Cardiovascular Malformations Among Preterm Infants

Population Base

We based this study on the population of the former Northern Health Region of England, which includes North and East Cumbria, Northumberland, Tyne and Wear, Durham, and Cleveland. All infants with suspected cardiovascular malformations are referred to a single pediatric cardiology center. The population of ∼3 million is stable and geographically well defined. The recent average annual live birth rate has been ∼35000 births per year. The ethnic composition of the population is 97.6% white, 0.1% black, 1.5% Asian, 0.5% mixed, and 0.3% other.⁴

We included all live-born infants with cardiovascular malformations diagnosed in the first 1 year of life. The infants were identified from the regional pediatric cardiology database, which includes the gestational age and details of the diagnosis. The database has had prospective ascertainment since 1990, with retrospective ascertainment back to 1985.⁵

Case Definition

In common with most previous epidemiologic studies, we defined a cardiovascular malformation as “a gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional importance.”⁶ We limited ascertainment to malformations diagnosed by the age of 12 months. Although most significant heart disease has presented by this time, relatively few cases of patent ductus arteriosus and atrial septal defect are diagnosed in the first 1 year.⁷ Therefore, both of these diagnoses were excluded, to avoid ascertainment bias, particularly because preterm infants are more likely to have patent ductus arteriosus and are more likely to undergo echocardiography in a NICU. We also excluded from the study infants with physiologic pulmonary artery branch stenosis, patent foramen ovale, isolated cardiac arrhythmia, isolated bicuspid aortic valve, mitral valve prolapse without regurgitation, isolated dextrocardia, and cardiac tumors. Because of their relative rarity, we grouped together under the diagnostic label “single ventricle” infants with mitral atresia, tricuspid atresia, and double-inlet left ventricle. Ventricular septal defects were classified according to whether they required surgery in the first 1 year. This subanalysis was limited to surviving infants because the contribution of the ventricular septal defect to death could not be determined retrospectively, especially for preterm infants. Analysis of ventricular septal defects including deaths yielded findings very similar to those described below.

We defined gestational age as the number of completed weeks from the first day of the mother's last menstrual period to the day of delivery. If the menstrual history was in doubt, then gestational age was estimated from obstetric assessments, including physical examination and ultrasonography.⁸

The Northern Congenital Abnormality Survey provided data on the numbers of live births and total infant mortality rates.⁹ There are no data for our population on the gestational age at birth for all infants or on total infant mortality rates according to gestational age. To be able to predict the size of the denominator groups, we plotted data for populations similar to our own described in the literature^10–13 and in the All Wales Perinatal Survey (1993–2000)¹⁴ (Fig 1). Data points from the various publications were given equal weight and, from the line of best fit in Fig 1, we predicted that 0.4% of live births occur at <28 weeks of gestation, 0.9% at 28 to 31 weeks, and 6% at 32 to 36 weeks. Therefore, overall 7.3% of live-born infants are preterm. Some of these studies also provided data on the relationship between preterm birth and mortality rates.^10,11 The study was approved by the Newcastle and North Tyneside Local Research Ethics Committee.

• Download figure
• Open in new tab
• Download powerpoint

Fig 1.

Prevalence of live births at various gestational ages of <37 weeks in 5 publications regarding populations similar to our own. Data points represent estimates of frequency at less than the indicated gestational age. The reports show sufficient consistency for us to derive predictions of the prevalence of preterm birth at <28 weeks, <32 weeks, and <37 weeks from the line of best fit. We assumed that 0.4% of live births in our own denominator population were at <28 weeks, 0.9% at 28 to 31 weeks, and 6.0% at 32 to 36 weeks and thus the cumulative prevalence of preterm birth was 0.4% at <28 weeks, 1.3% at <32 weeks, and 7.3% at <37 weeks. Data points are as follows: A, Joseph et al,¹² 1992–1994; B, Centers for Disease Control and Prevention,¹³ 1989; C, Centers for Disease Control and Prevention,¹³ 1996; D, Alexander et al,¹⁰ 1995–1997; E, All Wales Perinatal Survey,¹⁴ 1993–2000; F, Tin et al,¹¹ 1987–1990; G, Tin et al,¹¹ 1991–1994.

Statistical Analyses

We limited statistical analysis to calculation of odds ratios (ORs) and their associated confidence intervals (CIs)¹⁵ and comparisons of proportions with the χ² test.

Cardiovascular Malformations Among Preterm Infants

Of 521619 live births in the study population in 1987–2001, 2964 infants were recognized as having a cardiovascular malformation (excluding atrial septal defect and patent ductus arteriosus) in infancy (Table 1). This gives a prevalence of 5.7 cases per 1000 live births. With our assumption that 7.3% of all live births are preterm, the prevalence at live birth of cardiovascular malformations among preterm infants was 12.5 cases per 1000 live births. In comparison, cardiovascular malformations were present at 5.1 cases per 1000 term infants, giving an OR for cardiovascular malformations in prematurity of 2.4 (95% CI: 2.2–2.7). Cardiovascular malformations were present at 12.8 cases per 1000 infants born at 32 to 36 weeks of gestation, 12.8 cases per 1000 infants born at 28 to 31 weeks of gestation, and 6.2 cases per 1000 infants born at <28 weeks of gestation (Table 1). There was no strong evidence of a real difference between these groups because of the small number of infants born at <28 weeks of gestation.

Preterm Births Among Infants With Cardiovascular Malformations

Using published data, we assumed that 7.3% of all infants are born at <37 weeks of gestation (Fig 1). We found that 474 infants (16%) with cardiovascular malformations were born before 37 weeks of gestation, giving an OR for prematurity among infants with cardiovascular malformations of 2.4 (95% CI: 2.2–2.7). More infants were born preterm with diagnoses of pulmonary atresia with ventricular septal defect (23%), complete atrioventricular septal defect (22%), and coarctation of the aorta, tetralogy of Fallot, and pulmonary valve stenosis (each 20%) (Table 2 and Fig 2). Fewer were born preterm with diagnoses of pulmonary atresia and intact ventricular septum (7%), transposition of the great arteries (8%), and single ventricle (9%). Statistical analysis showed that the differences between these diagnostic groups were significant (χ² = 28.0, P = .005).

• Download figure
• Open in new tab
• Download powerpoint

Fig 2.

Prevalence of premature births among infants with specific cardiovascular malformations, ranked according to the prevalence of prematurity, and among infants without cardiovascular malformations. Vertical bars indicate 95% CIs. PA/VSD indicates pulmonary atresia with ventricular septal defect; CAVSD, complete atrioventricular septal defect; CoA, coarctation of the aorta; ToF, tetralogy of Fallot; PS, pulmonary valve stenosis; VSD, ventricular septal defect; AS, aortic valve stenosis; TAPVC, total anomalous pulmonary venous connection; CAT, common arterial trunk; HLH, hypoplastic left heart; SV, single ventricle; TGA, transposition of the great arteries; PA/IVS, pulmonary atresia with intact ventricular septum; CVM cardiovascular malformation.

To investigate the possibility of an ascertainment bias toward increased detection of more minor malformations among preterm infants because of increased medical surveillance early in life, infants with ventricular septal defect were analyzed according to the need for surgery in the first 1 year. We found that 18% of infants in the surgical group were preterm, compared with 13% in the nonsurgical group. Preterm infants with ventricular septal defect required surgery in 30% of cases, compared with 23% of term infants with ventricular septal defect. These figures show that the excess of cardiovascular malformations among preterm infants cannot be explained by greater ascertainment of minor ventricular septal defects. Most of the other malformations considered (with the exception of some cases of aortic valve stenosis and pulmonary valve stenosis) are major and would have complete ascertainment in infancy regardless of gestational age. The median age at diagnosis for preterm infants was 19 days (interquartile range: 4–59 days), and that for term infants was 12 days (interquartile range: 4–74 days).

Other Influences

The strong associations between complete atrioventricular septal defect and trisomy 21 and between pulmonary atresia with ventricular septal defect and 22q11 deletion are well recognized. To investigate the possible contribution of chromosomal abnormalities to preterm birth in these groups, we analyzed the gestational age of all infants with trisomy 21 or with 22q11 deletion in the same population. In our 15-year study period, 646 live-born infants were recognized as having trisomy 21; gestational age data were available for 609. Of these, 149 (25%; 95% CI: 21–28%) were born preterm. Complete atrioventricular septal defect was diagnosed for 16% of preterm infants with trisomy 21 and 16% of term infants with trisomy 21. Previously published work from this unit showed that approximately two thirds of infants with complete atrioventricular septal defect have trisomy 21.¹⁶ Therefore, the increase in preterm births among infants with trisomy 21 probably explains some of the excess of preterm births among infants with complete atrioventricular septal defect.

Only 4 of 38 infants (11%; 95% CI: 4–24%) with 22q11 deletion were born preterm. None of those infants had pulmonary atresia with ventricular septal defect; therefore, 22q11 deletion does not explain the excess of preterm births among infants with pulmonary atresia with ventricular septal defect.

To investigate the possible influence of prematurity of twins on our findings, we analyzed data from the Northern Multiple Pregnancy Register.¹⁷ Since 1998, this survey has collected prospective data on all multiple pregnancies for the same population as in our study. In 1998–2002, there were 4115 live-born twins, representing 2.7% of all live births. This is consistent with findings in published reports dealing with the same years.¹⁸ Most reports showed an increase in the incidence of live-born twins from ∼2% in the 1980s to ∼3% in the 1990s; therefore, a more accurate twin rate over the 15 years of our study might be 2.5%.¹⁸ In the Northern Multiple Pregnancy Register data, 46 of 4115 live-born twins were recognized as having a cardiovascular malformation in the first 1 year of life, a rate of 1.1 case per 1000 live births. In the same data, 52% of twin maternities (pregnancies resulting in ≥1 live birth or stillbirth) were delivered preterm. This finding is also consistent with reports in the literature showing that ∼50% of twins are born before 37 weeks of gestation.¹⁹ In our study, 112 of 2964 infants with cardiovascular malformations were twins (3.8%) and 88 of these (79%) were born preterm. From these data, we can conclude that 18% of all preterm infants are twins, 1.3% of all term infants are twins, 23% of preterm infants with cardiovascular malformations are twins, and 1.3% of term infants with cardiovascular malformations are twins. Therefore, twins do not contribute significantly to the excess of cardiovascular malformations we observed among preterm infants.

Influence on Outcomes

The total 1-year mortality rate for infants of all gestational ages with cardiovascular malformations was 393 of 2964 infants (13%), and that for preterm infants with cardiovascular malformations was 97 of 494 infants (20%). Published studies of preterm infants, including our own population, predict that the overall 1-year mortality rate for preterm infants is 5.8%.^10,11,14 In a comparison of our data for preterm infants with cardiovascular malformations with these population data, the OR for death in prematurity with cardiovascular malformations was 4.2 (95% CI: 3.1–5.5). Specific mortality rates for gestational age groups with and without cardiovascular malformations are shown in Fig 3. The mortality rate was higher at all gestational ages, but the effect was most marked for near-term (OR: 11.0) and term (OR: 35.6) infants.

• Download figure
• Open in new tab
• Download powerpoint

Fig 3.

Total infant (12-month) mortality rates for different gestational age groups. Dark bars indicate infants without cardiovascular malformations; light bars, infants with cardiovascular malformations. ORs are for excess deaths among infants with cardiovascular malformations in each gestational age group.