Investigating the Shape and Strength of the Relationship Between Maternal Weight Gain and Gestational Age at Delivery in Twin and Singleton Pregnancies.

Both inadequate and excessive maternal weight gain are correlated with preterm delivery in singleton pregnancies, yet this relationship has not been adequately studied in twins. We investigated the relationship between time-varying maternal weight gain and gestational age at delivery in twin pregnancies and compared it with that in singletons delivered in the same study population. We used serial weight measurements abstracted from charts for twin and singleton pregnancies delivered during 1998-2013 in Pittsburgh, Pennsylvania. Our exposure was time-varying weight gain z score, calculated using gestational age-standardized and prepregnancy body mass index-stratified twin- and singleton-specific charts, and our outcome was gestational age at delivery. Our analyses used a flexible extension of the Cox proportional hazards model that allowed for nonlinear and time-dependent effects. We found a U-shaped relationship between weight gain z score and gestational age at delivery among twin pregnancies (lowest hazard of delivery observed at z score = 1.2), which we attributed to increased hazard of early preterm spontaneous delivery among pregnancies with low weight gain and increased hazard of late preterm delivery without labor among pregnancies with high weight gain. Our findings may be useful for updating provisional guidelines for maternal weight gain in twin pregnancies.

What Has the Pandemic Revealed about the Shortcomings of Modern Epidemiology? What Can We Fix or Do Better?

In this commentary, we discuss themes that emerged from our symposium about what modern epidemiology as a science may learn from the COVID-19 pandemic. We reflect on the successes and limitations of this discipline from multiple perspectives, including from junior and senior epidemiologists and scientists on the front lines of generating evidence for the COVID-19 pandemic response in Wuhan, China, to Ontario, Canada. These themes include the role of the traditional scientific process in a public health emergency; epidemiologic methods and data that are critical for an effective pandemic response; the interventions that epidemiologists recommended and interventions that we may explore in the future; inequitable impacts of the COVID-19 pandemic contrasted with homogeneity in the epidemiologist workforce; effective and honest communication of uncertainty; trust and collaboration; and the extent to which these themes are currently reflected in our training programs and discipline. We look forward to insights from field epidemiologists directly involved in the ongoing response to the COVID-19 pandemic and further reflection from epidemiologists throughout our discipline.

Gestational Diabetes in Twin Versus Singleton Pregnancies With Normal Weight or Overweight Pre-Pregnancy Body Mass Index: The Mediating Role of Mid-Pregnancy Weight Gain.

BACKGROUND: Gestational diabetes might be more common in twin versus singleton pregnancies, yet the reasons for this are unclear. We evaluated the extent to which this relationship is explained by higher mid-pregnancy weight gain within normal weight and overweight pre-pregnancy body mass index (BMI) strata. METHODS: We analyzed serial weights and glucose screening and diagnostic data abstracted from medical charts for twin (n = 1397) and singleton (n = 3117) pregnancies with normal or overweight pre-pregnancy BMI delivered from 1998 to 2013 at Magee-Womens Hospital in Pennsylvania. We used causal mediation analyses to estimate the total effect of twin versus singleton pregnancy on gestational diabetes, as well as those mediated (natural indirect effect) and not mediated (natural and controlled direct effects) by pathways involving mid-pregnancy weight gain. RESULTS: Odds of gestational diabetes were higher among twin pregnancies [odds ratios (ORs) for total effect = 2.83 (95% CI = 1.54, 5.19) for normal weight and 2.09 (95% CI = 1.16, 3.75) for overweight pre pregnancy BMI], yet there was limited evidence that this relationship was mediated by mid-pregnancy weight gain [ORs for natural indirect effect = 1.21 (95% CI = 0.90, 1.24) for normal weight and 1.06 (95% CI = 0.92, 1.21) for overweight pre-pregnancy BMI] and more evidence of mediation via other pathways [ORs for natural direct effect = 2.34 (95% CI = 1.24, 4.40) for normal weight and 1.97 (95% CI = 1.08, 3.60) for overweight pre-pregnancy BMI]. CONCLUSIONS: While twin pregnancies with normal weight or overweight pre-pregnancy BMI experienced higher odds of gestational diabetes versus singletons, most of this effect was explained by pathways not involving mid-pregnancy weight gain.

Consider This Before Using the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic as an Instrumental Variable in an Epidemiologic Study.

Epidemiologists sometimes use external sources of variation to explore highly confounded exposure-outcome relationships or exposures that cannot be randomized. These exogenous sources of variation, or natural experiments, are sometimes proposed as instrumental variables to examine the effects of given exposures on given outcomes. Previous epidemiologic studies have applied this technique using famines, earthquakes, weather events, and previous pandemics as exogenous sources of variation for other exposures; interest in applying this technique using the current severe acute respiratory system coronavirus 2 (SARS-CoV-2) pandemic is already documented. Yet large-scale events like these likely have broad and complicated impacts on human health, which almost certainly violates the exclusion restriction assumption of instrumental variable analyses. We review the assumptions of instrumental variable analyses, highlight previous applications of this method with respect to natural experiments with broad impacts or "shocks," and discuss how these relate to our current observations of the SARS-CoV-2 pandemic. While we encourage thorough investigation of the broad impacts of the SARS-CoV-2 pandemic on human health, we caution against its widespread use as an instrumental variable to study other exposures of interest.

The Impact of Parental and Medical Leave Policies on Socioeconomic and Health Outcomes in OECD Countries: A Systematic Review of the Empirical Literature.

Policy Points: Historically, reforms that have increased the duration of job-protected paid parental leave have improved women's economic outcomes. By targeting the period around childbirth, access to paid parental leave also appears to reduce rates of infant mortality, with breastfeeding representing one potential mechanism. The provision of more generous paid leave entitlements in countries that offer unpaid or short durations of paid leave could help families strike a balance between the competing demands of earning income and attending to personal and family well-being. CONTEXT: Policies legislating paid leave from work for new parents, and to attend to individual and family illness, are common across Organisation for Economic Co-operation and Development (OECD) countries. However, there exists no comprehensive review of their potential impacts on economic, social, and health outcomes. METHODS: We conducted a systematic review of the peer-reviewed literature on paid leave and socioeconomic and health outcomes. We reviewed 5,538 abstracts and selected 85 published papers on the impact of parental leave policies, 22 papers on the impact of medical leave policies, and 2 papers that evaluated both types of policies. We synthesized the main findings through a narrative description; a meta-analysis was precluded by heterogeneity in policy attributes, policy changes, outcomes, and study designs. FINDINGS: We were able to draw several conclusions about the impact of parental leave policies. First, extensions in the duration of paid parental leave to between 6 and 12 months were accompanied by attendant increases in leave-taking and longer durations of leave. Second, there was little evidence that extending the duration of paid leave had negative employment or economic consequences. Third, unpaid leave does not appear to confer the same benefits as paid leave. Fourth, from a population health perspective, increases in paid parental leave were consistently associated with better infant and child health, particularly in terms of lower mortality rates. Fifth, paid paternal leave policies of adequate length and generosity have induced fathers to take additional time off from work following the birth of a child. How medical leave policies for personal or family illness influence health has not been widely studied. CONCLUSIONS: There is substantial quasi-experimental evidence to support expansions in the duration of job-protected paid parental leave as an instrument for supporting women's labor force participation, safeguarding women's incomes and earnings, and improving child survival. This has implications, in particular, for countries that offer shorter durations of job-protected paid leave or lack a national paid leave entitlement altogether.

Maternal vitamin D supplementation during pregnancy and lactation to prevent acute respiratory infections in infancy in Dhaka, Bangladesh (MDARI trial): protocol for a prospective cohort study nested within a randomized controlled trial.

BACKGROUND: Early infancy is a high-risk period for severe acute respiratory infection (ARI), particularly in low-income countries with resource-limited health systems. Lower respiratory tract infection (LRTI) is commonly preceded by upper respiratory infection (URTI), and often caused by respiratory syncytial virus (RSV), influenza and other common community-acquired viral pathogens. Vitamin D status is a candidate modifiable early-life determinant of the host antiviral immune response and thus may influence the risk of ARI-associated morbidity in high-risk populations. METHODS/DESIGN: In the Maternal Vitamin D for Infant Growth (MDIG) study in Dhaka, Bangladesh (NCT01924013), 1300 pregnant women are randomized to one of five groups: placebo, 4200 IU/week, 16,800 IU/week, or 28,000 IU/week from 2nd trimester to delivery plus placebo from 0-6 months postpartum; or, 28,000 IU/week prenatal and until 6-months postpartum. In the Maternal Vitamin D for ARI in Infancy (MDARI) sub-study nested within the MDIG trial, trained personnel conduct weekly postnatal home visits to inquire about ARI symptoms and conduct a standardized clinical assessment. Supplementary home visits between surveillance visits are conducted when caregivers make phone notifications of new infant symptoms. Mid-turbinate nasal swab samples are obtained from infants who meet standardized clinical ARI criteria. Specimens are tested by polymerase chain reaction (PCR) for 8 viruses (influenza A/B, parainfluenza 1/2/3, RSV, adenovirus, and human metapneumovirus), and nasal carriage density of Streptococcus pneumoniae. The primary outcome is the incidence rate of microbiologically-positive viral ARI, using incidence rate ratios to estimate between-group differences. We hypothesize that among infants 0-6 months of age, the incidence of microbiologically-confirmed viral ARI will be significantly lower in infants whose mothers received high-dose prenatal/postpartum vitamin D supplements versus placebo. Secondary outcomes include incidence of ARI associated with specific pathogens (influenza A or B, RSV), clinical ARI, and density of pneumococcal carriage. DISCUSSION: If shown to reduce the risk of viral ARI in infancy, integration of maternal prenatal/postpartum vitamin D supplementation into antenatal care programs in South Asia may be a feasible primary preventive strategy to reduce the burden of ARI-associated morbidity and mortality in young infants. TRIAL REGISTRATION: NCT02388516 , registered March 9, 2015.

Utility and feasibility of integrating pulse oximetry into the routine assessment of young infants at primary care clinics in Karachi, Pakistan: a cross-sectional study.

BACKGROUND: Hypoxemia may occur in young infants with severe acute illnesses or congenital cardiac anomalies, but is not reliably detected on physical exam. Pulse oximetry (PO) can be used to detect hypoxemia, but its application in low-income countries has been limited, and its feasibility in the routine assessment of young infants (aged 0-59 days) has not been previously studied. The aim of this study was to characterize the operational feasibility and parent/guardian acceptability of incorporating PO into the routine clinical assessment of young infants in a primary care setting in a low-income country. METHODS: This was a cross-sectional study of 862 visits by 529 infants at two primary care clinics in Karachi, Pakistan (March to June, 2013). After clinical assessment, oxygen saturation (Sp02) was measured by a handheld PO device (Rad-5v, Masimo Corporation) according to a standardized protocol. Performance time (PT) was the time between sensor placement and attainment of an acceptable PO reading (i.e., stable SpO2 + 1% for at least 10 s, heart rate displayed, and adequate signal indicators). PT included the time for one repeat attempt at a different anatomical site if the first attempt did not yield an acceptable reading within 1 min. Parent/guardian acceptability of PO was based on a questionnaire and unprompted comments about the procedure. All infants underwent physician assessment. RESULTS: Acceptable PO readings were obtained in ≤ 1 and ≤ 5 min at 94.4% and 99.8% of visits, respectively (n = 862). Median PT was 42 s (interquartile range 37; 50). Parents/guardians overwhelmingly accepted PO (99.6% overall satisfaction, n = 528 first visits). Of 10 infants with at least one visit with Sp02 <92% on a first PO attempt, 3 did not have a significant acute illness on physician assessment. There were no PO-related adverse events. DISCUSSION: Using a commercially available handheld pulse oximeter, acceptable Sp02 measurements were obtained in nearly all infants in under 1 minute. The procedure was readily integrated into existing assessment pathways and parents/guardians had positive views of the technology. CONCLUSIONS: When incorporated into routine clinical assessment of young infants at primary care clinics in a low-income country, PO was feasible and acceptable to parents/guardians. Future research is needed to determine if the introduction of routine PO screening of young infants will improve outcomes in low-resource settings.

How global is global health research? A large-scale analysis of trends in authorship.

Many have called for greater inclusion of researchers from low- and middle-income countries (LMICs) in the conduct of global health research, yet the extent to which this occurs is unclear. Prior studies are journal-, subject-, or region-specific, largely rely on manual review, and yield varying estimates not amenable to broad evaluation of the literature. We conducted a large-scale investigation of the contribution of LMIC-affiliated researchers to published global health research and examined whether this contribution differed over time. We searched titles, abstracts, and keywords for the names of countries ever classified as low-, lower middle-, or upper middle-income by the World Bank, and limited our search to items published from 2000 to 2017 in health science-related journals. Publication metadata were obtained from Elsevier/Scopus and analysed in statistical software. We calculated proportions of publications with any, first, and last authors affiliated with any LMIC as well as the same LMIC(s) identified in the title/abstract/keywords, and stratified analyses by year, country, and countries' most common income status. We analysed 786 779 publications and found that 86.0% included at least one LMIC-affiliated author, while 77.2% and 71.2% had an LMIC-affiliated first or last author, respectively; however, analagous proportions were only 58.7%, 36.8%, and 29.1% among 100 687 publications about low-income countries. Proportions of publications with LMIC-affiliated authors increased over time, yet this observation was driven by high research activity and representation among upper middle-income countries. Between-country variation in representation was observed, even within income status categories. We invite comment regarding these findings, particularly from voices underrepresented in this field.

Guidance for design and analysis of observational studies of fetal and newborn outcomes following COVID-19 vaccination during pregnancy.

COVID-19 vaccines are now being deployed as essential tools in the public health response to the global SARS-CoV-2 pandemic. Pregnant individuals are a unique subgroup of the population with distinctive considerations regarding risk and benefit that extend beyond themselves to their fetus/newborn. As a complement to traditional pharmacovigilance and clinical studies, evidence to comprehensively assess COVID-19 vaccine safety in pregnancy will need to be generated through observational epidemiologic studies in large populations. However, there are several unique methodological challenges that face observational assessments of vaccination during pregnancy, some of which may be more pronounced for COVID-19 studies. In this contribution, we discuss the most critical study design, data collection, and analytical issues likely to arise. We offer brief guidance to optimize the quality of such studies to ensure their maximum value for informing public health decision-making.

Comparison of methods for interpolating gestational weight gain between clinical visits in twin and singleton pregnancies.

PURPOSE: Researchers are interested in studying longitudinal patterns of gestational weight gain, yet this requires daily/weekly weights, and maternal weight is measured only during prenatal visits. We evaluated the relative accuracy and precision of methods for estimating maternal weight gain between prenatal visits among twin and singleton pregnancies. METHODS: We analyzed cohorts of dichorionic twin and singleton pregnancies delivered from 1998-2013 in Pittsburgh, Pennsylvania. We mimicked a typical study by retaining pre-pregnancy, first prenatal visit, glucose screening visit, and delivery weights, using these to fit interpolation models, estimating weight throughout pregnancy using 16 different methods, and calculating the difference in kilograms between predicted and measured values among remaining weights. We evaluated the performance of each model by calculating root mean squared error (RMSE). RESULTS: RMSE ranged from 1.55 to 6.09 kg in twins (n = 2067) and 1.45 to 4.87 kg in singletons (n = 7331). The most accurate and precise methods incorporated restricted cubic splines, random intercepts and slopes for pregnancy, and internal knots demarcating trimesters/quantiles (RMSE = 1.55/1.56 kg in twins, 1.45/1.45 kg in singletons), while individual-level linear interpolation between proximal measurements also performed well. CONCLUSIONS: Accuracy and precision of methods for estimating maternal weight gain between measurements differed by model, and were best among individually-tailored and flexible models.

Effects of Maternal Vitamin D Supplementation During Pregnancy and Lactation on Infant Acute Respiratory Infections: Follow-up of a Randomized Trial in Bangladesh.

BACKGROUND: We examined the effect of maternal vitamin D supplementation during pregnancy and lactation on risk of acute respiratory infection (ARI) in infants up to 6 months of age in Bangladesh. METHODS: This study was nested in a randomized, double-blind, placebo-controlled, 5-arm dose-ranging trial of prenatal and postpartum vitamin D supplementation. One group of women received 0 IU vitamin D per week during pregnancy and for 26 weeks post delivery ("placebo" group), one group received high-dose prenatal vitamin D supplementation of 28 000 IU per week and 26 weeks post delivery, and there were 3 additional dose-ranging groups receiving vitamin D supplementation during pregnancy only (4200, 16 800, and 28 000 IU per week, respectively). Episodes of ARI were identified by active and passive surveillance. The primary outcome was microbiologically confirmed ARI, and the primary analysis compared the high-dose prenatal plus postpartum vitamin D vs placebo groups. RESULTS: In total, 1174 mother-infant pairs were included. Among infants born to mothers in the placebo group, 98% had a venous umbilical cord 25(OH)D level below 30 nmol/L compared with none in the high-dose prenatal plus postdelivery vitamin D group. Incidence of microbiologically confirmed ARI in the high-dose prenatal plus postpartum vitamin D (1.21 episodes per 6 person-months; N = 235) and placebo groups (1.07 episodes per 6 person-months; N = 234) was not significantly different (hazard ratio of 1.12 [95% confidence intervals: 0.90-1.40]). There were no differences in the incidence of microbiologically confirmed or clinical ARI, upper, lower, or hospitalized lower respiratory tract infection between high-dose prenatal plus postpartum vitamin D and placebo groups. CONCLUSIONS: Despite a high prevalence of maternal baseline vitamin D deficiency and significant effects of maternal vitamin D supplementation on infant vitamin D status, the intervention did not reduce the risk of microbiologically confirmed ARI in infants up to 6 months of age.

Effect of weekly high-dose vitamin D3 supplementation on serum cholecalciferol concentrations in pregnant women.

Vitamin D status is conventionally defined by the serum concentration of 25-hydroxyvitamin D. However, it has been proposed that the serum cholecalciferol concentration (D3) also determines functional vitamin D sufficiency. The objective of this study was to describe the effect of weekly high-dose vitamin D3 supplementation on inter-dose serum D3 in pregnant women. We conducted a sub-study of a completed randomized double-blind placebo-controlled trial of vitamin D3 (35,000 IU/week) supplementation in late pregnancy (AViDD trial) in Dhaka, Bangladesh. This study included pregnant women enrolled at 26-29 weeks gestation who fully adhered to the prenatal supplement intervention for ≥8 consecutive weeks and for whom serum samples were available for D3 analysis (n=65). Serum D3 was uniformly low at enrolment. Mean D3 increased and was maximal at 1 day after vitamin D dose administration (152.09nmol/L, SD 25.11nmol/L) and remained significantly higher in VitD vs. Pl at 7 days (29.59nmol/L vs. 1.92nmol/L, p=0.007). Daily average of the group mean D3 during the week following dosing was 66.97nmol/L in VitD versus 2.13nmol/L in Pl. In conclusion, serum D3 remained significantly elevated throughout the week following ≥8 consecutive weekly doses of 35,000 IU D3 in pregnant women. However, the clinically significant minimum threshold of serum D3 remains to be established.

Maternal vitamin D supplementation during pregnancy and lactation to promote infant growth in Dhaka, Bangladesh (MDIG trial): study protocol for a randomized controlled trial.

BACKGROUND: Vitamin D regulates bone mineral metabolism and skeletal development. Some observational studies have suggested that prenatal vitamin D deficiency increases the risk of adverse pregnancy and/or birth outcomes; however, there is scant evidence from controlled trials, leading the World Health Organization to advise against routine vitamin D supplementation in pregnancy. Importantly, little is known about the effect of maternal vitamin D status on infant linear growth in communities in South Asia where stunting is highly prevalent and maternal-infant vitamin D status is commonly suboptimal. METHODS/DESIGN: The Maternal Vitamin D for Infant Growth study is a randomized, placebo-controlled, dose-ranging trial of maternal vitamin D supplementation during pregnancy and lactation in Dhaka, Bangladesh. The primary aims are to estimate (1) the effect of maternal prenatal oral vitamin D3 supplementation (4200 IU/wk, 16,800 IU/wk, or 28,000 IU/wk, administered as weekly doses) versus placebo on infant length at 1 year of age and (2) the effect of maternal postpartum oral vitamin D3 supplementation (28,000 IU/wk) versus placebo on length at 1 year of age among infants born to women who received vitamin D 28,000 IU/wk during pregnancy. Generally healthy pregnant women (n = 1300) in the second trimester (17-24 weeks of gestation) are randomized to one of five parallel arms: placebo 4200 IU/wk, 16,800 IU/wk, or 28,000 IU/wk in the prenatal period and placebo in the postpartum period or 28,000 IU/wk in the prenatal period and 28,000 IU/wk in the postpartum period. Household- and clinic-based follow-up of mother-infant pairs is conducted weekly by trained personnel until 26 weeks postpartum and every 3 months thereafter. The primary trial outcome measure is length for age z-score at 1 year of age. Anthropometric measurements, clinical information, and biological specimens collected at scheduled intervals will enable the assessment of a range of maternal, perinatal, and infant outcomes. DISCUSSION: The role of vitamin D in maternal and infant health remains unresolved. This trial is expected to contribute unique insights into the effects of improving maternal-infant vitamin D status in a low-income setting where stunting and adverse perinatal outcomes represent significant public health burdens. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01924013. Registered on 13 August 2013.

Bioavailability of enteric-coated microencapsulated calcium during pregnancy: a randomized crossover trial in Bangladesh.

BACKGROUND: Prenatal calcium and iron supplements are recommended in settings of low dietary calcium intake and high prevalence of anemia. However, calcium administration may inhibit iron absorption. To overcome calcium-iron interactions, we developed a multi-micronutrient powder containing iron (60 mg), folic acid (400 µg), and calcium carbonate granules microencapsulated with a pH-sensitive enteric coating to delay intestinal release. OBJECTIVES: We aimed to establish in vivo evidence that enteric-coated (EC) calcium is bioavailable in pregnant women and to explore the dose-responsiveness of fractional calcium absorption (FCA) in pregnancy. DESIGN: This was a randomized crossover trial in pregnant women (26-28 wk of gestation) in Dhaka, Bangladesh. Participants were allocated to 1 of 3 dose groups (500, 1000, or 1500 mg elemental Ca). FCA was estimated in random order for EC and non-EC (control) granules by a dual-stable-isotope method ((44)Ca-labeled granules and intravenous (42)Ca) on the basis of the relative recovery of (44)Ca compared with (42)Ca in urine over 48 h. RESULTS: Forty-nine participants with FCA for both EC and non-EC granules were included in the primary analyses. FCA geometric means were as follows: 21.8% (500 mg), 9.2% (1000 mg), and 11.7% (1500 mg) for non-EC granules compared with 3.3% (500 mg), 1.2% (1000 mg), and 2.1% for EC granules. Cumulative 48-h FCA of EC calcium was 85% lower (P < 0.001) than that of non-EC calcium, after adjustment for dose. In comparison to 500 mg, the FCA for the 1000-mg dose was 61% lower (P < 0.001) and was 42% lower (P = 0.002) for the 1500-mg dose, after adjustment for formulation. CONCLUSIONS: A pH-sensitive enteric coating substantially reduced calcium absorption from a prenatal multi-micronutrient powder. In its current formulation, this novel supplement is not suitable for clinical use. FCA was highly dose-dependent, such that doses of 1000 and 1500 mg delivered only negligibly more bioavailable calcium than the 500-mg dose. This trial was registered at clinicaltrials.gov as NCT01678079.