Maternal Depletion Research Articles

Ocular Effects of Prenatal Carotenoid Supplementation in the Mother and Her Child: The Lutein and Zeaxanthin in Pregnancy (L-ZIP) Randomized Trial - Report Number 2

PurposeLutein and zeaxanthin are xanthophyll carotenoids that have been promoted to enhance maternal health and infant visual and neurodevelopment. In this study, we determined the effects of prenatal lutein and zeaxanthin supplementation on systemic and ocular carotenoid status in the mother and her newborn infant (NCT03750968). This report focuses on the ocular effects of prenatal carotenoid supplementation. DesignA prospective randomized clinical trial with 47 subjects randomly assigned by 1:1 allocation to receive standard-of-care prenatal vitamins along with 10 mg lutein and 2 mg zeaxanthin softgel (Carotenoid Group) or standard-of-care prenatal vitamins with a placebo softgel (Control Group) starting in the first trimester. SubjectsWe enrolled low-risk pregnancy subjects aged 18 years and above from the obstetrics and gynecology clinic of the University of Utah Hospital. MethodsMaternal macular, skin, and serum carotenoid concentrations were measured using autofluorescence imaging, resonance Raman spectroscopy, and high-performance liquid chromatography, respectively. Infants’ ocular carotenoids and retinal architecture were measured by blue light reflectance imaging and spectral domain optical coherence tomography, respectively. Main Outcome MeasuresChanges in maternal and infant macular pigment, skin, and serum carotenoid status over the study period. Differences in infants’ retinal maturity indicators between the two study groups. ResultsFollowing supplementation, there was a statistically significant increase in maternal macular pigment optical volume (p < 0.001) in the Carotenoid Group relative to the Control Group at all study time points, and there was no detectable maternal ocular carotenoid depletion. Infant skin and serum carotenoids increased significantly in the Carotenoid Group compared to the Control Group. As exploratory endpoints, infants in the Carotenoid Group had a 20% increase in macular pigment optical density (p = 0.242) and more mature foveal parameters compared to those in the Control Group. ConclusionPrenatal carotenoid supplementation significantly increased maternal and infant systemic carotenoids and caused a pattern of increased infant ocular carotenoid status, which may benefit both mothers and their infants’ ocular development and function. This study provides important data to design and power a future multicenter study of prenatal carotenoid supplementation in higher-risk pregnancies.

Influence of maternal folate depletion on Art3 DNA methylation in the murine adult brain; potential consequences for brain and neurocognitive health.

The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. In particular, epigenetic marks, including DNA methylation, are thought to be key mechanisms through which environmental exposures programme later-life health. Adequate maternal folate status before and during pregnancy is essential in the protection against neural tube defects, but data are emerging that suggest early-life folate exposures may also influence neurocognitive outcomes in childhood and, potentially, thereafter. Since folate is key to the supply of methyl donors for DNA methylation, we hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19-21 days) and lactation (mean 22 days) compared with controls (n = 6, 2 mg folic acid/kg diet). Genes were selected as methylation of their promoters had previously been found to be altered by maternal folate intake in mice and humans across the life course, and because they have potential associations with neurocognitive outcomes. Maternal folate depletion was significantly associated with Art3 gene hypomethylation in subcortical brain tissue of adult mice at 28 weeks of age (mean decrease 6.2%, P = .03). For the other genes, no statistically significant differences were found between folate depleted and control groups. Given its association with neurocognitive outcomes, we suggest Art3 warrants further study in the context of lifecourse brain health. We have uncovered a potential biomarker that, once validated in accessible biospecimens and human context, may be useful to track the impact of early-life folate exposure on later-life neurocognitive health, and potentially be used to develop and monitor the effects of interventions.

Maternal care in wild toque macaques (Macaca sinica) involves prolonged lactation and interbirth intervals as adaptations to reduce maternal depletion and infant mortality in harsh environments.

Weaning age in primates has been challenging to measure and new methods, involving molecular biomarkers in feces, tissue, or teeth have contributed to a solution. Here, we used a direct approach by briefly anesthetizing 442 female toque macaques (Macaca sinica) of Sri Lanka (over a 17-year period) and manually testing their mammary tissue for the presence or absence of milk. Milk tests were related to known offspring ages and maternal care behaviors and indicated that older infants suckled milk well past the weaning age of 7 months that is often reported for food-provisioned primates. Mothers strongly rejected their infants' nursing attempts in two phases, the first at 7 months as an honest signal "giving notice" promoting a shift to greater independence from milk to solid food, and when "shutting down" at final weaning after 12-18 months. The shift to supplementary lactation coincided also with the cessation of mothers carrying their infants and a resumption of cycling. All infants up to 7.2 months suckled milk, 91% of them did up to 18 months, this continued for 42% of infants beyond 18 months, and normally none received milk after 22 months. Lactation extended into 2.2% of cycling and 10.7% of pregnant females (up to 50% of gestation). The interbirth interval was prolonged by factors predicted to draw on female metabolic energy reserves and included the duration of lactation, growth among primiparas, and dietary limitations. The last also increased menarche. Females offset the metabolic costs of lactation with increased foraging and catabolism, but infants died when lactation costs seemingly compromised maternal condition. The prolonged lactation and slowed reproduction are considered adaptations to promote infant survival and growth in an environment where the natural food supply limits population growth and competition for food and water impacts the mortality of the youngest the most.

Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation

BackgroundIntrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC.MethodsUsing transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure.ResultsDCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes.ConclusionsThough maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies.

Maternal Energy Depletion Is Buffered among Malnourished Women in Punjab, Pakistan ,

Women's nutritional status is believed to deteriorate with increasing reproductive stress (so-called maternal depletion). To evaluate this phenomenon, a new theoretical framework has been suggested that incorporates the concepts of a full reproductive cycle, relative lengths of potential depletion and repletion phases, and initial plane of nutrition. We developed the corresponding statistical model and tested predictions provided by the framework about the effect of reproductive pattern on maternal overall weight change (deltaW) during one reproductive cycle. Seventy-six Pakistani women were classified as well-nourished, marginally nourished or malnourished. The relationship between deltaW and length of all phases of the reproductive cycle, each of which is characterized by varying degrees of reproductive stress, was evaluated with multiple regression analysis. Across the reproductive cycle, well-nourished women had a slight weight increase. Surprisingly, malnourished women gained weight in contrast to marginally nourished women. Also surprisingly, for the latter two groups, periods of moderate reproductive stress were associated with weight loss but periods of high reproductive stress were associated with weight gain. Mechanisms such as efficiency and nutrient partitioning are discussed.

Factors associated with men’s participation in postpartum family planning: a study of Kiswa Health Centre III, Kampala, Uganda

Low uptake of family planning among women is predominantly attributed to low participation of men in postpartum family planning. In order to improve maternal health, strengthening male participation in family planning is an important public health initiative. This study aimed to assess factors associated with participation of men in postpartum care at Kiswa Health Centre III, Nakawa division, Kampala. An analytical cross-sectional study design involving collection of quantitative data was used. Systematic random sampling was used to select study participants. Data was collected using semi-structured questionnaires. Data entry and cleaning was performed using EpiData version 12 and analysed using Stata version 14. 80.0% of respondents participated in postpartum family planning. Approval of family planning use, knowledge on family planning and information source were significantly associated with male involvement in postpartum family planning. Respondents who approved family planning use at home were 15.5 times more likely to get involved in family planning services as compared to those who didn’t approve family planning. Conclusively, there was a generally high level of male involvement in postpartum family planning in comparison with the national levels. Approval of family planning at home increased the likelihood of men’s participation in family planning. IMPACT STATEMENT What is already known on this subject? Evidence has it that short birth intervals of less than 15 months have been found to be associated with adverse pregnancy outcomes including induced abortions, miscarriages, preterm births, neonatal and child mortalities, still births and maternal depletion syndrome. In Africa, generally, low family uptake among women is also attributed to low men participation in postpartum family planning. What do the results of this study add? Approval of family planning use, knowledge on family planning and information source were associated with male involvement in postpartum family planning. Respondents who approved family planning use at home were 15.5 times more likely to get involved in postpartum family planning services as compared to those who didn’t approve family planning. What are the implications of these findings for clinical practice and/or further research? In this study, the involvement of men was relatively high, but more studies are needed in other locations to compare with this finding. Otherwise, consolidation of such high involvement is highly needed, as this can be a starting point for further improvement.

Parity, dental caries and implications for maternal depletion syndrome in northern Nigerian Hausa women.

Female reproductive history, especially high parity, affects general health and may impact negatively on oral health. While parity has been positively linked to tooth loss, the specific association between parity and caries has not been adequately investigated. To determine the association between parity and caries in a population of higher parity women. Influences of likely confounders (age, socio-economic status, reproductive parameters, oral health practices and sugar consumption between meals) were considered. This was a cross-sectional study involving 635 Hausa women of varying parity aged 13-80 years. Socio-demographic status, oral health practices and sugar consumption were obtained using a structured interviewer-administered questionnaire. All decayed, missing and filled teeth due to caries (excluding third molars) were noted, and tooth loss etiology was queried. Associations with caries were evaluated through correlation, ANOVA, post hoc analyses and Student's t tests. Effect sizes were considered for magnitude of differences. Multiple regression (binomial model) was used to investigate predictors of caries. Hausa women had a high prevalence of caries (41.4%) despite low sugar consumption; nonetheless the overall mean DMFT score was very low (1.23 ± 2.42). Older, higher parity women experienced more caries, as did those with longer reproductive spans. Additionally, poor oral hygiene, use of fluoride toothpaste and frequency of sugar consumption were significantly associated with caries. Higher parity (>6 children) was associated with higher DMFT scores. These results suggest that a form of maternal depletion, expressed as heightened caries susceptibility and subsequent tooth loss, occurs with higher parity.

Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development.

Maternal neutrophils cells are players in gestational tolerance and fetus delivery. Nonetheless, their actions in each phase of the pregnancy are unknown. We here investigated the role of maternal neutrophil depletion before the blastocyst implantation phase and outcomes in the pregnancy index, placenta, and fetus development. Neutrophils were pharmacologically depleted by i.p. injection of anti-Gr1 (anti-neutrophils; 200 µg) 24 hours after plug visualization in allogeneic-mated C57BL/6/BALB/c mice. Depletion of peripheral neutrophils lasted until 48 hours after anti-Gr1 injection (gestational day 1.5-3.5). On gestational day 5.5, neutrophil depletion impaired the blastocyst implantation, as 50% of pregnant mice presented reduced implantation sites. On gestational day 18.5, neutrophil depletion reduced the pregnancy rate and index, altered the placenta disposition in the uterine horns, and modified the structure of the placenta, detected by reduced junctional zone, associated with decreased numbers of giant trophoblast cells, spongiotrophoblast. Reduced number of placenta cells labeled for vascular endothelial growth factor (VEGF), platelet-endothelial cell adhesion molecule (PECAM-1), and intercellular cell adhesion molecule (ICAM-1), important markers of angiogenesis and adhesiveness, were detected in neutrophil depleted mice. Furthermore, neutrophil depletion promoted a higher frequency of monocytes, natural killers, and T regulatory cells, and lower frequency of cytotoxic T cells in the blood, and abnormal development of offspring. Associated data obtained herein highlight the pivotal role of neutrophils actions in the early stages of pregnancy, and address further investigations on the imbricating signaling evoked by neutrophils in the trophoblastic interaction with uterine epithelium.

Characterizing the extent human milk folate is buffered against maternal malnutrition and infection in drought‐stricken northern Kenya

AbstractObjectivesFolate is an essential nutrient fundamental to human growth and development. Human milk maintains high folate content across the maternal folate status range, suggesting buffering of milk folate with prioritized delivery to milk at the expense of maternal depletion. We investigated whether and how the extent of this buffering may diminish under prolonged nutritional and/or disease stress, while taking into consideration infants' varying vulnerability to malnutrition‐related morbidity/mortality.MethodsA cross‐sectional study analyzed milk specimens from northern Kenyan mothers (n = 203), surveyed during a historic drought and ensuing food shortage. Multiple regression models for folate receptor‐α (FOLR1) in milk were constructed. Predictors included maternal underweight (BMI &lt; 18.5), iron‐deficiency anemia (hemoglobin &lt;12 g/dl and dried‐blood‐spot transferrin receptor &gt;5 mg/L), folate deficiency (hyperhomocysteinemia, homocysteine &gt;12 or 14 μmol/L), inflammation (serum C‐reactive protein &gt;5 mg/L), infant age and sex, and mother‐infant interactions.ResultsIn adjusted models, milk FOLR1 was unassociated with maternal underweight, iron‐deficiency anemia and inflammation. FOLR1 was positively associated with maternal folate deficiency, and inversely associated with infant age. There was interaction between infant age and maternal underweight, and between infant sex and maternal folate deficiency, predicting complex changes in FOLR1.ConclusionsOur results suggest that mothers buffer milk folate against their own nutritional stress even during a prolonged drought; however, the extent of this buffering may vary with infant age, and, among folate‐deficient mothers, with infant sex. Future research is needed to better understand this variability in maternal buffering of milk folate and how it relates to folate status in nursing infants.

Prevalence of anemia and associated risk factors among the lactating and nonpregnant-nonlactating Tangkhul women.

Anemia is a major public health issue throughout the world. Nutritional deficiencies in terms of iron, B12 (cobalamin) and B9 (folate) are the main causes of anemia in the absence of genetic abnormalities and chronic diseases in many countries. Lactating mothers are susceptible to anemia because of maternal iron depletion during lactation as well as blood loss during childbirth. The present study examines the prevalence of anemia among the lactating (cases) and nonpregnant-nonlactating (control) married Tangkhul women of Ukhrul district. A community-based cross-sectional study was conducted among 400 individuals (lactating: 150; nonpregnant-nonlactating women: 250) from 11 villages of the Ukhrul district in Manipur. A pretested schedule, which included height, weight, and socio-demographic parameters were used. Body mass index = weight (in kg)/height (in metre2) was computed of each subject and categorized. Hemoglobin concentration was measured using Sahli's method. Statistical methods namely Chi-square (χ2) test and binary logistic regression were applied. The prevalence of anemia was higher in the lactating women (62.0%) than nonpregnant-nonlactating women (56.8%). Odds ratio (OR) of multivariate logistic regression analysis indicated that anemia was significantly associated in both cases and control with low literacy level (OR = 5.03 and 3.71), low income (OR = 2.51 and 3.56), cultivator (OR = 6.20 and 3.86), and multigravida >4 (OR = 5.25 and 2.67), respectively. Dietary practices play an important role in causing anemia. Low literacy level, low income, cultivator, and high gravidity were identified as the associated risk factors of anemia.

Maternal B-cell depletion nor TNF-α blockade worsen offspring outcomes in a rat model of preeclampsia

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with maternal death and morbidity, low birth weight in offspring, increased tumor necrosis factor alpha (TNF-α) and B cells producing autoantibodies. We have shown that Etanercept (E), a TNF-α inhibitor, improves blood pressure in the reduced uterine perfusion pressure (RUPP) rat model of PE and that Rituximab (R), used clinically for B cell depletion, lowered blood pressure and B cells in RUPP rats. Clinical use of R or E during pregnancy has not resulted in adverse outcomes for the mother, however, the effects of maternal B cell depletion or TNF-α blockade on offspring immune cells in response to placental ischemia is unknown.

Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice.

Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.

The Lutein and Zeaxanthin in Pregnancy (L-ZIP) study\u2014carotenoid supplementation during pregnancy: ocular and systemic effects\u2014study protocol for a randomized controlled trial

BackgroundLutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), collectively called the macular pigment (MP), are dietary carotenoids that preferentially localize in the macula of the human eye. MP protects the macula from photo-oxidative damage and enhances visual function. Inadequate maternal intake of carotenoids, coupled with the placental transfer of maternal carotenoids to support fetal brain and retina development, potentially put mothers at risk of depletion systemically and in their ocular tissues. Presently, maternal carotenoid status throughout pregnancy remains poorly characterized, and no prospective randomized controlled trial of L and Z supplementation via prenatal vitamins has assessed maternal and infants’ systemic and ocular carotenoid status during pregnancy. We hypothesize that prenatal maternal carotenoid supplementation will counteract maternal carotenoid depletion during pregnancy and will improve biomarkers of carotenoid status of both mothers and infants.MethodsLutein and Zeaxanthin in Pregnancy (L-ZIP) is a phase 2, single-center, prospective, double-masked, randomized active-controlled clinical trial conducted at the John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA. Participants consume a daily standard prenatal multivitamin with no added carotenoids and are randomized (1:1 allocation) to receive either a capsule containing 10 mg L and 2 mg Z in safflower oil (Carotenoid group) or a capsule containing only safflower oil with no added carotenoids (Control group) for a period of 6 to 8 months. Skin, serum, and ocular carotenoids are measured at every study visit (i.e., within the first trimester [baseline], second trimester, third trimester, and 0–2 weeks postpartum). Skin carotenoid assessment is by resonance Raman spectroscopy (RRS); serum carotenoid status is quantified using high-performance liquid chromatography (HPLC); and MP is measured with the dual-wavelength autofluorescence. Infants’ MP and foveal anatomy are assessed using RetCam retinal camera and Bioptigen SD-OCT, respectively. The primary outcomes are changes in maternal systemic and ocular carotenoid status during pregnancy.DiscussionL-ZIP is the first prospective RCT to investigate maternal carotenoid status throughout pregnancy and to determine whether prenatal maternal carotenoid supplementation will offset maternal carotenoid depletion and improve biomarkers of maternal and infant’s carotenoid status. Findings from L-ZIP will strengthen recommendations regarding prenatal carotenoid supplementation and consequently inform policy decisions.Trial registrationClinicalTrials.gov NCT03750968. Registered on November 23, 2018

Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos.

Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing the formation of mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains until the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.

Human milk banks: a need for further evidence and guidance

Human milk banks: a need for further evidence and guidance

Associations between interpregnancy interval and preterm birth by previous preterm birth status in four high-income countries: a cohort study.

To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term. Cohort study. USA (California), Australia, Finland, Norway (1980-2017). Women who gave birth to first and second (n=3213855) singleton livebirths. Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random effects meta-analysis. PTB (gestational age<37weeks). Absolute risk of PTB for each IPI was 3-6% after a previous term birth and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction≤0.001). For women with a previous term birth, pooled ORs were increased for IPI<6months (OR 1.50, 95% CI 1.43-1.58); 6-11months (OR 1.10, 95% CI 1.04-1.16); 24-59months (OR 1.16, 95% CI 1.13-1.18); and≥60months (OR 1.72, 95%CI 1.60-1.86), compared with 18-23months. For previous PTB, ORs were increased for<6months (OR 1.30, 95% CI 1.18-1.42) and≥60months (OR 1.29, 95% CI 1.17-1.42), but were less than ORs among women with a previous term birth (P<0.05). Associations between IPI and PTB are modified by whether or not the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given the high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB. Short versus long interpregnancy intervals associated with higher ORs for preterm birth (PTB) after a previous PTB.

Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation

Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyltransferase leading to H4K16ac loss causes aberrant RNA Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA, and causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation.

Kin-based alloparenting and infant hospital admissions in the UK Millennium cohort

Abstract Background and objectives Kin-selected altruism is an evolutionary explanation for why biological kin other than parents are willing childcare providers or alloparents. Kin alloparents may increase lineage fitness by reducing maternal energy depletion and improving child survival through childcare activities. The aim of this research was to apply the hypothesis that kin-based alloparental care has benefits for child health in a western, educated, industrialized, rich, democratic context. Methodology The hypothesis was tested using the first sweep of the UK Millennium Cohort Study (n = 18 552 infants). The outcome was number of hospitalizations by age 9 months, and the main predictors were kin-based alloparental care during work hours, socioeconomic position and infant health-related variables and their interactions with kin-based alloparenting. Analysis of hospitalizations was carried out using negative binomial regression. Results Kin alloparents were primary day carers in 17% of households. Infants whose main care arrangement during work hours was with kin allocarers had statistically significantly fewer hospitalizations than infants in all other care arrangements combined (Incidence rate ratio = 0.86, P &amp;lt; 0.03), and when contrasted with maternal day care (Incidence rate ratio = 0.79, P &amp;lt; 0.02). Conclusions and implications Kin-based allocare was associated with about a 15% reduction in the risk of infant hospitalization in the first 9 months. The difference appeared to be due in part to a difference in the risk of hospitalization for infectious diseases. Sensitivity analyses indicated that infants cared for by their mother during the day rather than in day-care facilities were most at risk of hospitalization compared with those in kin-based care. Lay summary Modern industrialized societies are generally characterized by nuclear family households, with grandparents and other extended family often living a considerable distance away. Studies carried out in societies which have not undergone the fragmentation of extended families have shown that grandmothers and other biological kin reduce infant mortality, most likely because they distribute the burden of infant care so that it does not fall exclusively on the mother. Here, the hypothesis that grandparental and other family care would be beneficial for infant health in the contemporary UK was testing using the UK Millennium cohort. Infant health was measured as number of hospitalizations in the first 9 months from birth. The main findings were that kin-based infant care, which was most commonly by grandparents, was associated with a 15% reduction in the risk of hospitalization in infants up to 9 months of age. Further analysis suggested that the difference was larger for risk of infant hospitalization due to infectious diseases rather than non-infectious diseases. The results also suggested that the finding may have been driven by increased risk for infants of mothers caring for their infant during normal working hours with no other help, such as from the father or pay-for day-care.

Polycomb Group Proteins Regulate Chromatin Architecture in Mouse Oocytes and Early Embryos.

In mammals, chromatin organization undergoes drastic reorganization during oocyte development. However, the dynamics of three-dimensional chromatin structure in this process is poorly characterized. Using low-input Hi-C (genome-wide chromatin conformation capture), we found that a unique chromatin organization gradually appears during mouse oocyte growth. Oocytes at late stages show self-interacting, cohesin-independent compartmental domains marked by H3K27me3, therefore termed Polycomb-associating domains (PADs). PADs and inter-PAD (iPAD) regions form compartment-like structures with strong inter-domain interactions among nearby PADs. PADs disassemble upon meiotic resumption from diplotene arrest but briefly reappear on the maternal genome after fertilization. Upon maternal depletion of Eed, PADs are largely intact in oocytes, but theirreestablishment after fertilization is compromised. By contrast, depletion of Polycomb repressive complex 1 (PRC1) proteins attenuates PADs in oocytes, which is associated with substantial gene de-repression in PADs. These data reveal a critical role of Polycomb in regulating chromatin architecture during mammalian oocyte growth and early development.

Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice.

Gestational nutrition is widely recognized to affect an offspring's future risk of lifestyle-related diseases, suggesting the involvement of epigenetic mechanisms. As folic acid (FA) is a nutrient essential for modulating DNA methylation, we sought to determine how maternal FA intake during early pregnancy might influence tumor sensitivity in an offspring. Dams were maintained on a FA-depleted (FA(-)) or normal (2 mg FA/kg; FA(+)) diet from 2 to 3 days before mating to 7 days post-conception, and their offspring were challenged with chemical tumorigenesis using 7,12-dimethylbenz[a)anthracene and phorbol 12-myristate 13-acetate for skin and 4-nitroquinoline N-oxide for tongue. In both squamous tissues, tumorigenesis was more progressive in the offspring from FA(-) than FA(+) dams. Notably, in the skin of FA(-) offspring, the expression and activity of cylindromatosis (Cyld) were decreased due to the altered DNA methylation status in its promoter region, which contributed to increased tumorigenesis coupled with inflammation in the FA(-) offspring. Thus, we conclude that maternal FA insufficiency during early pregnancy is able to promote neoplasm progression in the offspring through modulating DNA methylation, such as Cyld. Moreover, we propose, for the first time, "innate" utero nutrition as the third cause of tumorigenesis besides the known causes-hereditary predisposition and acquired environmental factors.