Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation. Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance. Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB. The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes.

Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long‐term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and pro‐inflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro‐inflammatory mediators is emerging as a major factor in the ‘fetal inflammatory response syndrome’ that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll‐like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel small‐molecule inhibitors of TLR4 signalling, specifically the non‐opioid receptor antagonists (+)‐naloxone and (+)‐naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat‐killed Escherichia coli, or the TLR4‐dependent pro‐inflammatory lipid, platelet‐activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.

The climate crisis is the existential threat of our times and for generations to come. This is no longer a threat but a reality affecting us, our children, and the generations that follow. Pregnant mothers, their fetuses, and their children are among those at greatest risk in every population and every jurisdiction. A timely consideration is the health of racialized groups who are particularly vulnerable owing to the confluence of several risk factors that are compounded by climate change. Included among these are Indigenous communities that are the most directly threatened by climate change. This review discusses the main health challenges faced by mothers, fathers, and their children during the climate crisis, focusing on mental health as a causal factor. Exploration of this topic includes the role of prenatal maternal and paternal stresses, allostatic load, and the effect of degradation of the environment and ecosystems on individuals. These will be examined in relation to adverse pregnancy outcomes and altered developmental trajectories of children. The climate crisis is a health threat multiplier that amplifies the health inequities of the most at-risk populations and individuals. It accelerates the increase in allostatic load of those at risk. The path of tragedy begins with an accumulating allostatic load that overwhelms both individual and socio-ecological resilience. This can lead to worse mental health including depression and anxiety and, in the case of pregnant women and their children, more adverse pregnancy outcomes and impaired developmental trajectories for their newborn children. We argue that there is an urgent need to develop new (or re-discover or re-purpose existing) tools that will predict communities and individuals who are experiencing the highest levels of climate-related hazards and intervene to reduce stress and increase resilience in pre-conceptual women and men, pregnant and post-partum women, and their young children.

Evidence relating maternal history of abuse before pregnancy with pregnancy outcomes is controversial. This study aims to examine the association between maternal histories of abuse before pregnancy and the risk of preterm delivery and low birth weight. We searched Subject Headings and keywords for exposure and the outcomes through MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Psycinfo, CINAHL, Scopus, PILOTS, ProQuest Dissertations & Theses Global and Web of Science Core Collection in April 2017. We selected original studies that reported associations between maternal histories of abuse of any type and either preterm delivery or low birth weight. Studies that included interventions during pregnancy to lower maternal stress but reported no control data were excluded. We utilized the Newcastle-Ottawa Quality Assessment Scales for observational studies to assess the risk of bias in the primary studies. Two independent reviewers performed the selection of pertinent studies, assessment of risk of bias, and data extraction. Unadjusted pooled odds ratios (OR) with 95% Confidence Interval (CI) were calculated for the two outcomes of preterm delivery and low birth weight in 16 included studies. Maternal history of abuse before pregnancy was significantly associated with preterm delivery (OR 1.28, 95% CI: 1.12–1.47) and low birth weight (OR 1.35, 95% CI: 1.14–1.59). A substantial level of heterogeneity was detected within the two groups of studies reporting preterm birth and low birth weight (I2 = 75% and 69% respectively). Subgroup analysis based on the specific time of abuse before pregnancy indicated that childhood abuse increases the risk of low birth weight by 57% (95% CI: 0.99–2.49). When the included studies were categorized based on study design, cohort studies showed the highest effect estimates on preterm delivery and low birth weight (OR: 1.69, 95%CI: 1.19–2.40, OR: 1.56, 95% CI: 1.06–2.3, respectively). We recommend that more high quality research studies on this topic are necessary to strengthen the inference. At the practice level, we suggest more attention in detecting maternal history of abuse before pregnancy during antenatal visits and using this information to inform risk assessment for adverse pregnancy outcomes. Registration number: PROSPERO ( CRD42016033231 ).

Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.