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Necrotizing Enterocolitis

WHAT’S KNOWN ON THIS SUBJECT: Fetal factors that predispose infants to necrotizing enterocolitis (NEC) have been extensively studied. Maternal factors that may affect future risk for NEC are less clear.

WHAT THIS STUDY ADDS: We hypothesized that maternal factors were the primary cause of NEC. Through a case-control design we determined that maternal smoking predisposes infants to the development of NEC. Our results highlight the importance of smoking cessation in pregnancy.

abstract

BACKGROUND:The maternal variables that affect fetal development and correlate with necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in premature infants, are not well defined. We hypothesized that maternal risk factors were the primary determi-nant of future development of NEC.

METHODS:Patients with NEC were identified from an established NICU database and were control-matched with 2 neonates treated at the same institution. The medical records of each patient during the NICU admission as well as the prenatal and delivery record of the patient’s mother were reviewed. Perinatal data, including maternal smoking, maternal hypertension, maternal BMI, maternal gestational diabetes, conduct of labor and type of delivery, Apgar scores, types of feedings, and placental pathology, were examined, with P , .05 deemed significant.

RESULTS:A total of 73 neonates diagnosed with NEC and 146 matched controls were identified. Medical records for each subject and their mothers were reviewed (438 records total). Maternal cigarette smok-ing was significantly associated with the future development of NEC (P= .02). Maternal gestational diabetes, maternal hypertension, for-mula feeding, and pathologic chorioamnionitis or uteroplacental in-sufficiency did not correlate with NEC.

CONCLUSIONS: These data identified maternal cigarette smoking as the only risk factor that is associated with the development of NEC in premature infants. Our data imply that smoking delivers toxins and nicotine to the uterine microenvironment that can affect microvas-cular development and may predispose the fetus to future NEC. Pedi-atrics2012;130:78–82

AUTHORS:Cynthia D. Downard, MD, MMSc,aStephanie N. Grant, MD,aAlexandra C. Maki, MD,bMary C. Krupski, DO,c Paul J. Matheson, PhD,bRobert W. Bendon, MD,dMary E. Fallat, MD,aand R. Neal Garrison, MDb

aPediatric Surgery,bSurgery, andcPediatrics, University of

Louisville, Louisville, Kentucky; anddPathology, Kosair Childrens

Hospital, Louisville, Kentucky

KEY WORDS

smoking, pregnancy, necrotizing enterocolitis

ABBREVIATION

NEC—necrotizing enterocolitis

All authors listed have met criteria as authors of thisfinal article. Each has made substantial contributions to the concept and design, acquisition of data and analysis, interpretation of the data, and the drafting and revising of thefinal content of the following article.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-3808

doi:10.1542/peds.2011-3808

Accepted for publication Mar 1, 2012

Address correspondence to Cynthia D. Downard, MD, MMSc, Division of Pediatric Surgery, Department of Surgery, University of Louisville, 315 East Broadway, Suite 565, Louisville, KY 40202. E-mail: c0down01@louisville.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:The authors have indicated they have nofinancial relationships relevant to this article to disclose.

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Necrotizing enterocolitis (NEC) is the most common gastrointestinal emer-gency in neonates and is poised to become the leading cause of death in this population.1,2The search for risk

factors for development of NEC has focused largely on postnatal events such as infection, hypothermia, and hyp-oxia. To this end, it has been determined that NEC occurs almost uniformly in premature infants, but other factors such as formula feedings, infection with certain bacterial pathogens, prolonged ventilation, and prenatal glucocorticoid exposure have been variably associated with NEC.3,4

Although several well-designed pro-spective studies have not definitively determined which premature infants will develop NEC, few have evaluated the role of prenatal events in the ultimate outcome of the infant.3,5,6We

hypothe-sized that maternal variables are the primary factor that affect fetal de-velopment and that these correlate with future development of NEC. We specifically thought that maternal risk factors such as smoking, age, hyper-tension, high BMI, and gestational di-abetes might predispose infants to develop NEC. We also wanted to evalu-ate the idea that placental insults such as chorioamnionitis or uteroplacental insufficiency may be present in infants who ultimately develop NEC. We corre-lated prenatal maternal variables and postnatal data in neonates with and without NEC by using a retrospective, paired-control design to assess the potential role of maternal factors in the development of NEC.

METHODS

After institutional review board approval (09.0337) was obtained, a preexisting database containing prospectively col-lected information of all infants hospi-talized in the NICU at a single institution from 2004 to 2009 was queried. Patients were identified as cases (NEC) if they

were classified in the database as having NEC and subsequent review of their medical record confirmed clinical or radiographic signs of NEC (ie, bloody stools, abdominal distension, throm-bocytopenia, pneumatosis intestinalis, portal venous air, pneumoperitoneum). Two control patients were selected from the database for each case patient and were matched for date of birth (,6 month difference), estimated gestational age (,1 week apart), and birth weight (,100 g difference). Maternal records for each case and control were obtained and reviewed, with particular attention given to known and suspected risk fac-tors for later development of NEC (ie, smoking status, age, hypertension, BMI, and gestational diabetes).

Placental specimens of a selected group of NEC and control patients were reviewed by a blinded pathologist. Particular attention was paid to ir-regularities in vascular development, chorioamnionitis, and uteroplacental insufficiency. Chorioamnionitis was deemed“severe”if it included funisitis (neutrophils in the cord) or purulence. Uteroplacental insufficiency was

de-fined as severe if it was described as having multiple infarcts, retroplacental hematomas.10% of surface area, or atherosis.

Univariate statistical analyses were performed by using unpaired t test for continuous variables andx2analysis

for categorical variables (Jandel SigmaPlot Version 11.1.0.102, Systat Software, Inc, San Jose, CA). The signif-icance level was set atP,.05 a priori. Thefindings from the univariate analy-sis were confirmed with the multivariate general linear model (SPSS Version 19.0.0, IBM, Armonk, NY).

RESULTS

Seventy-three infants were identified with NEC, and 146 controls were selected after controlling for date of birth, esti-mated gestational age, and birth weight. Maternal records for all cases and controls were reviewed as well. De-mographic information of the NEC and control patients is depicted in Table 1.

Table 2 shows the maternal and fetal factors thought likely to be associated with development of NEC based on our literature review. Of note, maternal smoking is the only risk factor signifi -cantly associated with future develop-ment of NEC (P= .02). Other commonly held risk factors, such as formula feed-ing, transfusions, low Apgar scores, gestational diabetes, and maternal hy-pertension, were not statistically signif-icantly different among the 2 groups.

Table 3 shows our evaluation of the placental specimens of a select group of case NEC patients (n= 48) and control patients (n= 46). It is noteworthy that there were no differences in placental

TABLE 1 Demographics of Studied Patients With Associated Statistical Analyses

Neonatal Demographics Control (n= 146) NEC (n= 73) Test P

Gender

Male 85 47 x2= 0.536 .464

Female 61 26

Race

White 79 38 x2= 5.060 .409

Black 64 31

American Indian/Alaskan 0 1

Hispanic 2 2

Asian 1 0

Other 0 1

Fetal weight 1263.4652.1 1257.1674.6 t=20.0692 .945

Fetal height 36.760.4 37.760.6 t= 1.264 .208

There were no significant differences between the Control and NEC groups. Numbers represent patients in each group, and variables are denoted by mean6standard error of the mean (SEM).

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demonstration of pathologic chorioam-nionitis or uteroplacental insufficiency, regardless of severity, between the NEC and control groups.

DISCUSSION

This study is the first to definitively determine the association of maternal smoking with future development of NEC. By the design of this study, several factors that have previously been as-sociated with future development of NEC, such as birth weight and gesta-tional age, have been controlled for. In addition, we selected controls based on the approximate “era” of birth, such that, if significant changes in clinical care occurred over time, these changes should be inconsequential.

This study represents a novel evalua-tion of risk factors for NEC in that maternal factors are the primary determinants of outcome in this study. We used a case-control study design to maximize the likelihood that the ma-ternal factors are the only different variables in the patients and therefore

should be the critical determinants by which infants go on to develop NEC.

In addition, factors such as younger maternal age (,20 years of age,P= .08) and formula feeding (P = .07) neared statistical significance. We limited our study population to those infants in a single NICU to facilitate acquisition of accurate records, but both of these factors might become statistically sig-nificant if we had a larger population.

Potential downfalls in this study are that, although the information in the database is prospectively collected, it does require retrospective review to identify cases and controls. We tried to validate diagnoses of NEC and ensure that cases actually had NEC by evaluating their medical records and ensuring that they had clinical symptoms and objective signs of NEC, but retrospective deter-mination of this information is certainly limited by the data that are available. Another potential downfall is that we did not investigate whether mothers were using a nicotine replacement program during pregnancy.

an area of interest in neonatology. Chorioamnionitis has been studied as a potential correlate for the develop-ment of NEC. A recent study in 2009 ex-amined placentas and patients who had clinically evident chorioamnionitis ei-ther limited to the placenta or extending to the fetus at delivery. They found that evidence of chorioamnionitis in the fetus increased the rate of NEC from 2% to 8%.7

Of note, chorioamnionitis seemed to increase the risk of NEC only when it had invaded the fetal tissues. We did not specifically evaluate this in our review of the placentas.

There has been a strong interest in the vascularflow patterns to the placenta and the possible development of NEC or growth retardation. One study of 404 severely growth-retarded infants found no meaningful predictive value of pre-natal Doppler studies of placental function for NEC.8

The effects of nicotine and smoking on the developing placenta have long been of clinical interest. In 1985, Luck and colleagues9described the transport of

nicotine and 1 of its active metabolites, cotine, across the placenta. They found that the human fetus is exposed to higher levels of nicotine than the mother, determining amnioticfluid and mater-nal serum nicotine levels and expressing this as a ratio. They described the level increase as a ratio of 1.54 (amniotic

fluid/maternal vein serum levels) at 16 to 24 weeks’gestation, meaning that the amniotic fluid had a nicotine concen-tration 1 ½ times that of the mother’s serum. The reason this is important is that the human fetus lacks keritinization during the second trimester; therefore, nicotine can easily be absorbed from the amniotic fluid into the fetus; in fact, nicotine is easily absorbed by adult hu-man skin. This study overall showed that nicotine is concentrated in the amniotic

Maternal factors

Smoking 46 (32%) 35 (48%) x2= 4.959 .026

Age, y 26.160.5 24.760.6 t=21.752 .081

Gestational diabetes 12 (8.2%) 2 (2.7%) x2= 1.612 .204

Hypertension 42 (29%) 14 (19%) x2= 1.874 .171

Neonatal factors

Formula feeding 80 (55%) 50 (68%) x2= 3.239 .072

Apgar 1 min 5.760.2 6.060.3 t= 0.940 .348

Apgar 5 min 7.660.1 7.760.2 t= 0.233 .816

The only factor significantly different in the 2 groups is maternal smoking. It is noteworthy that formula feeding did not influence the future development of NEC. These factors have previously been associated with the development of NEC. Depicted values aren(% of group) and variables are means6standard error of the mean (SEM). APvalue of .05 is considered significant.

TABLE 3 Placental Comparison Between NEC and Control Patients

NEC (n= 48) Control (n= 46) Statistical Analysis P

All chorioamnionitis 22 14 x2 .186

Severe chorioamnionitis 12 8 x2 .959

All uteroplacental insufficiency 13 16 x2 .559

Severe uteroplacental insufficiency 6 6 x2 .956

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fluid exposing the fetus to a higher level of nicotine than the mother.

More recently, nicotine has been under additional investigation because of the widespread availability of nicotine replacements that are presumed to be a better alternative to smoking.10With

this change in clinical recommenda-tions, recent animal studies on prena-tal nicotine exposure have shown feprena-tal programming of vascular oxidative stress in the adult offspring of these nicotine-exposed dams.11Nicotine, itself,

has been shown to have significant effects on placental development.

Nicotine exposure impairs the initial stage of placental vascularization, the invasion of maternal blood vessels into the cytotrophoblasts.12,13A prospective

study looking at Dopplerflow of uterine vessels during pregnancy found smok-ing to be associated with abnormal waveforms. Later, those women with abnormal waveforms delivered infants with significantly lower birth weights, even after controlling for gestational age.14

During normal fetal development, pla-cental nitric oxide synthase activity is highest during the first trimester.15

Endothelial nitric oxide causes vasodi-latation and therefore increases blood

flow; such actions are obviously impor-tant for the placenta of a developing fetus. The enzyme is decreased, how-ever, in a dose-dependent fashion in the placentas of smoking women.16 Low

levels have also been found in the pla-centas of women with preeclampsia

and other growth-restricted pregnan-cies.17A relationship, therefore, can also

be made between low levels of nitric oxide and smaller placental blood ves-sels delivering nutrients to the fetus. Tobacco exposure has been associated with lower gestational age at birth, de-creased birth weight, and shorter crown-heel length in multiple studies.16,18All of

the aforementioned studies link smoking and nicotine to abnormal vascular de-velopment, but few studies actually show a causal relationship that describes a mechanism for this relationship. This could be an area for further future re-search in which the focus is on the mechanisms behind smoking, nicotine itself, and vascular development in the neonate.

CONCLUSIONS

Although care of the infant with NEC is primarily provided by neonatologists and pediatric surgeons, thefindings of the current study are relevant to a much broader audience. Physicians in the outpatient setting have a major role in identifying potential at-risk infants and providing earlier, primary prevention of this devastating disease. Obstetricians and gynecologists typically provide counseling and smoking cessation programs to their pregnant patients, and these techniques can be successful. However, not all women seek prenatal care in a timely fashion, or even at all, after discovering their pregnancy. A novel approach at preventing this

costly disease can start with the general pediatrician.

Most women come in contact with a pe-diatrician at some point during their pregnancy. Either they are trying tofind a new health care provider for the infant, or they are visiting their established pe-diatrician with 1 of their other children while they are pregnant. These inter-actions between pediatrician and future mother can be a critical point of in-tervention for the smoking woman. The role of the pediatrician is to be an advo-cate for his/her patient. This can be done by asking the mother about her tobacco use; counseling heron the negative effects smoking can have on her developing baby, including the possibility of future de-velopment of NEC; and providing resour-ces to help her with smoking resour-cessation.

Obviously, in addition to improved pre-vention and treatment strategies, more research is necessary to further elucidate the risk factors and patho-genesis of NEC. With the current study linking maternal cigarette smoking to development of NEC, and the knowledge we have of the effects of tobacco and nicotine on placental vascularization, in the future it would be worthwhile to evaluate blood vessel development in the gastrointestinal tract of affected infants. Our hope is that this study urges stronger counseling and more aggressive pro-grams to stop smoking in pregnant women and in the antenatal period, be-cause the delicate vascular development of the placenta and the fetus occurs in the

first weeks of gestation.

REFERENCES

1. Henry MC, Moss RL. Necrotizing enteroco-litis.Annu Rev Med. 2009;60:111–124 2. Henry MC, Moss RL. Neonatal necrotizing

enterocolitis.Semin Pediatr Surg. 2008;17 (2):98–109

3. Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enteroco-litis among neonates in the United States.

J Perinatol. 2003;23(4):278–285

4. Carter BM, Holditch-Davis D. Risk factors for necrotizing enterocolitis in preterm infants:

how race, gender, and health status con-tribute.Adv Neonatal Care. 2008;8(5):285–290 5. Hällström M, Koivisto AM, Janas M, Tammela O. Laboratory parameters predictive of de-veloping necrotizing enterocolitis in infants born before 33 weeks of gestation.J Pediatr Surg. 2006;41(4):792–798

6. Sood BG, Lulic-Botica M, Holzhausen KA, et al. The risk of necrotizing enterocolitis

after indomethacin tocolysis. Pediatrics. 2011;128(1). Available at: www.pediatrics. org/cgi/content/full/128/1/e54

7. Jasper VB, Rours IG, Kornelisse RF, Passos VL, et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects

on neonatal outcome in preterm infants.

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Predictors of necrotizing enterocolitis in preterm growth-restricted neonates.

Am J Obstet Gynecol. 2008;198(6):638.e1– e5

9. Luck W, Nau H, Hansen R, Steldinger R. Ex-tent of nicotine and cotinine transfer to the human fetus, placenta and amnioticfluid of smoking mothers.Dev Pharmacol Ther. 1985;8(6):384–395

10. Lim R, Sobey CG. Maternal nicotine expo-sure and fetal programming of vascular oxidative stress in adult offspring. Br J Pharmacol. 2011;164(5):1397–1399 11. Xiao D, Huang X, Yang S, Zhang L.

Ante-natal nicotine induces heightened oxida-tive stress and vascular dysfunction in rat

Concordant in situ and in vitro data show that maternal cigarette smoking negatively regulates placental cytotrophoblast pas-sage through the cell cycle.Reprod Toxicol. 2000;14(6):495–506

13. Zdravkovic T, Genbacev O, McMaster MT, Fisher SJ. The adverse effects of maternal smoking on the human placenta: a review.

Placenta.2005;26(suppl A):S81–S86 14. Campbell S, Black RS, Lees CC, Armstrong

V, Peacock JL. Doppler ultrasound of the maternal uterine arteries: disappearance of abnormal waveforms and relation to birthweight and pregnancy outcome.

Acta Obstet Gynecol Scand. 2000;79(8): 631–634

16. Andersen MR, Simonsen U, Uldbjerg N, Aalkjaer C, Stender S. Smoking cessation early in pregnancy and birth weight, length, head circumference, and endothelial nitric oxide synthase activity in umbilical and chorionic vessels: an observational study of healthy singleton pregnancies.Circulation. 2009;119(6):857–864

17. Toda N, Toda H. Nitric oxide-mediated blood flow regulation as affected by smoking and nicotine.Eur J Pharmacol. 2010;649(1-3):1–13 18. Bardy AH, Seppälä T, Lillsunde P, et al. Ob-jectively measured tobacco exposure during pregnancy: neonatal effects and relation to maternal smoking.Br J Obstet Gynaecol. 1993;100(8):721–726

HOW HIGH?:My wife and I have lived in Vermont for almost 20 years. In that time, we have raised four kids and a host of farm animals, seen a million soccer and lacrosse games, and been to countless dinners and functions. Whether on the

“farm,”at a game, or at work in Montpelier, I think the largest heel I saw on a pair of shoes was about an inch on a pair of muck boots. So, I was pretty surprised when, during a recent trip to Milan, I saw droves of women walking the streets perched on immensely high high-heeled shoes. The windows of the upscale fashion houses and department stores were stuffed with women’s shoes that had heels measuring anywhere from two to six inches. According to an article inThe Wall Street Journal(On Style: April 5, 2012), creating a stable, comfortable high-heeled shoe takes talent and is big business. Last year, women in the U.S. spent more than $20 billion on shoes with heels of at least three inches. High-heeled shoes are popular because they are thought to project sexiness and power. Designing high-heeled shoes is similar to an architectural project. The elements consist of: a toe box into which the toes mustfit comfortably, a platform or area beneath the balls of the feet, a shank for the base of the foot, a heel bed on which the heel rests, andfinally the shoe heel, which needs to be carefully centered beneath the heel of the foot. The heel and shank need to be very rigid and stable, and in expensive shoes are usually made of high-quality steel. Because the height of the heels tends to force the weight forward to the balls of the feet, leading to leg and foot fatigue, designs that distribute the weight under the arch and heel are more comfortable. The maximum heel height that most women can tolerate is approximately four inches. To create shoes that incorporate heels that can be up to six inches high, designers build platforms that may be two inches in height. In this way, the foot still is not bent over a distance greater than four inches. While I am sure that my wife would look great in some tall“Manolos,”she is pretty fast chasing kids and soccer balls. I suspect I won’t be seeing her in anything over an inch anytime soon–and I don’t have to worry much about her breaking an ankle.

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DOI: 10.1542/peds.2011-3808 originally published online June 11, 2012;

2012;130;78

Pediatrics

J. Matheson, Robert W. Bendon, Mary E. Fallat and R. Neal Garrison

Cynthia D. Downard, Stephanie N. Grant, Alexandra C. Maki, Mary C. Krupski, Paul

Maternal Cigarette Smoking and the Development of Necrotizing Enterocolitis

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DOI: 10.1542/peds.2011-3808 originally published online June 11, 2012;

2012;130;78

Pediatrics

http://pediatrics.aappublications.org/content/130/1/78

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Figure

TABLE 1 Demographics of Studied Patients With Associated Statistical Analyses
TABLE 2 Comparison of NEC-Affected and Control Patients, Maternal and Fetal Factors

References

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