Skip to main content
NCBI home page
Medicine logoLink to Medicine
. 2018 Jul 20;97(29):e11471. doi: 10.1097/MD.0000000000011471

Prenatal limb defects

Epidemiologic characteristics and an epidemiologic analysis of risk factors

Yue Shi a, Bin Zhang a, Fanbin Kong b,∗, Xilian Li a,∗
Editor: Milan Perovic
PMCID: PMC6086500  PMID: 30024522

Abstract

To analyze prenatal ultrasound data for fetal limb deformities in high-risk pregnant women and the risk factors for prenatal limb defects in high-risk pregnant women.

This was a retrospective study of high-risk pregnant women at the multidisciplinary consultation center from January 2006 to December 2015. When deformities were definitively diagnosed in the first trimester by ultrasound, patients were recommended to undergo an abortion, and fetal abnormalities were confirmed by pathological examination (both gross anatomic examinations and fetal chromosome and genetic tests). The risk factors for fetal limb deformities and other congenital malformations were analyzed by multifactor analysis.

Of the 4088 fetuses recorded, 144 (3.52%) were diagnosed with limb abnormalities. The abnormalities included 70 (48.61%) clubfoot/clubhand cases, with 5 polydactyly, 5 syndactyly, 4 flexion toe, 4 split hand/foot malformation, 3 overlapping fingers, and 49 congenital talipes equinovarus. A total of 6 (4.17%) and 13 (9.02%) fetuses had phocomelia and imperfect osteogenesis, respectively; 22 (15.28%) cases showed achondrogenesis; 19 (13.19%) and 12 (8.33%) had partial limb deletion absence and joint movement malfunction, respectively.

In the high-risk population with limb deformities (144 patients), 19 (13.19%) were ≥35 years old, 6 (4.17%) had family history of congenital malformations, 14 (9.72%) had abnormal reproductive history, 21 (14.6%) had harmful chemical exposure, 6 (4.2%) had early TORCH infections, 16 (11.1%) had gestational diabetes, 9 (6.3%) had hypertension, 3 (2.1%) took glucocorticoid, 9 (6.3%) took sedatives.

In the high-risk population with other congenital malformations except limb deformities (3766 patients), 144 pregnant women were randomly selected. In the high-risk population with other congenital malformations (144 patients), 9 (6.25%) were ≥35 years old, 7 (4.86%) had family history of congenital malformations, 10 (6.94%) had abnormal reproductive history, 22 (15.28%) had harmful chemical exposure, 5 (3.47%) had early TORCH infections, 12 (8.33%) had gestational diabetes, 11 (7.64%) had hypertension, 4 (2.78%) took glucocorticoid, 11 (7.64%) took sedatives.

Ultrasound can provide adequate evidence for fetal limb deformities evaluation in most patients. Fetal limb deformity cases showed a significantly higher rate than other congenital malformations for advanced maternal age (≥35 years old).

Keywords: fetal limb deformity, high-risk pregnant women, screening, ultrasound

1. Introduction

Congenital limb abnormalities may be caused by genetic syndromes or can be isolated and sporadic events; therefore, their prognoses are highly variable. In China, the prevalence of fetal limb abnormalities is 0.38%.[1] In Europe, it varies from 1.4 to 30 cases per 10,000 births.[2,3] In Canada, this rate is about 5.6 per 10,000 births.[4] Early detection of such abnormalities is important in providing counseling to families in the optimal time window.

First-trimester screening for fetal limb abnormalities was introduced since the 1980s and 1990s.[5–7] It is widely accepted that first-trimester screening can be performed as early as 9 weeks of gestation using transvaginal ultrasound. Recently, the increasing use of NIPT (noninvasive prenatal testing) prompted many researchers to assess the clinical value of early screening for fetal limb abnormalities.[8–17] Indeed, except fingers, most abnormalities can be observed using a combination of transabdominal and transvaginal ultrasound sessions.[13–23] Nevertheless, many of these studies were based on small sample sizes, with the scarcity of fetal abnormalities rendering their interpretations difficult. Liao et al[1] assessed 9438 fetuses and identified 36 cases (0.38%) of fetal limb abnormalities, of which 28 (78%) were detected prenatally and 23 (64%) during the first trimester of pregnancy.

Some pregnant women are considered to be at high risk for having fetuses with structural abnormalities. Maternal risk factors for structural abnormalities include age (≥35 years old), maternal gestational diseases (gestational diabetes mellitus (GDM) and hypertension), early TORCH infections, harmful chemical exposure, history of abnormal delivery, family history of congenital, taking glucocorticoid, taking sedatives, and abnormal genetic examination.[24–27] Nevertheless, few studies were done to identify which factors were more closely and specifically associated with prenatal limb defects, compared with the incidence of the risk factors for other congenital malformations. Therefore, the present study aimed to analyze prenatal ultrasound data for fetal limb deformities in high-risk pregnant women and the incidence of risk factors with prenatal limb defects in high-risk pregnant women.

2. Materials and methods

2.1. Subjects

This was a retrospective study of pregnant women and fetuses with fetal limb abnormality detected or confirmed with ultrasound scan at the multidisciplinary consultation center of the Obstetrics and Gynecology Hospital of Fudan University (Huangpu District, Shanghai, China) from January 2006 to December 2015.

Patients with fetal limb deformities diagnosed with ultrasound were reviewed. High-risk pregnancy was defined as with at least one of the following factors: maternal age ≥35 years old; family history of congenital; abnormal reproductive history; maternal gestational complications (GDM, pregnancy-induced hypertension, hypothyroidism, subclinical hypothyroidism, chronic renal disease, etc.); early TORCH infections; harmful chemical exposure; taking glucocorticoid or sedatives. High-risk patients were included and a total of 3910 high-risk pregnant women with suspicious congenital fetal malformations were reviewed.

All the included clinical cases consulted physicians at the prenatal Multidisciplinary Consultation Center. Our team consists of obstetricians, pediatricians, pediatric surgeons, radiologists, and researchers from biochemistry and genetic laboratories. The study complied with the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University. The need for informed consent was waived because of the retrospective nature of the study.

2.2. Ultrasound examination

Routine ultrasonography included fetal head, face, spine, thoracoabdominal wall, thoracoabdominal organs, limbs, placenta, amniotic fluid, and umbilical cord. The fetal biparietal diameter, head circumference, abdominal circumference, femur length, humerus length, transverse cerebellar diameter, amniotic fluid depth, and systolic and diastolic peak velocity ratios were also measured in addition to resistance and pulse indexes of the umbilical artery. Ultrasound examinations were performed on an E8 color Doppler ultrasonic diagnostic system (GE Healthcare, Waukesha, WI) with a probe of 3.5 to 5.0 MHz.

A continuous track scan was successively performed on fetal limbs from the proximal region to the distal side along the longitudinal axis. Both longitudinal and horizontal axis sections were scanned, including humerus, ulna and radius, femur, tibia, and fibula. The number, length, shape, structure, posture, position, and activity of every long bone in each limb were recorded.

In cases for which the limbs could not be shown clearly due to fetal posture, the patients were asked to walk for 15 to 30 minutes, and then ultrasound was repeated. The initial ultrasound examinations were performed at 12 to 14 weeks of gestation. For fetuses with suspicious abnormalities, ultrasound was repeated at 22 to 26 weeks of gestation.

2.3. Data collection

Clinical information, including age, reproductive history, delivery method, gestational week, and high-risk pregnancy risk factors were collected.

2.4. Follow-up

When deformities were definitively diagnosed in the first trimester by ultrasound, patients were recommended to undergo an abortion, and fetal abnormalities were confirmed by pathological examination (both gross anatomic examinations and fetal chromosome and genetic tests). In cases of suspicious fetal limb deformities, a second-trimester ultrasound examination was performed at 18 to 24 weeks of gestation. Ultrasound examination assessed fetal position, upper limbs (upper arms, forearms, and hands), lower limbs (thighs, calves, and feet), and morphology and number of fingers and toes. Fatal limb abnormalities detected again in the second examination prompted the team to recommend pregnancy termination, while fetuses with strephenopodia alone were recommended to get corrective therapy later; these patients were followed-up till delivery, with limb abnormalities assessed definitively for confirmation.

2.5. Statistical analysis

Excel was used to establish the database of the risk factors of fetal congenital malformation. SPSS 22.0 software was applied to perform the multi-factor non-conditional logistic regression analysis of fetal limb deformity and other congenital malformation.

3. Results

3.1. Patient characteristics

A total of 3910 high-risk pregnant women with suspicious congenital fetal malformations who underwent prenatal multidisciplinary consultation were included. The mean maternal age was 29.1 ± 4.5 years (range, 20–43 years). A total of 4088 fetuses from 3910 women (178 twin pairs) were subjected for analysis.

3.2. Fetal limb abnormalities

Deformities occurred in 2496 (61.6%) fetuses, and included 1168 (46.8%) cardiac, 847 (33.9%) renal, and 720 (28.8%) bone deformities. Among the 4088 fetuses, 144 (3.5%) were diagnosed with limb abnormalities; all were singlet (Table 1). Of these, 70 (48.6%) had clubhand/clubfoot (Figs. 1–3), including 5 polydactyly, 5 syndactyly, 4 flexion toe, 4 split hand/foot malformation, 3 overlapping finger, and 49 congenital talipesequinovarus cases; 13 (9.0%) had imperfect osteogenesis (Fig. 4); 22 (15.3%) cases with achondrogenesis (Figs. 5–7) were found, including 7 and 15 with fatal dysplasia and cartilage hypoplasia, respectively; 19 (13.2%) and 12 (8.3%) cases had partial deletion limb (Fig. 8) and joint movement malfunction, respectively; 6 (4.2%) fetuses had phocomelia.

Table 1.

Characteristics of the fetuses with limb abnormalities.

3.2.

Open in a new tab

Figure 1.

Figure 1

Open in a new tab

Representative strephenopodiaimages. The arrows indicate that the left (left panel) and right (right panel) feet are inverted.

Figure 3.

Figure 3

Open in a new tab

Representative sirenomelia image. This suggested lower limb fusion. LEF= left femur, RFL=right femur.

Figure 4.

Figure 4

Open in a new tab

Representative images showing imperfect osteogenesis. The right femur was bent to angle (arrow in the left image) and the left femur was discontinuous (arrow in the right image).

Figure 5.

Figure 5

Open in a new tab

Representative achondroplasia images. The fetus was 19 weeks and 4 days, with short upper limbs. 1, length of right humerus; 2, length of right ulna; 3, length of right radius; 4, length of left humerus; 5, length of left ulna; length of left radius.

Figure 7.

Figure 7

Open in a new tab

Fatal dysplasia. Cartilage formation was incomplete in this fetus (27 weeks and 3 days). The left side of the first 6 to 11 thoracic vertebrae and rib fusion were missing, and short limbs could be observed.

Figure 8.

Figure 8

Open in a new tab

Partial limb deletion. In this fetus (22 weeks and 1 day), the right forearm ulnar was short, and the right hand was missing.

Figure 2.

Figure 2

Open in a new tab

Representative image showing a bent right finger (arrow) with no activity.

Figure 6.

Figure 6

Open in a new tab

Representative achondroplasia images. The fetus was 19 weeks and 4 days, with short lower limbs. 1, length of right femur; 2, length of right tibia; length of right fibula; length of left femur; 5, length of left tibia; 6, length of left fibula.

3.3. An epidemiologic analysis of risk factors

The frequency of prenatal limb deformities is significantly elevated in high-risk pregnant women compared with the low-risk population.[24–27] As it is obvious that congenital malformations are associated with these risk factors, more analyses were done to identify which factors are more closely associated with fetal limb deformities compared with other congenital malformations this time.

In the high-risk population with limb deformities (144 patients), 19 (13.19%) were ≥35 years old, 6 (4.17%) had family history of congenital malformations, 14 (9.72%) had abnormal reproductive history, 21 (14.6%) had harmful chemical exposure, 6 (4.2%) had early TORCH infections, 16 (11.1%) had gestational diabetes, 9 (6.3%) had hypertension, 3 (2.1%) used glucocorticoid, 9 (6.3%) used sedatives.

In the high-risk population with other congenital malformations except limb deformities (3766 patients), 144 pregnant women were randomly selected. In the high-risk population with other congenital malformations (144 patients), 9 (6.25%) were ≥35 years old, 7 (4.86%) had family history of congenital malformations, 10 (6.94%) had abnormal reproductive history, 22 (15.28%) had harmful chemical exposure, 5 (3.47%) had early TORCH infections, 12 (8.33%) had gestational diabetes, 11 (7.64%) had hypertension, 4 (2.78%) took glucocorticoid, 11 (7.64%) took sedatives.

3.4. Multi-variant analysis

Fetal limb deformities cases had a significantly higher rate than other congenital malformations for advanced maternal age ≥ 35 years old (P < .05,OR = 2.774), but there were no significant difference between the incidence of family history of congenital malformations, abnormal reproductive history, harmful chemical exposure, early TORCH infections, gestational diabetes, hypertension, taking glucocorticoid and taking sedatives in the fetal limb deformities population compared with other congenital malformations (Table 2).

Table 2.

Correlation univariate analysis of mother characteristics between fetal limb deformities and other congenital malformations.

3.4.

Open in a new tab

3.5. Combined abnormalities

Table 3 presents combined deformities with abnormality. Cardiac deformities were found in 41 fetuses (27.5%), urinary tract abnormalities in 11 (7.4%), neurological disorders in 20 (13.4%), and digestive system deformities in 28 (18.8%). Moreover, genetic abnormalities were recorded in 4 (14.8%) of 27 patients tested. These results suggested that limb abnormalities are frequently accompanied with other deformities and present as genetic syndromes.

Table 3.

Combined deformity.

3.5.

Open in a new tab

4. Discussion

So far, few reports have assessed prenatal limb deformity and investigated the associated risk factors in a real-life setting. Therefore, this study aimed to retrospectively review the epidemiologic characteristics of prenatal limb defects and also investigate the gestational risk factors associated with fetal limb deformities.

A Chinese study reported a prevalence of fetal limb abnormalities of 0.38%.[1] Previous studies in Europe and Northern America found that such defects occur in 1.4 to 30 cases per 10,000 births.[2–4] In the present study, the prevalence of fetal limb abnormalities was substantially higher (3.7%), which is probably because only high-risk pregnant women were included. Indeed, maternal risk factors for congenital malformations include age (≥35 years old), family history of congenital malformations, abnormal reproductive history, harmful chemical exposure, pregnancy TORCH virus infection, diabetes, hypertension, pregnancy taking glucocorticoid, sedative.[24–27]

As shown above, clubfoot/clubhand was the most frequent abnormality, followed by limp dysplasia. A previous study showed that radial aplasia and clubhand are the most frequent abnormalities found in the first trimester,[19] corroborating our findings. On the other hand, Liao et al[1] showed in a Chinese population that transverse limb reduction defects were the most frequent. Meanwhile, a study from The Netherlands indicated that polydactylywasthe most frequent defect.[2] Discrepancies among studies could be due to small sample size and population differences.

The present study showed that fetal limb abnormalities were often found in combination with other bone and cardiac abnormalities, which in themselves could be fatal or result in poor prognosis. Indeed, multiple limb abnormalities are associated with vascular factors,[28] which can be related to other developmental defects. Nevertheless, our findings indicated that ultrasound could be used to guide the next step of pregnancy management. Indeed, the presence of fetal limb abnormalities could lead to the recommendation of pregnancy termination. It should be stressed that counseling should be tailored to each specific case; for example, in case of strephenopodia, medical treatment could be suggested. Of course, the parents have the final call.

Additional analyses were done to identify which factors were more closely associated with fetal limb deformities compared with other congenital malformations. Fetal limb deformity cases had a significantly higher rate than other congenital malformations for advanced maternal age (≥35 years old),but there was no significant difference between the incidence of congenital malformation, abnormal reproductive history, harmful chemical exposure, pregnancy TORCH virus infection, diabetes, hypertension, pregnancy taking hormones, and sedatives in fetal limb deformities compared with other congenital malformations.

Two early studies of prenatal limb defects did not examine the pattern of occurrence according to maternal age,[29,30] while another study[31] demonstrated a positive relation between maternal age and increasing birth prevalence of fetal limb deformities. Here, we also reached similar conclusion that advanced maternal age (≥35 years old) should also be a risk factor more related to fetal limb deformities amongst gestational risk factors leading to congenital malformations, for which more elaborate and frequent examinations during the pregnancy should be done for them to screen for potential limb deformities.

Ultrasound for structural abnormality screening is a convenient, inexpensive, and highly accepted procedure, making it one of the most common diagnostic procedures for prenatal evaluation performed in an office setting without anesthesia.[28] It can provide adequate evidence for prenatal structural abnormality evaluation in most patients.[2] The high sensitivity and specificity of ultrasound for the detection of structural abnormalities are widely accepted.[1,8,10,15,19,32]

The present study had some limitations. First, the sample size was relatively small, with the subjects being from a single center. Secondly, its retrospective nature limited data availability. In particular, no data were available regarding folic acid supplementation or pollutant exposure. Additional studies are required to refine and supplement the present results. In addition, more investigations need to be done for further analysis on risk factors such as abnormal reproductive history, harmful chemical exposure, pregnancy TORCH virus infection, diabetes, hypertension, pregnancy taking glucocorticoid, sedative. An additional problem, so far not evaluated, is that parental age may be a confounder.

In conclusion, fetal limb deformity cases showed a significantly higher rate than other congenital malformations for advanced maternal age (≥35 year old).

Author contributions

YS and XL contributed to the acquisition of data, or analysis and interpretation of data; FK and XL contributed to conception and design; XL, YS, BZ and FK have been involved in drafting the manuscript or revising it critically for important intellectual content; all authors have given final approval of the version to be published.

Data curation: XiLian Li.

Formal analysis: XiLian Li.

Funding acquisition: FanBin Kong.

Investigation: XiLian Li.

Project administration: FanBin Kong.

Resources: Bin Zhang, XiLian Li.

Software: Yue Shi.

Supervision: FanBin Kong.

Validation: Bin Zhang.

Writing – original draft: XiLian Li.

Writing – review & editing: Yue Shi.

Footnotes

Abbreviations: GDM = gestational diabetes mellitus, NIPT = noninvasive prenatal testing, TORCH = toxoplasmosis, other (syphilis), rubella, cytomegalovirus (CMV), herpes simplex virus (HSV).

Sources of financial support: This study was funded by National Key R&D Program of China, 2016YFC 1000403 and Shanghai Committee of Science and Technology, China (16411969400).

The authors have no conflicts of interest to disclose.

References

  • [1].Liao YM, Li SL, Luo GY, et al. Routine screening for fetal limb abnormalities in the first trimester. Prenat Diagn 2016;36:117–26. [DOI] [PubMed] [Google Scholar]
  • [2].Vasluian E, van der Sluis CK, van Essen AJ, et al. Birth prevalence for congenital limb defects in the northern Netherlands: a 30-year population-based study. BMC Musculoskelet Disord 2013;14:323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Aro T, Heinonen OP, Saxen L. Incidence and secular trends of congenital limb defects in Finland. Int J Epidemiol 1982;11:239–44. [DOI] [PubMed] [Google Scholar]
  • [4].Bedard T, Lowry RB, Sibbald B, et al. Congenital limb deficiencies in Alberta—a review of 33 years (1980–2012) from the Alberta Congenital Anomalies Surveillance System (ACASS). Am J Med Genet A 2015;167A:2599–609. [DOI] [PubMed] [Google Scholar]
  • [5].Green JJ, Hobbins JC. Abdominal ultrasound examination of the first-trimester fetus. Am J Obstet Gynecol 1988;159:165–75. [DOI] [PubMed] [Google Scholar]
  • [6].Timor-Tritsch IE, Farine D, Rosen MG. A close look at early embryonic development with the high-frequency transvaginal transducer. Am J Obstet Gynecol 1988;159:676–81. [DOI] [PubMed] [Google Scholar]
  • [7].Timor-Tritsch IE, Monteagudo A, Peisner DB. High-frequency transvaginal sonographic examination for the potential malformation assessment of the 9-week to 14-week fetus. J Clin Ultrasound 1992;20:231–8. [DOI] [PubMed] [Google Scholar]
  • [8].Grande M, Arigita M, Borobio V, et al. First-trimester detection of structural abnormalities and the role of aneuploidy markers. Ultrasound Obstet Gynecol 2012;39:157–63. [DOI] [PubMed] [Google Scholar]
  • [9].Syngelaki A, Chelemen T, Dagklis T, et al. Challenges in the diagnosis of fetal non-chromosomal abnormalities at 11–13 weeks. Prenat Diagn 2011;31:90–102. [DOI] [PubMed] [Google Scholar]
  • [10].Abu-Rustum RS, Daou L, Abu-Rustum SE. Role of first-trimester sonography in the diagnosis of aneuploidy and structural fetal anomalies. J Ultrasound Med 2010;29:1445–52. [DOI] [PubMed] [Google Scholar]
  • [11].Dane B, Dane C, Sivri D, et al. Ultrasound screening for fetal major abnormalities at 11–14 weeks. Acta Obstet Gynecol Scand 2007;86:666–70. [DOI] [PubMed] [Google Scholar]
  • [12].Souka AP, Snijders RJ, Novakov A, et al. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10–14 weeks of gestation. Ultrasound Obstet Gynecol 1998;11:391–400. [DOI] [PubMed] [Google Scholar]
  • [13].Timor-Tritsch IE, Bashiri A, Monteagudo A, et al. Qualified and trained sonographers in the US can perform early fetal anatomy scans between 11 and 14 weeks. Am J Obstet Gynecol 2004;191:1247–52. [DOI] [PubMed] [Google Scholar]
  • [14].McAuliffe FM, Fong KW, Toi A, et al. Ultrasound detection of fetal anomalies in conjunction with first-trimester nuchal translucency screening: a feasibility study. Am J Obstet Gynecol 2005;193(3 pt 2):1260–5. [DOI] [PubMed] [Google Scholar]
  • [15].Luchi C, Schifano M, Sacchini C, et al. Detailed fetal anatomy assessment in the first trimester at 11, 12 and 13 weeks of gestation. J Matern Fetal Neonatal Med 2012;25:675–8. [DOI] [PubMed] [Google Scholar]
  • [16].Ebrashy A, El Kateb A, Momtaz M, et al. 13-14-week fetal anatomy scan: a 5-year prospective study. Ultrasound Obstet Gynecol 2010;35:292–6. [DOI] [PubMed] [Google Scholar]
  • [17].Souka AP, Pilalis A, Kavalakis Y, et al. Assessment of fetal anatomy at the 11–14-week ultrasound examination. Ultrasound Obstet Gynecol 2004;24:730–4. [DOI] [PubMed] [Google Scholar]
  • [18].Bianca S, Bartoloni G, Libertini C, et al. Fetal upper limb amelia with increased nuchal translucency. Congenit Anom (Kyoto) 2009;49:121–2. [DOI] [PubMed] [Google Scholar]
  • [19].Rice KJ, Ballas J, Lai E, et al. Diagnosis of fetal limb abnormalities before 15 weeks: cause for concern. J Ultrasound Med 2011;30:1009–19. [DOI] [PubMed] [Google Scholar]
  • [20].Bronshtein M, Keret D, Deutsch M, et al. Transvaginal sonographic detection of skeletal anomalies in the first and early second trimesters. Prenat Diagn 1993;13:597–601. [DOI] [PubMed] [Google Scholar]
  • [21].Van Keirsbilck J, Cannie M, Robrechts C, et al. First trimester diagnosis of sirenomelia. Prenat Diagn 2006;26:684–8. [DOI] [PubMed] [Google Scholar]
  • [22].Singh C, Lodha P, Arora D, et al. Diagnosis of sirenomelia in the first trimester. J Clin Ultrasound 2014;42:355–9. [DOI] [PubMed] [Google Scholar]
  • [23].Souter V, Nyberg D, Siebert JR, et al. Upper limb phocomelia associated with increased nuchal translucency in a monochorionic twin pregnancy. J Ultrasound Med 2002;21:355–60. [DOI] [PubMed] [Google Scholar]
  • [24].Sunitha T, Prasoona KR, Kuman TM, et al. Risk factors for congenital anomalies in high risk pregnant women: a large study from South India Egypt. J Med Human Henet 2017;18:79–85. [Google Scholar]
  • [25].Yang Q, Khoury MJ, Olney RS, et al. Does periconceptional multivitamin use reduce the risk for limb deficiency in offspring? Epidemiology 1997;8:157–61. [DOI] [PubMed] [Google Scholar]
  • [26].Rosano A, Botto LD, Olney RS, et al. Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems. Am J Med Genet 2000;93:110–6. [DOI] [PubMed] [Google Scholar]
  • [27].Allen VM, Armson BA, Wilson RD, et al. Teratogenicity associated with pre-existing and gestational diabetes. J Obstet Gynaecol Can 2007;29:927–44. [DOI] [PubMed] [Google Scholar]
  • [28].Ermito S, Dinatale A, Carrara S, et al. Prenatal diagnosis of limb abnormalities: role of fetal ultrasonography. J Prenat Med 2009;3:18–22. [PMC free article] [PubMed] [Google Scholar]
  • [29].Smith DW. Distal limb hypoplasia in the fetal hydantoin syndrome. Birth Defects Orig Artic Ser 1977;13:355–9. [PubMed] [Google Scholar]
  • [30].Czeizel A, Keller S, Bod M. An aetiological evaluation of increased occurrence of congenital limb reduction abnormalities in Hungary, 1975–1978. Int J Epidemiol 1983;12:445–9. [DOI] [PubMed] [Google Scholar]
  • [31].Hay S, Barbano H. Independent effects of maternal age and birth order on the incidence of selected congenital malformations. Teratology 1972;6:271–9. [DOI] [PubMed] [Google Scholar]
  • [32].Victoria T, Shakir NU, Andronikou S, et al. Normal fetal long bone length from computed tomography: potential value in the prenatal evaluation of skeletal dysplasias. Fetal Diagn Ther 2016;40:291–7. [DOI] [PubMed] [Google Scholar]

Articles from Medicine are provided here courtesy of Wolters Kluwer Health

RESOURCES