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Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants.
To determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality.
Secondary analysis of data from a multi-site randomized placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intent-to-treat (ITT) analysis, infants born to women randomized to antibiotics or placebo were compared. Additionally, non-ITT analysis was performed because some women received non-study antibiotics for various clinical indications.
Overall, 2659 pregnant women were randomized. Of these, 2466 HIV-1-infected and -uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs. 8.6%, p=0.03) and more admissions to the Special Care Baby Unit (12.6% vs. 9.8%, p = 0.04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Further analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received non-study antibiotics than of mothers who received study antibiotics.
There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive non-study antibiotics.
Perinatal mortality and morbidity are significant global health problems. The major causes of perinatal deaths include preterm birth, neonatal infection and asphyxia1, 2. However, the roles of other factors that may predispose neonates to these direct causes of mortality are less well understood. Pregnant women may receive antibiotics during the antepartum period or during labor for various reasons, including treatment of syphilis and bacterial vaginosis (BV) or the prevention of preterm labor and adverse outcomes associated with pre-labor rupture of membranes (PROM). Such treatment with antibiotics may benefit the neonate either by eliminating maternal infection or by treating intrauterine fetal infection if the antibiotic crosses the placenta. In such cases, there is a clear benefit to the baby. However, it is also known that intrapartum antibiotic use may be associated with adverse effects in late neonatal life, including increased frequency of neonatal infection and necrotizing enterocolitis3 or delayed clinical or microbiological diagnosis of neonatal infections and development of antibiotic resistance4–6. These reports do not differentiate early from late onset neonatal morbidity and mortality that may result from intrapartum antibiotic exposure. There is also a possibility that transplacental transfer of antibiotics used for maternal indications may result in sub-therapeutic levels in the neonate and contribute to early neonatal morbidity. This may in turn increase the number of neonates admitted to and who die in a special care baby unit, due to early neonatal disease.
We therefore analyzed data from a randomized clinical trial of antibiotics to reduce chorioamnionitis-related mother-to-child transmission (MTCT) of HIV and preterm birth7. In this trial, mothers received antibiotics (erythromycin and metronidazole) antepartum starting at 20–24 weeks gestation and intrapartum (ampicillin and metronidazole) starting at onset of labor. The antibiotics were chosen to ensure broad coverage against microorganisms associated with BV, trichomoniasis and chorioamnionitis. The rates of BV and trichomoniasis8 were reduced in the antibiotic group compared to the placebo group. However, the rates of chorioamnionitis were not different following treatment with these antibiotics8. This may be because the antibiotics were administered late after the subclinical (histological) chorioamnionitis was already established. In a planned secondary analysis, we hypothesized that infants born to women who received intrapartum antibiotics would have higher rates of infectious morbidity and mortality than would infants born to women who did not receive intrapartum antibiotics. The main objective of this analysis was to evaluate the association between intrapartum exposure to antibiotics and early neonatal health.
HPTN 024 was a randomized, double blind, placebo-controlled, phase III study of antibiotics to reduce MTCT of HIV. This trial has been previously described in detail7–8. It was conducted in four African sites: Blantyre and Lilongwe (Malawi), Lusaka (Zambia) and Dar es Salaam (Tanzania). Enrollment began in July 2001, and the last delivery occurred in August 2003. This study was approved by appropriate Institutional Review Boards in Zambia, Malawi, and Tanzania and in the U.S. at Johns Hopkins University, University of Alabama at Birmingham, University of North Carolina at Chapel Hill, and Harvard University. All women were counseled and provided written informed consent.
Enrollment of HIV-1-infected women at 20–24 weeks’ gestation was based on serologically confirmed HIV-1 infection status. In addition to HIV-1-infected women, HIV-1-uninfected women were enrolled at three of the four study sites (one HIV-1-uninfected woman for every five HIV-1-infected women enrolled). HIV-1-uninfected women were included in the trial to reduce stigma among HIV-1-infected women enrolled in the study, and to ensure generalizability of results of the study, especially with regard to the effect of antibiotic treatment on preterm birth8.
At 20–24 weeks of pregnancy, all enrolled women received either antibiotics (metronidazole 250 mg and erythromycin 250 mg) or identically appearing placebos, all drugs administered orally three times a day for seven days. With the onset of labor contractions and/or pre-labor rupture of membranes (PROM), study participants initiated a second oral course of antibiotics consisting of metronidazole 250 mg and ampicillin 500 mg, or identically appearing placebos, every four hours until delivery and continued postpartum for a total of seven days. When data presented at an interim Data Safety and Monitoring Board review justified the conclusion that the antibiotic regimen did not reduce MTCT of HIV-1, the protocol team was advised to cease enrollment; thus no further participants were recruited as of February 21, 2003. No further antibiotics were administered after this decision was made and therefore some enrolled women did not receive study intrapartum antibiotics.
HIV-1-infected women were provided with nevirapine (NVP) prophylaxis according to the HIVNET 012 regimen9. Women also received antibiotic treatment for any clinical indication for which an antibiotic was indicated. Structured questionnaires were used to collect information on maternal demographics, obstetric history, medical history, sexual history, as well as use of concomitant antibiotics and other medications.
The inclusion criterion for this analysis was: live born infants born to women (both HIV-1-infected and uninfected) enrolled in the HPTN 024 trial. The initial analysis was based on intention-to-treat (ITT). However, some women who were randomized to the treatment arm did not receive study antibiotics (mainly because they did not deliver at the study clinic) while other women randomized to placebo arm received (non-study) antibiotics. Therefore, further analysis based on “actual” maternal receipt or non-receipt of intrapartum antibiotics also was performed (non-ITT analysis). To determine the actual receipt of antibiotics by women enrolled in HPTN 024, we reviewed both generic and brand names of antimicrobial agents recorded on the study concomitant medication form. Early neonatal morbidity included outcomes occurring within the first seven days of life, based on the following variables: infant illness at birth, admission to SCBU and duration of stay, and neonatal infections. Early neonatal mortality meant deaths within the first seven days of life. Since admission to SCBU information was extracted from the infant birth form, the analysis of this variable was restricted to infants born in the study hospital (88.1% antibiotic arm and 86.6% in the placebo arm, p= 0.25). Similarly, discharge status refers to those admitted to the SCBU. The main trial was not designed to detect associations between intrapartum antibiotics and neonatal morbidity and mortality. For this secondary analysis, no separate power calculations were conducted.
Statistical analyses were conducted using SAS version 8.2. Independent two sample T-tests, Fischer’s exact test and two sample chi-square tests were performed to compare means and medians, respectively. Proportions of neonatal characteristics and outcomes were compared using chi-square tests. Univariate logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations of intrapartum antibiotics and neonatal outcomes.
Overall, 2659 pregnant women were randomized antenatally. Of these, 193 were excluded, and the remaining 2466 women delivered 2497 infants. Eighty-four infants (40 in the placebo arm and 44 in the antibiotics arm) were excluded because they were stillborn. This analysis is restricted to 2413 live born infants. Of these 1214 (166 from HIV-1-uninfected and 1048 from HIV-1-infected mothers) were born to 1197 mothers randomized to antibiotics and 1199 (169 from HIV-1-uninfected, 1030 from HIV-1-infected mothers) were born to 1187 mothers in the placebo arm (Figure 1). There were no significant differences in the maternal and infant characteristics according to randomization arm (Table 1).
In the ITT analysis, there were no differences between maternal intrapartum antibiotic receipt and early neonatal morbidity and mortality (Table 2). The non-ITT cohort was defined as infants born to women who either received or did not receive antepartum and intrapartum antibiotics (including non-study antibiotics). The antibiotics used were penicillins (ampicillin, crystalline penicillin, benzathine penicillin, amoxicillin, cloxacillin), metronidazole, chloramphenicol, cotrimoxazole, erythromycin and gentamicin. The antibiotics were used for cesarean section prophylaxis, PROM and chorioamnionitis, respiratory tract infections (pneumonia, bronchitis, and upper respiratory tract infection), malaria, sepsis (breast abscess, Bartholin’s abscess and paronychia), lower genital tract infection (BV and trichomoniasis), genital ulcer disease including syphilis, gastroenteritis including dysentery and urinary tract infection. In the non-ITT analysis (based on the actual receipt of antibiotics Table 3), there were more infant illnesses at birth among those born to mothers who received intrapartum antibiotics than among those born to women who did not receive antibiotics (p = 0.03). Most of the infant illnesses occurring at birth were infections, including congenital pneumonia, neonatal sepsis, pyrexia of unknown etiology and umbilical cord infection. The non-infectious illnesses were asphyxia, respiratory distress syndrome, neonatal jaundice, hepatosplenomegaly, hypoglycemia, hypothermia, hypoxic encephalopathy, transient apnea of the newborn, dysmaturity, umbilical cord hemorrhage and, more rarely, congenital anomalies such as anal atresia. In addition, the number of infants admitted to SCBU was significantly higher in neonates exposed to intrapartum antibiotics than neonates who were not exposed to antibiotics (p = 0.04). However, differences in early neonatal infection, duration of stay in SCBU, early neonatal deaths and deaths due to infectious causes were not statistically significant in the two groups.
There were no statistically significant differences between infants exposed and not exposed to intrapartum antibiotics and neonatal infections occurring within the first week of birth, duration of stay in the special care baby unit, death before discharge or status at discharge from hospital. There were also no statistically significant differences in the reported causes of death for the infants who died in the SCBU (data not shown). The cause of death was in most cases based on clinical judgment by the investigators at the study sites. The commonest cause was infections [15.5% (13/84)] followed by congenital anomalies [7.1% (6/84)]. Although the proportion of deaths due to an infectious etiology among the exposed infants was higher in the exposed group (8/37 or 21.6%) than the unexposed (5/47 or 10.6%), this difference was not statistically significant (p= 0.23), Table 3.
With respect to HIV-1 infection status of the mother and infant HIV-1 exposure at birth, the maternal and infant characteristics and rates of neonatal infections and neonatal deaths were similar in neonates exposed to intrapartum antibiotics compared to the antibiotic unexposed group (data not shown). This was true for both analyses based on ITT and non-ITT. However, the frequency of neonatal infections among neonates with unknown HIV-1 infection status at birth (5.6% vs. 0%, p=0.02) was higher among those whose mothers received intrapartum antibiotics (Table 3).
Additional non-ITT analyses were performed to further evaluate early neonatal outcomes according to not only maternal receipt or non-receipt of intrapartum antibiotics, but also according to whether, if intrapartum antibiotics were received, these were study antibiotics or non-study antibiotics (Table 4). There were three categories of intrapartum antibiotic receipts: “yes” - received study antibiotics, “yes” - received non-study antibiotics, and “no” - did not receive antibiotics at all. The proportion of mothers who delivered at a study hospital differed significantly according to maternal intrapartum antibiotic receipt category. Similarly, all infant characteristics at birth (except gender) varied significantly according to maternal intrapartum antibiotic receipt: birth weight, Ballard score, Apgar score, and infant illness at birth. Two infant outcomes varied by maternal intrapartum antibiotic receipt category: admission to the SCBU and early neonatal mortality.
Additionally, mothers who received non-study antibiotics were more likely to have rupture of membranes > 4 hours (31.6%) than mothers who received study antibiotics (20.2%) or no antibiotics (17.2%) (p<0.0001). Women who received non-study antibiotics also were more likely to have clinical and histological chorioamnionitis (1.3% and 40.4%, respectively) than women who received study antibiotics (0.3% and 35.9%, respectively) or no antibiotics (0.2% and 34.5%, respectively). The differences in clinical chorioamnionitis among the three groups of women were statistically significant (p=0.04) but not significant (p=0.37) for histological chorioamnionitis. The proportion of infants who died of infectious causes and born to mothers who received or did not receive antibiotics were not significantly different (26.1% [95% CI 8.1 – 44.0], 14.3% [95% CI 0 – 32.6] and 10.6% [95% CI 1.8 – 19.4] if the mother received, respectively, study antibiotic, non-study antibiotic and no antibiotic, p=0.27), Table 4.
In the ITT analysis, there were no effects observed between maternal intrapartum receipt of antibiotics and early neonatal morbidity or mortality. In non-ITT analyses, a greater proportion of infants born to women who received intrapartum antibiotics had illnesses at birth and admission to the SCBU. However, upon further analysis i.e. intrapartum antibiotic receipt categorization analysis (Table 4), the greatest early neonatal morbidity and mortality were observed among those infants whose mothers received non-study antibiotics, compared to infants of mothers who received study antibiotics or who did not receive antibiotics at all. These results suggest sicker women, who received antibiotics for a reason other than participation in and randomization to antibiotics, had infants with greater early neonatal morbidity and mortality because of the underlying maternal illness – and not because of exposure to the antibiotics per se. This interpretation is supported by the observation that more mothers with prolonged rupture of membranes (and subsequently chorioamnionitis) were among those who received antibiotics. It is a common practice in obstetrics to treat women with PROM and chorioamnionitis with antibiotics.
Other studies have shown increased risks of neonatal sepsis due to drug-resistant microorganisms among infants of mothers treated with intrapartum antibiotics compared to unexposed infants6,10,11. The underlying mechanism may be a sub-therapeutic antibiotic level in such infants. Contrary to these findings, we did not find increased rates of neonatal infection associated with maternal intrapartum antibiotic receipt, perhaps because we confined our analysis to the early neonatal period. Additionally, diagnostic capabilities were limited at the study sites where most of the neonatal outcomes were based on clinical criteria and laboratory confirmation was not consistently available. Bacterial resistance testing was not performed. Therefore, under-estimation of early neonatal morbidity may have occurred.
Infants may become exposed to maternal antibiotics either through the placental route or through breast milk. In the areas where this study was performed, breastfeeding is nearly universal12 and is usually initiated soon after birth. Previously published data have suggested an increased risk for late onset neonatal sepsis in infants exposed to peripartum antibiotics4. Our analysis showed no association between exposure to intrapartum antibiotics and early neonatal infection. This finding is similar to previous reports that did not find evidence of potential adverse effects of intrapartum antibiotics and late onset neonatal disease. However, our data suggest there may not be a difference in the adverse outcomes of antibiotics between late onset and early onset infectious morbidity and mortality. This finding means that clinicians may be more comfortable addressing early neonatal life safety concerns when prescribing antibiotics for pregnant women intrapartum. They should be more able than before to give appropriate advice when asked questions such as, “Will my baby be alright doctor if I take these antibiotics during labor?”.
Further evaluation of the role of intrapartum antibiotics on early neonatal morbidity and mortality as the primary outcome in resource-constrained settings is needed. The design of such studies should take into account confounding factors such as PROM and other maternal infectious conditions that are firstly, indications of antibiotics in the intrapartum period and, secondly, determinants of early neonatal infectious morbidity and mortality. The influence of both maternal and infant HIV infection in these populations should be part of the focus for future studies. Such data may be invaluable in both clarifying the contradictory findings in the literature and in guiding more rational antibiotic use in pregnancy and labor in resource-limited countries.
Funding and Technical Support: The HPTN 024 Trial was supported by the HIV Network for Prevention Trials (HIVNET) and the HIV Prevention Trials Network (HPTN) and was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research of the National Institutes of Health, U.S. Department of Health and Human Services.
The HPTN 024 Trial was supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH), Department of Health and Human Services, through contracts NO1-AI-35173 with Family Health International, NO1-AI-45200 with Fred Hutchinson Cancer Research Center, and subcontract NO1-AI-35173-117/412 with Johns Hopkins University. In addition, the trial was supported by the HIV Prevention Trials Network (HPTN) and sponsored by NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, the National Institutes of Mental Health, and the Office of AIDS Research of the National Institutes of Health, U.S. Department of Health and Human Services, Harvard University (UA 1-A1-48006) Johns Hopkins University (U01-AI-48005), and the University of Alabama at Birmingham (U01-AI-47972). Nevirapine (Viramune®) for the study was provided by Boehringer Ingelheim Pharmaceuticals, Inc. The conclusions and opinions expressed in this paper are those of the authors and do not necessarily reflect those of the funding agencies and participating institutions.
HPTN 024 Team: Protocol Co-Chairs: Taha E. Taha, MD, PhD (Johns Hopkins University Bloomberg School of Public Health); Robert Goldenberg, MD (University of Alabama at Birmingham); In-Country Co-Chairs/Investigators of Record: Newton Kumwenda, PhD, George Kafulafula, MBBS, FCOG (Blantyre, Malawi); Francis Martinson, MD, PhD (Lilongwe, Malawi); Gernard Msamanga, MD, ScD (Dar es Salaam, Tanzania); Moses Sinkala, MD, MPH, Jeffrey Stringer, MD (Lusaka, Zambia); US Co-Chairs: Irving Hoffman, PA, MPH (University of North Carolina, Chapel Hill); Wafaie Fawzi, MD, DrPH (Harvard School of Public Health); In-Country Investigators, Consultants, and Key Site Personnel: Robin Broadhead, MBBS, FRCP, George Liomba, MBBS, FRCPath, Johnstone Kumwenda, MBChB, MRCP, Tsedal Mebrahtu, ScM, Pauline Katundu, MHS, Maysoon Dahab, MHS (Blantyre, Malawi); Peter Kazembe, MBChB, David Chilongozi, CO, MPH, Charles Chasela, CO, MPH, George Joaki, MD, Willard Dzinyemba, Sam Kamanga (Lilongwe, Malawi); Elgius Lyamuya, MD, PhD, Charles Kilewo, MD, MMed, Karim Manji, MD, MMed, Sylvia Kaaya, MD, MS, Said Aboud, MD, MMed, Muhsin Sheriff, MD, MPH, Elmar Saathoff, PhD, Priya Satow, MPH, Illuminata Ballonzi, SRN, Gretchen Antelman, ScD, Edgar Basheka, Bpharm (Dar es Salaam, Tanzania); Victor Mudenda, MD, Christine Kaseba, MD, Maureen Njobvu, MD, Makungu Kabaso, MD, Muzala Kapina, MD, Anthony Yeta, MD, Seraphine Kaminsa, MD, MPH, Constantine Malama, MD, Dara Potter, MBA, Maclean Ukwimi, RN, Alison Taylor, BSc, Patrick Chipaila, MSc, Bernice Mwale, Bpharm (Lusaka, Zambia); US Investigators, Consultants, and Key Site Personnel: Priya Joshi, BS, Ada Cachafeiro, BS, Shermalyn Greene, PhD, Marker Turner, BS, Melissa Kerkau, BS, Paul Alabanza, BS, Amy James, BS, Som Siharath, BS, Tiffany Tribull, MS (UNC-CH); Saidi Kapiga, MD, ScD, George Seage, PhD (HSPH); Sten Vermund, MD, PhD, William Andrews, PhD, MD, Deedee Lyon, BS, MT(ASCP) (UAB); NIAID Medical Officer: Samuel Adeniyi-Jones, MD; NICHD Medical Officer: Jennifer S. Read, MD, MS, MPH, DTM&H; Protocol Pharmacologist: Scharla Estep, RPh, MS; Protocol Statisticians: Elizabeth R. Brown, ScD, Thomas R. Fleming, PhD, Anthony Mwatha, MS, Lei Wang, PhD, Ying Q. Chen, PhD; Protocol Virologist: Susan Fiscus, PhD; Protocol Operations Coordinator: Lynda Emel, PhD; Data Coordinators: Debra J. Lands, Ed.M, Ceceilia J. Dominique; Systems Analyst Programmers: Alice H. Fisher, BA, Martha Doyle; Protocol Specialist: Megan Valentine, PA-C, MS.
Conflict of interest: None.
MeSH: Intrapartum antibiotics. neonatal morbidity and mortality. Africa
ClinicalTrials.gov Identifier: NCT00021671