Michéle Hansen, MPH, Jennifer J Kurinczuk, MD, Carol Bower, MB, BS, PhD, and Sandra Webb, PhD.
ABSTRACT
‡ †
Background It is not known whether infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have a higher risk of birth defects than infants conceived naturally.
Methods We obtained data from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997. We assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmic sperm injection or in vitro fertilization.
Results Twenty-six of the 301 infants conceived with intracytoplasmic sperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception). As compared with natural conception, the odds ratio for a major birth defect by one year of age, after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings, was 2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmic sperm injection, and 2.0 (95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization. Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects.
Conclusions Infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants. (N Engl J Med 2002;346:725-30.)
From the Telethon Institute for Child Health Research and the Center for Child Health Research, University of Western Australia (M.H., J.J.K., C.B.); the Health Department of Western Australia (M.H., S.W); and the Western Australian Birth Defects Registry (C.B.) - all in Perth, Australia; and the Department of Epidemiology and Public Health, University of Leicester, Leicester, United Kingdom (J.J.K.). Address reprint requests to Dr. Kurinczuk at the Department of Epidemiology and Public Health, University of Leicester, 22-28 Princess Rd. W, Leicester LE1 6TP, United Kingdom, or at jjk6@le.ac.uk
IN vitro fertilization was introduced into practice with little formal evaluation of its effects on the health of the children conceived with this procedure. When intracytoplasmic sperm injection was introduced in 1992, earlier concern reemerged that infants conceived with the use of assisted reproductive technology might have an increased risk of birth defects.I-4
In general, studies have not shown an increased risk of major birth defects in children conceived with either intracytoplasmic sperm injection or standard in vitro fertilization.' Much of this research, however, has had methodologic problems, including inadequate sample sizes and a lack of appropriate data for comparison. Moreover, the definitions of major birth defects used for infants conceived with assisted reproductive technology were different from those used for infants conceived naturally; this difference may have led to an underestimation of the relative prevalence of birth defects among infants conceived with assisted reproductive technology.6
Treatment with assisted reproductive technology is provided by three private clinics in Western Australia. Treatment is regulated by the Human Reproductive Technology Act 1991, which established the statutory Reproductive Technology Register that contains information on all procedures performed with assisted reproductive technology in Western Australia since April 1993.7 We compared the prevalence of major birth defects among infants conceived with such procedures with that in a random sample of naturally conceived infants, using the same system of classification for all birth defects.
METHODS
Collection of Data
We used data from the Reproductive Technology Register to identify all pregnancies of at least 20 weeks' gestation resulting from intracytoplasmic sperm injection or standard in vitro fertilization treatment undertaken between 1993 and 1997 and all terminations of such pregnancies because of fetal abnormalities (regardless of the length of gestation). The three private clinics performed 719, 1191, and 2931 cycles of embryo transfer, respectively, during this period.
The Midwives' Notification System collects information on all infants delivered in Western Australia at 20 weeks' gestation or later.8 A random sample of 4000 infants born in Western Australia between 1993 and 1997 was selected after the exclusion of the infants conceived with assisted reproductive technology.
The Western Australian Birth Defects Registry collects information on birth defects occurring in liveborn and stillborn infants delivered in Western Australia, and on pregnancies terminated because of fetal malformations.9 For the purposes of the registry, birth defects are defined as abnormalities that are probably of prenatal origin, including structural, chromosomal, and genetic defects. The classification system of the British Paediatric Association, based on the International Classification of Diseases, 9th Repision (ICD-9), is used to code each defect, and all defects are classified as major or minor according to a method devised by the Centers for Disease Control and Prevention.9 Most minor defects (listed in Supplementary Appendix 1, available with the full text of this article at http://www.nejm.org) are excluded from the registry; however, defects on the exclusion list that require treatment or are disfiguring are included. Approximately 90 percent of cases in the registry involve at least one major defect (with or without minor defects); the remainder involve minor defects only.9 Birth defects diagnosed prenatally and in children up to six years of age are included. Cases are reported by multiple statutory and voluntary sources with a high level of ascertainment and accuracy.10
Automatch (probabilistic matching software)11 was used to link the records of the three registers. When linkage was complete, birth records were available for all infants in the study; records of birth defects were available for those for whom a link was found within the Birth Defects Registry.
To assess the potential effects of differential surveillance according to mode of conception, a list of all birth defects reported for each child was prepared without identification of whether conception was assisted or natural. An independent pediatrician examined the list and identified, on the basis of clinical experience, defects that might have been diagnosed because of closer surveillance and might not otherwise have been detected in a child less than one year of age.
Approval for the study was obtained from the appropriate institutional ethics committee.
Prevalence of Birth Defects
The prevalence of major birth defects diagnosed by one year of age was calculated for the intracytoplasmic-sperm-injection, invitro-fertilization, and natural-conception groups. We compared the groups by calculating odds ratios for major birth defects and exact 95 percent confidence intervals on the basis of prevalence. The use of these odds ratios rather than relative risks facilitated the comparison with the odds ratios that were subsequently calculated by logistic regression. Two-tailed P values were calculated with the use of SPSS software.l2
Multiple logistic-regression analysis was used to assess the effect of maternal age and parity and the sex of the infant on the oddsratio estimates. Generalized-estimating-equation analyses were performed with the use of Stata software13 to examine the effect of potential correlations of risk between siblings in the data set.
Although our study dealt primarily with birth defects diagnosed at or after birth, it is possible that the rates of termination of pregnancy because of fetal anomalies might have differed between the assisted-conception groups and the natural-conception group and that investigating only births may have led to a biased result. We identified all terminations of pregnancy after the prenatal diagnosis of birth defects in the assisted-conception groups; there were four such terminations among the women who underwent in vitro fertilization and none among the women who underwent intracytoplasmic sperm injection. In Western Australia, there are 3.5 terminations of pregnancy because of fetal anomalies per 1000 total births. For the sake of comparison, we conducted a secondary analysis including 14 pregnancies that had resulted from natural conception and that had been terminated because of birth defects; these pregnancies were randomly selected from the Birth Defects Registry and added to the 4000 births for this analysis.
RESULTS
The study included 301 infants conceived with intracytoplasmic sperm injection, 837 infants conceived with standard in vitro fertilization, and 4000 naturally conceived infants. As compared with the mothers of the natural-conception group of infants, the women who had undergone treatment with assisted reproductive technology were, on average, older and less likely to have had a child previously (Table 1). They were more likely to be married or cohabiting, to be white, and to live in the metropolitan area of Perth. As compared with the infants in the natural-conception group the infants conceived with assisted reproductive technology were more likely to be delivered by cesarean section, to have low birth weight, and to be born before term (Table 2). When only singleton infants were considered, low birth weight and delivery by cesarean section were significantly more common in both the in-vitro-fertilization group and the intracytoplasmic-sperm-injection group than in the natural-conception group, and preterm birth was significantly more common in the in-vitro-fertilization group than in the natural-conception group.
TABLE 1. Characteristics of 4916 women who conceived with intracytoplasmic sperm injection, with in vitro fertilization, or naturally*
ICSI IVF NC
Group Group Group
CHARACTERISTIC (N=240) (N=676) (N=4000)
Age - yr 32.6±4.0t 34.1±4.6t 28.2±4.4
Parity-no. (%)
0 183(76)† 454 (67) 1612(40)
>1 57(24) 222(33) 2388(60)
Married or cohabiting 237(99)† 664(98)† 3564(89)
- no. (%)
Ethnic group-no. (%)
White 230(96)† 639(95)† 3500(88)
Aboriginal or Torres 1 (<1) 3(<l) 220(6)
Strait Islander
Other 9(4) 34(5) 280(7)
Place of residence -
no. (%)‡
Metropolitan Perth 197(82)† 557(82)† 2884 (72)
Rural area 43(18) 119(18) 1112 (28)
Unknown - - 4(<1)
* Plus-minus values are means ±SD.
Numbers of mothers do not match numbers of infants because of multiple births.
ICSI=intracytoplasmic sperm injection; IVF=in vitro fertilization; NC=natural conception
† P<0.001 for the comparison with the natural-conception group.
‡ Data were missing for four mothers of infants in the natural-conception group.
In a total of 26 of the infants conceived with intracytoplasmic sperm injection (8.6 percent [95 percent confidence interval, 5.7 to 12.4 percent] ), 75 of the infants conceived with in vitro fertilization (9.0 percent [95 percent confidence interval, 7.1 to 11.1 percent] ), and 168 of the naturally conceived infants (4.2 percent [95 percent confidence interval, 3.6 to 4.9 percent]), a major birth defect was diagnosed by one year of age (P<0.001 for the comparisons between the natural-conception group and the assisted-conception groups). There were no significant differences in prevalence among the clinics (data not shown). When all the infants were considered, those conceived with assisted reproductive technology were more than twice as likely as naturally conceived infants to have a major birth defect diagnosed by one year of age (Table 3). The results were similar and remained significant when only singleton infants were considered, when the analyses were further restricted to singletons born at term (at least 37 weeks of gestation), and when the analyses were adjusted for maternal age and parity, the sex of the infant, and correlation of the risk of birth defects between siblings (Table 3).
About two thirds of the major defects were diagnosed during the first week of life (Fig. 1), and more than 90 percent were diagnosed by six months of age. The defects in three infants in the natural-conception group (all renal defects), four infants in the intracytoplasmic-sperm-injection group (two with renal defects and two musculoskeletal defects), and one infant in the in-vitro-fertilization group (a musculoskeletal defect) were identified by the independent pediatrician as possibly having been diagnosed early because of close surveillance. When these infants were excluded from the analysis, the odds ratio for a major birth defect diagnosed by one year of age as compared with the natural-conception group was 1.8 (95 percent confidence interval, 1.1 to 2.9) in the intracytoplasmic-sperm-injection group and 2.2 (95 percent confidence interval, 1.7 to 3.0) in the in-vitro-fertilization group.
When pregnancies terminated because of fetal abnormalities were included in the analysis, the overall prevalence of major birth defects was 4.5 percent in the natural-conception group and 9.4 percent in the in-vitro-fertilization group; it was unchanged at 8.6 percent in the intracytoplasmic-sperm-injection group. When the nine infants with known inherited conditions and the seven with metabolic disorders were excluded from the analysis, the overall prevalence of birth defects was 8.0 percent in the intracytoplasmic sperm-injection group, 8.5 percent in the in-vitro fertilization group, and 4.0 percent in the natural conception group. The odds ratios for a major birth defect associated with assisted conception in these analyses remained similar to those calculated in the primary analysis (data not shown). All the infants in our study with unilateral undescended testis or hypospadias had undergone surgery and were therefore included in our primary analyses. Nevertheless, in some systems of classification of birth defects, these defects would be regarded as minor. When infants with these conditions were excluded from the analysis, the odds ratio for a major birth defect was 2.5 (95 percent confidence interval, 1.6 to 4.0) in the intracytoplasmic-sperm-injection group and 2.2 (95 percent confidence interval, 1.6 to 3.0) in the in-vitro fertilization group.
TABLE 2. Mode of delivery and characteristics of infants conceived with intracytoplasmic sperm injection, with in vitro fertilization, or naturally*
ALL INFANTS SINGLETONS ONLY .
ICSI P IVF P CONCEPTION ICSI P IVF P CONCEPTION
(N=301) VALUE (N=837) VALUE (N=4000) (N=186) VALUE (N=527) VALUE (N=3906)
Delivered by cesarean 95(32) <0.001 365(44) <0.001 816(20) 48(26) 0.05 183(35) <0.001 776(20)
section - no. (%)
Male sex-no.(%) 165(55) 454(54) 2048(51) 102(55) 286(54) 2000(51)
Stillborn-no.(%) 2(l) 17(2) <0.001 26(l) 0 6(1) 25(1)
Birth weight-g 2847±799 0.02 2806±844 0.005 3345±592 3271±552 0.02 3182±686 <0.001 3368±571
Preterm delivery(<37wk) 93(31) <0.001 265(32) <0.001 273(7) 16(9) 73(14) 0.001 225(6)
- no. (%)
Multiple birth - no.(%) 115(38) <0.001 310(37) <0.001 94(2) - - -
Low birth weight- no.(%)
<1500 g 18(6) <0.001 65(8) <0.001 51(1) 2(l) 19(4) <0.001 41(1)
<2500 g 75 (25) <0.001 188(22) <0.001 196(5) 12(6) 38(7) 0.002 163(4)
Gestational age - wk 37.0±3.3 0.004 36.7±3.8 0.002 39.0±2.1 38.6±2.2 38.0±3.0 0.03 39.1±2.0
* Plus-minus values are means ±SD.
P values are for the comparisons with the natural-conception group and
are not significant if not shown.
ICSI denotes intracytoplasmic sperm injection, and IVF in vitro fertilization.
TABLE 3. Prevalence of major birth defects diagnosed by one year of age*
Unadjusted Adjusted No. of Prevalence Odds Ratio Odds Ratio Group Infants no.(%) (95% CI) (95% CI)† All infants NC 4000 168(4.2) 1.0 1.0 ICSI 301 26(8.6) 2.2(1.3-3.3) 2.0 (1.3-3.2) IVF 837 75(9.0) 2.6(1.7-3.0) 2.0 (1.5-2.9) All singletons NC 3906 164(4.2) 1.0 1.0 ICSI 186 18(9.7) 2.4(1.4-4.1) 2.2 (1.3-3.9) IVF 527 50(9.5) 2.4(1.7-3.4) 2.2 (1.5-3.2) Term singletons‡ NC 3681 149(4.0) 1.0 1.0 ICSI 170 15(8.8) 2.3(1.2-4.0) 2.2 (1.2-4.0) IVF 454 38(8.4) 2.2(1.5-3.2) 2.1 (1.4-3.2) * CI denotes confidence interval. † The odds ratios were adjusted for maternal age and parity, the sex of the infant, and correlation between siblings. ‡ Term was defined as at least 37 weeks of gestation.
Figure 1. Cumulative Prevalence of Diagnosed Major Birth Defects in Singleton Infants, According to Age at Diagnosis. ICSI denotes intracytoplasmic sperm injection, and IVF in vitro fertilization.
As compared with infants conceived naturally, a significantly greater proportion of those conceived with assisted reproductive technology had musculoskeletal and chromosomal defects (Table 4). Those conceived with in vitro fertilization, but not those conceived with intracytoplasmic sperm injection, had a significantly greater prevalence of cardiovascular, urogenital, and other defects. Some, but not all, of these findings persisted when the analysis was restricted to singletons (Table 4). We also compared the proportions of infants with multiple major defects, defined as two or more defects affecting different systems. Six of the infants conceived with intracytoplasmic sperm injection (2.0 percent), 13 of those conceived with in vitro fertilization (1.6 percent), and 20 of the naturally conceived infants (0.5 percent) had multiple major defects. Overall, the infants conceived with assisted reproductive technology were significantly more likely to have multiple major defects than the naturally conceived infants (odds ratio associated with intracytoplasmic sperm injection, 4.1 [95 percent confidence interval, 1.6 to 10.2]; odds ratio associated with in vitro fertilization, 3.1 [95 percent confidence interval, 1.6 to 6.3 >1 A complete list of the birth defects is provided in Supplementary Appendix 2 (available with the full text of this article at http://www. nejm.org).
TABLE 4. Prevalence of major birth defects according to the organ system affected.*
ALL INFANTS SINGLETONS ONLY ICSI P IVF P NC ICSI P IVF P NC TYPE OF (N=301) VALUE (N=837) VALUE (N=4000) (N=186) VALUE (N=527) VALUE (N=3906) MAJOR DEFECT no.(%) no.(%) no.(%) no.(%) no.(%) no.(%) Any 26(8.6) <0.001 75(9.0) <0.001 168(4.2) 18(9.7) <0.001 50(9.5) <0.001 164(4.2) Cardiovascular 4(1.3) 15(1.8) <0.001 24(0.6) 3(1.6) 7(l.3) 24(0.6) Urogenital 7(2.3) 22(2.6) 0.01 54(l.4) 5(2.7) 14(2.7) 0.03 52(l.3) Musculoskeletal 10(3.3) 0.004 28(3.3) <0.001 45(1.1) 5 (2.7) 20(3.8) <0.001 44(l.1) Gastrointestinal 3(1.0) 5(0.6) 25(0.6) 2(l.1) 2(0.4) 24(0.6) Central nervous 0 3(0.4) 6(0.2) 0 2(0.4) 6(0.2) system Chromosomal 3(1.0) 0.05 6(0.7) 0.03 9(0.2) 3(1.6) 0.02 3(0.6) 9(0.2) Metabolic 1(0.3) 2(0.2) 4(0.1) 0 1(0.2) 4(0.1) Other† 2(0.7) 21(2.5) <0.001 25(0.6) 2(1.1) 15(2.8) <0.001 25(0.6) * If an infant had more than one major birth defect diagnosed by one year of age and the defects affected different organ systems, the infant appears more than once in the table. If an infant had two unrelated major defects affecting the same organ system, the infant appears only once in the table. P values are for the comparisons with the natural-conception group. † Other major birth defects included major defects of the respiratory system, Klippel-Trénaunay-Weber syndrome, Holt-Gram syndrome, infantile Marfan's syndrome, and nonimmune hydrops fetalis, among others.
Although minor birth defects were not the primary focus of this study, the Birth Defects Registry collects details of defects that would otherwise be considered minor but are disfiguring or require treatment (e.g., polydactyly). Such defects were diagnosed by one year of age in I infant in the intracytoplasmic sperm-injection group (0.3 percent), 7 infants in the in-vitro-fertilization group (0.8 percent), and 25 infants in the natural-conception group (0.6 percent).
DISCUSSION
We found that infants conceived with assisted reproductive technology were more than twice as likely as naturally conceived infants to have major birth defects diagnosed during the first year of life and were also more likely to have multiple major defects. The increase in the risk of a major birth defect associated with assisted conception remained significant when only singleton or term singleton infants were considered, as well as after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings. Furthermore, the estimates of the prevalence of defects reported to the registry by one year of age in the assisted-conception groups were well in excess of the 6 percent prevalence of major birth defects reported by six years of age during the same period in the general population.9 The risk of birth defects was similar among infants conceived with in vitro fertilization and those conceived with intracytoplasmic sperm injection.
We designed our study to address the major methodologic problems of previous research. We used the same source of data and the same birth-defect classification system for all three groups of infants. Furthermore, data on birth defects were collected without reference to the mode of conception. There is nevertheless a risk of differential diagnostic vigilance, given that infants conceived with assisted reproductive technology may be more closely examined than naturally conceived infants, because of either the history of their conception or a clinical condition associated with prematurity or multiple birth. If so, major birth defects might have been diagnosed earlier in the assisted-conception groups. However, the results were essentially unchanged when we excluded defects that might be more likely to be detected with closer surveillance. We also found that the excess risk remained when only term singletons were considered.
Pregnancies that result from treatment with assisted reproductive technology may be more closely monitored than those that result from natural conception. However, detailed ultrasonographic examinations of fetal anatomy are performed at 16 to 20 weeks of gestation in almost all pregnancies in Western Australia. Furthermore, the majority of the defects diagnosed prenatally in the infants in both the assisted conception groups and the natural-conception group would have been clinically obvious at birth. We also minimized the likelihood of differential diagnostic vigilance by including defects diagnosed up to one year after birth, by which time most major defects are likely to have been detected; in Western Australia 70 percent of all major birth defects are diagnosed by one year of age.9 Increased diagnostic vigilance may also increase the rate of detection of more subtle defects; however, such vigilance is unlikely to explain the excess risk in the infants conceived with assisted reproductive technology, since the majority of the defects in this group were either visible (e.g., cleft lip and palate) or would have been clinically obvious at, or soon after, birth (e.g., tracheoesophageal fistula). Finally, although the likelihood of terminating a pregnancy because of fetal anomalies may vary with the mode of conception, the inclusion of pregnancies that were terminated because of birth defects had little effect on our findings.
An excess risk of major birth defects in infants conceived with assisted reproductive technology is plausible. Factors that may increase the risk of birth defects include the relatively advanced age of infertile couples; the underlying cause of their infertility; the medications used to induce ovulation or to maintain the pregnancy in the early stages; and factors associated with the procedures themselves, such as the freezing and thawing of embryos, the potential for polyspermic fertilization, and the delayed fertilization of the oocyte.14-17 Although older maternal age and low parity did not appear to explain our results, it is not possible to separate the excess risk that may be associated with infertility treatment from the excess risk related to the underlying causes of infertility.
Recent data have suggested that there is an increased risk of birth defects in infants conceived with in vitro fertilization18 or intracytoplasmic sperm injection,19 but these results might have been attributed to conditions associated with multiple and preterm birth.19 Our results cannot be explained by these factors, since they remained similar when we restricted our analyses to term singletons.
We found that there may be an excess occurrence of major cardiovascular, urogenital, chromosomal, and musculoskeletal defects associated with assisted conception. However, these findings regarding specific organ systems should be interpreted with caution, since they are based on small numbers of infants in each group. Although the prevalence of a specific defect is rarely reported for infants conceived with assisted reproductive technology, others have also suggested that the prevalence of these defects is increased among such infants.6,16,19-21
Supported by a research grant (6-FY98-497) from the March of Dimes Birth Defects Foundation, New York, and a program grant (003209) from the National Health and Medical Research Council of Australia. Dr. Bower is supported by a research fellowship (172303) from the National Health and Medical Research Council of Australia.
We are indebted to all the contributors to the Birth Defects Registry, the Midwives' Notification System, and the Reproductive Technology Register; to Ms. Carol Garfield for providing data linkage between registers; to Mrs. Gail Reading, Mr. Peter Cosgrove, Dr. Desiree Silva, Prof. Paul Burton, Ms. Edwina Rudy, Ms. Aandra Ryan, Mrs. Vivien Gee, and Ms. Margo O'Neill for their contributions to this study; and to the Confidentiality of Health Information Committee of Western Australia and the Western Australian Reproductive Technology Council for granting permission, on behalf of the Commissioner for Health, for us to use the data from the registries.
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COMPLETE LIST OF ALL 269 INFANTS IN THE STUDY WITH A DESCRIPTION OF THEIR BIRTH DEFECTS ORDERED BY THE PRIMARY SYSTEM AFFECTED (SOME INFANTS HAVE DEFECTS AFFECTING MORE THAN ONE SYSTEM, THESE INFANTS APPEAR ONLY ONCE IN THIS TABLE) - for confidentially reasons we are not able to identify how each child was conceived, however, on request the authors will remove particular infants from the analysis and report the results of comparison having excluded these infants
CARDIO-VASCULAR SYSTEM
Tetralogy of Fallot + patent ductus arteriosus Tetralogy of Fallot
Ventricular septal defect - large
Ventricular septal defect - moderate perimembranous Ventricular septal defect - perimembranous
Ventricular septal defects - multiple + patent ductus arteriosus Ventricular septal defect - muscular + talipes equinovarus Ventricular septal defect -small/muscular +distal hypospadias + minimal chordee
Ventricular septal defect - small perimembranous + unspecified atrial septal defect
Ventricular septal defect - small/moderate + congenital dislocation of the hip (2 infants)
Ventricular septal defect - perimembranous + unspecified atrial septal defect + patent ductus arteriosus + possible interrupted inferior vena cava Unspecified ventricular septal defect + atresia of pulmonary valve + patent ductus arteriosus
Unspecified ventricular septal defect + patent ductus arteriosus + interrupted aortic arch + hypoplasia of aorta arch
Ventricular septal defect - mid muscular moderate + unspecified atrial septal defect small
Ventricular septal defect'- muscular + ostium secundum defect + absent right forearm & hand + absent fingers + hypoplastic left radius + humeral hypoplasia + finger anomalies + Holt-Gram Syndrome
Ventricular sentall defects x 2 small + unspecified atrial septal defect Ventricular Septal Defect - moderately large, perimembranous Ventricular septal defect + Dysmorphic/unusual facies +cleft lip and cleft soft palate + finger anomalies + fetal alcohol syndrome
Ventricular septal defect small midmuscular + patent ductus arteriosus + misshapen ears +facial asymmetry + accessory toes bilateral + overriding 6th toe left foot
Hypoplastic left heart syndrome
Mitral incompetence + ventricular septal defect - trivial Aortic stenosis severe + mitral incompetence ?Bicuspid pulmonary valve + aortic stenosis
Trace aortic incompetence + mitral incompetence + patent ductus arteriosus tiny + Infantile Marfan Syndrome
Bicuspid aortic valve + coarctation of aorta + posterior urethral valves Stenosis of pulmonary valve
Patent ductus arteriosus
Patent ductus arteriosus + papillary calcification of kidneys Common (single) ventricle + common a-v canal atrial septal defect/ventricular septal defect + stenosis of pulmonry valve + double outlet right ventricle + total anom pul ven return + gastrointestinal malrotation + duplication cyst + asplenia + Ivemark Syndrome + situs inversus abdominus
Single common atrium + common a-v canal defect + double outlet right ventricle + dextrocardia without situs inversus + asplenia
Common (single) ventricle + Ventricular septal defects - multiple + malaligned common AVSD + atresia of pulmonary valve + dysplastic tricuspid valve + bilateral superior venaecavae + superior vena cava to coronary sinus
Unspecified atrial septal defect (2 infants)
Ostium secundum defect + stenosis of pulmonary valve + mitral valve prolapse + mitral incompetence + congenital heart block + Patent ductus arteriosus
Ostium secundum defect
Atrial dilatation + scoliosis + defect lower sternum + left sided diaphragm abnormal + exomphalos + pentalogy of Cantrell
Vascular ring + aberrant subclavian artery
UROGENITAL
Unilateral undescended testis (23 infants)
Unilateral undescended testis + testicular atrophy
Unilateral undescended testis + ectopic testis
Unilateral undescended testis + congenital dislocation of the hip Unilateral undescended testis + vesico-ureteric reflux Unilateral undescended testis + coronal hypospadias (2 infants)
Bilateral undescended testes
Hypospadias (4 infants) Subcoronal hypospadias Glandular hypospadias (2 infants) Hypospadias + congenital sinus left thigh Hypospadias unspecified + congenital chordee + scrotalised penis Penoscrotal web/phimosis
Penoscrotal web + Congenital dislocation of the hip Partial scrotalised penis
Congenital chordee + glandular hypospadias Congenital chordee + peno-scrotal fusion Congenital chordee + mid shaft hypospadias Congenital chordee + eventration of diaphragm Congenital chordee + coronal hypospadias (3 infants) Congenital chordee + subcoranal hypospadias Congenital chordee + coronal glandular hypospadias + clinodactyly Vesico-ureteric reflux (9 infants)
Vesico-ureteric reflux +ventricular septal defect - small/moderate Duplex ureter + vesico-ureteric reflux
Hydronephrosis bilateral + double kidney Hydronephrosis + vesico-ureteric reflux Hydronephrosis bilateral + mildly dilated left ureter + ureterocoele left Hydronephrosis bilateral + pelvi-ureteric junction obstruction Hydronephrosis + ectopic ureter
Hydronephrosis + megaloureter Hydronephrosis left Hydronephrosis + duplex ureter + vesico-ureteric reflux + ureterocoele Multicystic dysplastic left kidney
Ambiguous genitalia + hydronephrosis + cloaca exstrophy + exomphalos Hypoplasia kidney right + hydronephrosis right + vesico-ureteric reflux right
Partial duplication right kidney + vesico-ureteric reflux Fused kidneys
Unilateral absent kidney + vesico-ureteric reflux right
Right pelvic kidney + abnormal vertebrae other + absent rib right side
MUSCULO-SKELETAL SYSTEM
Congenital dislocation of the hip (34 infants) Congenital dislocation of the hip+ dysmorphic/unusual facies + plagiocephaly+ short stature
Congenital dislocation of the hip + accessory finger right hand Talipes equinovarus (11 infants)
Talipes+genu recurvatum Metatarsus varus right Metatarsus adductus + tibial torsion Reduction deformity right fingers/palm Congenital diaphragmatic hernia Congenital diaphragmatic hernia+ hypoplasia of lungs Congenital diaphragmatic hernia + dilated cerebral ventricles Congenital diaphragmatic hernia+ hypoplasia of lungs Abnormal vertebrae
Abnormal vertebrae + bilateral 13 pairs ribs Craniosynostosis (2 infants)
Shortening of right leg + curly toes
GASTRO-INTESTINAL SYSTEM
Pyloric stenosis (8 infants)
Pyloric stenosis+dysmorphic/unusual facies + fetal valproate effects Cleft lip unilateral (2 infants)
Cleft lip + cleft soft palate
Cleft lip unilateral with cleft palate (5 infants) Gastroschisis (2 infants)
Exomphalos
Exomphalos +ventricular septal defect - perimembranous + hypospadias unspecified + bifid scrotum
Gastrointestinal malrotation + exomphalos Patent ompholomesenteric duct (2 infants) Hirschprung disease (2 infants) Duodenal web
Meckels diverticulum
Meckels diverticulum + ileal duplication cyst Ectopic salivary gland + skin tag over trachea Esophageal atresia with tracheo-esophageal fistula+ventricular septal defect - moderate mid muscular
CENTRAL NERVOUS SYSTEM
Encephalocoele + hydrops + dysgenesis of corpus callosum + talipes equinovarus + amniotic bands left leg
Partial agenesis corpus callosum + hydrocephalus unspecified Dilated cerebral ventricles
Coloboma optic nerve right + microphthalmos + coloboma retina right + left choroid-retina coloboma
Intracranial calcification + congenital CMV
Coloboma of lens + Small notch eyelid + Abnormally shaped pupil Microcephaly + hydranencephaly + dysmorphic/unusual facies + ventricular septal defect - perimembranous + ectopic anus/anteriorly placed + micrognathia + congenital dislocation of the hip + finger anomalies + ? Neu laxova syndrome
Hydrocephalus
Holoprosencephaly + abnormal nose + cleft lip central + hypotelorism
CHROMOSOMAL
Trisomy 21 (6 infants) Trisomy 21 + hydrops fetalis Trisomy 21+common a-v canal atrial septal defect/ventricular septal defect + hypoplastic right ventricle + stenosis pulmonary artery + left superior vena cava to coronary sinus
Trisomy 21+ventricular septal defects - multiple + common a-v canal + atrial septal defect/ventricular septal defect + patent ductus arteriosus Trisomy 21+ventricular septal defect - small perimembranous + patent ductus arteriosus
Trisomy 21+unspecified ventricular septal defect + unspecified atrial septal defect + patent ductus arteriosus
Trisomy 18+unspecified ventricular septal defectsx2+congenital dislocation of the hip+ finger anomalies+ congential diaphragmatic hernia +nail hypoplasia
Turner mosaic xo/xxx+ Cleft soft palate central
Turner syndrome +dysmorphic/unusual facies + pelvi-ureteric junction obstruction
Y chromosome anomaly Chromosomal anomaly 47,XYY Chromosomal anomaly 46,XY,del(X)(p11.3) Additional marker autosomal
METABOLIC
Hypothyroidism (3 infants) Phenylketonuria
G6PD deficiency (2 infants)
Unknown metabolic disease + talipes equinovarus + overriding 5th toes
OTHER
Naevus/haemangnioma (5 infants)
Naevus/haemangioma +branchial fistula/remnant Naevus/haemangnioma - multiple Haemangioma right orbit/ back
Large portwine haemangioma Klippel-Trenaunay-Weber Syndrome Hydrops fetalis
Dysmorphic/unusual facies + ventricular septal defect - tiny mid muscular + ectopic kidney + congenital dislocation of the hip + anomaly thoracic vertebra + anomaly sacral vertebra + extra ribs + abnormal ribs + osteogenesis imperfecta
Coloboma of right eyelid + facial cleft lip to eye + ?amniotic band syndrome
Krabbe disease Angioma right upper lip Cutis aplasia Dysmorphic/unusual facies + finger anomalies + hydrops fetalis Choanal stenosis
Craniofacial dysmorphism
Exophthalmos + dysmorphic/unusual facies + bulbous nose + large cranium
Cataract right
Ptosis + multiple exostosis + large facial naevus
Preauricular tags + macrostomia + facial asymmetry + facio-auricular vertebral spectrum
Rhabdomyoma heart + scoliosis + thoraco-lumbar kyphosis + abnormal ribs + tuberous sclerosis
Glaucoma
External angular dermoid, right eye Prader-Willi Syndrome
Left cheek lymphangioma
Ocular albinism + congenital nystagmus
Criteria used for inclusion/exclusion of particular defects:
VSD - Ventricular septal defect - ventricular septal defects: coded as minor if they are specified by notifier as trivial or are now closed, otherwise coded as major.
PDA - Patent ductus arteriosus - patent ductus arteriosus: isolated ductus is coded as major if still patent at 3 months of age in a child born at term or at 6 months in a child born preterm. If the ductus is ligated in a full term infant or in a preterm infant over 2 months chronological age, it is also coded as major. Isolated ductus not meeting the above criteria is not registered. A ductus in the presence of other congenital heart disease is always included.
UDT = undescended testes: the majority of cases of undescended testes are only registered at the time of surgery (usually at about 2 years of age) regardless of when the defect was actually diagnosed. This approach ensures that cases of undescended testes that are simply retractile and descend spontaneously without surgery are excluded from the Registry.
CDH - congenital dislocation of the hip: coded as a major birth defect if treated by abduction splinting, surgery, or both. Children with clicky hips or for whom the sole treatment prescribed was the use of double diapers are excluded.
Talipes equinovarus, clubfoot, metatarsus adductus: coded as a major birth defect if treated by splinting or surgery, otherwise not registered.
Angioma and congenital naevus: included in the registry classification if they are multiple or >4cm2. They are coded as minor unless they are disfiguring or require extensive surgery, in which case they are coded as major. If they do not meet the above criteria, they are not registered.
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