Nicole L. Davis

Perinatal regionalization: a geospatial view of perinatal critical care, United States, 2010–2013

BACKGROUND: Perinatal services exist today as a dyad of maternal and neonatal care. When perinatal care is fragmented or unavailable, excess morbidity and mortality may occur in pregnant women and newborns. OBJECTIVE: The objective of the study was to describe spatial relationships between women of reproductive age, individual perinatal subspecialists (maternal‐fetal medicine and neonatology), and obstetric and neonatal critical care facilities in the United States to identify gaps in health care access. STUDY DESIGN: We used geographic visualization and conducted surface interpolation, nearest neighbor, and proximity analyses. Source data included 2010 US Census, October 2013 National Provider Index, 2012 American Hospital Association, 2012 National Center for Health Statistics Natality File, and the 2011 American Academy of Pediatrics directory. RESULTS: In October 2013, there were 2.5 neonatologists for every maternal‐fetal medicine specialist in the United States. In 2012 there were 1.4 level III or higher neonatal intensive care units for every level III obstetric unit (hereafter, obstetric critical care unit). Nationally, 87% of women of reproductive age live within 50 miles of both an obstetric critical care unit and a neonatal intensive care unit. However, 18% of obstetric critical care units had no neonatal intensive care unit, and 20% of neonatal intensive care units had no obstetric critical care unit within a 10 mile radius. Additionally, 26% of obstetric critical care units had no maternal‐fetal medicine specialist practicing within 10 miles of the facility, and 4% of neonatal intensive care units had no neonatologist practicing within 10 miles. CONCLUSION: Gaps in access and discordance between the availability of level III or higher obstetric and neonatal care may affect the delivery of risk‐appropriate care for high‐risk maternal fetal dyads. Further study is needed to understand the importance of these gaps and discordance on maternal and neonatal outcomes.

Cytomegalovirus infection in pregnancy

Cytomegalovirus (CMV) is a DNA herpesvirus that is common worldwide. The two known main sources of primary CMV infection during pregnancy are through sexual activity and contact with young children. Primary infection occurs in approximately 1 to 4% of pregnancies, and is mostly asymptomatic in immunocompetent adults. However, primary infection may manifest as a mild mononucleosis or flu‐like syndrome with persistent fever and fatigue. CMV can be transmitted from mother‐to‐child in utero, intrapartum, or during breastfeeding. Intrauterine transmission can lead to congenital CMV infection, a leading cause of permanent hearing and vision loss and neurological disability among children. Congenital CMV transmission rates are as high as 50% in women who acquire primary CMV infection during pregnancy, and less than 2% in women with nonprimary infection. There is no licensed CMV vaccine. Good hygiene practices and avoiding intimate contact with young children (e.g., kissing on the mouth and sharing utensils) have been suggested as an approach to prevent maternal primary CMV infection during pregnancy, but remains an unproven method of reducing the risk of congenital CMV infection. Approximately 1 in 10 infants who acquire CMV in utero will have clinical signs at birth, and an additional 10 to 15% will go on to develop late‐onset sequelae. Antiviral treatment prenatally and postnatally has not proven effective at preventing congenital or postnatal CMV infection, and is not recommended for routine clinical care. However, antiviral treatment when initiated in the first month of life for symptomatic congenital CMV infection is recommended for improved neurodevelopmental and audiologic outcomes. Birth Defects Research 109:336–346, 2017.

Maternal and breastmilk viral load: Impacts of adherence on peripartum HIV infections averted - The breastfeeding, antiretrovirals, and nutrition study

Background:Antiretroviral (ARV) interventions are used to reduce HIV viral replication and prevent mother-to-child transmission. Viral suppression relies on adherence to ARVs. Methods:A 2-phase study was conducted using data from the Breastfeeding, Antiretrovirals, and Nutrition study. We included mothers randomized to 28 weeks of postpartum ARVs with ≥1 plasma or breastmilk specimen. All mothers who transmitted HIV to their infants from 2–28 weeks (n = 31) and 15% of mothers who did not (n = 232) were included. Adherence was measured by pill count [categorized as poor (0%–80%), partial (81%–98%), and near perfect (>98%)]. Associations between adherence and breastmilk RNA were assessed using mixed-effects models. Cox models were used to estimate associations between breastmilk RNA and HIV transmission. Using Monte Carlo simulation, we estimated the number of transmissions that would occur had everyone randomized to maternal ARVs been 90% and 100% adherent. Results:Partial or near perfect ARV adherence significantly reduced the odds of having detectable (≥40 copies/mL) breastmilk RNA, compared with poor adherence (Odds Ratio (OR) 0.23, 95% CI: 0.08 to 0.67; OR 0.36, 95% CI: 0.16 to 0.81, respectively). Detectable breastmilk RNA was associated with increased breastmilk transmission compared with undetectable breastmilk RNA (hazard ratio 3.8, 95% CI: 1.2 to 12.1). All transmitting mothers had ≥1 plasma viral load specimen >100 copies per milliliter. An estimated similar number of transmissions would occur with 90% adherence compared with 100%. Conclusions:Helping patients adhere to ARVs throughout breastfeeding is important for realizing the full potential of recommended ARV interventions to prevent mother-to-child HIV transmission. Maintaining plasma viral load <100 copies per milliliter may prevent breastmilk transmission.

Brief Report: Hormonal Contraception Is Not Associated With Reduced ART Effectiveness Among Women Initiating ART: Evidence From Longitudinal Data.

Background: To explore the association between concomitant hormonal contraceptive and antiretroviral therapy (ART) use and (1) plasma viral suppression and (2) genital HIV shedding among HIV-positive women initiating ART. Methods: We analyzed plasma viral load and genital viral RNA shedding from 1079 HIV-positive women initiating ART who were followed prospectively in 3 sub-Saharan African HIV prevention studies. Plasma and endocervical swab samples were collected every 6 months. Self-reported contraceptive use was categorized into injectable, implant, oral, or nonhormonal/no contraception. We used multivariate Cox regression to assess time to plasma viral suppression and logistic regression with generalized estimating equations to assess genital viral shedding for each contraceptive method. Results: At the time of ART initiation, there were 211 (20%) injectable, 69 (6%) implant, 50 (5%) oral, and 749 (69%) nonhormonal or no method users. Plasma viral suppression was high (90% by 6 months) and hormonal contraceptives did not diminish time to plasma viral suppression as compared to nonhormonal/no methods [adjusted hazard ratios: injectables 0.89 (95% confidence interval: 0.75 to 1.07), implants 0.91 (0.68 to 1.23), and oral methods 1.33 (1.06 to 1.66)]. Genital viral shedding was uncommon any time after ART initiation (only 9% of samples had detectable viral shedding) and hormonal contraceptives were not associated with an increased detection of genital viral shedding [adjusted odds ratios: injectables 1.07 (0.69 to 1.65), implants 0.67 (0.31 to 1.49), and oral methods 0.56 (0.19 to 1.69)]. Conclusions: The hormonal contraceptives assessed were not associated with reduced ART effectiveness among HIV-positive women initiating ART. HIV-positive women should continue to be offered contraceptive options, including hormonal ones that best meet their needs.

Concordance of self-reported hormonal contraceptive use and presence of exogenous hormones in serum among African women

OBJECTIVES Studies that rely on self-report to investigate the relationship between hormonal contraceptive use and HIV acquisition and transmission, as well as other health outcomes, could have compromised results due to misreporting. We determined the frequency of misreported hormonal contraceptive use among African women with and at risk for HIV. STUDY DESIGN We tested 1102 archived serum samples from 664 African women who had participated in prospective HIV prevention studies. Using a novel high-performance liquid chromatography-mass spectrometry assay, we quantified exogenous hormones for injectables (medroxyprogesterone acetate or norethisterone), oral contraceptives (OC) (levonorgestrel or ethinyl estradiol) and implants (levonorgestrel or etonogestrel) and compared them to self-reported use. RESULTS Among women reporting hormonal contraceptive use, 258/358 (72%) of samples were fully concordant with self-report, as were 642/744 (86%) of samples from women reporting no hormonal contraceptive use. However, 42/253 (17%) of samples from women reporting injectable use, 41/66 (62%) of samples from self-reported OC users and 3/39 (8%) of samples from self-reported implant users had no quantifiable hormones. Among self-reported nonusers, 102/744 (14%) had ≥1 hormone present. Concordance between self-reported method and exogenous hormones did not differ by HIV status. CONCLUSION Among African women with and at risk for HIV, testing of exogenous hormones revealed agreement with self-reported contraceptive use for most women. However, unexpected exogenous hormones were identified among self-reported hormonal contraceptive users and nonusers, and an important fraction of women reporting hormonal contraceptive use had no hormones detected; absence of oral contraceptive hormones could be due, at least in part, to samples taken during the hormone-free interval. Misreporting of hormonal contraceptive use could lead to biased results in observational studies of the relationship between contraceptive use and health outcomes. IMPLICATIONS Research studies investigating associations between hormonal contraceptive use and HIV should consider validating self-reported use by objective measures; because both overreporting and underreporting of use occur, potential misclassification based on self-report could lead to biased results in directions that cannot be easily predicted.

Discordance between self-reported contraceptive use and detection of exogenous hormones among Malawian women enrolling in a randomized clinical trial

OBJECTIVE The objective was to assess the extent of concordance between self-reported contraceptive use and the presence of contraceptive progestins in serum. STUDY DESIGN We evaluated self-reported contraceptive use by using radioimmunoassay to examine baseline serum levels of medroxyprogesterone acetate (MPA) and levonorgestrel (LNG) among 97 Malawian women enrolling in a contraceptive trial. RESULTS Twelve percent (12/97) of study participants who reported no hormonal contraceptive use in the previous 6months had either MPA or LNG detected in their serum. CONCLUSIONS The observed discordance between self-report and detection of exogenous hormones in serum indicates that caution is warranted when drawing conclusions based on self-reported contraceptive use.

Contribution of maternal age and pregnancy checkbox on maternal mortality ratios in the United States, 1978–2012

Background Maternal mortality ratios (MMR) appear to have increased in the United States over the last decade. Three potential contributing factors are (1) a shifting maternal age distribution, (2) changes in age‐specific MMR, and (3) the addition of a checkbox indicating recent pregnancy on the death certificate. Objective To determine the contribution of increasing maternal age on changes in MMR from 1978 to 2012 and estimate the contribution of the pregnancy checkbox on increases in MMR over the last decade. Study Design Kitagawa decomposition analyses were conducted to partition the maternal age contribution to the MMR increase into 2 components: changes due to a shifting maternal age distribution and changes due to greater age‐specific mortality ratios. We used National Vital Statistics System natality and mortality data. The following 5‐year groupings were used: 1978–1982, 1988–1992, 1998–2002, and 2008–2012. Changes in age‐specific MMRs among states that adopted the standard pregnancy checkbox onto their death certificate before 2008 (n = 23) were compared with states that had not adopted the standard pregnancy checkbox on their death certificate by the end of 2012 (n = 11) to estimate the percentage increase in the MMR due to the pregnancy checkbox. Results Overall US MMRs for 1978–1982, 1988–1992, and 1998–2002 were 9.0, 8.1, and 9.1 deaths per 100,000 live births, respectively. There was a modest increase in the MMR between 1998–2002 and 2008–2012 in the 11 states that had not adopted the standard pregnancy checkbox on their death certificate by the end of 2012 (8.6 and 9.9 deaths per 100,000, respectively). However, the MMR more than doubled between 1998–2002 and 2008–2012 in the 23 states that adopted the standard pregnancy checkbox (9.0–22.4); this dramatic increase was almost entirely attributable to increases in age‐specific MMRs (94.9%) as opposed to increases in maternal age (5.1%), with an estimated 90% of the observed change reflecting the change in maternal death identification rather than a real change in age‐specific rates alone. Of all age categories, women ages 40 and older in states that adopted the standard pregnancy checkbox had the largest increase in MMR—from 31.9 to 200.5—a relative increase of 528%, which accounted for nearly one third of the overall increase. An estimated 28.8% of the observed change was potentially due to maternal death misclassification among women ≥40 years. Conclusion Increasing age‐specific maternal mortality seems to be contributing more heavily than a changing maternal age distribution to recent increases in MMR. In states with the standard pregnancy checkbox, the vast majority of the observed change in MMR over the last decade was estimated to be due to the pregnancy checkbox, with the greatest change in MMR occurring in women ages ≥40 years. The addition of a pregnancy checkbox on state death certificates appears to be increasing case identification but also may be leading to maternal death misclassification, particularly for women ages ≥40 years.

Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS

OBJECTIVE The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) and apply this method to human serum samples. STUDY DESIGN We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. We analyzed serum collected from women self-reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). RESULTS Limits of quantitation were 0.010ng/mL for E2, EE2 and P4; 0.020ng/mL for ENG, LNG and MPA; and 0.040ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%-108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. CONCLUSIONS We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. IMPLICATIONS This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing.

Prevalence, Magnitude, and Correlates of HIV-1 Genital Shedding in Women on Antiretroviral Therapy

Background Genital human immunodeficiency virus (HIV) RNA shedding can continue despite HIV being undetectable in blood, and can be associated with transmission. Methods We included African women on antiretroviral therapy (ART). Linear and generalized linear mixed models were used to compare the magnitude and prevalence of genital shedding, respectively, by time since ART initiation. Multivariable logistic regression with generalized estimating equations was used to assess predictors of genital shedding among women with undetectable plasma viral load (VL). Results Among 1114 women, 5.8% of visits with undetectable plasma VL and 23.6% of visits with detectable VL had genital shedding. The proportion of visits with genital shedding decreased with time since ART initiation but the magnitude of shedding remained unchanged when plasma VL was undetectable (P = .032). Prevalence of shedding did not vary by time since ART initiation when plasma VL was detectable (P = .195), though the magnitude of shedding significantly increased (P = .04). Predictors of genital shedding were HIV disease stage, antiretroviral regimen, and genital ulcers or cervical tenderness. Discussion In addition to ART, reducing immune activation through prevention and treatment of HIV-related conditions and genital tract infections may decrease the risk of HIV-1 shedding and potential transmission.