Association of H2-Blocker Therapy and Higher Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants

METHODS

RESULTS

Of 11936 infants born between September 1, 1998, and December 31, 2001, 11072 survived for at least 12 hours. Complete data including presence or absence of NEC, birth weight, center, race, gender, whether they were outborn or inborn, use of postnatal steroids, and 5-minute Apgar score were available for 10903 infants. The overall incidence of NEC was 7.1% (787 of 11072), with approximately half of the infants undergoing surgery. When stratified by birth weight the incidence was 11.4% in infants 401 to 750 g (5.0% receiving no surgery, 6.4% receiving surgery), 9.0% in infants 751 to 1000 g (4.5% receiving no surgery, 4.5% receiving surgery), 6.0% in infants 1001 to 1250 g (3.2% receiving no surgery, 2.8% receiving surgery), and 3.8% in infants 1251 to 1500 g (2.1% receiving no surgery, 1.7% receiving surgery). Several neonatal variables were associated with increased risk for NEC (Tables 1 and 2). Infants with proven NEC were more likely to be black (P < .0001), of lower birth weight (P < .0001), and outborn (P < .0001). In addition, both the incidence of NEC and frequency with which infants were treated with H2 blockers at any time during their hospitalization varied by clinical center (NEC: 4.26–11.25%, P < .0001; H2-blocker use: 6.5–72.2%, P < .0001). The Pearson correlation between H2-blocker use and NEC at each center is 0.33, which is not statistically significant (P = .165).

To determine if there was an association between the incidence of NEC and treatment with H2 blockers, a case-control analysis was done as described above. There were 787 NEC cases. Of the planned 2361 matched controls (3 per case), 2357 controls were matched successfully. In 1 center, only 21 of 24 controls could be matched because of unavailability of black control infants; in another center, only 5 of 6 controls could be matched because of unavailability of nonblack control infants. Thus, 3144 observations were used in a conditional logistic regression.

As described in “Methods,” H2-blocker use the day before diagnosis of NEC or later was not included as H2-blocker exposure. H2 blockers were started a mean of 18.9 ± 15.5 days before NEC (median: 14; range: 2–76 days).

The results of the conditional logistic regression with H2-blocker use truncated by postmenstrual age and those truncated by chronologic age were similar (Tables 3 and 4). H2-blocker use was associated with an increased incidence of NEC (odds ratio [OR]: 1.71; 95% confidence interval [CI]: 1.34–2.19; P < .0001, when data collection was truncated by postmenstrual age; OR: 1.49; 95% CI: 1.18–1.89; P = .0010, when data collection was truncated by chronologic age). In this analysis in which controls were matched for birth-weight category, race, and center, of the additional factors tested, only outborn versus inborn was significantly associated with the incidence of NEC.

DISCUSSION

In a large cohort of >11000 VLBW infants, treatment with H2 blockers was associated with a higher incidence of NEC, which is consistent with the results of a small randomized trial of acidification of feeds⁶ that showed that a lower gastric pH level was associated with a decreased incidence of NEC.

Previous studies of premature infants cared for in the NICHD Neonatal Research Network centers have suggested that there are many identifiable risk factors for NEC in the VLBW population. Uauy et al⁸ found (as did we in the current study) that the most significant factor in determining NEC prevalence was the center in which the infant was cared for. Our analysis, however, was limited by our inability to completely quantify illness severity at the time of birth or transfer to the tertiary center. Some referral hospitals may have chosen to transfer only the most vigorous infants to tertiary centers, whereas others would transfer only the sickest infants. It is also possible that some infants who were outborn were transferred to the network center because they had NEC in a NICU with no surgeon and arrived with both the diagnosis of NEC and use of H2 blockers. This may have contributed to the center differences in outcome. Uauy et al⁸ also reported an increased incidence of NEC associated with prolonged rupture of membranes, maternal age of <25 years, birth weight of <1000 g, Apgar score at 5 minutes of <7, and maternal hemorrhage. Decreased incidence of NEC was associated with maternal prenatal care, high maternal blood pressure, and delivery by cesarean section. Additional analyses suggested that early fluid and feeding regimens, which varied from center to center, may relate to NEC prevalence. Those centers with more aggressive fluid and feeding regimens tended to have a higher prevalence of NEC. The use of either prenatal or postnatal steroids was not examined, nor was the use of H2 blockers. In our study, although there was a significant difference in both the incidence of NEC and the frequency with which H2 blockers were prescribed among centers, the correlation between the 2 was not statistically significant.

Stoll et al⁹ examined the relationship between postnatal steroid exposure (beginning at 2 weeks of age) and late-onset sepsis in VLBW infants cared for in NICHD Neonatal Research Network centers and entered into a randomized, controlled trial that compared early and late exposure to dexamethasone. Although not the original hypothesis, they observed that treatment with dexamethasone and with H2 blockers was associated with an increased risk of bacteremia/sepsis and meningitis. The increased risk of infection in infants treated with H2 blockers before randomization to the study drug (steroid or placebo) was postulated to be the result of a change in small-bowel colonization after the development of hypochlorhydria. Similarly, in a prospective observational study, Beck-Sague et al¹⁰ reported that 12 (36%) of 33 VLBW neonates who received H2 blockers developed bloodstream infections, whereas only 30 (9%) of 343 of those not treated with H2 blockers developed bacteremia. In logistic-regression analysis, the risk of a bloodstream infection was independently associated with lower birth weight, respiratory illness at the time of admission, and receipt of H2 blockers. They postulated that gastric acidity may be a protective mechanism against respiratory and gastrointestinal tract colonization with nosocomial pathogens and subsequent bacteremia. The incidence of NEC was not examined separately in either study.

In a study of 34 infants who were <37 weeks' gestation with a mean birth weight of 1500 g, Hyman et al¹¹ reported that hypochlorhydria (pH > 4) was present in 19% of their study population at 1 week of age, 16% at 2 weeks of age, and 8% at 3 weeks of age. No infant had a basal gastric pH level of >4 after 6 weeks of age. In addition, stimulated acid output increased both as a function of postnatal and postmenstrual age (P < .01). Similarly, Kelly et al¹² showed that in 22 infants who were <30 weeks' gestation there was a trend for increasing gastric acidity with increasing postnatal age. However, even the infants who were born at 24 to 25 weeks' gestation had recorded gastric pH levels of 3 to 4 during the first 3 days after birth, and the pH level declined to <2 by day 16. In the infants who were 26 to 29 weeks' gestation, gastric pH levels were <3 throughout the testing period from days 1 to 17. These findings were in contrast with those of Carrion and Egan,⁶ who reported that in infants of <1250 g birth weight, the median gastric pH level was 4.0 for the first 4 weeks after birth. They were able to decrease the median pH level to 3.0 with the addition of 1 N HCl to the study infants' feeds. Higher gastric enteric bacterial colony counts were strongly correlated with gastric pH level of >4 (P < .001). In the Carrion and Egan study, there was a concomitant decrease in the reported incidence of NEC over the study period in those infants whose formula or maternal breast milk had been acidified (1 of 34 in infants receiving acidified feeds vs 8 of 34 in controls; P = .02).

In light of the findings of Carrion and Egan,⁶ we postulated that maintenance of a relatively less acidic gastric milieu would be associated with an increased incidence of NEC, possibly through bacterial overgrowth. There was no clear evidence of benefit of the use of H2 blockers; in fact, H2-blocker therapy seemed to be a significant risk factor for the development of NEC. This result is consistent with the literature on adult intensive-care patients in whom use of H2 blockers has been associated with an increase in the incidence of pneumonia.¹³ However, we cannot dismiss the possibility that the use of H2 blockers may be a marker for clinical signs of fragility, inflammation, or other problems that are harbingers for NEC. In this retrospective study, without information on the indication for H2 therapy use, the use of such therapy may be an indication of the level of illness among the study cohort rather than a cause of disease.

NEC is a complex disease with multiple predisposing factors. Although focusing on one factor at a time may contribute to our understanding of the etiology of this disease, it is unlikely that a single intervention will markedly change its overall incidence. Between-center differences far outweigh any of the biological factors examined in this and other studies. However, it seems prudent to not use prophylactic H2-blocker therapy in VLBW infants without additional data from a randomized, controlled trial. Additional basic science research and a more global approach to modifying the care of extremely low birth weight infants, perhaps by using “benchmarking” techniques, may be alternatives to a randomized, controlled trial in gaining a greater understanding of gastrointestinal development and iatrogenic or environmental factors contributing to the risk of NEC.¹⁴

NICHD NEONATAL RESEARCH NETWORK MEMBERS

The following are the members of the NICHD Neonatal Research Network (NICHD grant numbers are listed in parentheses): Alan Jobe, MD (University of Cincinnati), Chairman; Case Western Reserve University (U10 HD21364): Avroy A. Fanaroff, MB, BCh (principal investigator), Michele Walsh, MD, and Nancy Newman, RN; University of Cincinnati (U10 HD27853): Edward F. Donovan, MD (principal investigator), Vivek Narendran, MD, MRCP, and Marcia Mersmann, RN; Emory University (U10 HD27851): Barbara J. Stoll, MD (principal investigator), and Ellen Hale, RN; Indiana University (U10 HD27856): James A. Lemons, MD (principal investigator), Brenda Poindexter, MD, and Diana Appel, RN; University of Miami (U10 HD21397): Charles R. Bauer, MD (principal investigator), Shahnaz Duara, MD, and Ruth Everett, RN; University of New Mexico (U10 HD27881): Lu-Ann Papile, MD (principal investigator), and Conra Backstrom, RN; Stanford University (U10 HD27880): David K. Stevenson, MD (principal investigator), Krisa Van Meurs, MD, and Bethany Ball, BS; University of Tennessee at Memphis (U10 HD21415): Sheldon B. Korones, MD (principal investigator), Henrietta Bada, MD, and Tina Hudson, RN; University of Texas Southwestern Medical Center (U10 HD40689): Abbot R. Laptook, MD (principal investigator), Walid Salhab, MD, and Gay Hensley, RN; University of Texas at Houston (U10 HD21373): Jon E. Tyson, MD, MPH (principal investigator), Kathleen Kennedy, MD, MPH, and Susie Madison, RN; Wayne State University (U10 HD21385): Seetha Shankaran, MD (principal investigator), Ganesh Konduri, MD, and Geraldine Muran, RN; Women and Infants Hospital (U10 HD27904): William Oh, MD (principal investigator), Barbara Stonestreet, MD, and Angelita Hensman, RN; Yale University (U10 HD27871): Richard A. Ehrenkranz, MD (principal investigator), and Patricia Gettner, RN; University of Alabama at Birmingham (U10 HD34216): Waldemar A. Carlo, MD (principal investigator), Namasivayam Ambalavanan, MD, and Monica V. Collins, RN; Harvard University (U10 HD34167): Ann R. Stark, MD (principal investigator), and Kerri Fournier, RN; Duke University (U10 HD40492): Ronald N. Goldberg, MD (principal investigator), Michael Cotten, MD, and Kathy Auten, RN; Wake Forest University (U10 HD40498): T. Michael O'Shea, MD (principal investigator), Robert Dillard, MD, and Nancy Peters, RN; University of Rochester (U10 HD40521): Dale L. Phelps, MD, Ronnie Guillet, MD, PhD, and Linda Reubens, RN; University of California at San Diego (U10 HD40461): Neil N. Finer, MD (principal investigator), Maynard Rassmussen, MD, and Wade Rich, BS, RRT, Research Triangle Institute (U01 HD36790): W. Kenneth Poole, PhD (principal investigator), Abhik Das, PhD, Betty Hastings, and Carolyn M. Petrie, MS; and NICHD: Linda L. Wright, MD, Rosemary Higgins, MD, and James Hansen, MD.