Serum Aminotransferase Flares in Pregnant and Postpartum Women With Current or Prior Treatment for Chronic Hepatitis B.

BACKGROUND AND AIMS: Antiviral therapy is recommended for pregnant women with chronic hepatitis B (CHB) and hepatitis B virus (HBV) DNA>200,000 IU/mL, but there is less consensus on management of women who discontinue therapy in anticipation of pregnancy or who become pregnant while on therapy. The goal of this study was to describe flares in alanine aminotransferase (ALT) during pregnancy and postpartum in CHB women with current and/or prior treatment. METHODS: This was a multicenter, retrospective study of 67 pregnancies in 56 CHB women treated before and/or during pregnancy. Main outcomes were frequency, severity, and resolution of ALT flare (≥5× upper limit of normal or ≥3× baseline, whichever was higher). RESULTS: During pregnancy, ALT flares (95 to 1064 U/L) were observed in 16% (7/43) of women who stopped treatment before pregnancy and 31% (4/13) of women who discontinued treatment during first trimester, many of whom had high HBV DNA levels (4.9 to 8.0 log IU/mL). No flares (0/11) were observed in women who continued treatment. Postpartum ALT flares (104 to 1584 U/L) were observed in 0% (0/15) of women who were completely untreated during pregnancy, 29% (2/7) of women who discontinued treatment in first trimester, 33% (3/9) of women who stopped treatment at delivery, and 22% (4/18) of women who continued treatment postpartum. CONCLUSIONS: In previously treated women with CHB, ALT flares were common during pregnancy and postpartum, especially if antiviral therapy was discontinued shortly before pregnancy, during first trimester, or at delivery. Thus, these pregnant women should be monitored closely throughout pregnancy and the early postpartum period; larger studies are needed to further characterize the natural history of HBV infection during pregnancy and postpartum.

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy.

Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1ß were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1ß response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1ß and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.

Increased Proinflammatory Responses of Monocytes and Plasmacytoid Dendritic Cells to Influenza A Virus Infection During Pregnancy.

Pregnancy-induced alterations in immunity may contribute to the increased morbidity associated with influenza A virus infection during pregnancy. We characterized the immune response of monocytes and plasmacytoid dendritic cells (pDCs) to influenza A virus infection in 21 pregnant and 21 nonpregnant women. In pregnant women, monocytes and pDCs exhibit an exaggerated proinflammatory immune response to 2 strains of influenza A virus, compared with nonpregnant women, characterized by increased expression of major histocompatibility complex class II (approximately 2.0-fold), CD69 (approximately 2.2-fold), interferon γ-induced protein 10 (approximately 2.0-fold), and macrophage inflammatory protein 1ß (approximately 1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following influenza A virus infection.

Serum Alanine Aminotransferase and Hepatitis B DNA Flares in Pregnant and Postpartum Women with Chronic Hepatitis B.

OBJECTIVES: Alterations in the immune system during pregnancy have been associated with reactivation of hepatitis B virus (HBV) in chronic hepatitis B (CHB) women. However, the effects of pregnancy on CHB remain not well understood. The goal of this study was to examine flares in HBV DNA and serum alanine aminotransferase (ALT) during pregnancy and postpartum in CHB women untreated prior to pregnancy. METHODS: This was a multicenter retrospective study of 113 pregnancies in 101 CHB women who presented during pregnancy at two community gastroenterology clinics and two tertiary medical centers in the United States during 1997-2015. Outcomes analyzed included onset, severity, and resolution of flares in HBV and ALT that occurred prior to starting antiviral therapy, if antiviral therapy was subsequently initiated. Women who initiated antiviral therapy during pregnancy were not included in the analysis of postpartum flares. RESULTS: HBV DNA flares were observed in 9% (8/90) of women during pregnancy and 4% (2/48) of women during postpartum. Flares in ALT (99-2522 U/l) were observed in 6% (7/112) of women during pregnancy and 10% (5/51) of women within the first 3 months of delivery. Age, HBeAg positivity, baseline HBV DNA, baseline ALT, gravida, and parity were not found to be significant predictors of flare. CONCLUSIONS: Flares in HBV DNA and ALT can occur during late pregnancy and early postpartum in CHB women, and can be severe. Women with CHB should therefore be closely monitored during pregnancy and early postpartum.

Pregnancy Does Not Attenuate the Antibody or Plasmablast Response to Inactivated Influenza Vaccine.

BACKGROUND: Inactivated influenza vaccine (IIV) is recommended during pregnancy to prevent influenza infection and its complications in pregnant women and their infants. However, the extent to which pregnancy modifies the antibody response to vaccination remains unclear, and prior studies have focused primarily on hemagglutinin inhibition (HI) titers. A more comprehensive understanding of how pregnancy modifies the humoral immune response to influenza vaccination will aid in maximizing vaccine efficacy. METHODS: Healthy pregnant women and control women were studied prior to, 7 days after, and 28 days after vaccination with IIV. HI titers, microneutralization (MN) titers, and the frequency of circulating plasmablasts were evaluated in pregnant versus control women. RESULTS: Pregnant women and control women mount similarly robust serologic immune responses to IIV, with no significant differences for any influenza strain in postvaccination geometric mean HI or MN titers. HI and MN titers correlate, though MN titers demonstrate more robust changes pre- versus postvaccination. The induction of circulating plasmablasts is increased in pregnant women versus controls (median fold-change 2.60 vs 1.49 [interquartile range, 0.94-7.53 vs 0.63-2.67]; P = .03). CONCLUSIONS: Pregnant women do not have impaired humoral immune responses to IIV and may have increased circulating plasmablast production compared to control women.

Learning Lessons from the COVID-19 Pandemic-A Qualitative Assessment of the Experiences of Pregnant Latinas Infected with COVID-19 and Their Perspectives on Vaccination.

OBJECTIVES: To examine the experiences of pregnant Hispanic/Latine people with COVID-19, as well as their perspectives on COVID-19 vaccination in pregnancy. METHODS: We interviewed birthing parents who received care from a teaching hospital in California and tested positive for COVID-19 during pregnancy or delivery. We analyzed transcripts using the constant comparative method for analyzing data to using a phenomological epidemiological approach. We used root cause analysis to identify consistent themes across interviews and assess relationships between social determinants of health and COVID-19 infectivity. RESULTS: We interviewed 14 women from November 2021 to June 2022. Participants reported COVID-19 adversely impacted their clinical care and well-being during pregnancy or postpartum. Impacts among Spanish-speaking participants included unexpected financial hardships, challenges navigating in-patient experiences, and difficulty securing reliable childcare. While most participants were at least partially vaccinated, participants also described doubts and concerns about the vaccine. CONCLUSIONS: Our findings suggest that Spanish-speaking Hispanic/Latine patients could benefit from receiving more information about COVID-19 in pregnancy from their healthcare providers. Leveraging familial and social networks, providing reliable information in people's preferred language, and increasing communication through trusted partners may also help combat vaccine hesitancy.

Intrahepatic Cholestasis of Pregnancy and Transaminitis in Women with COVID-19: A Case Series.

Objective The four initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant women presenting at term gestation to our institution presented with transaminitis. Three of the four were diagnosed with intrahepatic cholestasis of pregnancy (IHCP). Growing evidence exists of an associated transaminitis in nonpregnant SARS-CoV-2 patients. However, there are limited data of hepatic involvement of SARS-CoV-2 in pregnancy, and no previous studies have assessed the association with IHCP in patients with coronavirus disease 2019 (COVID-19). Study Design This was a retrospective, single-center case series of four consecutive pregnant women with a positive result for SARS-CoV-2 presenting with transaminitis in third trimester. Results The clinical courses of four pregnant women with COVID-19 and transaminitis, three of four of whom were diagnosed with IHCP, are described. Testing for SARS-CoV-2 was done through a reverse transcription polymerase chain reaction test of a nasopharyngeal swab. Conclusion As we await larger studies ascertaining the incidence of IHCP in SARS-CoV-2, this prevalence highlights the importance of diagnosing IHCP among women with COVID-19 as a potential etiology of transaminitis, as IHCP risks may be ameliorated with earlier delivery. Moreover, delineating a hepatobiliary association in pregnancy may provide further information about the mechanism of liver impairment in SARS-CoV-2 in all patients.

Importance of inclusive leadership in the pandemic response: the critical role of the physician.

BACKGROUND: The COVID-19 pandemic has resulted in multiple logistical and communication challenges in the face of ever-changing guidance, disease prevalence and increasing evidence. METHODS: At Stanford Children's Health (SCH), we felt physician input was an important element of pandemic response infrastructure, given our lens into patient care across its continuum. We formed the COVID-19 Physician Liaison Team (CPLT) consisting of representative physicians across the care continuum. The CPLT met regularly and communicated to the SCH's COVID-19 task force responsible for the ongoing organisation pandemic response. The CPLT problem-solved around various issues including testing, patient care on our COVID-19 inpatient unit and communication gaps. RESULTS: The CPLT contributed to conservation of rapid COVID-19 tests for critical patient care needs, decreased incident reports on our COVID-19 inpatient unit and helped enhance communication across the organisation, with a focus on physicians. CONCLUSION: In retrospect, the approach taken was in line with a distributed leadership model with physicians as integral members contributing to active lines of communication, continual problem-solving and new pathways to provide care.

A first look at chorioamnionitis management practice variation among US obstetricians.

Objective. To examine practice patterns for diagnosis and treatment of chorioamnionitis among US obstetricians. Study Design. We distributed a mail-based survey to members of the American College of Obstetricians and Gynecologists, querying demographics, practice setting, and chorioamnionitis management strategies. We performed univariable and multivariable analyses. Results. Of 500 surveys distributed, 53.8% were returned, and 212 met study criteria and were analyzed. Most respondents work in group practice (66.0%), perform >100 deliveries per year (60.0%), have been in practice >10 years (77.3%), and work in a nonuniversity setting (85.1%). Temperature plus one additional criterion (61.3%) was the most common diagnostic strategy. Over 25 different primary antibiotic regimens were reported, including use of a single agent by 30.0% of respondents. A wide range of postpartum antibiotic duration was reported from no postpartum treatment (34.5% after vaginal delivery, 11.3% after cesarean delivery) to 48 hours of postpartum treatment (24.7% after vaginal delivery, 32.1% after cesarean delivery). No practitioner characteristic was independently associated with diagnostic or therapeutic strategies in multivariable analysis. Conclusion. There is a wide variation in contemporary clinical practices for the management of chorioamnionitis. This may represent a dearth of level I evidence. Future prospective clinical trials may provide more evidence-based practice recommendations for diagnosis and treatment of chorioamnionitis.

Antibody treatment promotes compensation for human cytomegalovirus-induced pathogenesis and a hypoxia-like condition in placentas with congenital infection.

Human cytomegalovirus (HCMV) is the major viral cause of birth defects worldwide. Affected infants can have temporary symptoms that resolve soon after birth, such as growth restriction, and permanent disabilities, including neurological impairment. Passive immunization of pregnant women with primary HCMV infection is a promising treatment to prevent congenital disease. To understand the effects of sustained viral replication on the placenta and passive transfer of protective antibodies, we performed immunohistological analysis of placental specimens from women with untreated congenital infection, HCMV-specific hyperimmune globulin treatment, and uninfected controls. In untreated infection, viral replication proteins were found in trophoblasts and endothelial cells of chorionic villi and uterine arteries. Associated damage included extensive fibrinoid deposits, fibrosis, avascular villi, and edema, which could impair placental functions. Vascular endothelial growth factor and its receptor fms-like tyrosine kinase 1 (Flt1) were up-regulated, and amniotic fluid contained elevated levels of soluble Flt1 (sFlt1), an antiangiogenic protein, relative to placental growth factor. With hyperimmune globulin treatment, placentas appeared uninfected, vascular endothelial growth factor and Flt1 expression was reduced, and sFlt1 levels in amniotic fluid were lower. An increase in the number of chorionic villi and blood vessels over that in controls suggested compensatory development for a hypoxia-like condition. Taken together the results indicate that antibody treatment can suppress HCMV replication and prevent placental dysfunction, thus improving fetal outcome.

Lactate and procalcitonin levels in peripartum women with intraamniotic infection.

BACKGROUND: Pregnant women are vulnerable to infection as their immune response is modulated. OBJECTIVE: Serum biomarkers are used to diagnose and manage severe infections, but data on their utility during labor are limited. We compared lactate and procalcitonin levels in women with and without an intraamniotic infection to determine whether they are useful biomarkers for infection during labor. STUDY DESIGN: We performed a prospective, observational cohort study of term, singleton pregnancies admitted with planned vaginal delivery in 2019 at a university medical center. The lactate and procalcitonin levels were determined during early labor, within 2 hours following delivery, and on postpartum day 1. Women with an intraamniotic infection in addition had their lactate and procalcitonin levels determined following an intraamniotic infection diagnosis. Samples were processed immediately in the hospital clinical laboratory. The primary outcome was the mean lactate level following delivery. The secondary outcomes were the lactate and procalcitonin levels at other time points. Comparisons based on infection status were performed using multivariate linear regressions. RESULTS: A total of 22 women with intraamniotic infection and 29 uninfected women were included. The mean early labor lactate level (1.47 vs 1.49 mmol/L) and mean procalcitonin level (0.048 vs 0.039 ng/mL) did not differ and were normal in the uninfected and intraamniotic infection groups. The mean lactate level was highest following delivery for women in both the uninfected and intraamniotic infection groups (2.00 vs 2.33 mmol/L; adjusted P=.08; 95% confidence interval, 0.98-1.53). The lactate level returned to normal by postpartum day 1 and did not differ significantly based on the infection status at any time point in the adjusted models. The procalcitonin level following delivery was higher among women with vs without an intraamniotic infection (0.142 vs 0.091 ng/mL; adjusted P=.03). The procalcitonin level rose further in both the intraamniotic infection and uninfected groups on postpartum day 1 (0.737 vs 0.408 ng/mL; adjusted P=.05). CONCLUSION: The lactate level is not significantly elevated in pregnant women with an intraamniotic infection above the physiological increase that is observed in women without infection at delivery. The procalcitonin level is elevated at delivery in women with an intraamniotic infection and warrants further investigation as a peripartum infection marker.

Data-driven queries between medications and spontaneous preterm birth among 2.5 million pregnancies.

BACKGROUND: Our goal was to develop an approach that can systematically identify potential associations between medication prescribed in pregnancy and spontaneous preterm birth (sPTB) by mining large administrative "claims" databases containing hundreds of medications. One such association that we illustrate emerged with antiviral medications used for herpes treatment. METHODS: IBM MarketScan® databases (2007-2016) were used. A pregnancy cohort was established using International Classification of Diseases (ICD-9/10) codes. Multiple hypothesis testing and the Benjamini-Hochberg procedure that limited false discovery rate at 5% revealed, among 863 medications, five that showed odds ratios (ORs) <1. The statistically strongest was an association between antivirals and sPTB that we illustrate as a real example of our approach, specifically for treatment of genital herpes (GH). Three groups of women were identified based on diagnosis of GH and treatment during the first 36 weeks of pregnancy: (a) GH without treatment; (b) GH treated with antivirals; (c) no GH or treatment. RESULTS: We identified 2,538,255 deliveries. 0.98% women had a diagnosis of GH. Among them, 60.0% received antiviral treatment. Women with treated GH had OR < 1, (OR [95% CI] = 0.91 [0.85, 0.98]). In contrast, women with untreated GH had a small increased risk of sPTB (OR [95% CI] =1.22 [1.14, 1.32]). CONCLUSIONS: Data-driven approaches can effectively generate new hypotheses on associations between medications and sPTB. This analysis led us to examine the association with GH treatment. While unknown confounders may impact these findings, our results indicate that women with untreated GH have a modest increased risk of sPTB.

Pregnancy-Induced Alterations in NK Cell Phenotype and Function.

Pregnant women are particularly susceptible to complications of influenza A virus infection, which may result from pregnancy-induced changes in the function of immune cells, including natural killer (NK) cells. To better understand NK cell function during pregnancy, we assessed the ability of the two main subsets of NK cells, CD56dim, and CD56bright NK cells, to respond to influenza-virus infected cells and tumor cells. During pregnancy, CD56dim and CD56bright NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ. To better understand the mechanisms driving this enhanced function, we profiled CD56dim and CD56bright NK cells from pregnant and non-pregnant women using mass cytometry. NK cells from pregnant women displayed significantly increased expression of several functional and activation markers such as CD38 on both subsets and NKp46 on CD56dim NK cells. NK cells also displayed diminished expression of the chemokine receptor CXCR3 during pregnancy. Overall, these data demonstrate that functional and phenotypic shifts occur in NK cells during pregnancy that can influence the magnitude of the immune response to both infections and tumors.

The newborn human NK cell repertoire is phenotypically formed but functionally reduced.

BACKGROUND: Infection is a leading cause of death worldwide in babies under 1 month of age. Better vaccines and therapeutics are desperately needed for this vulnerable population. METHODS: Because newborns rely heavily on the innate immune system, we evaluated cell phenotype and function of some of the earliest cellular responders during infection, natural killer (NK) cells. We used mass cytometry to provide a comprehensive comparison of NK cells from umbilical cord blood and adult peripheral blood. RESULTS: In unsupervised analyses, including viSNE and principal component analysis, the structure of the cord blood and adult NK cell repertoires are highly similar, distinguishable mainly by maturity-related markers expressed on rare subpopulations of cells. However, in functional analyses, cord blood NK cells show reduced degranulation and cytokine production following target recognition, as well as antibody-dependent cell-mediated cytotoxicity and apoptosis induction in targets. CONCLUSIONS: These findings show that the structure of the NK cell repertoire is intact at birth, suggesting great potential for vaccine and therapeutic strategies targeting this cell population. © 2016 International Clinical Cytometry Society.

Comparison of rapid intrapartum screening methods for group B streptococcal vaginal colonization.

OBJECTIVE: To compare optical immunoassay (OIA) and rapid polymerase-chain reaction (PCR) with enrichment broth culture for intrapartum detection of vaginal group B streptococcal (GBS) colonization. METHODS: Paired vaginal swabs from 315 consecutive term pregnant women at the time of presentation for delivery to a university medical center were tested for GBS by OIA, PCR, and culture. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Vaginal colonization was identified by culture in 56 subjects (17.8%). The sensitivity of OIA (7.1%, 95% confidence interval 5.1-9.5%) was significantly less than that of unenhanced rapid PCR (62.5%, 95% CI 48.5-74.8%). CONCLUSIONS: Neither PCR nor OIA is sufficiently sensitive for intrapartum detection of vaginal GBS colonization. Rapid PCR is more sensitive, but further improvements in technique to increase sensitivity will be necessary if PCR is to have a useful role in the management of women at time of presentation for delivery.

Severe intrauterine growth restriction associated with the development of a submucosal leiomyoma during pregnancy: a case report.

BACKGROUND: Small, intramural leiomyomas are not generally considered a risk factor for poor reproductive outcomes. CASE: A patient with a 6-mm intramural leiomyoma and a normal uterine cavity by hysteroscopic evaluation who conceived after in vitro fertilization developed severe early-onset intrauterine growth restriction (IUGR), leading to pregnancy termination at 23.4 weeks' gestation. At 6 weeks postpartum, a 1.7-cm, intracavitary leiomyoma was detected on ultrasound evaluation and removed by hysteroscopic resection. The patient conceived in a subsequent in vitro fertilization cycle and gave birth to monozygotic twins with appropriate weights at 34 weeks of gestation. In the absence of other identifiable etiologies of the IUGR, it is plausible that the small, intramural leiomyoma enlarged and migrated into the cavity, causing abnormal placentation and leading to fetal growth restriction in the first pregnancy. CONCLUSION: Uterine cavity reevaluation is recommended in the investigation of IUGR before a woman attempts further pregnancies.