Is maternal alcohol use a risk factor for early-onset sepsis in premature newborns?

Alcohol 33 (2004) 139–145

Is maternal alcohol use a risk factor for early-onset sepsis in premature newborns? Theresa W. Gauthier*, Martha H. Manar, Lou Ann S. Brown Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, USA Received 11 February 2004; received in revised form 20 May 2004; accepted 12 June 2004

Abstract Because chronic alcohol abuse alters immune defenses and increases infection in adults, we tested the hypothesis that maternal alcohol use during pregnancy would increase the risk of sepsis in very low birth weight (VLBW) premature newborns. We performed a casecontrolled analysis of VLBW newborns born at Grady Memorial Hospital (Atlanta, GA). Alcohol exposure, as the predictive variable, was assessed by maternal self-report. The outcome variables were early-onset and multiple late-onset sepsis. Univariate analysis with Fisher exact test and multivariate analysis with the use of binary logistic regression were performed. Early-onset sepsis was 15-fold higher in the alcohol-exposed group (n ⫽ 20) compared with findings for the matched control group (n ⫽ 168) [alcohol-exposed group, 10%, vs. control group, 0.6%: odds ratio (OR) 6.8 (95% confidence interval [CI], 2.7-17.1), P ⱕ .05]. Early-onset sepsis in the alcohol ⫹ cocaine– exposed group (n ⫽ 64) did not differ from findings for the control group. The prevalence of multiple late-onset sepsis did not differ among the exposure groups. Logistic regression analysis, controlling for chorioamnionitis and premature prolonged rupture of membranes, demonstrated an independent, increased risk of early-onset sepsis with alcohol exposure [OR 16 (95% CI, 1.2-210), P ⱕ .05]. We conclude that alcohol exposure significantly increased the risk of early-onset sepsis in this group of VLBW newborns. The effects of maternal alcohol abuse during pregnancy on the risk of infection in the VLBW newborn require further analysis. 쑖 2004 Elsevier Inc. All rights reserved. Keywords: Very low birth weight newborn; Infection; Fetal alcohol

1. Introduction The chronic use of alcohol has been well described to increase infections in the adult population (Baker & Jerrells, 1993). Alcohol alters the body’s immune defenses, increasing the risk of infection and also increasing the severity of infectious complications in the critically ill adult (Baughman & Roselle, 1987). Premature newborns are also at increased risk for infection. Because the developing immune system is immature, the risk of infection in the premature population is inversely related to gestational age (Lemons et al., 2001; Stoll et al., 1998), and, therefore, the most extremely immature newborns are at the highest risk. Although the survival of premature newborns continues to improve, sepsis disproportionately accounts for ∼50% of all deaths despite modern neonatal intensive care (Lemons

* Corresponding author. Tel.: ⫹1-404-727-1471; fax: ⫹1-404-727-7233. E-mail address: [email protected] (T.W. Gauthier). Editor: T.R. Jerrells 0741-8329/04/$ – see front matter 쑖 2004 Elsevier Inc. All rights reserved. doi: 10.1016/j.alcohol.2004.06.003

et al., 2001; Stoll et al., 1998). In addition, infectious complications in the neonatal intensive care unit can worsen respiratory status and prolong hospital stay in extremely preterm infants (Stoll et al., 2002). Indeed, infections or exposure to inflammatory cytokines has been implicated in the subsequent development of bronchopulmonary dysplasia (Jobe & Ikegami, 2001; Speer, 2001) and periventricular leukomalacia (Debillon et al., 2000; O’Shea, 2002; Willoughby & Nelson, 2002). Despite the apparent well-known hazards of drinking alcohol during pregnancy, fetal alcohol exposure remains a significant problem in the United States. Alcohol abuse or binge drinking by pregnant women remains a risk for the developing newborn (Ebrahim et al., 1999; Lester et al., 2001). Unfortunately, alcohol exposure in utero remains one of the leading causes of preventable mental retardation and developmental delay (American Academy of Pediatrics, Committee on Substance Abuse and Committee on Children With Disabilities, 2000). As demonstrated in a recent lifestyle study across four states in hospitals with diverse

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socioeconomic status (Lester et al., 2001), ∼35% of newborns were exposed to alcohol and ∼10% were exposed to cocaine. Those exposed to cocaine were six times more likely also to be exposed to alcohol. Maternal alcohol use during pregnancy frequently coincides with the abuse of other substances, especially cocaine (Singer et al., 1994). This indicates that a significant percentage of the population of premature newborns admitted to the newborn intensive care unit is exposed to alcohol in utero. However, the ability to identify those newborns exposed to alcohol in utero remains difficult even at term gestation (Astley et al., 2000; Little et al., 1990; Stoler & Holmes, 1999). Fetal alcohol syndrome (FAS) is estimated in ∼1 per 1,000 pregnancies (Sampson et al., 1997), but it is often diagnosed later in childhood. Most children exposed to alcohol in utero do not have FAS stigmata but, rather, are diagnosed with alcoholrelated neurodevelopmental disorder (ARND) later in childhood, with an estimated incidence of ARND as high as 9 per 1,000 babies (Koren et al., 2003). Proper identification of fetal alcohol exposure in a premature newborn has not been addressed. We postulate that a significant percentage of premature newborns routinely cared for in the neonatal intensive care setting have been exposed to alcohol in utero, and this exposure remains difficult to detect by the medical caregiver because of the lack of physical stigmata. The effects of fetal alcohol exposure in utero on the risk of sepsis in the premature newborn have not been addressed. Because prolonged alcohol exposure increases the risk of sepsis in adults, we hypothesized that maternal alcohol use during pregnancy would increase the risk of sepsis in the premature newborn. The purpose of the current study was to evaluate the effects of maternal alcohol use on the risk of early-onset and late-onset sepsis in the very low birth weight (VLBW) newborn born at ⬍1,500 g. 2. Materials and methods 2.1. Identification of alcohol use Very low birth weight infants (range in birth weight, 501 to 500 g), born at Grady Memorial Hospital (Atlanta, GA) between 1996 and 2002, were identified as exposed to maternal substance use (alcohol with/without cocaine) by using the Project Prevent database. Project Prevent is a funded organization that identifies and assists drug-abusing mothers in Atlanta, Georgia (Donna P. Carson, coordinator). We defined alcohol or drug use during pregnancy as a positive selfreport of any alcohol intake or drug use by the mother during her pregnancy as documented during a detailed confidential interview with a Project Prevent addiction counselor. Documentation of maternal use of cocaine was confirmed by positive findings on urine drug screen [Enzyme Multiple Immunoassay Test (EMIT)] in the mother or the newborn (or both) at delivery. Each identified alcohol-exposed newborn was assigned an identification number and was matched with two control newborns without alcohol or drug exposure born

within 2 months of the alcohol-exposed newborn at Grady Memorial Hospital. Control newborns were matched for race, sex, and birth weight (⫾200 g). Information regarding socioeconomic status was not available and therefore was not used in the matching of control newborns. The medical information was reviewed for maternal and infant demographics, maternal history, and neonatal hospital course by using routine data sheets compiled as part of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network at Emory University (Barbara Stoll, MD, Emory University). This investigation was approved with informed consent waived by the Emory University Institutional Review Board. The procedures followed were in accordance with the ethical standards of the Emory University Institutional Review Board and with the Helsinki Declaration of 1975, as revised in 1983. 2.2. Outcome analysis Neonatal outcomes included early-onset sepsis and multiple late-onset sepsis. Early-onset sepsis in the newborn was defined as a blood culture positive for microorganisms within the first 72 h of life, whereas multiple late-onset sepsis was defined as two or more blood cultures positive for microorganisms in the neonate after 7 days of life. Premature prolonged rupture of membranes (PPROM) was defined as rupture of the membranes ⬎12 h before delivery. Chorioamnionitis was an obstetrical clinical diagnosis as noted in the maternal database by using clinical criteria, such as maternal fever, elevated white blood cell count, and uterine tenderness. 2.3. Statistical analyses SPSS for Windows was used for statistical calculations. Univariate analysis was performed by using Fisher exact test for 2 × 2 tables with odds ratio (OR) and confidence intervals (CI) calculated. Binary logistic regression was used for multivariate analysis. A P value of ⱕ.05 was considered statistically significant. 3. Results 3.1. Patient demographics Eighty-four newborns (birth weight of each, ⬍1,500 g) were identified as alcohol-exposed by Project Prevent interviews. These patients were matched with 168 control newborns without drug or alcohol exposure. Within the alcohol-exposed newborns, 20 were exposed to alcohol without cocaine (defined as the alcohol-exposed group) and 64 patients were exposed to alcohol and cocaine (defined as the alcohol ⫹ cocaine–exposed group). In the control group, 4% of the mothers smoked cigarettes during the pregnancy. However, tobacco use was significantly higher in either the alcohol-exposed group (35%) or the alcohol ⫹ cocaine–exposed group (50%) compared with findings for the control

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Table 1 Clinical information obtained for sample of very low birth weight newborns Group (exposure to maternal substance use) Patient characteristics African-American (%) Male (%) Gestational age (weeks ⫾ S.D.) Birth weight (g ⫾ S.D.) Hyaline membrane disease (%) Apgar score Median (range) at 1 min Median (range) at 5 min Tobacco exposure (%) Marijuana exposure (%)

Control (n ⫽ 168)

Alcohol-exposed (n ⫽ 20)

Alcohol ⫹ cocaine–exposed (n ⫽ 64)

96.4 53.6 27.4 ⫾ 2.0 960 ⫾ 207 95.2

100 65.0 27.4 ⫾ 2.5 931 ⫾ 182 90.0

95.3 50.0 27.2 ⫾ 2.5 956 ⫾ 200 96.9

5 (0–9) 8 (1–9) 4 1

3 (1–8) 7 (1–9) 35* 20*

5 (0–9) 8 (1–9) 50* 7.8*

*P ⱕ .05 versus respective characteristics for control group. S.D. ⫽ Standard deviation.

group (P ⱕ .05). In addition, marijuana use was significantly higher in the alcohol-exposed group (20%) and the alcohol ⫹ cocaine–exposed group (7.8%) compared with findings for the control group (1%) (P ⱕ .05) (Table 1). Most newborns in all groups were of African-American race, reflective of the patient population. There were no differences in race or sex among the three exposure groups. As defined by matching study design, newborns in all groups had an individual birth weight of approximately 950 g and were each approximately 27 weeks of gestation (Table 1). Most of the babies were diagnosed with hyaline membrane disease requiring surfactant therapy, and there were no differences in the Apgar scores at 1 and 5 min (Table 1). 3.2. Maternal characteristics In terms of age and prenatal care, mothers who consumed alcohol were similar to mothers of newborn controls and to mothers of newborns in the alcohol ⫹ cocaine–exposed group. There was no statistical difference in the percentage of women with PPROM among the groups, although the prevalence of PPROM tended to be higher in mothers of newborns in the alcohol-exposed group (alcohol-exposed group, 50%, vs. control group, 30.8%). Similarly, the apparent increase in chorioamnionitis in the mothers of newborns in the alcohol-exposed group (alcohol-exposed group, 20%, vs. control group, 12.5%) did not reach significance (P ⫽ nonsignificant). There was no difference in the antenatal use of steroids in mothers of newborns in the alcoholexposed group compared with findings for either mothers of newborns in the control group or mothers of newborns in the alcohol ⫹ cocaine–exposed group. However, mothers who reported use of both alcohol and cocaine during pregnancy were older (P ⱕ .05), received less prenatal care (alcohol ⫹ cocaine–exposed group, 62.5%, vs. control group, 90.5%; P ⱕ .05), and received less steroids antenatally compared with findings for mothers of newborns in the control group (alcohol ⫹ cocaine–exposed group, 51.6%, vs. control group, 78%; P ⱕ .05). There were no differences

in the use of antibiotics during labor among the groups (Table 2). Two maternal deaths were documented in the medical record, both for mothers of newborns in the alcohol ⫹ cocaine use group. One woman was diagnosed with lupus and hepatitis B, and the second death was due to unknown causes. 3.3. Neonatal outcomes 3.3.1. Univariate analysis Early-onset sepsis was present in 1.9% of the total study population, with blood cultures being positive for group B Streptococcus, Escherichia coli, and Haemophilus influenzae (Table 3). Very low birth weight babies in the alcoholexposed group had a significant increase in early-onset sepsis compared with findings for babies in the control group [alcohol-exposed group, 10%, vs. control group, 0.6%: OR 18.5 (CI, 1.6-215), P ⱕ .05]. There was no statistical difference in early-onset sepsis in the alcohol ⫹ cocaine–exposed group compared with findings for either the alcohol-exposed group or the control group (P ⫽ nonsignificant). There were nine deaths in the neonatal patient population (3.5%). Of the five deaths in the control group, two patients died of necrotizing enterocolitis, both on day of life no. 11. One patient died due to overwhelming sepsis with anasarca despite negative blood culture results on day no. 29, one died due to deterioration with chronic lung disease on day no. 144, and one expired due to severe (grade IV) intraventricular hemorrhage on day no. 7. Both deaths in the alcohol-exposed group were due to overwhelming sepsis as described in the medical record. The first patient died on day no. 13 with blood cultures being positive for Pseudomonas aeruginosa, and the second patient died on day no. 2 with overwhelming hypotension, and clinical sepsis despite negative blood culture results. In the alcohol ⫹ cocaine–exposed group, one death was due to necrotizing enterocolitis totalis on day no. 20, with blood cultures being positive for E. coli and Enterobacter fecalis, and the second patient death occurred on day no. 151 after withdrawal of ventilatory support due to severe cor pulmonale and chronic lung disease. Death was

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Table 2 Maternal characteristics obtained at the time of delivery Group (exposure to maternal substance use) Maternal characteristics

Control

Alcohol-exposed

Alcohol ⫹ cocaine–exposed

Age (yr) Median Range Prenatal care (%) Antibiotic therapy (%) Steroid therapy (%) Premature prolonged rupture of membranes (%) Chorioamnionitis (%)

22 13–44 90.5 68.5 78.0 30.8 12.5

26 13–40 85.0 75.0 60.0 50.0 20.0

30 13–44* 62.5* 53.1 51.6* 37.7 10.9

*P ⬍ .01 versus respective characteristics for control group.

3.3-fold higher in the alcohol-exposed group compared with findings for the control group, but was not statistically significant with this sample size (alcohol-exposed group, 10%, vs. control group, 3%; P ⫽ nonsignificant). When early-onset sepsis and death were combined, there was a fourfold higher prevalence in the alcohol-exposed group compared with findings for the control group (alcoholexposed group, 15%, vs. control group, 3.6%), and it approached, but did not reach, statistical significance (P ⫽ .057). There were no statistical differences between earlyonset sepsis or death in the alcohol ⫹ cocaine–exposed group compared with findings for the alcohol-exposed group (alcohol-exposed group, 15%, vs. alcohol ⫹ cocaine–exposed group, 4.7%; P ⫽ nonsignificant) or compared with findings for the control group (alcohol ⫹ cocaine–exposed group, 4.7%, vs. control group, 3.6%; P ⫽ nonsignificant). There were no significant differences in the rate of multiple late-onset sepsis among the groups (Table 3). There were no differences in the rate of chronic lung disease (P ⫽ nonsignificant) or necrotizing enterocolitis (P ⫽ nonsignificant) among the groups. Maternal smoking was not significantly related to the development of either early-onset or multiple late-onset sepsis. However, the presence of maternal chorioamnionitis was significantly related to early-onset sepsis in the newborn (P ⬍ .01).

3.3.2. Multivariate analysis Multivariate analysis was performed by using a logistic regression model to determine the independent effect of alcohol on the outcome variable of early-onset sepsis in our study population. Because chorioamnionitis and PPROM demonstrated a very low, but significant, correlation with each other (Pearson correlation coefficient 0.163, P ⬍ .01), both variates were included in the model as independent variables. As expected, the presence of chorioamnionitis significantly increased the risk of early-onset sepsis [OR ∼15 (CI, 1.1-207), P ⱕ .05]. However, the maternal report of alcohol intake independently increased the risk of earlyonset sepsis [OR 16 (CI, 1.2-210), P ⱕ .05] (Table 4).

4. Discussion Although the effects of alcohol on the immune system and the risk of infection are well described in the adult population, the clinical effects of fetal alcohol exposure on the premature newborn’s risk of sepsis have not been investigated fully. Findings from the current study demonstrated that maternal alcohol use during pregnancy was a significant independent risk factor for early-onset sepsis in the VLBW newborn. We speculate that the mechanisms of increased early-onset sepsis in the VLBW newborn are

Table 3 Univariate analysis of outcomes of very low birth weight newborns Group (exposure to maternal substance use) Outcome Early-onset sepsis (%) (n) Multiple late-onset sepsis (%) (n) Death (%) (n) Early-onset sepsis/death (%) (n)

Control

Alcohol-exposed

Alcohol ⫹ cocaine–exposed

0.6 1/168

10.0* 2/20

3.1 2/64

12 20/166

5.3 1/19

17 11/64

3.0 5/168

10.0 2/20

3.1 2/64

3.6 6/168

15.0 3/20

4.7 3/64

*P ⱕ .05 versus respective outcomes for control group.

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Table 4 Multivariate analysis: chorioamnionitis, premature prolonged rupture of membranes, and alcohol exposure as independent risks of early-onset sepsis Dependent variable – early-onset sepsis Independent variable

Odds ratio

95% Confidence interval

P value

Chorioamnionitis Premature prolonged rupture of membranes Alcohol exposure

14.98 0.4 16.0

1.1-207 .03-6.3 1.2-210

.043 .53 .035

due to decreased maternal as well as neonatal immune functioning. Chronic alcohol exposure has been well recognized to inhibit the immune function of the adult who abuses alcohol (Baker & Jerrells, 1993; Jerrells & Weinberg, 1998). Alcohol impairs the function of inflammatory cells, such as macrophages (Bermudez et al., 1991; Bermudez & Young, 1991; Omidvari et al., 1998) and monocytes (Szabo et al., 2001), thereby increasing the risk of infection. Furthermore, findings obtained with experimental adult animal models demonstrate that ethanol diminishes cytokine responses to endotoxin stimulation (Kolls et al., 1995; Nelson et al., 1989). Lymphocyte proliferation and antibody production are also impaired with ethanol exposure (Jerrells et al., 1990), contributing to an increased susceptibility to infection (Jerrells et al., 1994). Because, in comparison with the male, the female is at a higher risk of alcohol-mediated complications (Kono et al., 2000; Naveau et al., 1997), we postulate that the detrimental effects of alcohol exposure on adult immunity also occur in the gravid female and have an adverse impact on the premature newborn. The effects of in utero alcohol exposure on the development of immune function remain under investigation. Findings obtained from experimental animal models of in utero ethanol exposure demonstrate impaired maturation of the fetal immune system. In particular, B-cell development (Biber et al., 1998; Robinson & Seelig, 2002) and T-cell development (Robinson & Seelig, 2002) are disrupted within the fetal liver during in utero ethanol exposure. Postnatally, experimental animals exposed to ethanol in utero demonstrate diminished proliferation of T cells, with increased death within the first year of life in a primate model owing to infection or failure to thrive (Grossmann et al., 1993). Thymic development and the functioning of T and B cells are also impaired in animal models of in utero ethanol exposure (Wolcott et al., 1995). Findings obtained with these animal models support the hypothesis that alcohol exposure in utero would increase the risk of infection in the newborn offspring. Nevertheless, the clinical ramifications of these experimental animal studies remain under investigation. Study findings addressing the risk of infection of premature newborns exposed to alcohol in utero are limited. Ahluwalia et al. (2000) have shown that chronic, heavy alcohol exposure in human beings increases the baseline synthesis of inflammatory cytokines in both the maternal and the fetal circulation, whereas fetal human lymphocytes exposed to

ethanol in vitro demonstrate an impaired release of cytokines when stimulated. The clinical ramifications of these in vivo and in vitro investigations are unclear. In cord blood, newborns exposed to alcohol in utero have reduced white blood cell counts, supporting a mechanism for the possible increased risk for infection in the neonatal period (Johnson et al., 1981). Results from the current study provide additional evidence that fetal alcohol exposure increased the risk of early-onset sepsis in the premature newborn. For the current study, we are uncertain why early-onset sepsis, although not statistically different, tended to be lower in the alcohol ⫹ cocaine–exposed group compared with findings for the alcohol-exposed group. We postulated that exposure to the combination of alcohol and cocaine would also increase the risk of early-onset sepsis in the premature newborn because the combination of these two substances would be more teratogenic to the developing fetus than would either substance alone (Pirozhkov et al., 1993). In addition, because cocaine impairs the immune response of human beings, we anticipated that this combination in the alcohol ⫹ cocaine–exposed group would have a negative impact on both maternal and neonatal immunity. However, results of the current study did not support this projection. Further, we did not demonstrate any differences between alcoholexposed and alcohol ⫹ cocaine–exposed groups in terms of antenatal use of antibiotics, chorioamnionitis, maternal use of steroids, PPROM, smoking, or maternal age. Cocaine diminishes human adult antimicrobial activity (Baldwin et al., 1997; Shay et al., 2003), lymphocyte production (Berkeley et al., 1994; Delafuente & DeVane, 1991), and cytokine production (Halpern et al., 2003; Mao et al., 1996, 1997) in response to stimuli. Pregnant cocaine abusers undergoing withdrawal have decreased cell surface markers required for phagocytosis and antigen processing, further supporting a role for cocaine impairing immunity (Johnson et al., 1996). In cocaine-exposed newborns, monocytes obtained from cord blood have diminished cytokine production (Karlix et al., 1998), suggestive of impaired immune defenses in the neonatal period. Cocaine has also been implicated to increase the risk of PPROM (Addis et al., 2001) and preterm delivery (Kliegman et al., 1994), factors that increase the risk of infection for the newborn. Therefore, one would predict that exposure to the combination of alcohol and cocaine would also increase the risk of early-onset sepsis in the premature newborn. However, the exact amount of consumption as well as the timing of alcohol and cocaine exposure throughout pregnancy were not known in

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the current study, and these factors may have contributed significantly to our findings. Additional clinical investigations are warranted. Although maternal smoking has been described as a risk factor for neonatal infection (Tuthill et al., 1999), we did not find a correlation between maternal smoking and sepsis in our study population. It is interesting that our findings agree with those of previous studies, in which smoking is described as a marker for additional illicit drug use during pregnancy, including alcohol and cocaine (Archie et al., 1997). The current case-controlled study of 252 subjects has limitations, in addition to those described for all case-controlled studies. Formal maternal interviewing, as done in the current study with extensive Project Prevent interviews, remains the mainstay for identification of alcohol use during pregnancy and has been reported as a reliable method for accurate assessment of maternal drinking during pregnancy (Bradley et al., 1998). However, the exact amount of alcohol consumed as well as the timing of consumption were not recorded and therefore were not available for the current study. Promising new technology to identify biomarkers of alcohol exposure (Bearer et al., 1999; Stoler et al., 1998) is, unfortunately, not routinely available for clinical use. Therefore, we relied on maternal self-reporting of alcohol use. We used a clinical diagnosis of maternal chorioamnionitis, and no histologic studies were performed for confirmation. We were unable to control for maternal nutrition, which has an impact on both maternal and fetal immunity (Chandra, 1991). The current study is further limited by the low sample size of our review. Our observations should be interpreted with caution, but support the suggestion that further investigations with a larger sample size are warranted. Our study findings show that maternal alcohol use increased the risk of early-onset sepsis in the vulnerable VLBW population studied. Findings obtained from the current study justify the need to identify mothers who are drinking alcohol during pregnancy. When routine prenatal care incorporates the treatment of maternal substance abuse, the outcomes of newborns are improved (Armstrong et al., 2003). A heightened clinical suspicion and identification of alcohol exposure in the premature population are warranted. By understanding the mechanisms of the detrimental effects of alcohol on the premature newborn, outcomes of our tiniest patients will improve.

Acknowledgments This study was funded in part by the Emory Medical Care Foundation Faculty Scholar Award, the NIH R03 HD39651, and R01 AA013979 (T.W.G.). We thank Dr. Augusto Sola for his guidance and assistance with the manuscript. We also thank Donna Carson (principal investigator, Project Prevent), Dr. Barbara Stoll, and the NICHD neonatal research nurses for their assistance in data collection.

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