Risks of congenital anomalies in large for gestational age infants

Risks of congenital anomalies in large for gestational age infants Pablo Lapunzina, MD, MSC, Jorge S. López Camelo, PhD, Monica Rittler, MD, PhD, and Eduardo E. Castilla, MD, PhD Objectives: To evaluate the association between large for gestational age (LGA) and demographic and medical risk factors as well as specific types of congenital anomalies. Study design: A retrospective, case-control study on 2,149,617 consecutive births was conducted. LGA was defined as 1.64 SD above the mean weight for gestational age, adjusted by sex and altitude. Risk factor frequency distributions were compared between LGA and normal birth weight neonates. Associations between LGA and 41 infants with isolated congenital anomalies were evaluated. Results: Of 31,897 neonates with congenital anomalies, 1800 were LGA. Five anomalies were associated with LGA: talipes calcaneovalgus, hydrocephaly, combined angiomatoses, hip subluxation, and non–brown-pigmented nevi. Multiparity, vaginal bleeding, diabetes, and delivery by cesarean section were more frequent in LGA than in appropriate for gestational age infants’ mothers. Several maternal but no paternal factors were statistically associated with an increased risk for LGA infants. Conclusions: The clinical observation that nevi are more commonly observed in LGA patients was supported. The higher frequencies of hip subluxation and talipes calcaneovalgus among LGA neonates reinforces their pathogenesis as deformations, whereas those of combined angiomatoses and hydrocephaly could reflect increased fluid or body mass. (J Pediatr 2002; 140:200-4)

High birth weight is associated with an increased risk for maternal and neonatal injury, mainly lacerations of the

birth canal, hemorrhage, and febrile morbidity in the mother and shoulder dystocia, brachial or Erb’s palsy, hypo-

From ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas) at Fiocruz, Rio de Janeiro, Brazil; CEMIC; IMBICE, La Plata; Clínica y Maternidad Suizo Argentina; and Hospital Ramón Sardá, Buenos Aires.

Supported by the Agencia Nacional de Promoción Científica y Tecnológica, the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) of Argentina, the Programa de Apoio a Pesquisa Estratégica em Saúde (PAPES) da Fundaçâo Oswaldo Cruz, and the Conselho Nacional de Desenvolvimiento Científico e Tecnológico (CNPq) of Brazil. Submitted for publication May 17, 2001; revisions received Aug 15, 2001, and Oct 25, 2001; accepted Nov 12, 2001. Reprint requests: Dr Eduardo E. Castilla, ECLAMC/Genetica/Fiocruz, CP 926, Rio de Janeiro RJ 20001—970, Brazil. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/121696 doi:10.1067/mpd.2002.121696

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glycemia, and polycythemia in the infant.1 There are many reports on a wide variety of diseases, including congenital anomalies (CA), in small for gestational age or premature neonates.2 High birth weight has mainly been associated, among other clinical features, in genetic syndromes such as Beckwith Wiedemann and Perlman syndromes.3 Nothing has been published regarding the incidence of isolated CA in large for gestational age (LGA) children. The aims of this work were to establish demographic and parental risk factors for LGA neonates and to determine whether there are specific isolated CA associated with high birth weight. AGA CA CI LGA OR

Appropriate for gestational age Congenital anomalies Confidence interval Large for gestational age Odds ratio

METHODS Population In ECLAMC (Spanish acronym for Latin American Collaborative Study for Congenital Malformations), cases are defined as those live-born or stillborn infants weighing ≥500 g, with ≥1 CA. Methodologic definitions for ECLAMC were published elsewhere.4

Definition of LGA Gestational age was established by last menstrual period and birth dates. LGA infants were defined as those neonates with a birth weight ≥1.64 SD above the mean for sex, gestational age, and altitude above sea level. This figure corresponds to approximately the 95th percentile of the normal weight chart.

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VOLUME 140, NUMBER 2 These birth weight standards were estimated from a sample of 102,928 infants (51,464 matched case-control sets) born with a gestational age between 168 and 301 days (24-43 weeks). Because sex and altitude affect birth weight,5 a regression was performed with the following equation: y = b1GA + b2GA2 + b3sex + b4altitude where y (weight) is expressed in grams, gestational age (GA) is expressed in days, sex is expressed as 0, female; 1, male; and altitude is expressed as 0 = <2000 meters, 1 = >2000 meters. Between 1967 and 1998, 51,464 neonates with isolated CA types were recorded by ECLAMC from 2,149,617 consecutive births. Isolated CA are defined as one minor or major CA without any other unrelated defect in the same infant. For each case, the next nonmalformed baby of the same sex, born in the same hospital, was selected as a control infant. Thus each case-control pair was matched by sex, time, and birthplace. After excluding 9807 pairs with low birth weight and 9760 with unspecified data on birth weight or gestational age, 31,897 case-control pairs remained. Initially, all CA registered at birth were included, and after excluding those with <100 cases, 41 CA types remained, corresponding to 26,976 case-control pairs. For a statistical power of 80% and a 5% significance level, this sample size will detect a 4-fold risk for LGA, with a defined population rate of 5%.

conditional logistic regression analysis was performed, with LGA as the independent variable. The following risk factors were analyzed: extremes of maternal age (≤19 years or ≥35 years) and paternal age (≤19 years or ≥40 years), extreme parities (primiparity or multiparity, defined as parity of ≥4), twinning, nonvertex fetal presentation, nonvaginal delivery, low maternal and paternal educational levels (defined as less than complete grammar school), low paternal occupational level (defined as unskilled laborer or unemployed), difficult conception ascertained by direct questioning, paternity different from that of the immediate previous gestation, black ancestry (with or without other racial admixtures), hospital belonging to public health system, and one or more of the following complications during the first trimester of pregnancy: diabetes (any type), other diseases, drugs, vaginal bleeding, miscarriage or stillbirth in the immediate previous gestation, and miscarriages and/or stillbirths in any previous gestation. The variables positively associated with high birth weight (b >0; 1-tailed P < .05) were considered as confounders. Because sex and altitude were included in the equation applied to define LGA, they were not considered as risk factors. The McNemar case-control intrapair method was used to assess the risk for CA for the LGA infants, and a multivariate conditional logistic regression analysis was performed to adjust the risks for confounders. The limit of significance was set at P < .05 (1-tailed).

Risk Factors and LGA

RESULTS

The normal, nonmalformed control infants for the 31,897 malformed infants were used to evaluate the association between selected demographic risk factors and high birth weight. Of these, 1615 were LGA, and they were compared with the 30,282 appropriate for gestational age (AGA) (between –1.64 and 1.64 SD) control neonates. An un-

Table I gives the distribution of demographic, obstetric, and reproductive variables in both LGA and AGA nonmalformed neonates. Mothers of LGA infants were more likely to be multiparous and to have had vaginal bleeding than those of normal birth weight. Other maternal factors associated with

the delivery of LGA infants included cesarean section and diabetes. Primiparity and maternal age <20 years showed a significantly negative association with LGA infants. Of the 31,897 infants with isolated CA, 1800 (5.6%) were LGA. Of those CA types with ≥100 cases, the following were positively associated with high birth weight: combined angiomatoses (flat plus cavernous, lymphangiomas, and extensive angiomatoses, such as Klippel–Trénaunay–Weber syndrome, among others), hydrocephaly, subluxation of the hip (following strict definitions and instructions for the Ortolani maneuver included in the ECLAMC Procedures Manual), non–brownpigmented nevi, and congenital heart defects of unspecified type. The association with talipes calcaneovalgus was slightly below the level of significance (Table II). After adjusting for confounders, 5 of the 6 CA, except for congenital heart defects, remained significantly associated with high birth weight: combined vascular lesions (pairs, 280; adjusted odds ratio [OR], 2.77; 95% confidence interval [CI], 1.33-5.78; P = .008); hydrocephaly (pairs, 361; adjusted OR, 3.10; 95% CI, 1.78-5.42; P = .001); hip subluxation (pairs, 1870; adjusted OR, 1.63; 95% CI, 1.21-2.19; P = .001); non–brown-pigmented nevi (pairs, 1833; adjusted OR, 1.46; 95% CI, 1.09-1.97; P = .012); and talipes calcaneovalgus (pairs, 442; adjusted OR, 4.82; 95% CI, 1.24-19.02; P = .021).

DISCUSSION There is no consensus regarding the definition of fetal macrosomia or LGA infants.1,4 Most authors have defined macrosomia by any of the following criteria: (1) birth weight of ≥4000 g, (2) birth weight of ≥4500 g, irrespective of gestational age, (3) birth weight >90th percentile, adjusted by sex and gestational age, or (4) birth weight 2 SD above the mean for sex and gestational age.1,6,7 Our work confirms the findings 201

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Table I. Risk factors in 1615 LGA and 30,282 appropriate for gestational age nonmalformed newborn infants

Risk factor Maternal age ≤19 y Maternal age ≥35 y Primiparity Multiparity (≥4) Twinning Presentation, nonvertex Delivery, nonvaginal Paternal age ≤19 y Paternal age ≥40 y Low maternal education Low paternal education Low paternal occupation Difficult conception Black ethnic ancestry Acute maternal disease Maternal diabetes Other chronic maternal diseases Maternal drug use Vaginal bleeding Public health system Previous fetal loss (a) Miscarriage (b) Stillbirth (c) Different paternity (d)

LGA (%) AGA (%) OR-adjusted 95% CI 11.17 17.06 20.12 37.77 0.12 2.77 30.28 3.40 14.88 35.21 27.84 37.65 7.87 13.54 15.87 2.87 9.31 31.09 5.77 55.73 25.50 10.61 1.99 10.02

18.48 9.73 34.89 25.00 0.48 3.44 26.07 4.80 8.93 29.02 24.45 34.46 7.39 15.40 15.18 0.48 6.68 30.93 5.03 52.35 25.39 11.79 1.24 11.57

0.73 1.16 0.59 1.25 0.61 1.06 1.47 0.89 1.28 1.09 1.02 0.97 0.86 0.95 0.92 6.20 1.37 0.83 1.44 1.07 0.89 0.94 1.38 0.82

0.55–0.97 0.90–1.48 0.48–0.73 1.04–1.51 0.05–7.82 0.72–1.58 1.22–1.77 0.52–1.51 0.99–1.63 0.90–1.31 0.84–1.24 0.82–1.16 0.61–1.22 0.65–1.27 0.68–1.25 3.39–11.33 0.98–1.92 0.67–102 1.03–2.00 0.90–1.28 0.72–1.08 0.69–1.29 0.79–2.40 0.65–1.04

LGA, Large for gestational age; AGA, appropriate for gestational age; OR adjusted, adjusted odds ratio; CI, confidence interval; a, miscarriage or stillbirth in immediate previous gestation; b, miscarriage in any previous gestation; c, stillbirth in any previous gestation; d, paternity different from that of immediate previous gestation.

reported in previous studies that there are several demographic and parental factors associated with LGA infants.8,9 In addition, we provide risks for CA associated with LGA infants. In nearly all studies on fetal macrosomia, multiparous women are disproportionately represented; macrosomic infants are 2 to 3 times more likely to be born to multiparous women,6,10 whereas grand multiparity did not appear to add to the risk.10 These reports, however, did not clearly state whether parity was an independent variable or if it could be related to other factors such as increased maternal age, social class, or ethnicity.6 Our regression analysis identified multiparity and not increased maternal age as being associated with LGA neonates. 202

Among maternal diseases, diabetes is a widely recognized cause for macrosomic infants, and in this study diabetes had the highest adjusted OR (6.2; 95% CI, 3.39-11.33). The association with other related maternal illnesses such as obesity, which is a risk factor frequently mentioned in the literature,11 was not analyzed. As expected and similar to several previous reports,11 cesarean delivery was more frequent in LGA infants than in the AGA reference group. Vaginal bleeding was also found to be a maternal risk factor for LGA babies. Previous studies have shown that mothers with vaginal bleeding during pregnancy were at risk for prematurity, intrauterine growth retardation, CA, cesarean delivery, and placental dysfunctions.12,13 There are several other

associations of interest that may relate to vaginal bleeding. First, high hormone levels (mainly estrogens) during pregnancy were implicated as a possible cause of vaginal bleeding.12 Second, pregnant women with increased levels of estriol and human placental lactogen appear to be “protected” from giving birth to small for gestational age children, and the levels of these hormones are directly related to the size of the fetus.14 Furthermore, women with increased levels of hormones, or those who had been exposed to exogenous hormones in the first trimester, had a higher rate hip luxation/subluxation15 in their children than those with normal levels. Thus, estrogens, vaginal bleeding, high birth weight, and hip luxation/subluxation appear to be related. Sack10 found a significantly increased paternal age among LGA infants, but this association was not significant in our analysis. Several other factors not considered here, such as maternal pregravid weight and weight gain during pregnancy,8 high maternal birth weight, macrosomia in previous infants,9 and preeclampsia,8,9 have also been related to LGA infants. The increased body and fluid mass of combined angiomatoses and of hydrocephalus could by themselves explain the high birth weight of affected infants, especially because only isolated defects were considered. Developmental dysplasia of the hip includes conditions of varying severity, from dislocated, dislocatable, or subluxatable hips to stable or “clicky” hips, with radiologic or ultrasound evidence of acetabular dysplasia.16 Talipes has been associated with developmental dysplasia of the hip as well as with other postural deformities. Mechanical factors during later fetal life, such as oversized fetuses or oligohydramnios, also have been implicated since ancient times in the origin of such deformities. These malformations are rare before 20 gestational weeks.17 Children with high birth weight are at risk for developmental dysplasia of the hip.16 The risk is de-

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VOLUME 140, NUMBER 2 pendent on birth weight; infants born with a weight of 4000 g to 4499 g had an OR of 1.55 (1.26-1.91) and those with weight ≥4500 g had an OR of 2.67 (1.81-3.94) for hip dysplasia. Low birth weight “protected” against developmental dysplasia of the hip. The results of a population study of CA in children with intrauterine growth restriction found that only 3 isolated defects (congenital hip dislocation, pyloric stenosis, and isolated polydactyly) were not associated with intrauterine growth restriction.2 Because the current study only considered CA recognizable at birth, pyloric stenosis was not evaluated. Cutaneous vascular lesions and macular stains are frequently found in the normal population, occurring in approximately 30% to 40% of neonates.18 In the present study, pigmented nevi, other than brown or café au lait spots, were more frequently observed in LGA than in AGA neonates. This association was described previously by Castilla et al,19 who showed that pigmented nevi were associated with higher mean values of both length of gestation and birth weight. The authors suggested that congenital pigmented nevi appear in the latest stages of intrauterine development. Several genetic diseases with somatic overgrowth have an increased frequency of skin anomalies. In patients with syndromes such as Beckwith-Wiedemann, macrocephaly-cutis marmorata telangiectatica, and Proteus, the frequency of pigmented spots and vascular stains is 40% to 90%.3,20-22 In addition, infants of diabetic mothers more commonly have pigmented spots and vascular birthmarks than the normal population.3 Finally, growth factors such as insulin-like growth factor 1 and 2, epidermal growth factor, fibroblast growth factors, and vascular endothelial growth factor could modulate both somatic and skin vascular growth in the fetus,23,24 leading to both high birth weight and macular and vascular stains. The strength of the present work is the size of the ECLAMC database and

Table II. Risks for congenital anomalies in LGA infants

Congenital anomaly Angioma, flat Angioma, cavernous Angioma, combined Neonatal tooth Anencephaly Spina bifida, cervicodorsal Spina bifida, lumbosacral Hydrocephaly Cephalocele Microcephaly Anotia/microtia Preauricular tag Preauricular sinus Heart defect, conotruncal Heart defect, septal Heart defect, unspecified Single umbilical artery Cleft palate Cleft lip Cleft lip and palate Anorectal atresia Undescended testes Hypospadias, distal (glans, sulcus) Hypospadias, proximal Hydronephrosis Talipes equinovarus Talipes calcaneovalgus Polydactyly, postaxial, hand Polydactyly, postaxial, foot Polydactyly, postaxial, both Polydactyly, preaxial, hand Syndactyly, 2nd–3rd toes Limb reduction, transverse terminal Hip subluxation Diaphragmatic hernia Pigmented nevus, brown Pigmented nevus, other Extra nipple Pilonidal defect Down syndrome, maternal age ≤34 y Down syndrome, maternal age ≥35 y

Pairs 1304 217 284 152 136 127 428 367 115 120 318 3356 1800 151 345 217 246 183 612 1247 171 259 272 383 148 1548 633 1350 333 148 228 102 150 1907 111 2867 1856 712 411 823 839

ORm 0.98 0.91 2.90 1.17 0.33 1.50 1.38 3.85 1.40 0.30 1.00 0.88 1.29 1.50 1.44 2.86 1.00 1.88 0.73 0.68 0.75 0.50 0.77 0.94 1.38 0.81 3.33 0.82 1.00 1.75 0.40 0.75 0.20 1.73 1.33 1.07 1.53 1.20 0.90 0.52 1.18

χ2

P value

0.01 0.05 9.26 0.08 2.00 0.60 1.28 33.50 0.33 3.77 0.00 1.42 2.53 0.60 1.26 6.26 0.00 2.13 0.62 1.13 0.29 2.33 0.39 0.03 0.47 1.60 3.57 1.25 0.00 0.82 0.57 0.14 5.33 13.94 0.14 0.39 8.13 0.55 0.11 4.79 0.50

.920 .823 .002 .777 .157 .438 .259 < .001 .566 .052 1.000 .233 .112 .438 .261 .013 1.000 .144 .431 .289 .590 .127 .532 .862 .493 .206 .057 .263 1.000 .365 .449 .708 .021* < .001 .708 .532 .004 .458 .740 .029* .479

Pairs, Number of case-control pairs; ORm, matched odds ratio; χ2, McNemar chi-square test; df = 1. *Significantly negative associations.

in its high level of specification regarding CA, including minor defects. This data base allowed the study of rare events such as CA in LGA infants. Birth weight largely depends on ethnic and geographic factors.5 Thus, for a

precise assignment of infants to each birth weight category, the definition of LGA infants was based on a birth weight curve obtained from the corresponding reference population in the present study. 203

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Weaknesses of the data are maternal recall bias or unawareness and unavailable data on recognized risk factors such as maternal obesity and high birth weight of previous children. Another limitation to this analysis is the limiting of the CA types to those with a sufficient number of cases for reliable ascertainment at birth. This excluded CA of most internal organs. However, if from a consecutive series of 2 million examined births the sample size for some CA was insufficient, this may be the practical limit for detecting associations with CA. Finally, gestational age based on the date of the last menstrual period is unreliable. However, complementary methods such as clinical examination or ultrasonography are not suitable for large epidemiologic data sets. The last menstrual period method was successfully applied in other similar investigations,25,26 and its inaccuracy is not likely to differ between malformed and nonmalformed neonates. Our results on 31,897 malformed neonates, recorded from >2 million births, validate the notion that minor CA are more commonly associated with LGA infants. No severe, isolated, major CA had a higher incidence in LGA than in AGA infants, if higher than expected birth weight in hydrocephaly is accepted as being secondary to increased fluid or body mass.

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