Maternal folate status and placental vascular malperfusion: Findings from a high-risk US minority birth cohort.

INTRODUCTION: Maternal folate deficiency was associated with preeclampsia (PE) and PE was associated with placental maternal vascular malperfusion (MVM). However, no study has examined the association of maternal folate status with placental MVM. METHODS: We examined the association of maternal folate status and placental MVM in the Boston Birth Cohort. Primary exposure variables were maternal self-reported multivitamin supplement (<2, 3-5, >5 times/week) per trimester; and plasma folate levels (nmol/L) after birth. Primary outcome was presence/absence of placental MVM defined by the Amsterdam Placental Workshop Group standard classification. Covariates included demographics, chronic hypertension, clinically diagnosed PE, eclampsia and HELLP syndrome, gestational and pre-gestational diabetes, overweight/obesity, maternal cigarette smoking and alcohol use. Associations between folate and placental MVM were evaluated using multivariate logistic regressions. RESULTS: Of 3001 mothers in this study, 18.8% of mothers had PE, 37.5% had MVM. Mothers with the lowest self-reported frequency of folate intake had the highest risk of MVM (OR 1.45, 95% CI 1.03-2.05), after adjusting for the covariates. Consistently, among a subset of 939 mothers with plasma folate levels, folate insufficiency was associated with increased risk of MVM (OR 1.65, 95% CI 1.03-2.63), after adjusting for the covariables. As expected, mothers with low folate and placental MVM had highest rates of PE compared to those of high folate and no MVM (p < 0.001). DISCUSSION: In this high-risk birth cohort, low maternal folate status was associated with increased risk of placental MVM. Further investigation should explore the association between folate status, placental findings and the great obstetrical syndrome.

Boston Birth Cohort profile: rationale and study design.

In1998, the Boston Birth Cohort (BBC) was initiated at Boston Medical Center (BMC) in response to persistently high rates of preterm birth (PTB, defined as birth before 37 weeks of gestation) in the US population and the longstanding profound PTB disparity among Black, Indigenous, and people of color (BIPOC). The BBC encompasses two linked study protocols: The PTB Study serves as the baseline recruitment in the BBC. It aims to address fundamental questions about the causes and consequences of PTB. The study oversamples preterm babies using a case/control study design, in which cases are defined as mothers who deliver a preterm and/or low birthweight baby (<2500 grams regardless of gestational age). Controls are enrolled at a 2:1 control/case ratio and matched by maternal age (±5 years), self-reported race and ethnicity, and date of delivery (± 7 days for case delivery). From inception, it was designed as a comprehensive gene-environmental study of PTB. As a natural extension, the Children's Health Study, under a separate but linked Institutional Review Board protocol, is a longitudinal follow-up study of the participants who were recruited at birth in the PTB Study and who continue pediatric care at BMC. This linked model allows for investigation of early life origins of pediatric and chronic disease in a prospective cohort design. The BBC is one of the largest and longest National Institutes of Health-funded prospective birth cohort studies in the United States, consisting of 8733 mother-child dyads enrolled in the PTB Study at birth, and of those, 3592 children have been enrolled in the Children's Health Study, with a median follow-up of 14.5 years. The BBC mirrors the urban, underresourced, and underrepresented BIPOC population served by BMC. A high proportion of BBC children were born prematurely and had chronic health conditions (e.g., asthma, obesity, and elevated blood pressure) in childhood. The BBC's long-term goal has been to build a large, comprehensive database (epidemiological, clinical, and multiomics) and biospecimen repository to elucidate early life origins of pediatric and chronic diseases and identify modifiable upstream factors (e.g., psychosocial, environmental, and nutritional) to improve health across the life course for BIPOC mothers and children.

Association of Placental Pathology With Childhood Blood Pressure Among Children Born Preterm.

BACKGROUND: The in utero pathologies underlying the link between preterm birth and offspring high blood pressure (BP) are still unknown. We investigated the prospective associations of placental histopathological findings with childhood BP among children born preterm. METHODS: Our study sample included 546 mother-child pairs with preterm birth (before 37 weeks gestation) enrolled from 1999 to 2013 at the Boston Medical Center. Early preterm birth was defined as gestational age between 23 and 34 weeks. We histologically classified maternal placental pathology using the latest recommended categories: no placental complications, histologic chorioamnionitis, maternal vascular malperfusion, and other placental complications. We calculated age-, sex-, and height-specific systolic BP (SBP) percentiles for children using the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models with generalized estimating equations to examine the associations. RESULTS: The mean (standard deviation (SD)) postnatal follow-up of the study children was 9.29 (4.1) years. After adjusting for potential confounders, histologic chorioamnionitis was associated with a 5.42 percentile higher childhood SBP (95% confidence interval: 0.32, 10.52) compared with no placental pathologic findings. This association was stronger among early preterm children. Maternal vascular malperfusion was associated with a 8.44 percentile higher childhood SBP among early preterm children (95% confidence interval: 1.54, 15.34) but the association was attenuated (6.25, 95% confidence interval: -0.76, 13.26) after additional adjustment for child standardized birthweight, a potential mediator of the association. CONCLUSIONS: These findings suggest that among children born preterm, especially those born early preterm, both placental histologic chorioamnionitis and vascular malperfusion may help to differentiate a child's risk of high BP.

Complications of Neurofibromatosis 1 (NF1) in an Adult With Multiple Comorbidities.

Neurofibromatosis (NF) is an autosomal genetic disorder with three types, including NF1, NF2, and schwannomatosis. It is characterized by bulging and deforming masses arising from multiple nerves involving skin folds and connective tissues. Prompt diagnosis and provision of care for NF1 patients by clinicians aware of the diverse clinical features of this disorder are needed for optimum patient care and management. A 65-year-old African American female with a past medical history significant for multiple neurofibromas covering more than 95% of her total body surface area (TBSA), presented to a primary care clinic with an enlarged ulcerated neurofibroma of the right elbow. She reported associated pulsating, sharp pain, which was radiating to her entire right upper extremity. For most of her adult life, the lesion has been present and began as the rest of the neurofibromas on her body but gradually enlarged with eventual ulceration three months before the visit. The patient reported a failed surgical resection for the same neurofibroma several years ago. She also reported diffuse tenderness of the lesion, which severely impaired her daily living activities and limited her sleep ability. She acknowledged using multiple over-the-counter analgesics, prescription hydrocodone/acetaminophen 5/325 mg as needed, and gabapentin 300 mg orally twice daily but denied significant symptom alleviation. The patient was started on oral clindamycin hydrochloride 300 mg every six hours for 10 days and a topical mupirocin ointment 2% three times daily for five days. Subsequent visits showed no improvement of the ulcer, which necessitated a referral to wound care. After multiple wound care visits without progress, the patient was referred to a plastic surgeon for evaluation for repeat ulcer resection. NF1 patients develop multiple tumors (neurofibromas); approximately 8%-15% percent of them present with malignant peripheral nerve sheath tumors (MPNST) within the patient's lifetime. Tumor ulceration is a rare but possible complication of NF1. Due to the acute ulcerated fibromas' complications, previous unsuccessful cosmetic management, and ambiguity about NF1 disorder, the patient's quality of life was impaired. The physical and emotional pain the patient experienced impacted her activities of daily living and likely contributed to or exacerbated her diagnoses of substance use disorder and major depressive disorder. NF1 is incurable and can be associated with complications that deteriorate the quality of life, depending on symptom severity. The condition impacts patients' bodies, minds, and spirits, as seen in this patient who had diagnoses of substance use disorder and major depressive disorder, as well as a history of suicidal ideation and suicide attempts. The treatment of conditions related to NF1 is best managed in centers equipped with doctors experienced in treating patients with NF1. A multidisciplinary management approach is ideal. Preferably, for the management of chronic pain and beyond, the osteopathic holistic approach, targeting the body, mind, and spirit, in combination with other innovative non-pharmacotherapies and pharmacotherapy methods, would be beneficial.

Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth.

BACKGROUND: Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent. METHODS: To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research. RESULTS: rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (PG × E = 4.7 × 10-8). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (PG × E = 0.088) and Caucasian mothers (PG × E = 0.023) from the GPN study. CONCLUSION: We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB. IMPACT: This was the first preterm study to demonstrate a significant genome-wide gene-stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth. The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study. Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.

Maternal vascular malperfusion of the placental bed associated with hypertensive disorders in the Boston Birth Cohort.

INTRODUCTION: The associations of maternal conditions, before or during pregnancy, with placental lesions have not been adequately studied in populations. METHODS: In the Boston Birth Cohort, we evaluated associations between three maternal medical conditions (hypertensive disorders [HDs], gestational/pre-gestational diabetes and obesity), and placental histological findings, using a standardized classification system proposed by the Amsterdam Placental Workshop Group. Placental pathology diagnoses and clinical data from 3074 mothers with clinical indications who delivered singleton live births at the Boston Medical Center between October 1998 and November 2013 were evaluated. Associations between each maternal condition and maternal vascular malperfusion (MVM) of the placental bed and its standardized subgroups were examined using multivariate logistic and multinomial regressions. RESULTS: Women with HDs (chronic hypertension, eclampsia, preeclampsia, HELLP syndrome) had significantly increased odds of MVM lesions when compared to women with no HD (aOR 2.08 95% CI 1.74-2.50), after adjusting for demographics, substance use, diabetes and body mass index. No significant differences in frequencies or aORs were seen in women with and without diabetes, or across body mass index categories. Co-morbid condition patterns that included HDs were more likely to be associated with MVM than those without. DISCUSSION: Using a standardized classification system, we showed that MVM is strongly and specifically associated with maternal HDs, but not other maternal conditions. Additional studies are needed to confirm and validate our findings, and evaluate the role of maternal vascular lesions of the placental bed in relation to postnatal growth and development of the offspring and effect modifiers.