A statistically significant positive relationship between hyperbilirubinemia and low birth weight, Oriental race, premature rupture of membranes, breast-feeding, neonatal infection, use of the "pill" at time of conception, instrumental delivery, and history of first trimester bleeding was found. A positive relationship between neonatal hyperbilinemia and maternal smoking and black race was also found.
A statistically significant positive relationship between hyperbilirubinemia and low birth weight, Oriental race, premature rupture of membranes, breast-feeding, neonatal infection, use of the "pill" at time of conception, instrumental delivery, and history of first trimester bleeding was found. A positive relationship between neonatal hyperbilinemia and maternal smoking and black race was also found.
A statistically significant positive relationship between hyperbilirubinemia and low birth weight, Oriental race, premature rupture of membranes, breast-feeding, neonatal infection, use of the "pill" at time of conception, instrumental delivery, and history of first trimester bleeding was found. A positive relationship between neonatal hyperbilinemia and maternal smoking and black race was also found.
Shai Linn, Stephen C. Schoenbaum, Richard R. Monson, Bernard Rosner, Phillip G. Epidemiology of Neonatal Hyperbilirubinemia http://www.pediatrics.org the World Wide Web at: The online version of this article, along with updated information and services, is located on Online ISSN: 1098-4275. Copyright 1985 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from 770 PEDIATRICS Vol. 75 No. 4 April 1985 Epidemiology of Neonatal Hyperbilirubinemia Shai Linn, MD, DrPH, Stephen C. Schoenbaum, MD, MPH, Richard R. Monson, MD, DSc, Bernard Rosner, PhD, Phillip G. Stubblefield, MD, and Kenneth J. Ryan, MD From the Departments of Medicine Obstetrics and Gynecology, Brigham and W omens Hospital, Harvard Medical School, Harvard Community Health Plan, and Department of Epidemiology, Harvard School of Public Health, Boston ABSTRACT. Interview and record review data from 12,023 singleton deliveries were analyzed to determine the relationships between neonatal hyperbilirubinemia (10 mg/dL or greater) and maternal characteristics. Con- founding variables were controlled by multiple logistic regression analysis. There was a statistically significant positive relationship between hyperbilirubinemia and low birth weight, Oriental race, premature rupture of mem- branes, breast-feeding, neonatal infection, use of the pill at time of conception, instrumental delivery, and history of first trimester bleeding. M aternal smoking and black race were negatively related to hyperbilirubinemia and statistically significant. In this study, other previ- ously suspected etiologic factors such as epidural anes- thesia, parity, use of oxytocin in labor, and white race were not associated with hyperbilirubinemia. Pediatrics 1985;75:770-774; neonatal hyperbilirubinem ia, low-birth- weight infants, breast-feedings, sm oking in pregnancy. Previous reports have indicated a relationship between neonatal hyperbilirubinemia and diverse factors including racial onigin,3 male gender, epi- dural anesthesia,35 and instrumental delivery.56 Oxytocin usage during delivery has been implicated by some,357#{176} but not confirmed by others.46114 Two studies56 have suggested a dose-response m e- lationship with neonatal hyperbillirubinemia oc- cunning only in association with very high doses of oxytocin. Low birth weight and short gestation,3 neonatal infections,6 and breast-feeding617 have also been reported to be associated with the occur- rence of neonatal hypenbilirubinemia. Some189 have suggested that the effect of breast-feeding may Received for publication April 18, 1984; accepted July 25, 1984. Reprint requests to (S.C.S.) Harvard Community Health Plan, M anagement Office, One Fenway Plaza, Boston, M A 02215. PEDIATRIcS (ISSN 0031 4005). Copyright 1985 by the American Academy of Pediatrics. be enhanced by prior use of oral contraceptives, but another study2 has not confirmed this. In the present study, we have examined the oc- currence of hyperbilirubinemia in the offspring of more than 12,000 women who were interviewed during their delivery hospitalization. Recognizing that neonatal hyperbilirubinemia has multiple risk factors that are likely to be interrelated, we have focused the analysis on trying to determine the independent contribution of each. METHODS Study Population and Collection of Data The data derive from the Delivery Interview Pro- gram (DIP) at the Boston Hospital for W omen Division of the Brigham and W omens Hospital. The program was designed to examine the relation- ship of late pregnancy outcomes and a variety of exposures. During the study period (Aug 8, 1977 to M arch 31, 1980), 14,458 women (84.4% of all women delivering at the hospital) were approached for an interview following delivery. Reasons for not being approached were lack of sufficient personnel to coven all deliveries (14.1% ), and treatment by one physician who refused permission for his pa- tients to participate in this study (1.5% ). On days when there were not sufficient personnel to inter- view all delivery patients, a random selection was made. Of those who were approached and who had singleton deliveries, 90.0% were interviewed. Rea- sons for not being interviewed were early discharge (5.4% ), refusal (2.9% ), language barrier (1.6% ), and/or medical conditions that precluded an inter- view (0.1% ). Information obtained from each woman included previous medical and obstetric his- tory and habit characteristics. W omen were also asked about their last method of contraception. . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from ARTICLES 771 W e did not influence the ordering of bilinubin determinations. Prior to the collection of data, we defined hyperbilirubinemia as the presence of one on more bilirubin determinations of 10 mg/dL or greater. Information about the infants gestation and delivery, the occurrence of hypenbilirubinemia, and the highest bilirubin level (recorded only in the last year of the study) were obtained by review of the medical record. The analysis was limited to the 12,023 nondi- abetic women who had singleton live deliveries. W e excluded 70 cases of Rh on ABO incompatibility and 71 cases in which infants received photothenapy prophylactically before reaching a bilirubin level of 10 mg/dL (Table 1). Analytic Techniques W e compared maternal demographic character- istics and habits, pregnancy and delivery events, and neonatal outcomes for those infants who had hypenbilirubinemia v those whose record did not T A B L E 1 . Potential Subjects (17,136), Exclusions, and Subjects Included in Final Analysis (12,023)* Deliveries in study period 17,136 Subjects approached 14,458 Singleton deliveries 14,255 Nondiabetics 13,807 Interviewed 12,440 Live birth 12,364 No prophylactic phototherapy 12,293 No ABO or Rh incom patibility 12,023 * Fach category is a subset of the higher category. show hyperbilirubinemia. For each characteristic, the odds ratio (relative odds) of having hypembili- rubinemia and the 95% confidence interval were calculated. The odds ratio is the estimate of relative risk which can be derived from case-control studies. W e then perform ed an analysis by logistic negres- sion to examine the odds ratio of having hyperbili- nubinemia when all suspected confoundens were controlled. For this analysis, all variables were di- chotomized. W e chose cutoff points on the basis of the distribution of the characteristics in the deliv- ery population on according to a natural cutoff point of interest (eg, one or more previous pregnancies v no previous pregnancy). The final regression model included the variables listed in Table 5. Because various studies have reported an association be- tween black, Oriental, and white race and neonatal hypenbilirubinemia, we analyzed race in four cate- gonies-black, Oriental, white, and other. Other was then used as the reference category for the remaining three groups. R E S UL T S Some of the characteristics of the study popula- tion are presented in Table 2. In the crude data, the characteristics older maternal age, being single, having had a college education, receiving welfare, higher gravidity, and higher parity were all statis- tically significantly related to the occurrence of neonatal hyperbilirubinemia. Neonatal hyperbili- rubinemia was significantly more prevalent among those who were Oriental. As has been previously T A B L E 2 . Occurrence of Neonatal Hyper Characteristics in 12,023 Patients bilirubinemia in Re! ation to Selected M a temnal Demo graphic and M edical No. with Neonatal Odds Ratio 95% Confidence Characteristic Hyperbilirubinemia Interval (%) Demographic Age 35 yr 1,048 22.2 1.20 1.03, 1.40 Single 1,502 14.9 0.70 0.60, 0.81 Race W hite 1,836 20.0 0.83 0.70, 0.98 Oriental 183 49.2 5.19 3.83, 7.05 Black 1,819 12.1 0.46 0.47, 0.64 College education 782 20.9 1.29 1.17, 1.42 Receiving welfare 1,905 16.3 0.78 0.68, 0.89 Habits Smoking 3+ cigarettes/d at delivery 2,625 15.5 0.71 0.63, 0.80 ( v all others) Alcohol in 1st trimester 2,732 19.7 1.02 0.91, 1.13 M arijuana use during pregnancy 1,217 18.9 0.96 0.83, 1.12 Previous history Gravidity >1 4,915 20.5 1.12 1.03, 1.23 Parity >1 6,107 20.7 1.17 1.07, 1.28 Previous induced abortion(s) 2,178 19.2 0.98 0.87, 1.10 Using pill at time of conception 206 22.3 1.12 0.93, 1.35 M aternal ponderal index <18 kg/m2 113 27.4 1.57 1.04, 2.37 (light weight) . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from 772 NEONATAL HYPERBILIRUBINEMIA reported, being black was related to a lower occur- rence of hyperbilirubinemia. These relationships were observed further within the group of babies with hyperbilirubinemia. For example, 19% of the Oriental infants with hypenbilirubinemia had a bil- irubin 15 mg/dL whereas the percentages among white and black infants were 6.9% and 2.2% , me- spectively. Offspring of women who were smokers at the time of delivery had a substantially lower occur- rence of hyperbilirubinemia. Compared with women who reported never smoking, women who were smoking at least one pack of cigarettes a week at the time of delivery had the lowest chance of having a child with hyperbilirubinemia (odds ratio 0.69; 95% confidence interval 0.61, 0.78), whereas women who smoked less had a slightly higher oc- currence of hyperbilirubinemia in their offspring (odds ratio 0.75; confidence interval of 0.57, 0.97). Though not statistically significant, the effect of smoking was discernible even for women who stopped smoking during their pregnancy. The odds ratio for those who stopped smoking in the second or third trimester was 0.70 (confidence interval 0.48, 1.03); for those who stopped smoking in the first trimester, it was 0.94 (confidence interval 0.76, 1.16); for those who stopped smoking before preg- nancy, it was 0.98 (confidence interval 0.87, 1.09). Other habits, such as marijuana usage during pregnancy, alcohol consumption in the first trimes- ten, and previous induced abortions were not related to hyperbilirubinemia. The use of oral contracep- tion at the time of conception was not statistically significantly related to the occurrence of neonatal hypenbilirubinemia. Bleeding in the first and third tnimestens, cervical incompetence, abruptio placen- tae, placenta previa, premature rupture of mem- branes, abnormal presentation, and instrumental delivery were statistically significantly related to neonatal hypembilirubinemia in the crude data (Ta- ble 3). Toxemia, the occurrence of fetal distress, use of oxytocin, and epidumal anesthesia were not related. As shown in Table 4, low birth weight and short gestation were strongly related to the occur- TABLE 3. Occurrence of Neonatal Hyperbilirubinemia in Relation to Selected Preg- nancy Events and Delivery Characteristics No. with Neonatal Odds 95% Confi- Characteristic Hyperbilirubi- Ratio dence nemia Interval (%) Pregnancy events Bleeding in: 1st trimester 1,142 24.9 1.45 1.26, 1.68 2nd trimester 445 20.2 1.11 0.88, 1.41 3rd trimester 575 24.0 1.39 1.14, 1.69 Toxemia or eclampsia 422 17.3 0.86 0.76, 1.11 Delivery characteristics Abruptio placentae 127 29.1 1.71 1.17, 2.50 Placenta previa 65 36.9 2.43 1.49, 3.97 Premature rupture of membranes 241 22.2 1.22 1.08, 1.38 Instrumental delivery 4,303 22.0 1.28 1.18, 1.40 Oxytocin use 5,136 20.1 1.07 0.98, 1.17 Epidural anesthesia 5,207 20.0 1.07 0.97, 1.17 Fetal distress 381 18.1 0.91 0.70, 1.19 TABLE 4. Occurrence of Neonatal Hyperbilirubinemia in Relation to Selected Infant Characteristics No. with Neonatal Odds 95% Confi- Characteristic Hyperbilirubi- Ratio dence nemia Interval (%) Birth weight <2,500 g 834 42.7 3.45 3.01, 3.96 Gestation <37 wk 777 47.5 4.34 3.77, 4.98 M ajor malformations 310 28.4 1.66 1.30, 2.13 M inor malformations 745 16.5 0.82 0.67, 1.00 Neonatal infection or sepsis 121 40.5 2.85 2.01, 4.05 1-mm Apgar score <6 830 21.6 1.15 0.97, 1.36 S p e c i a l c a r e n u r s e r y 1 , 9 9 8 3 1 . 9 2 . 2 9 2 . 0 7 , 2 . 5 4 Breast-feeding 7,311 22.7 1.74 1.58, 1.92 M ale gender 6,210 21.1 1.25 1.14, 1.37 . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from TABLE 5. Odds Ratio and Confidence Characteristics Potentially Associated Interval Estimation by Logistic Regression for with Neonatal Hyperbilirubinemia* Characteristics Odds Ratio Confidence Interval of 95% Low birth weight (<2,500 g) 3.60 3.10, 4.25 Being Oriental 3.56 2.53, 5.01 Premature rupture of membranes 1.91 1.55, 2.35 Breast-feeding 1.80 1.61, 2.01 Infants infection 1.55 1.04, 2.32 Use of the pill at time of conception 1.42 1.01, 2.01 M ale gender 1.28 1.17, 1.41 Instrumental delivery 1.25 1.12, 1.40 M ajor malformation 1.24 0.94, 1.63 Bleeding in 1st trimester 1.21 1.04, 1.41 W elfare 1.14 0.97, 1.34 Age >35 yr 1.09 0.97, 1.23 Epidural anesthesia 1.09 0.98, 1.22 Parity >1 1.03 0.93, 1.14 Oxytocin during labor 0.99 0.89, 1.10 No college education 0.98 0.87, 1.11 Being white 0.89 0.88, 1.06 Smoking 3+ cigarettes/d at delivery 0.77 0.68, 0.87 Being black 0.49 0.40, 0.60 * Listed are the odds ratios of having a baby with hyperbilirubinemia, controlling simul- taneously for the other characteristics in the list. ARTICLES 773 rence of neonatal hyperbilirubinemia. M ale gender, major malformations, neonatal infection or sepsis, being treated in the special care nursery, and breast-feeding also were related to hypenbilirubi- nemia. Several of these factors, which showed relation- ships to neonatal hyperbilinubinemia in the crude data, are obviously interrelated. The remainder of the analysis was directed toward determining the independent contribution of various factors. The results of the logistic regression analysis are pre- sented in Table 5. Low birth weight, being Oriental, having premature rupture of membranes, breast- feeding, neonatal infection, using the pill at time of conception, having a male baby, instrumental deliv- eny, bleeding in the first trimester were all positively and independently statistically significantly related to neonatal hyperbilirubinemia. Negatively related variables were smoking three on more cigarettes pen day at delivery and being black. Other variables, including oxytocin usage and epidural anesthesia were not found to be statistically significantly me- lated. DI S CUS S I ON This study characterizes the occurrence of neo- natal hyperbilirubinemia in an American popula- tion. W e recognize that hyperbilirubinemia of 10 mg/dL might be of little clinical importance and that the major clinical concern is associated with higher levels of bilinubin. Nevertheless, we chose for this study to define hypembilirubinemia at the level of 10 mg/dL to have a sufficient number of patients so that we could analyze the independent contributions of each of the several associated van- ables. Using this cutoff level may also give a clearer picture of each of the variables. Infants who are most likely to develop the highest bilirubin levels, ie, very low-birth-weight infants, routinely undergo interventions to prevent the development of hyper- bilinubinemia before having reached the highest levels, and this precludes full assessment of the contribution of other factors. From our more lim- ited analysis of the subset of data on infants with bilirubin levels 10 mg/dL, it does appear that the epidemiology of clinically significant hyperbiliru- binemia ( 15 mg/dL) follows the epidemiology of hypenbilirubinemia in general. The positive relationship between Oriental eth- nicity and the negative relationship of black origin to the occurrence of neonatal hyperbilirubinemia could be superficially explained by failure to detect the condition among blacks or an increased tend- ency to draw blood for bilirubin tests among infants of Oriental mothers simply on the basis of their colon. Our data, however, do not support this, be- cause the relationship held even in the subset of the study population in which all had bilinubin levels 10 mg/dL. This high occurrence of hyper- bilirubinemia among neonates of Oriental origin supports previous findings of higher bilirubin levels among Asiatic neonates in Singapore2 and in Eng- land.3 To date, no pathophysiologic basis for this finding has been established. Also ofspecial interest was the negative relationship between maternal smoking and neonatal hyperbilirubinemia. Consist- ent underreporting or overreporting of previous events by women who had an adverse pregnancy . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from 774 NE O NATAL HYP E R BILIR UBINE MIA outcome woul d consti tute a recal l bi as. A l though recal l bi as coul d be an expl anati on of our f i ndi ngs, we do not bel i eve that thi s real l y occurred. The i ntervi ews were conducted accordi ng to a standard questi onnai re, and nei ther the women nor the i n- tervi ewers were f ul l y aware of the study f ocus. M oreover, most of the data were obtai ned f rom the record i n addi ti on to the i ntervi ew, whi ch wi l l mm- i mi ze any tendency to such a recal l bi as. Fi nal l y, recal l bi as shoul d be consi stent. I t coul d not expl ai n the f act that i n thi s study maternal hi story of pi l l use at concepti on i s posi ti vel y associ ated wi th hypenbi l i nubi nemi a, whereas maternal hi story of smoki ng i s negati vel y associ ated. A l though neonatal hyperbi l i rubi nemi a i s a com- mon event, i t i s of i nterest because at i ts extreme i t has cl i ni cal si gni f i cance and i t al so can be the source of consi derabl e parental concern. Cl i ni ci ans need to be aware of the mul ti pl e i ndependent ri sk f actors f or hypembi l i rubi nemi a and shoul d f ol l ow cl osel y neonates wi th one or more ri sk f actors. ACKNOWLEDGMENT Thi s work was supported by a grant f rom the Nati onal Bi rth Def ects Foundati on. REFERENCES 1. Brown W R, Boon W H: Ethni c group di f f erences i n pl asma bi l i rubi n l evel s on f ul l -term, heal thy Si ngapore newborns. Pediatrics 1965;36:745-751 2. Si vasuri ya M , Tan K L , Sal mon Y M , et al : Neonatal serum bi l i rubi n l evel s i n spontaneous and i nduced l abour. Br J Obstet Gynaecol 1978;85:619-623 3. Fri edman L , L ewi s PJ, Cl i f ton P, et al : Factors i nf l uenci ng the i nci dence of neonatal j aundi ce. Br Med J 1978;1:1235- 1237 4. W ood B, Cul l ey P, Rogi nski C, et al : Factors af f ecti ng neonatal j aundi ce. Arch Dis Child 1979;54:111-115 5. Campbel l N, Harvey D, Norman A P: I ncreased f requency of neonatal j aundi ce i n a materni ty hospi tal . 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Gray HG, M i tchel l R: Neonatal hyperbi l i rubi nemi a and oxytoci n. Lancet 1974;2:115 14. Thi ery M , de Hempti nne D, Schuddi nck L , et al : Neonatal j aundi ce af ter i nducti on of l abour. Lancet 1975;1:161 15. Davi es DP, Gomersal l R, Robertson R, et al : Neonatal j aundi ce and maternal oxytoci n i nf usi on. Br Med J 1973;3:476-477 16. Jef f ares M J: A mul ti f actori al survey of neonatal j aundi ce. Br J Obstet Gynoecol 1977;84:452-455 17. Newman A J, Gross S: Hyperbi l i rubi nemi a i n breast f ed infants. Pediatrics 1963;32:995-1000 18. W ong Y K , W ood BSB: Breast mi l k j aundi ce and oral con- tracepti ves. Br Med J 1971;4:404-405 19. M cConnel l JB, Gl asgow JFT, M cNai R: Ef f ect on neonatal j aundi ce of oestrogens and progestogens taken bef ore and af ter contracepti on. Br Med J 1973;3:605-607 . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from 1985;75;770-774 Pediatrics Stubblefield and Kenneth J. Ryan Shai Linn, Stephen C. Schoenbaum, Richard R. Monson, Bernard Rosner, Phillip G. Epidemiology of Neonatal Hyperbilirubinemia & Services Updated Information http://www.pediatrics.org including high-resolution figures, can be found at: Citations http://www.pediatrics.org#otherarticles This article has been cited by 24 HighWire-hosted articles: Permissions & Licensing http://www.pediatrics.org/misc/Permissions.shtml its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or in Reprints http://www.pediatrics.org/misc/reprints.shtml Information about ordering reprints can be found online: . Provided by Indonesia:AAP Sponsored on January 13, 2011 www.pediatrics.org Downloaded from