Vanessa L. Rogers

Effect of influenza vaccination in the first trimester of pregnancy

OBJECTIVE: To estimate the effect of first-trimester influenza vaccination on fetal and neonatal outcomes. METHODS: This was a retrospective cohort study examining delivery and neonatal outcomes after antepartum exposure to the seasonal trivalent inactive influenza vaccine. Data were collected and entered into an established computerized database. Outcomes by trimester of vaccination were then compared with women who did not receive the vaccine. RESULTS: During the 5-year study period, 10,225 women received the seasonal influenza vaccine antepartum; 8,690 of these delivered at our institution, 439 in the first trimester and 8,251 in the second and third trimesters. Women vaccinated antepartum were significantly older with higher parity than women who declined vaccination. Neonates born to mothers receiving the vaccine in any trimester did not have an increase in major malformations regardless of trimester of vaccination (2% regardless of vaccination group, P=.9). Stillbirth (0.3% compared with 0.6%, P=.006), neonatal death (0.2% compared with 0.4%, P=.01), and premature delivery (5% compared with 6%, P=.004) were significantly decreased in the vaccinated group. CONCLUSION: Influenza vaccination in the first trimester was not associated with an increase in major malformation rates and was associated with a decrease in the overall stillbirth rate. This information will aid in counseling women regarding the safety of influenza vaccination in the first trimester. LEVEL OF EVIDENCE: II

Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications

Pregnant women are at increased risk of severe morbidity and mortality, secondary to influenza infection. Vaccination programs are the cornerstone of influenza preventive efforts and when they fail, 2 classes of antiviral drugs are important for both postexposure prophylaxis and treatment. The first class, the M2 ion channel inhibitors, includes amantadine and rimantadine, and is effective for the prophylaxis and treatment of influenza A. The second class, the neuraminidase inhibitors, includes oseltamivir, which is effective against both influenza A (including novel H1N1) and B. Because of increasing resistance to oseltamivir, this drug has been used with M2 ion channel inhibitors as 2-drug therapy for influenza A. Little data are not available on the safety of these 2 drug classes when used for treatment of influenza in pregnant women. This retrospective cohort study compared the maternal and neonatal outcomes of pregnant women treated antepartum for influenza with M2 ion channel inhibitors (amantadine, rimantadine), oseltamivir, or a control group. The study was conducted during 5 influenza seasons at a hospital in Texas. The comparative data showed that antepartum treatment with M2 ion channel inhibitors (n = 104), oseltamivir (n = 135), and a control group (n = 82,097) were not associated with increased rates of the following outcomes: gestational diabetes (P = 0.388), preterm birth (P = 0.190), premature rupture of the membranes (P = 0.154), or preeclampsia (P = 0.209). No differences were found among the 3 groups regarding the duration of hospital stay for the mother or the infant, the incidence of fever in labor, stillbirth, or major or minor malformations. Moreover, there were no significant differences among singleton live-born neonates without major malformations in fetal weight (P = 0.186), number of neonates who required intubation (P = 0.552) or intensive care nursery admission (P = 0.418), or the incidence of hyperbilirubinemia (P = 0.282). There were no neonatal deaths among live-born singletons and none had grade 3 or 4 intraventricular hemorrhages or seizures. Two preterm neonates exposed to antivirals in the second trimester developed necrotizing enterocolitis. One was exposed to amantadine and the other to oseltamivir. These findings show that antepartum-antiviral exposure does not increase the risk of adverse maternal or neonatal outcomes.

Pharmacokinetics of oseltamivir according to trimester of pregnancy

The purpose of this study was to determine pharmacokinetic parameters for oseltamivir in all trimesters of pregnancy. Thirty pregnant women, 10 per trimester, who were receiving oseltamivir phosphate (75 mg) were recruited to study first-dose pharmacokinetics. Plasma samples were obtained at 0, 0.5, 1, 2, 4, 8, and 12 hours after the first dose. Samples were analyzed for oseltamivir and oseltamivir carboxylate levels. With the use of a noncompartmental model, we estimated the area-under-the-curve, maximum concentration, time-to-maximum concentration, and half-life. There were no significant differences in the pharmacokinetics of oseltamivir by trimester, except for an increased half-life in the first trimester for oseltamivir phosphate and an increased maximum concentration in the third trimester for oseltamivir carboxylate. The levels of oseltamivir carboxylate that were observed were within the range that was needed to achieve inhibitory concentrations at 50% for pandemic H1N1. The pharmacokinetics of oseltamivir does not change significantly according to trimester of pregnancy.

Presentation of seasonal influenza A in pregnancy: 2003-2004 influenza season.

OBJECTIVE: To describe the clinical course of influenza in pregnant women followed at our institution during the 2003–2004 influenza season. METHODS: This was a prospective evaluation of all pregnant women diagnosed with influenza A between October 22, 2003, and January 18, 2004. Pregnant women presenting with a flu-like illness were evaluated using a rapid diagnostic test, culture, or both. Patients were admitted in accordance with prospectively developed clinical protocols. Women with a laboratory-confirmed diagnosis were treated with Centers for Disease Control-recommended antivirals. RESULTS: Influenza A was confirmed in 107 patients. All viral isolates obtained were of the H3N2 strain. Influenza was most commonly diagnosed in the third trimester (45%). Cough was the most commonly reported symptom (93%), followed by myalgias (61%), nausea or vomiting (60%), and rhinorrhea (56%). Eighty-four percent of the women had no comorbid conditions; however, 62% required admission. Twenty-one percent of patients had a maximum heart rate higher than 130 beats per minute. Complications of influenza A included pneumonia (12%), meningitis (1%), and myocarditis (1%). There were no maternal deaths. Eighty-one (76%) of the women delivered at our institution. When compared with our general obstetric population, there was no significant difference in obstetric or neonatal complications. CONCLUSION: Influenza A in pregnancy is characterized by cough, myalgia, nausea or vomiting, and rhinorrhea. Profound tachycardia disproportionate to maternal fever uniquely affected the majority of the women in our cohort. Pneumonia complicated one in eight cases; however, the anticipated excess maternal morbidities and mortality did not occur. LEVEL OF EVIDENCE: III

Pharmacokinetics of oseltamivir in breast milk and maternal plasma

OBJECTIVE Women in the postpartum period are at high risk for complications from influenza. Pharmacokinetic data of oseltamivir phosphate in postpartum women, however, are lacking. STUDY DESIGN Seven healthy patients within 48 hours of delivery were recruited. Each woman received 75 mg of oseltamivir phosphate. Plasma and breast milk samples were obtained at times 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the first dose. The samples were analyzed for oseltamivir and oseltamivir carboxylate levels. Using a noncompartmental model, area under the curve (AUC), maximum concentration (C(max)), time to maximum concentration, and half-life were estimated. RESULTS Oseltamivir phosphate and oseltamivir carboxylate were found in breast milk, although later and in lower levels than that found in plasma. The C(max) and AUC 0-24 was higher for the active metabolite than for the prodrug in both plasma and breast milk. CONCLUSION Oseltamivir carboxylate was present in breast milk but in concentrations significantly lower than considered therapeutic in infants.

Infant outcomes among women with Zika virus infection during pregnancy: results of a large prenatal Zika screening program

Background: Zika virus infection during pregnancy is a known cause of congenital microcephaly and other neurologic morbidities. Objective: We present the results of a large‐scale prenatal screening program in place at a single‐center health care system since March 14, 2016. Our aims were to report the baseline prevalence of travel‐associated Zika infection in our pregnant population, determine travel characteristics of women with evidence of Zika infection, and evaluate maternal and neonatal outcomes compared to women without evidence of Zika infection. Study Design: This is a prospective, observational study of prenatal Zika virus screening in our health care system. We screened all pregnant women for recent travel to a Zika‐affected area, and the serum was tested for those considered at risk for infection. We compared maternal demographic and travel characteristics and perinatal outcomes among women with positive and negative Zika virus tests during pregnancy. Comprehensive neurologic evaluation was performed on all infants delivered of women with evidence of possible Zika virus infection during pregnancy. Head circumference percentiles by gestational age were compared for infants delivered of women with positive and negative Zika virus test results. Results: From March 14 through Oct. 1, 2016, a total of 14,161 pregnant women were screened for travel to a Zika‐affected country. A total of 610 (4.3%) women reported travel, and test results were available in 547. Of these, evidence of possible Zika virus infection was found in 29 (5.3%). In our population, the prevalence of asymptomatic or symptomatic Zika virus infection among pregnant women was 2/1000. Women with evidence of Zika virus infection were more likely to have traveled from Central or South America (97% vs 12%, P < .001). There were 391 deliveries available for analysis. There was no significant difference in obstetric or neonatal morbidities among women with or without evidence of possible Zika virus infection. Additionally, there was no difference in mean head circumference of infants born to women with positive vs negative Zika virus testing. No microcephalic infants born to women with Zika infection were identified, although 1 infant with hydranencephaly was born to a woman with unconfirmed possible Zika disease. Long‐term outcomes for infants exposed to maternal Zika infection during pregnancy are yet unknown. Conclusion: Based on a large‐scale prenatal Zika screening program in an area with a predominantly Hispanic population, we identified that 4% were at risk from reported travel with only 2/1000 infected. Women traveling from heavily affected areas were most at risk for infection. Neonatal head circumference percentiles among infants born to women with evidence of possible Zika virus infection during pregnancy were not reduced when compared to infants born to women without infection.

Ampicillin resistance and outcome differences in acute antepartum pyelonephritis

Objective. To measure the incidence of ampicillin-resistant uropathogens in acute antepartum pyelonephritis and to determine if patients with resistant organisms had different clinical outcomes. Study design. This was a secondary analysis of a prospective cohort study of pregnant women admitted with pyelonephritis, diagnosed by standard clinical and laboratory criteria. All patients received ampicillin and gentamicin. Results. We identified 440 cases of acute pyelonephritis. Seventy-two percent (316 cases) had urine cultures with identification of organism and antibiotic sensitivities. Fifty-one percent of uropathogens were ampicillin resistant. The patients with ampicillin-resistant organisms were more likely to be older and multiparous. There were no significant differences in hospital course (length of stay, days of antibiotics, ECU admission, or readmission). Patients with ampicillin-resistant organisms did not have higher complication rates (anemia, renal dysfunction, respiratory insufficiency, or preterm birth). Conclusion. A majority of uropathogens were ampicillin resistant, but no differences in outcomes were observed in these patients.

Prevention of mother-to-infant transmission of influenza during the postpartum period.

OBJECTIVES The optimal management of infants born to mothers with peripartum influenza infection is not known. The objective of this study is to describe our experience with a practice guideline that promotes rooming-in and breast-feeding and to determine whether infants managed in this way acquire influenza infection. STUDY DESIGN All mothers diagnosed with influenza infection within 8 days of delivery and their infants were included. Demographics, clinical characteristics, and outcome data were collected. Mothers were contacted at ~1 month after giving birth to determine if their infants had developed any signs suggestive of influenza infection. RESULTS Forty-two women were diagnosed with peripartum influenza over the 2003 to 2005 and 2009 to 2010 seasons. Median onset of symptoms was 3 days before delivery, and median day of diagnosis was 1 day before delivery. The 42 infants had a median gestational age of 39 weeks; none were born earlier than 35 weeks. Ninety-five percent of the infants roomed-in with their mothers. Follow-up information was available on 95% of infants by 1 month; no infants had illness suggestive of influenza through the follow-up period. CONCLUSION A guideline for the management of infants born to mothers with peripartum influenza infection, based on attention to hand hygiene, antiviral treatment for mothers, and encouragement of rooming-in and breast-feeding, was not associated with mother-to-infant influenza transmission over three separate influenza seasons.

The Use of Protease Inhibitors in Pregnancy: Maternal and Fetal Considerations.

Background. Previous studies examining protease inhibitor use in pregnancy and the rate of preterm and small-for-gestational-age infants have yielded conflicting results. Methods. This was a retrospective study of HIV-infected women who delivered singleton infants at our institution between 1984 and 2014. Women with protease inhibitor use were compared to women on regimens without a protease inhibitor as well as those who received no antepartum antiretroviral therapy. Infants were considered preterm if less than 37 completed weeks of gestation and small-for-gestational-age if less than 10th percentile. Results. During the study period 1,004 pregnancies met inclusion criteria. Of those, 597 received a protease inhibitor as part of their regimen, 230 ART without a protease inhibitor, and 177 no ART. There was no difference in the rate of preterm birth between groups who received ART with or without a protease inhibitor, 14% versus 13%. There was no difference in the rate of small-for-gestational-age infants between the three groups. Use of a protease inhibitor was associated with a greater fall in viral load during pregnancy, p < 0.001. Conclusion. In this population with access to prenatal care and ART, treatment with protease inhibitors was associated with a greater fall in viral load, but not an increase in small or preterm infants.

Diagnostic accuracy of fourth-generation ARCHITECT HIV Ag/Ab Combo assay and utility of signal-to-cutoff ratio to predict false-positive HIV tests in pregnancy

BACKGROUND: False‐positive HIV screening tests in pregnancy may lead to unnecessary interventions in labor. In 2014, the Centers for Disease Control and Prevention released a new algorithm for HIV diagnosis using a fourth‐generation screening test, which detects antibodies to HIV as well as p24 antigen and has a shorter window period compared with prior generations. A reactive screen requires a differentiation assay, and supplemental qualitative RNA testing is necessary for nonreactive differentiation assay. One screening test, the ARCHITECT Ag/Ab Combo assay, is described to have 100% sensitivity and >99% specificity in nonpregnant populations; however, its clinical performance in pregnancy has not been well described. OBJECTIVE: The objective of the study was to determine the performance of the ARCHITECT assay among pregnant women at a large county hospital and to assess whether the relative signal‐to‐cutoff ratio can be used to differentiate between false‐positive vs confirmed HIV infections in women with a nonreactive differentiation assay. STUDY DESIGN: This is a retrospective review of fourth‐generation HIV testing in pregnant women at Parkland Hospital between June 1, 2015, and Jan. 31, 2017. We identified gravidas screened using the ARCHITECT Ag/Ab Combo assay (index test), with reflex to differentiation assay. Women with reactive ARCHITECT and nonreactive differentiation assay were evaluated with a qualitative RNA assay (reference standard). We calculated sensitivity, specificity, predictive value, and false‐positive rate of the ARCHITECT screening assay in our population and described characteristics of women with false‐positive HIV testing vs confirmed infection. Among women with a nonreactive differentiation assay, we compared interventions among women with and without a qualitative RNA assay result available at delivery and examined relative signal‐to‐cutoff ratios of the ARCHITECT assay in women with false‐positive vs confirmed HIV infection. RESULTS: A total of 21,163 pregnant women were screened using the ARCHITECT assay, and 190 tested positive. Of these, 33 of 190 (17%) women had false‐positive HIV screening tests (28 deliveries available for analysis), and 157 of 190 (83%) had confirmed HIV‐1 infection (140 available for analysis). Diagnostic accuracy of the ARCHITECT HIV Ag/Ab Combo assay in our prenatal population (with 95% confidence interval) was as follows: sensitivity, 100% (97.7–100%); specificity, 99.8% (99.8–99.9%); positive likelihood ratio, 636 (453–895); negative likelihood ratio, 0.0 (NA); positive predictive value, 83% (77–88%); and false positive rate, 0.16% (0.11–0.22%), with a prevalence of 7 per 1000. Women with false‐positive HIV testing were younger and more likely of Hispanic ethnicity. A qualitative RNA assay (reference standard) was performed prenatally in 24 (86%) and quantitative viral load in 22 (92%). Interventions occurred more frequently in women without a qualitative RNA assay result available at delivery, including intrapartum zidovudine (75% vs 4%, P = .002), breastfeeding delay (75% vs 8%, P = .001), and neonatal zidovudine initiation (75% vs 4%, P = .002). The ARCHITECT signal‐to‐cutoff ratio was significantly lower for women with false‐positive HIV tests compared with those with established HIV infection (1.89 [1.27, 2.73] vs 533.65 [391.12, 737.22], respectively, P < .001). CONCLUSION: While the performance of the fourth‐generation ARCHITECT HIV Ag/Ab Combo assay among pregnant women is comparable with that reported in nonpregnant populations, clinical implications of using a screening test with a positive predictive value of 83% in pregnancy are significant. When the qualitative RNA assay result is unavailable, absence of risk factors in combination with an ARCHITECT HIV Ag/Ab assay S/Co ratio <5 and nonreactive differentiation assay provide sufficient evidence to support deferral of unnecessary intrapartum interventions while awaiting qualitative RNA results.