Incidence of Patent Ductus Arteriosus and Patent Foramen Ovale in Normal Infants

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cardiac operations. The incidence of POAF in this predictor of atrial fibrillation and flutter after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1990;100:338Ð342. study was similar to that in other surgical cardiac 4. Creswell LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postopera- populations despite our patients being younger than tive atrial arrhythmias. Ann Thorac Surg 1993;56:539Ð549. most surgical cohorts. However, patients with POAF 5. Crosby LH, Pifalo WB, Woll KR, Burkholder JA. Risk factors for atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 1990;66:1520Ð1522. in this study did not seem to have more acute symp- 6. Hashimoto K, Ilstrup DM, Schaff HV. Influence of clinical and hemodynamic toms (need for inotropic support, need for reoperation, variables on risk of supraventricular tachycardia after coronary artery bypass. J Thorac Cardiovasc Surg 1991;101:56Ð65. duration of intensive care unit stay) than patients 7. Mathew JP, Parks R, Savino JS, Friedman AS, Koch C, Mangano DT, Browner remaining in sinus rhythm. This longer hospital stay WS. Atrial fibrillation following coronary artery bypass graft surgery: predictors, was generally attributable to ensuring adequate heart outcomes, and resource utilization. MultiCenter Study of Perioperative Ischemia Research Group. JAMA 1996;276:300Ð306. rate control, restoring sinus rhythm, and administering 8. Aranki SF, Shaw DP, Adams DH, Rizzo RJ, Couper GS, VanderVliet M, anticoagulation therapy. Collins JJ Jr, Cohn LH, Burstin HR. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation The treatment of POAF depends in large part 1996;94:390Ð397. 9. Chung MK, Asher CR, Dykstra D, Dimengo J, Weber M, Whitman G, on the timing, duration, and hemodynamic milieu. McCarthy PM, Nissen SE. Atrial fibrillation increases length of stay and cost after This small study does not support a prophylactic cardiac surgery in low risk patients targeted for early discharge (abstr). J Am Coll strategy, because one third of patients developing Cardiol 1996;27(suppl):309A. 10. Mohr R, Schaff HV, Danielson GK, Puga FJ, Pluth JR, Tajik AJ. The POAF were receiving amiodarone before opera- outcome of surgical treatment of hypertrophic obstructive cardiomyopathy. Ex- tion. Our results suggest that POAF occurs in ap- perience over 15 years. J Thorac Cardiovasc Surg 1989;97:666Ð674. 11. McCully RB, Nishimura RA, Tajik AJ, Schaff HV, Danielson GK. Extent of proximately 30% of patients with obstructive HC clinical improvement after surgical treatment of hypertrophic obstructive cardio- after septal myectomy. AF was not associated with myopathy. Circulation 1996;94:467Ð471. a more complicated postoperative period and is 12. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation 1995;92:1680Ð1692. relatively easily controlled or converted. 13. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89:724Ð730. 14. Pozzoli M, Cioffi G, Traversi E, Pinna GD, Cobelli F, Tavazzi L. Predictors 1. Ommen SR, Odell JA, Stanton MS. Atrial arrhythmias after cardiothoracic of primary atrial fibrillation and concomitant clinical and hemodynamic changes surgery. N Engl J Med 1997;336:1429Ð1434. in patients with chronic heart failure: a prospective study in 344 patients with 2. Fuller JA, Adams GG, Buston B. Atrial fibrillation after coronary artery bypass baseline sinus rhythm. J Am Coll Cardiol 1998;32:197Ð204. grafting. Is it a disorder of the elderly? J Thorac Cardiovasc Surg 1989;97:821Ð 15. Ommen SR, Tsang TSM, Ammash NM, Mahoney DW, Seward JB. Useful- 825. ness of serial echocardiographic parameters for predicting the subsequent occur- 3. Leitch JW, Thomson D, Baird DK, Harris PJ. The importance of age as a rence of atrial fibrillation. Am J Cardiol 2001;87:1298Ð1301.

Incidence of Patent Ductus Arteriosus and Patent Foramen Ovale in Normal Infants

David Connuck, MD, Jing Ping Sun, MD, Dennis M. Super, MD, MPH, H. Lester Kirchner, PhD, Linda Goetz Fradley, RN, Rose A. Harcar-Sevcik, PNP, Ann Salvator, MS, Lynn Singer, PhD, and Sudhir Ken Mehta, MD, MBA

s part of a study on the effects of in-utero cocaine and neonatal causes. We excluded infants born to Aexposure on the heart, a cohort of 104 full-term, mothers who used medications during pregnancy, healthy infants who did not have intrauterine drug such as bronchodilators, that may have affected the exposure underwent extensive echocardiographic ex- cardiovascular system. We also excluded infants of amination at birth and at 2 to 6 months of age. These mothers with acute or chronic diseases such as sys- studies were evaluated for the presence of a patent temic hypertension, hepatitis, diabetes mellitus, sep- ductus arteriosus (PDA) and patent foramen ovale sis, and human immnunodeﬁciency virus infection, (PFO). Infants were eligible for the study if they were symptomatic infants who required administration of Ͻ Ͼ 72 hours old, weighed 1,500 g, and were between oxygen beyond 5 minutes, ventilatory support, or ad- 33 and 42 weeks gestation. In all, 64 infants were mission to neonatal intensive care unit; and newborns excluded from the study because of various maternal with associated congenital anomalies including cardiac defects (except PDA, PFO, or physiologic mitral, From the Department of Pediatrics, MetroHealth Medical Center, Case tricuspid, or pulmonary regurgitation). Western Reserve University; Cleveland Clinic Foundation; Rainbow ¥¥¥ Babies and Children’s Hospital; and Fairview Hospital, Cleveland, Ohio. This study was supported by Grant RO1-DA09049 from the Demographic and medical characteristics at the National Institute on Drug Abuse, and Clinical Research Center Grant time of infant birth were abstracted from the hospital MO1RR00080 from the National Institutes of Health, Bethesda, Mary- record. A pediatric cardiologist conﬁrmed all physical land. Dr. Connuck’s address is: Division of Pediatric Cardiology, examinations in infants with PDA. The study was MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, Ohio, 44109-1998. E-mail: [email protected]. Manuscript re- approved by the institutional review board for human ceived July 13, 2001; revised manuscript received and accepted investigation at MetroHealth Medical Center and Case September 17, 2001. Western Reserve University. Informed written con-

244 ©2002 by Excerpta Medica, Inc. All rights reserved. 0002-9149/02/$–see front matter The American Journal of Cardiology Vol. 89 January 15, 2002 PII S0002-9149(01)02214-7 Doppler. We defined a PFO as a left- TABLE 1 Demographic Data of Normal Newborns by PDA Status at Birth to-right atrial shunt through the se- PDA Absent (n ϭ 56) PDA Present* (n ϭ 46) cundum atrial septum, with a diam- Ͻ Infants eter of 3 mm, and a flap derived Time evaluated (h) 29 Ϯ 11 (5–58) 26 Ϯ 10 (9–49) from the septum primum. Body surface area (m2) 0.21 Ϯ 0.02 (0.18–0.27) 0.21 Ϯ 0.01 (0.18–0.25) Data were analyzed using SAS Boys 27 (48%) 25 (54%) Version 8.0 (SAS Inc., Cary, North Birth weight (kgs) 3.32 Ϯ 0.44 (2.4–4.6) 3.18 Ϯ 0.38 (2.4–4.1) Birth length (cm) 50 Ϯ 2 (47–57) 50 Ϯ 2 (45–55) Carolina). To examine differences Gestational age (wks) 40 Ϯ 1 (36–42) 39 Ϯ 1 (36–42) between infants with or without a Head circumference (cm) 34 Ϯ 1 (31–40) 34 Ϯ 1 (31–37) PDA or PFO, the demographic data Apgar 1 min 8.5 Ϯ 0.7 (7–9) 8.5 Ϯ 1.2 (4–9) were analyzed using Pearson’s chi- Ϯ Ϯ Apgar 5 min 9.0 0(9–9) 8.9 0.5 (6–9) square and the Wilcoxon rank-sum Mothers Age (yrs) 22 Ϯ 4 (18–37) 22 Ϯ 3 (18–32) test for categorical and continuous Caucasian 14 (25%) 7 (15%) data, respectively. The proportion of African-American 37 (66%) 32 (70%) PDA and PFO was analyzed, using Hispanic 5 (9%) 7 (15%) the Cochran-Armitage trend test, to Prenatal visits 8.4 Ϯ 3.4 (2–15) 7.1 Ϯ 3.5 (1–16) Gravida 2.7 Ϯ 1.7 (1–10) 2.9 Ϯ 1.4 (1–8) test for trend in binomial proportions Employed 14 (25%) 19 (42%) across hours of life categories. In Parity 2.2 Ϯ 1.3 (1–8) 2.2 Ϯ 0.9 (1–5) comparison of the overall proportion Education (yrs) 11.6 Ϯ 1.5 (8–16) 11.8 Ϯ 1.7 (7–15) of PDA and PFO between birth and *There were no statistically significant differences between groups for any of the demographic 2- to 6-month follow-up, the gener- characteristics. alized estimating equations were Values are expressed as mean Ϯ SD (range). used to account for the correlated data and the fact that some infants were lost to follow-up. Exact 95% confidence intervals are also reported. Statistical significance was TABLE 2 Demographic Data of Normal Newborns by PFO Status at Birth defined as p Ͻ0.05 (2-tail). PFO Absent (n ϭ 39) PFO Present* (n ϭ 63) Although our inclusion criteria al- Infants lowed infants in the age range of 33 Time evaluated (h) 25.8 Ϯ 10.8 (5–46.3) 28.9 Ϯ 10.8 (6–57.6) to 42 weeks gestation, the youngest Body surface area (m2) 0.21 Ϯ 0.02 (0.18–0.27) 0.21 Ϯ 0.01 (0.18–0.25) gestational age infant enrolled in this Boys 19 (49%) 33 (52%) study was 36 weeks. Likewise, in- Birth weight (kg) 3.29 Ϯ 0.47 (2.44–4.61) 3.24 Ϯ 0.38 (2.45–4.18) Birth length (cm) 49.8 Ϯ 2.6 (45–56.5) 49.8 Ϯ 2.1 (45–55) fants up to 72 hours of age were Gestational age (wks) 39 Ϯ 1 (36–42) 39 Ϯ 1 (36–42) eligible for inclusion in this cohort, Head circumference (cm) 34 Ϯ 1 (32–40) 34 Ϯ 1 (31–37) but the oldest infant in the cohort Apgar 1 min 8.5 Ϯ 0.9 (4–9) 8.5 Ϯ 0.9 (4–9) was 57 hours of age at the time of Ϯ Ϯ Apgar 5 min 8.9 0.5 (6–9) 8.9 0.1 (8–9) first echocardiographic study. Mothers Age (yrs) 22 Ϯ 4 (18–32) 22 Ϯ 4 (18–37) One hundred four infants met cri- Caucasian 9 (23%) 12 (19%) teria for inclusion in this cohort. Two African American 27 (69%) 42 (67%) infants did not have complete echo- Hispanic 3 (8%) 9 (14%) cardiographic studies at birth, and Prenatal visits 8.4 Ϯ 3.9 (1–16) 7.5 Ϯ 3.2 (2–15) Gravida 2.8 Ϯ 1.8 (1–10) 2.8 Ϯ 1.5 (1–8) were excluded from analysis. The Employed 9 (24%) 24 (38%) average age of evaluation as a new- Parity 2.3 Ϯ 1.4 (1–8) 2.1 Ϯ 0.9 (1–5) born was 28 Ϯ 11 hours of age. The Education (yrs) 11.8 Ϯ 1.6 (8–16) 11.6 Ϯ 1.5 (7–15) average age of evaluation for fol- *There were no statistically significant differences between groups for any of the demographic low-up was 2.2 Ϯ 1.0 months (range characteristics. 1.7 to 6.8) of age. There was no Values are expressed as mean Ϯ SD (range). significant difference in any of the demographic characteristics of infants with or without PDA or with or sent was obtained from the legal guardians/parents of without PFO at birth (Tables 1 and 2). There was a all participants. predominance of African-Americans in this cohort. All infants underwent echocardiography including However, there was no difference between races in the color flow Doppler with a 5-MHz transducer (SONOS incidence of PDA (p ϭ 0.35) or PFO (p ϭ 0.58). 5500 Ultrasonograph, Hewlett-Packard Company, Overall, 46 infants (45%) had presence of PDA at Andover, Massachusetts) by an experienced pediatric- the time of initial study. Results of the Cochran- trained sonographer. Echocardiographic tapes were Armitage trend test concluded that there was no sig- reviewed by at least 1 cardiologist (JPS or DC). Pres- nificant trend in the incidence of PDA over the first 60 ence of PFO and PDA were determined by color flow hours of life (p ϭ 0.118). In a logistic regression Doppler recordings of the subcostal and parasternal model, we controlled for the effect of gender on the short-axis view, with confirmation by pulsed-wave linear trend across time. When controlling for gender,

BRIEF REPORTS 245 were available for further follow-up, TABLE 3 Incidence of PDA and PFO in Newborns and at Two to Six Months of Age 1 had continued echocardiographic evidence of a PDA at 9 months of Birth (n ϭ 102) 2–6mo(nϭ 89) p Value† age, whereas the other had spontane- PDA present 46 4 Ͻ0.001 ous closure of the PDA by 23 months (45.1%, 95% CI 35.2, 55.3) (4.5%, 95% CI 1.2, 11.1) of age. This provides evidence con- PFO present 63 48 0.221 firming that the silent PDA may (61.8%, 95% CI 51.6, 71.2) (54.5%, 95% CI 43.6, 65.2)* close spontaneously up to 2 years of 1 *PFO at follow-up is out of 88 infants. age, as has been reported. This also †The p value from generalized estimation equation models testing the proportion of PDA and PFO supports the practice, as occurs in presence, equal at birth and at 2 to 6 months. our institutions, of using endocarditis CI ϭ confidence interval. prophylaxis, but not intervening to close the silent PDA. We observed the presence of a male and female infants were similar (p ϭ 0.642), and PDA in 45% of normal infants. There are at least 4 the linear trend in proportion across time was not studies in which newborns were sequentially evalu- significant (p ϭ 0.102). ated for PDA over the first 4 to 6 days of life.2Ð5 Our Eighty-nine of the 102 infants (87.2%) returned for data for the first 60 hours of life are similar to the first the follow-up visit at 2 to 6 months of age. Four of the 60 hours of data in these studies. We observed that 1 89 infants (4.5%) had PDA. All the infants with PDA infant had persistence of ductal flow at 57 hours, at follow-up also had a PDA noted during their initial which is consistent with data from these 4 studies— examination. None of the 4 had an audible murmur at that persistence of ductal patency occurs at this age. any examination during the study or at follow-up. At Each of the aforementioned studies shows a trend follow-up evaluation, the age of the infants with a toward ductal closure with time. Two studies con- PDA was 3.3 Ϯ 1.9 months (range 1.8 to 6.1) versus cluded that all PDAs were closed based on 2-dimen- 2.2 Ϯ 1.0 months (range 1.7 to 6.8) for infants without sional and pulsed or continuous-wave Doppler exam- a PDA. Two of the 4 infants with PDA were male. inations without the use of color flow Doppler.1,3 This Two of the infants with PDA were lost to follow-up may have resulted in missing very small ductal shunts. after the second visit (1 male and 1 female infant). Of In each of the 4 studies, follow-up ended with the the remaining 2 infants, 1 PDA spontaneously closed closure of the ductus. Because there is a high rate of by 23 months of age (female) and the other still had a reopening of the ductus after initial closure (6 of 20 clinically undetectable PDA by echo at 9 months of infants on postnatal days 4, 5, and 6 in 1 report),6 the age. use of the criterion of ductal closure may cause an At the time of initial study, 63 infants (62%) had underestimation of the incidence of PDA after the evidence of a PFO. Results of the Cochran-Armitage early newborn period. Our data show no difference in trend test concluded that there is no significant change the presence of PDA in the early newborn period in the proportion of infants with a PFO over the first between male and female infants or based on other 60 hours of life (p ϭ 0.287). In a logistic regression demographic parameters. model, we controlled for the effect of gender on the We observed a PFO in 62% of infants in the first 60 linear trend across time. There was no difference in hours of life and in 54% at 2 to 6 months of age. Despite the overall incidence of PFO between male and female knowing the possibility of a PFO at 2 to 6 months of age infants (p ϭ 0.60). The linear trend across time was from catheterization and echocardiographic experience, different between male and female infants (p ϭ the high incidence noted in our follow-up examination 0.033). The proportion of female infants with a PFO has not been reported. The high incidence is most likely increased over time, whereas male infants did not a result of the sensitivity of color flow Doppler. We also show evidence of a linear trend. Data were available noted an increased presence of flow through a PFO in for the detection of a PFO in 88 subjects at the newborn female infants over the first 60 hours of life, follow-up visit. Forty-eight of 88 infants (55%) had a which was not present in male infants, or in the group PFO. The age of the infants at the time of the fol- taken as a whole. This gender difference has also not Ϯ low-up visit was 2.2 0.8 months (range 1.7 to 6.1) previously been reported. It is possible that this is a Ϯ for those with versus 2.3 1.3 months (range 1.7 to statistical difference due to decreased sample size when 6.8) for those without a PFO. There was no difference dividing our cohort into 2 groups. However, it could be in the proportion of infants with a PFO at follow-up a hemodynamic marker for factors that result in better compared with the initial evaluation (Table 3), and survival of preterm female than preterm male infants.7 there was no difference in the proportion of male to female infants with a PFO at follow-up. In summary, our findings suggest that 45% and ¥¥¥ 62% of full-term, healthy, newborn infants have a The key finding of our study is the presence of a PDA and/or PFO, respectively, during the first 60 “silent” PDA in 4.5% of normal infants at 2 to 6 hours of life. The incidences of silent PDA (4.5%) and months of age. This is higher than has previously been PFO (54.5%) at 2 to 6 months of age, as observed by reported. Infants with a PDA were asymptomatic and color flow Doppler, have not been previously re- had no clinical signs of PDA. Of the 2 subjects who ported. A larger, long-term prospective study is

246 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 89 JANUARY 15, 2002 needed to study the natural history and the long-term 4. Mandorla S. The ductus arteriosus in healthy newborn infants studied by continuous Doppler guided by two-dimensional Doppler color echocardiography. clinical implications of these lesions. G Ital Cardiol 1990;20:705Ð712. 5. Hiraishi S, Misawa H, Oguchi K, Kadoi N, Saito K, Fujino N, Hojo M, Horiguchi Y, Yashro K. Two-dimensional echocardiographic assessment of clo- 1. Glickstein J, Friedman D, Langsner A, Rutkowski M. Doppler ultrasound and sure of the ductus arteriosus in normal newborn infants. J Pediatr 1987;111:755Ð the silent ductus arteriosus. Br Heart J 1993;69:193. 760. 2. Gentile R, Stevenson G, Dooley T, Franklin D, Kawabori I, Pearlman A. 6. Lim MK, Hanretty K, Houston AB, Lilley S, Murtagh EP. Intermittent ductal Pulsed Doppler echocardiographic determination of time of ductal closure in patency in healthy newborn infants: demonstration by colour Doppler flow normal newborn infants. J Pediatr 1981;98:443Ð448. mapping. Arch Dis Child 1992;67:1217Ð1218. 3. Reller MD, Ziegler ML, Rice MJ, Solin RC, MacDonald RW. Duration of 7. Cartlidge PH, Stewart JH. Survival of very low birthweight and very ductal shunting in healthy preterm infants: an echocardiographic color flow preterm infants in a geographically defined population. Acta Paediatr 1997; Doppler study. J Pediatr 1988;112:441Ð446. 86:105Ð110.

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