than reliance only on the 10 11,12 International Classification of Diseases, Ninth Revision, clude arthrogryposis and bowel atresia. codes of the discharge diagnoses. The prevalence rate of Previous studies of the frequency of limb reduc- limb reduction defects as a result of presumed vascular tion defects were based on large populations, such as disruption was 0.22/1000. Pediatrics 2001;108(4). URL: an entire country (eg, Sweden),13 or a large region, http://www.pediatrics.org/cgi/content/full/108/4/e64; limb (eg, eastern France)14 or a province (eg, British Co- deficiency, vascular disruption. lumbia).15 Unfortunately, the details on the specific deficiencies in each affected infant are not always available in a large population survey. Another prob- ABBREVIATIONS. CVS, chorionic villus sampling; BWH, lem is the lack of a consensus as to the best way to Brigham and Women’s Hospital; ICD-9, International Classification 16 of Diseases, Ninth Revision. classify limb reduction defects. In particular, should there be a category for limb deficiencies at- tributed to amniotic bands? In studies of the limb reduction defects associated with CVS, some authors excluded this group17 and others included it.18 How- ever, several reported CVS-exposed infants with From the *Genetics and Teratology Unit, Pediatric Service, Massachusetts limb reduction defects have had absence of the distal General Hospital, Boston, Massachusetts; the ‡Department of Newborn 19 Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and the portion of the third finger (J. Zachary, personal §Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. communication, January 3, 2000; D. Wilson, personal Received for publication Nov 20, 2000; accepted May 29, 2001. communication, September 22, 1999), fingers 2 and Reprint requests to (C.K.M.) Genetics and Teratology Unit, Warren 801, 3,5,20 and fingers 3 and 420 with or without tapering Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114-2696. E-mail address: [email protected] and stiffness, which could be considered consistent PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- with the diagnosis of the amniotic band syndrome. emy of Pediatrics. Therefore, if a deficiency of 1 or 2 digits can be http://www.pediatrics.org/cgi/content/full/108/4/Downloaded from www.aappublications.org/newse64 PEDIATRICS by guest on October Vol. 2,108 2021 No. 4 October 2001 1of7 caused by exposure to a teratogen, then these specific presence of the deficiency diagnosed in prenatal sonography was outcomes must be included in the assessment of the not confirmed in the postmortem examination. The term “isolated limb reduction defect” was used to refer to the infant who had no fetal risks from these exposures. major malformations involving nonlimb structures; the infant We used an active hospital-based malformations with an isolated limb reduction defect could have abnormalities in surveillance program of newborn infants to establish 1 or more limbs, including arms and legs. The infant with multiple the frequency of all types of limb deficiency, includ- malformations had major malformations of both limb(s) and non- ing those caused by vascular disruption. We also limb structures. In the Active Malformations Surveillance Program, the index included a tabulation of absence/hypoplasia of any cases were identified from the review of the findings either in the single digit or any combination of digits in the hands initial examinations by the pediatricians of each liveborn infant or and feet (Fig 1). by the pathologist at autopsy or the surgeon in an operation. In addition, a questionnaire was administered by a research assistant METHODS to the mother postpartum to review the pregnancy, medical, and family histories. Other sources of information were chromosome This study used the data that had been obtained by the Active Malformations Surveillance Program at Brigham and Women’s analyses; diagnostic studies, such as ultrasound, magnetic reso- Hospital (BWH), the methodology of which has been described nance imaging, and computed tomographic scans; and the report previously.21 The study period was 1972 to 1974 and 1979 to 1994, of all consultants who had evaluated each affected infant. Clinical during which time all infants with major malformations were diagnoses were established from a review of the clinical and identified among liveborn and stillborn infants and all elective laboratory findings, rather than by reliance on the diagnosis coded terminations performed in the second trimester because of sus- on discharge or on birth certificates. pected fetal abnormalities. The initial study period was February To be an index case in this study, the infant with the limb 16, 1972, to February 15, 1975, but is referred to as 1972 to 1974; the reduction defect had to have been identified by surveillance per- surveillance program was not conducted from February 16, 1975, sonnel within the first 5 days of life, even if the diagnosis was not to December 31, 1978, because of a lack of space and funds. clarified. The period of 5 days was established in the first study A major malformation was defined as a structural abnormality period, 1972 to 1974, when the infants who were born after a with surgical, medical, or cosmetic importance. A limb deficiency vaginal delivery were discharged from the hospital routinely on was defined as the absence or hypoplasia of a phalanx, metacarpal the fifth day postpartum. or metatarsal bone, or portion of any long bone large enough to All infants in the computerized database with diagnoses of produce a significant deformity that could be detected at birth by International Classification of Diseases, Ninth Revision (ICD-9) codes the examining physician. Excluded from this tabulation was mild 755.2 to 755.4 were identified; these codes designate reduction shortening of digits as a result of brachydactyly as an isolated defects of the upper limbs, lower limbs, and unspecified locations. finding or as part of a skeletal dysplasia, curvature (eg, clinodac- The surveillance program questionnaire was used as the primary tyly of the fifth finger or bowing of the tibia due to fetal position- source of information as to the sex, gestational age, race, possible ing), and digits considered “hypoplastic” in appearance but not multiple gestations, exposure to a known teratogen, and family shortened. A product of conception delivered by a destructive history. When this information had not been recorded at the time procedure to terminate the pregnancy was excluded when the of the initial enrollment, it was obtained from the infant’s and the mother’s medical records and the surgeon’s records. Photographs and radiographs taken of any of these infants at birth were re- viewed to confirm the anatomic findings.