Centre for Fetal and Maternal Medicine, Queen Charlotte's and Chelsea Hospital,. Imperial College London, Du Cane Road, London W12 0HS, United Kingdom.
Fetal Transverse Limb Defects: Case Series and Literature Review Ferha Saeed, MRCOG, Gowrishankar Paramasivam, MD, Marcin Wiechec, MD, Sailesh Kumar, DPhil(Oxon), FRANZCOG, FRCOG, FRCS, CMFM Centre for Fetal and Maternal Medicine, Queen Charlotte’s and Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, United Kingdom Received 11 June 2010; accepted 23 February 2011
imb reduction defects are relatively uncommon congenital malformations.1,2 The reported incidence is approximately 3.5–6.9 per 10,000 births with a prenatal detection rate of 55%, although this varies considerably depending on the population studied.3–5 Abnormalities of the limbs can vary with respect to part of the limb involved and may be either a complete absence of the limb (amelia) or a partial absence (meromelia). The most common limb reduction defect is a terminal transverse defect, which is usually unilateral, isolated, and sporadic in occurrence.6 A terminal transverse limb defect is defined as the partial or complete absence of one or more fetal limbs beyond a certain point, leaving a stump, and is usually categorized according to the last remaining bone segment. Isolated simple transverse limb defects without associated abnormalities account for most cases of limb reduction defects. The aim of this paper is to present a case series of transverse limb defects in fetuses diagnosed by prenatal ultrasound at a tertiary fetal medicine center and to review the literature about the prevalence, pathogenesis, and outcome of these defects.
ABSTRACT: Purpose. To investigate the incidence and outcome of antenatally diagnosed isolated transverse limb defects at a major tertiary center and to review the literature relevant to this rare condition. Methods. This was a retrospective review of all cases (2000–2009) diagnosed with an isolated transverse limb defect referred to a tertiary fetal medicine center. Isolated transverse limb defects were defined as partial or complete absence of a part of one or more limbs in the absence of other abnormalities. Results. Nine cases were identified. The upper limbs were affected in seven cases. The median gestational age at diagnosis was 2215 weeks (range 21– 29 weeks). The defects ranged from absence of digits to the absence of three limbs in one case. Four women opted to have termination of pregnancy. Postnatal and postmortem examination confirmed the ultrasound findings. No obvious risk factors could be identified in the majority of cases. Conclusions. Most cases of limb defects are believed to be secondary to a vascular insult occurring early in embryonic life. The reason for upper limb predominance remains unclear. Perinatal outcome in this series was poor with the majority of pregnancies terminated. Long-term functional outcome depends on the severity of the limb reduction C 2011 Wiley Periodicals, Inc. J Clin Ultradefect. V sound 39:454–457, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ jcu.20825
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Keywords: transverse limb defects; limb reduction; vascular disruption; reduction deformity; obstetrics; sonography
This was a retrospective observational review of all cases diagnosed with an isolated transverse limb defect referred to the Centre for Fetal Care at Queen Charlotte’s and Chelsea Hospital between 2000 and 2009. An isolated transverse limb defect was defined as a partial or complete absence of one or more limbs in the absence of other abnormalities. Details of clinical infor-
Correspondence to: S. Kumar ' 2011 Wiley Periodicals, Inc.
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METHODS
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TRANSVERSE LIMB DEFECTS TABLE 1 List of Nine Cases of Transverse Limb Defects Diagnosed Antenatally
Cases
Maternal Age Gestational Age Risk Factors for and Parity at Diagnosis Transverse Limb Defects
Type of Abnormality
Outcome Live birth. Amputation of the rudimentary foot and application of prosthesis at a later date. TOP
1
39 years/P0
21 weeks
IDDM
Absent left fibula, rudimentary foot
2
28 years /P1
21 weeks
None apparent
3 4 5 6
25 years/P0 19 years/P0 29 years/P0 28 years/P0
21 weeks 22 weeks 20 weeks 24 weeks
None apparent None apparent None apparent None apparent
Bilateral below elbow amputations and right below knee amputation Absent right hand Absent right foot Absent left hand Absent left hand
7
25 years/P1
29 weeks
8
33 years/P1
21 weeks
Maternal intake of rifampicin None apparent
Absence of four digits on the left hand Absence of right hand (Figure 1)
9
36 years/P0
23 weeks
None apparent
Absence of two digits on the right hand
TOP TOP TOP Live birth. Application of a prosthesis at a later date. Live birth Live birth. Application of a prosthesis at a later date. Live birth
Abbreviations: IDDM, insulin-dependent diabetes mellitus; P, parity; TOP, termination of pregnancy. Risk factors, bleeding, ingestion of vasospastic medication, invasive intrauterine procedures, smoking, or alcohol intake.
RESULTS
FIGURE 1. 3D sonogram of a fetus with a transverse forearm defect resulting in an absent right hand (case #8) (arrow).
mation were obtained from the fetal medicine and obstetric databases supplemented by review of obstetric and neonatal discharge summaries. As this was a clinical audit, Research Ethics Committee approval was not required. In all cases, in addition to a detailed maternal and pregnancy history including details about coexisting medical disorders, smoking, or drug intake, a careful skeletal survey was performed. This included measurements of all long bones, detailed assessment of fetal anatomy, and examination of the amniotic cavity for the presence of amniotic bands. Karyotyping and genetic counseling were offered in all cases. Depending on the severity of the fetal abnormality and gestational age, termination of pregnancy as an option was discussed. All patients were referred to a pediatric orthopedic specialist for further counseling. VOL. 39, NO. 8, OCTOBER 2011
We identified nine cases of isolated transverse limb defects during study. The median age of the women was 29 years (range 19–39). The median gestational age at diagnosis was 22 weeks (range 21–29). The most commonly affected limb in our series was the upper limb (7/9). The severity of the limb defects ranged from absence of digits to the absence of three limbs in one case (Table 1).The majority of women (6/9) were nulliparous. None of them smoked nor used alcohol or any known vasospastic drugs during pregnancy. Only one woman was a known diabetic and one patient had used rifampicin during the pregnancy. None of the women had any invasive procedures performed during the index pregnancy. Amniotic bands were not identified in any case. Four of the nine women opted to have termination of pregnancy at a median gestational age of 21 weeks (range 20–23). Postnatal and postmortem examination confirmed the ultrasound findings. No genetic syndromes were identified in our series. All live births occurred at term. We have limited longer term outcome data for the five cases that were live born. Case 1 required amputation of the rudimentary foot. The longterm orthopedic plan for cases 1, 6, and 8 were the application of prosthesis once the child was older. The cases where the only defects were digits did not require any surgery but rather physiotherapy and future occupational therapy. DISCUSSION
Transverse limb defects are rare congenital abnormalities that can range in severity from 455
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absent digits to major malformations involving part of an extremity. In most cases a definite etiology is difficult to identify and it is generally believed that this is a sporadic abnormality with a very low risk of recurrence, with the lesion being usually unilateral and rarely associated with other structural anomalies. Transverse limb defects should be differentiated from phocomelia, where there is absence of long bones with only rudimentary hands and feet being present.4 There are numerous classifications for limb anomalies in the medical literature. An embryologic classification defines the abnormality according to the type of malformation, while a teratology approach classifies the limb defects according to the severity of appearance. Although most existing classification approaches attempt to shed some light on the embryological aspects of this abnormality, they are still far from satisfactory.7,8 Most embryologic classifications are of limited value in clinical management and as yet an ideal classification system does not exist. In our series, the upper limbs were involved more frequently. This is consistent with other publications,9 which show that the left upper limb appears to be more commonly affected. One large study showed that etiologic causes included a genetic basis in 24% of cases, aneuploidy in 6%, teratogens in 4%, vascular disruption in 35%, and an unknown cause in 32%.7 During the study period there were no cases of a major limb malformation that was missed. In our series we failed to find any definitive etiologic link for the limb malformations. Given the rarity of these abnormalities, etiologic associations are best elucidated from large-population-based studies or dysmorphology databases. The exact mechanism leading to transverse defects is controversial. In the fourth and fifth week of embryonic life the fetus is particularly sensitive to teratogen-induced limb defects. There is substantial evidence from experimental studies that severe hypoxia in the first trimester can cause birth defects. The spectrum of possible hypoxia-induced defects is wide, but certain defects, in particular, transverse limb reduction defects, seem to be more common. Animal experiments using mammalian embryos suggest that after a moderate period (30–60 min) of sublethal hypoxia transverse limb reduction defects were more common.10 Webster and Abela suggest that such malformations might be used as a visible marker for an antenatal hypoxic event. In addition to transverse limb defects, it is also proposed that other anomalies such as cleft lip or palate and cardiac defects share a similar etiology. 456
It is easy to see how constriction from an amniotic band causing extrinsic vascular obstruction can cause hypoplasia or amputation of part of an extremity.11 Amniotic bands can arise as a consequence of any intrauterine manipulation such as chorionic villous sampling, amniocentesis, or even following abdominal trauma. Drugs that are potentially vasospastic such as ergotamine or misoprostol can also cause interruption to blood flow to distal parts of the developing limb, causing transverse defects.12 Indeed where there is no obvious explanation for the defect, it is often proposed that interruption in vascular flow in early embryonic life in a vessel supplying a limb has caused these abnormalities. A similar hypothesis is proposed for the spectrum of abnormalities seen in the Poland, Klippel-Feil, and Mo¨bius syndromes. A similar vascular pathology could also play a role in fetuses of diabetic mothers.13 Werler et al have published the largest series of transverse limb defects with or without amniotic bands and suggest that these phenotypes are distinct entities.14 They investigated maternal exposure to vasoactive substances as risk factors for vascular disruption and found that vasoactive substances were not always implicated and therefore suggested that vascular disruption was not a key factor in the pathogenesis of all transverse limb defects. These authors also found that maternal smoking was significantly associated with amniotic band-type transverse limb defects. This finding is also consistent with some older studies.15,16 Transverse limb defects were also found to be associated with low intake of dietary riboflavin.17 The use of an intrauterine contraceptive device has also been implicated in a case of transverse limb reduction defect.18 Medication use including decongestants, bronchodilators, and nonsteroidal anti-inflammatory drugs have also been implicated, although a precise mechanism is unclear.14 In animal experiments when the antineoplastic drug busulfan was given to pregnant rats, radial and ulnar abnormalities were induced.19,20 Misoprostol use in pregnancy is a strong risk factor for limb and vascular abnormalities. A systematic review and meta-analysis of misoprostol and pregnancy concluded that prenatal exposure of misoprostol was associated with a 12-fold increase in the risk of transverse limb defects.21 In addition, there are also reports suggesting that multiple gestation and Hispanic ethnicity22 or severe migraine in expectant mothers23 are risk factors for the development of transverse limb defects. It is very likely that in many cases JOURNAL OF CLINICAL ULTRASOUND
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the underlying pathological mechanism is some form of vascular disruption to the developing limb or extremity. What is however clear from both the literature and the clinical practice is that in the vast majority of cases no obvious cause is evident. Although one patient in our series was exposed to rifampicin during her pregnancy, a recent review suggested that rifampicin was an unlikely teratogen, based on a reasonable amount of data.24
CONCLUSIONS
Counseling of patients following the prenatal diagnosis of a limb reduction defect is difficult because, depending of the degree of severity, these malformations can be associated with significant physical disability. Early prenatal diagnosis of a transverse limb defect is therefore important as it initiates a search for other accompanying anomalies and allows the parents to consider all options including termination of pregnancy. In selected cases, intrauterine therapy in the form of division of a constricting amniotic band may be possible. In the majority of cases however no antenatal treatment is possible and the aim of management should be appropriate referral to a pediatric orthopedic specialist for comprehensive counseling. REFERENCES 1. Makhoul IR, Goldstein I, Smolkin T, et al. Congenital limb deficiencies in newborn infants: prevalence, characteristics and prenatal diagnosis. Prenat Diagn 2003;23:198. 2. Froster UG, Baird PA. Congenital defects of the limbs in stillbirths: data from a population-based study. Am J Med Genet 1993;46:479. 3. Stoll C, Calzolari E, Cornel M, et al. A study on limb reduction defects in six European regions. Ann Genet 1996;39:99. 4. Stoll C, Wiesel A, Queisser-Luft A, et al. Evaluation of the prenatal diagnosis of limb reduction deficiencies. EUROSCAN Study Group. Prenat Diagn 2000;20:811. 5. Kallen B. A prospective study of some aetiological factors in limb reduction defects in Sweden. J Epidemiol Community Health 1989;43:86. 6. Bod M, Czeizel A, Lenz W. Incidence at birth of different types of limb reduction abnormalities in Hungary 1975-1977. Hum Genet 1983;65:27. 7. McGuirk CK, Westgate MN, Holmes LB. Limb deficiencies in newborn infants. Pediatrics 2001; 108:E64. 8. Ogino T. Clinical features and teratogenic mechanisms of congenital absence of digits. Dev Growth Differ 2007;49:523. VOL. 39, NO. 8, OCTOBER 2011
9. Stephens TD, Shepard TH. A review of limb defects in a large fetus collection. Am J Hum Genet 1983;35:508. 10. Webster WS, Abela D. The effect of hypoxia in development. Birth Defects Res C Embryo Today 2007;81:215. 11. Kaufman MH, Chang HH. Studies of the mechanism of amniotic sac puncture-induced limb abnormalities in mice. Int J Dev Biol 2000;44:161. 12. Gonzalez CH, Vargas FR, Perez AB, et al. Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy. Am J Med Genet 1993;47:59. 13. Correa A, Cragan JD, Kucik JE, et al. Reporting birth defects surveillance data 1968-2003. Birth Defects Res A Clin Mol Teratol 2007;79:65. 14. Werler MM, Bosco JL, Shapira SK. Maternal vasoactive exposures, amniotic bands, and terminal transverse limb defects. Birth Defects Res A Clin Mol Teratol 2009;85:52. 15. Czeizel AE, Vitez M, Kodaj I, et al. A morphological and family study on isolated terminal transverse type of congenital limb deficiency in Hungary, 1975-1984. Teratology 1993;48:323. 16. Wasserman CR, Shaw GM, O’Malley CD, et al. Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb. Teratology 1996;53:261. 17. Robitaille J, Carmichael SL, Shaw GM, et al. Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997-2003. Birth Defects Res A Clin Mol Teratol 2009; 85:773. 18. Weissmann-Brenner A, Lerner A, Peleg D. Transverse limb reduction and intrauterine device: case report and review of the literature. Eur J Contracept Reprod Health Care 2007;12:294. 19. Ogino T, Kato H. Clinical and experimental studies on ulnar ray deficiency. Handchir Mikrochir Plast Chir 1988;20:330. 20. Kato H, Ogino T, Minami A, et al. Experimental study of radial ray deficiency. J Hand Surg Br 1990;15:470. 21. Da Silva Dal Pizzol T, Knop FP, Mengue SS. Prenatal exposure to misoprostol and congenital anomalies: systematic review and meta-analysis. Reprod Toxicol 2006;22:666. 22. Husain T, Langlois PH, Sever LE, et al. Descriptive epidemiologic features shared by birth defects thought to be related to vascular disruption in Texas, 1996-2002. Birth Defects Res A Clin Mol Teratol 2008;82:435. 23. Banhidy F, Acs N, Horvath-Puho E, et al. Maternal severe migraine and risk of congenital limb deficiencies. Birth Defects Res A Clin Mol Teratol 2006;76:592. 24. Nahum GG, Uhl K, Kennedy DL. Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic risks. Obstet Gynecol 2006;107:1120.
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