Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery.

Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3- and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.

Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype.

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14(+) cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype.

Enhanced identification of maternal hepatitis C virus infection using existing public health surveillance systems.

BACKGROUND: Hepatitis C virus (HCV) infection is under-recognized among US adults and children. Prenatal HCV screening may help close the diagnosis gap among women while also identifying at-risk infants. Current surveillance efforts for maternal HCV rely primarily on birth certificate data. We sought a more accurate assessment of HCV prevalence among pregnant women in Ohio by combining existing public health surveillance data. METHODS: Vital Statistics (VS) birth certificate data and Ohio Disease Reporting System (ODRS) HCV case data, both available through the Ohio Department of Health, were linked to determine rates of past or present HCV infection among women giving birth from 2012 to 2015 in Ohio, overall and by county. Among women with available test results, the proportion with present HCV infection indicated by detectable viraemia during pregnancy was calculated. RESULTS: Birth certificate data identified 4695 deliveries to women with past/present HCV infection during the study period. Linkage to ODRS revealed an additional 1778 deliveries to women with past/present infection, including 355 with confirmed viraemia during pregnancy. The prevalence of past/present HCV among pregnant women in Ohio rose from 0.82% in 2012 to 1.54% in 2015. CONCLUSIONS: Maternal HCV infection is under-recognized and increasing in prevalence. Current case identification processes are inadequate in pregnancy, even among women with prior positive HCV testing. Alternative approaches, including enhanced risk factor-based screening or universal prenatal screening in high prevalence settings, are needed to improve rates of HCV recognition among reproductive-aged women and newborns at risk of vertical transmission.

Hepatitis C virus in pregnancy.

Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.

Obstetric and neonatal outcomes of cancer treated during pregnancy.

Cancer diagnosed during pregnancy is a rare occurrence with an incidence of 0.1% of all pregnancies. However, its management can be challenging at times as one balances maternal benefit to fetal risk. Various treatment modalities are used in this context including surgical intervention, chemotherapy, and radiologic therapy. This review seeks to address the impact of pregnancy on disease as well as the effect of malignancy and its treatment on both mother and fetus. Attention is focused on the more common malignancies associated with pregnancy: cervix, breast, melanoma, and hematologic malignancies. In addition, special emphasis is placed on timing of delivery and how that affects neonatal outcomes.

Post-Cesarean Delivery Analgesic Outcomes in Patients Maintained on Methadone and Buprenorphine: A Retrospective Investigation.

BACKGROUND: Despite the increasing prevalence of opioid use disorder (OUD) in pregnant women, there are limited studies on their anesthesia care and analgesic outcomes after cesarean delivery (CD). METHODS: Patients with OUD on either buprenorphine or methadone maintenance therapy who underwent CD at our institution from 2011 to 2018 were identified. Anesthetic details and analgesic outcomes, including daily opioid consumption and pain scores, were compared between patients maintained on buprenorphine and methadone. Analgesic outcomes were also evaluated according to anesthetic type (neuraxial or general anesthesia) and daily buprenorphine/methadone dose to determine if these factors impacted pain after delivery. RESULTS: A total of 146 patients were included (buprenorphine n=99 (67.8%), methadone n=47 (32.2%)). Among all patients: 74% had spinal/CSE, 15% epidural, and 11% general anesthesia. Anesthesia types were similar among buprenorphine and methadone patients. For spinal anesthetics, intrathecal fentanyl (median 15 µg) and morphine (median 100 µg) were commonly given (97.2% and 96.3%, respectively), and dosed similarly between groups. Among epidural anesthetics, epidural morphine (median 2 mg) was commonly administered (90.9%), while fentanyl (median 100 µg) was less common (54.5%). Buprenorphine and methadone groups consumed similar amounts of oxycodone equivalents per 24 hours of hospitalization (80.6 vs 76.3 mg; p=0.694) and had similar peak pain scores (8.3 vs 8.0; p=0.518). Daily methadone dose correlated weakly with opioid consumption (R=0.3; p=0.03), although buprenorphine dose did not correlate with opioid consumption or pain scores. General anesthesia correlated with greater oxycodone consumption in the first 24 hours (median 156.1 vs 91.7 mg; p=0.004) and greater IV PCA use (63% vs 7%; p<0.001) compared to neuraxial anesthesia. CONCLUSION: Patients on buprenorphine and methadone had similar high opioid consumption and pain scores after CD. The anesthetic details and analgesic outcomes reported in this investigation may serve as a useful reference for future prospective investigations and aid in the clinical care of these patients.

CD4+ T cell restoration and control of hepatitis C virus replication after childbirth.

Chronic hepatitis C virus (HCV) infection is characterized by persistent high-level viremia and defective cellular immunity, including a lack of functional HCV-specific CD4+ T cells. We previously described an exceptional period of viral control that occurs in some chronically infected women after childbirth. Here, we investigated whether reduced HCV replication after pregnancy is associated with recovery of CD4+ T cell immunity. Class II tetramer analysis revealed significantly greater frequencies of circulating HCV-specific CD4+ T cells at 3 months postpartum in women with concurrent declines in viremia compared with those with stable viremia. These HCV-specific CD4+ T cells had an effector-memory phenotype. Inhibitory coreceptor expression on these cells corresponded to the degree of viral control. Circulating CD4+ T cells produced IL-2 and IFN-γ after HCV antigen stimulation, demonstrating Th1 functionality. These data provide direct evidence that the profound loss of HCV-specific CD4+ T cell help that results in chronic infection is reversible following pregnancy, and this recovery of CD4+ T cells is associated with at least transient control of persistent viral replication.

High-dose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome.

OBJECTIVE: The purpose of this study was to examine high-dose methadone in pregnant women and its effect on the duration of neonatal abstinence syndrome. STUDY DESIGN: This was a retrospective chart review of 68 neonates and their mothers who received methadone therapy during pregnancy. The last dosage of maternal methadone just before delivery and the length of treatment for neonatal abstinence syndrome were examined with an analysis of variance model. RESULTS: When the data were analyzed for methadone dosages as a continuous variable, each 1-mg increase in the last maternal methadone dosage before delivery was associated with an additional 0.18 days of infant treatment for neonatal abstinence syndrome (P < .001; 95% CI, 0.112-0.255). In other words, every increase of 5.5 mg of methadone in the mother was associated statistically with 1 additional day of neonatal abstinence syndrome treatment for the infant. Gestational age at delivery and birthweight were not statistically significant. CONCLUSION: Higher doses of maternal methadone were associated with an increase in diagnosis and longer duration of neonatal abstinence syndrome.

The clinical content of preconception care: women with chronic medical conditions.

This article reviews the medical conditions that are associated with adverse pregnancy outcomes for women and their offspring. We also present the degree to which specific preconception interventions and treatments can impact the effects of the condition on birth outcomes. Because avoiding, delaying, or achieving optimal timing of a pregnancy is often an important component of the preconception care of women with medical conditions, contraceptive considerations particular to the medical conditions are also presented.

The clinical content of preconception care: infectious diseases in preconception care.

A number of infectious diseases should be considered for inclusion as part of clinical preconception care. Those infections strongly recommended for health promotion messages and risk assessment or for the initiation of interventions include Chlamydia infection, syphilis, and HIV. For selected populations, the inclusion of interventions for tuberculosis, gonorrheal infection, and herpes simplex virus are recommended. No clear evidence exists for the specific inclusion in preconception care of hepatitis C, toxoplasmosis, cytomegalovirus, listeriosis, malaria, periodontal disease, and bacterial vaginosis (in those with a previous preterm birth). Some infections that have important consequences during pregnancy, such as bacterial vaginosis (in those with no history of preterm birth), asymptomatic bacteriuria, parvovirus, and group B streptococcus infection, most likely would not be improved through intervention in the preconception time frame.

Anti-D in Rh positive pregnancies.

OBJECTIVE: The purpose of this study was to review the clinical outcomes of anti-D isoimmunization in a series of women who typed Rh positive or Rh weak positive. STUDY DESIGN: This was a review of The Ohio State University Medical Center Fetal Therapy Program Database. RESULTS: Of 1068 pregnancies affected by anti-D, 5 pregnancies (0.47%) occurred in 4 women between 1994 and 2004, who were serologically typed as Rh positive or Rh weak positive. All 5 pregnancies delivered at term. All newborns were confirmed affected either by a positive direct antiglobulin test (DAT) or were Rh positive. Newborns were not anemic at birth and subsequently did not require transfusion. No newborns were treated for jaundice. All newborns were discharged home with their mothers. CONCLUSION: Anti-D hemolytic disease of the fetus and newborn (HDFN) is a rare complication of Rh positive and Rh weak positive pregnancies. Although the potential for severe HDFN exists in this clinical scenario, our experience suggests that in Rh positive or Rh weak positive pregnancies with anti-D isoimmunization, clinical HDFN is mild. Nonetheless, Rh positive or Rh weak positive patients with anti-D should be monitored for potentially significant HDFN.

Association between infertility treatment and symptoms of postpartum depression.

OBJECTIVE: To examine the association between infertility treatment and subsequent symptoms of postpartum depression. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Women who delivered live-born infants from 2009-2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Odds of symptoms of postpartum depression. RESULT(S): Data were obtained from the Center for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS). Data on infertility treatment were available for 16 states in which mothers were sampled 2 to 4 months after delivery to complete the standardized PRAMS questionnaire. Infertility treatment status was as reported on the birth certificate. Maternal mental health was obtained via the maternal questionnaire. Data were analyzed in Stata 12.0 with sample weights to produce population-based estimates. Among the 42,614 women who resided in states in which infertility treatment data were collected, infertility treatment status was missing for 2,277 (5.3%) women. Among the 40,337 eligible women, 12.9% reported feeling down, depressed or sad, and 6.0% reported feeling hopeless. These women were considered to have symptoms of postpartum depression. Even after adjustment for confounders, there was no independent association between infertility treatment status and symptoms of postpartum depression. In contrast, having a child admitted to neonatal intensive care, smoking, experiencing a higher number of stressors in the 12 months before delivery, and a history of having prepregnancy mental health care were associated with an increased odds of having symptoms of postpartum depression. CONCLUSION(S): In a population-based sample of U.S. women, conceiving with the help of infertility treatment did not increase the odds of experiencing symptoms of postpartum depression.

Association between body mass index and the timing of pregnancy recognition and entry into prenatal care.

OBJECTIVE: To assess whether prepregnancy body mass index (BMI) is independently associated with the timing of pregnancy recognition and initiation of prenatal care. METHODS: Data from 2009 to 2010 were obtained from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System. The 30 participating states contacted sampled mothers 2-4 months after delivery and had them complete the standardized Pregnancy Risk Assessment Monitoring System questionnaire. Prepregnancy BMI was calculated from the participants' self-reported prepregnancy weight and height. Timing of pregnancy recognition and initiation of prenatal care were also self-reported on the questionnaire. RESULTS: Among the 72,913 participants, 69,872 (96%) met the eligibility criteria for analysis. After adjustment for maternal race, ethnicity, smoking status in the 3 months before pregnancy, pregnancy intentions, insurance status, maternal age, marital status, maternal education, and parity, there was no association between prepregnancy BMI status and the week of pregnancy recognition. Obese women initiated prenatal care 0.20 weeks earlier on average compared with normal-weight women, although the difference was not clinically important (mean difference -0.20, 95% confidence interval [CI] -0.38 to -0.03). When examining the odds of receiving late or no prenatal care, there was no association with prepregnancy BMI. Uninsured women, however, reported initiating prenatal care almost 3 weeks later on average than privately insured women (mean difference 2.83, 95% CI 2.27-3.38) and had a more than fourfold increased odds of receiving late or no prenatal care (odds ratio 4.04, 95% CI 3.13-5.23). CONCLUSION: Prepregnancy BMI was not meaningfully associated with a delay in pregnancy recognition or with increased odds of receiving late or no prenatal care.

Neonatal outcomes following in utero exposure to buprenorphine/naloxone or methadone.

OBJECTIVES: To study neonatal outcomes following buprenorphine/naloxone and methadone exposure during pregnancy. METHODS: This study is a retrospective review of clinical and demographic information of 58 infants whose mothers were treated with buprenorphine/naloxone and 92 infants whose mothers were treated with methadone for opioid dependence during pregnancy. RESULTS: Gestational age, birth weight, prematurity, admission to neonatal intensive care unit, and length of stay were similar between both groups of infants. Neonatal abstinence syndrome occurred less frequently among infants of mothers treated with buprenorphine/naloxone than those treated with methadone (64% and 80%, respectively, p = 0.03). All infants with neonatal abstinence syndrome were treated postnatally with methadone. There was a trend toward shorter duration of treatment and lower cumulative dosages of methadone among the buprenorphine/naloxone-exposed infants. CONCLUSIONS: No apparent significant adverse neonatal outcomes were detected following treatment with either maintenance medication; however, further prospective research is necessary to examine the safety and efficacy of buprenorphine/naloxone in pregnancy and its effects on the neonate.

Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.

Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.