Antenatal interventions to reduce risk of low birth weight related to maternal infections during pregnancy.

BACKGROUND: Maternal infections during pregnancy have been linked to increased risk of adverse birth outcomes, including low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and stillbirth (SB). OBJECTIVES: The purpose of this article was to summarize evidence from published literature on the effect of key interventions targeting maternal infections on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and CINAHL Complete between March 2020 and May 2020 with an update to cover until August 2022. We included randomized controlled trials (RCTs) and reviews of RCTs of 15 antenatal interventions for pregnant women reporting LBW, PTB, SGA, or SB as outcomes. RESULTS: Of the 15 reviewed interventions, the administration of 3 or more doses of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine [IPTp-SP; RR: 0.80 (95% CI: 0.69, 0.94)] can reduce risk of LBW compared with 2 doses. The provision of insecticide-treated bed nets, periodontal treatment, and screening and treatment of asymptomatic bacteriuria may reduce risk of LBW. Maternal viral influenza vaccination, treatment of bacterial vaginosis, intermittent preventive treatment with dihydroartemisinin-piperaquine compared with IPTp-SP, and intermittent screening and treatment of malaria during pregnancy compared with IPTp were deemed unlikely to reduce the prevalence of adverse birth outcomes. CONCLUSIONS: At present, there is limited evidence from RCTs available for some potentially relevant interventions targeting maternal infections, which could be prioritized for future research.

A modular systematic review of antenatal interventions to address undernutrition during pregnancy in the prevention of low birth weight.

BACKGROUND: Poor nutrition during pregnancy can lead to adverse birth outcomes including low birth weight (LBW). OBJECTIVE: This modular systematic review aimed to provide evidence for the effects of seven antenatal nutritional interventions on the risks of LBW, preterm birth (PTB), small-for-gestational-age (SGA) and stillbirth (SB). METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between April and June 2020, with a further update in September 2022 (Embase only). We included randomized controlled trials (RCTs) and reviews of RCTs to estimate the effect sizes of the selected interventions on the four birth outcomes. RESULTS: Evidence suggests that balanced protein and energy (BPE) supplementation for pregnant women with undernutrition can reduce the risk of LBW, SGA and SB. Evidence from low and lower middle-income countries (MIC) suggests that multiple micronutrient (MMN) supplementation can reduce the risk of LBW and SGA in comparison with iron or iron and folic acid supplementation and lipid-based nutrient supplements (LNS) with any quantity of energy can reduce the risk of LBW in comparison with MMN supplementation. Evidence from high and upper MIC suggests that supplementation with omega-3 fatty acids (O3FA) can reduce the risk and supplementation with high-dose calcium might possibly reduce the risk of LBW and PTB. Antenatal dietary education programs might possibly reduce the risk of LBW in comparison with standard-of-care. No RCTs were identified for monitoring weight gain followed by interventions to support weight gain in women who are underweight. CONCLUSIONS: Provision of BPE, MMN and LNS to pregnant women in populations with undernutrition can reduce the risk of LBW and related outcomes. The benefits of O3FA and calcium supplementation to this population require further investigation. Targeting interventions to pregnant women who are not gaining weight has not been tested with RCTs.

Antenatal interventions to address harmful behaviors and psychosocial risk factors in the prevention of low birth weight.

BACKGROUND: Risk factors related to the harmful behaviors, psychosocial wellbeing, and socio-economic circumstances in the lives of pregnant women can lead to adverse birth outcomes, including low birth weight (LBW). OBJECTIVE: This systematic search and review aims to provide a comparative evidence synthesis on the effect of eleven antenatal interventions targeted to address psychosocial risk factors on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between March 2020 and May 2020. We included randomized controlled trials (RCTs) and reviews of RCTs of eleven antenatal interventions for pregnant females reporting LBW, preterm birth (PTB), small-for-gestational-age or stillbirth as outcomes. For interventions where randomization was either not feasible or unethical, we accepted non-randomized controlled studies. RESULTS: Seven records contributed data to the quantitative estimates of the effect sizes and 23 contributed to narrative analysis. Psychosocial interventions for reducing smoking in pregnancy likely reduced the risk of LBW, and professionally provided psychosocial support for at-risk women possibly reduced the risk of PTB. Financial incentives or nicotine replacement therapy as smoking cessation aids, or virtually delivered psychosocial support did not appear to reduce the risk of adverse birth outcomes. The available evidence on these interventions was primarily from high-income countries. For other reviewed interventions (psychosocial interventions to reduce alcohol use, group based psychosocial support programs, intimate partner violence prevention interventions, antidepressant medication, and cash transfers) there was little evidence in any direction regarding the efficacy or the data was conflicting. CONCLUSIONS: Professionally provided psychosocial support during pregnancy in general and specifically as a means to reduce smoking can potentially contribute to improved newborn health. The gaps in the investments for research and implementation of psychosocial interventions should be addressed to better meet the global targets in LBW reduction.

A modular systematic review of antenatal interventions targeting modifiable environmental exposures in improving low birth weight.

BACKGROUND: Low birth weight (LBW) increases the risk of short- and long-term morbidity and mortality from early life to adulthood. Despite research effort to improve birth outcomes the progress has been slow. OBJECTIVE: This systematic search and review of English language scientific literature on clinical trials aimed to compare the efficacy antenatal interventions to reduce environmental exposures including a reduction of toxins exposure, and improving sanitation, hygiene, and health-seeking behaviors, which target pregnant women to improve birth outcomes. METHODS: We performed eight systematic searches in MEDLINE (OvidSP), Embase (OvidSP), Cochrane Database of Systematic Reviews (Wiley Cochrane Library), Cochrane Central Register of Controlled Trials (Wiley Cochrane Library), CINAHL Complete (EbscoHOST) between 17 March 2020 and 26 May 2020. RESULTS: Four documents identified describe interventions to reduce indoor air pollution: two randomised controlled trials (RCTs), one systematic review and meta-analysis (SRMA) on preventative antihelminth treatment and one RCT on antenatal counselling against unnecessary caesarean section. Based on the published literature, interventions to reduce indoor air pollution (LBW: RR: 0.90 [0.56, 1.44], PTB: OR: 2.37 [1.11, 5.07]) or preventative antihelminth treatment (LBW: RR: 1.00 [0.79, 1.27], PTB: RR: 0.88 [0.43, 1.78]) are not likely to reduce the risk of LBW or Preterm birth (PTB). Data is insufficient on antenatal counselling against caesarian-sections. For other interventions, there is lack of published research data from RCTs. CONCLUSIONS: We conclude that there is a paucity of evidence from RCT on interventions that modify environmental risk factors during pregnancy to potentially improve birth outcomes. Magic bullets approach might not work and that it would be important to study the effect of the broader interventions, particularly in LMIC settings. Global interdisciplinary action to reduce harmful environmental exposures, is likely to help to reach global targets for LBW reduction and sustainably improve long-term population health.

Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Modular literature review: a novel systematic search and review method to support priority setting in health policy and practice.

BACKGROUND: There is an unmet need for review methods to support priority-setting, policy-making and strategic planning when a wide variety of interventions from differing disciplines may have the potential to impact a health outcome of interest. This article describes a Modular Literature Review, a novel systematic search and review method that employs systematic search strategies together with a hierarchy-based appraisal and synthesis of the resulting evidence. METHODS: We designed the Modular Review to examine the effects of 43 interventions on a health problem of global significance. Using the PICOS (Population, Intervention, Comparison, Outcome, Study design) framework, we developed a single four-module search template in which population, comparison and outcome modules were the same for each search and the intervention module was different for each of the 43 interventions. A series of literature searches were performed in five databases, followed by screening, extraction and analysis of data. "ES documents", source documents for effect size (ES) estimates, were systematically identified based on a hierarchy of evidence. The evidence was categorised according to the likely effect on the outcome and presented in a standardised format with quantitative effect estimates, meta-analyses and narrative reporting. We compared the Modular Review to other review methods in health research for its strengths and limitations. RESULTS: The Modular Review method was used to review the impact of 46 antenatal interventions on four specified birth outcomes within 12 months. A total of 61,279 records were found; 35,244 were screened by title-abstract. Six thousand two hundred seventy-two full articles were reviewed against the inclusion criteria resulting in 365 eligible articles. CONCLUSIONS: The Modular Review preserves principles that have traditionally been important to systematic reviews but can address multiple research questions simultaneously. The result is an accessible, reliable answer to the question of "what works?". Thus, it is a well-suited literature review method to support prioritisation, decisions and planning to implement an agenda for health improvement.

Cervical leukocytes and spontaneous preterm birth.

The objective was to characterise cervical leukocyte populations and inflammatory mediators associated with term and recurrent spontaneous preterm birth (SPTB) in pregnant women with a history of SPTB. A prospective observational study was undertaken on 120 women with a history of SPTB. A cytobrush was used to sample cells from the cervix at 12-25 weeks' gestation. Cells were enumerated and characterised by flow cytometry. Cytokines and chemokines were also measured. Participants were then grouped according to delivery at term (>36+6 weeks), late SPTB (34-36+6 weeks) or early SPTB (<34 weeks). Differences in leukocyte sub-populations, cytokine and chemokine levels were compared with outcome. Cervical leukocytes comprised up to 60% of the host-derived cells. Most of these (90-100%) were polymorphonuclear cells (PMN). Most of the remaining cells were mucosal macrophages expressing CD68 and CD103 in addition to markers shared with blood-borne monocytes. Failure to detect cervical macrophages in at least 250,000 cervical epithelial cells was a feature of women who experienced early SPTB (6 out of 6 cases, 95% CI 61-100%) compared with 34% (30 out of 88 cases, 95% CI 25-43%, P<0.001) of women delivering after 34 weeks. CCL2 (MCP-1) was also low in SPTB before 34 weeks and levels above 75 ng/g and/or the presence of macrophages increased the specificity for birth after 34 weeks from 66% to 82% (55 out of 67 cases, 95% CI 73-91%). Absence of cervical macrophages and low CCL2 may be features of pregnancies at risk of early SPTB.

Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression.

OBJECTIVE: To identify biomarkers in the first synovial fluid (SF) aspirate obtained from children with oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype. METHODS: Patients with recent-onset oligoarticular JIA were identified and grouped according to those whose mild disease persisted (persistent disease) or those whose disease would extend from a mild to more severe phenotype (extended-to-be disease) at 1 year after diagnosis. Flow cytometry was used to delineate differences in the mononuclear cell populations between the first blood sample and first SF aspirate from the same patient and between outcome (persistent versus extended-to-be) groups. Proportions of lymphocytes in the joint were modeled on chemotaxis of lymphocytes to CCL5, using Transwell migration assays. Levels of CCL5 in the SF were quantified by enzyme-linked immunosorbent assay. RNA profiles of SF mononuclear cells were compared between groups using the Affymetrix GeneChip hybridization protocol and hierarchical clustering analyses. RESULTS: Compared with peripheral blood mononuclear cells, SF mononuclear cells displayed an expansion of CD8+ T cells, reduced proportion of B cells, and expansion of CD16- natural killer cells. The lower CD4:CD8 ratio in the SF was recapitulated in vitro by the observed migration of blood T cells in response to CCL5. Synovial CCL5 levels were higher in children whose disease extended to a more severe phenotype. The CD4:CD8 ratio in the SF was significantly lower in patients with extended-to-be oligoarticular JIA (0.57 compared with 0.90 in the persistent disease group, difference 0.33, 95% confidence interval 0.04-0.62; P = 0.009). Gene expression profiling revealed that 344 genes were >1.5-fold differentially expressed between outcome groups (P < 0.05), and these included genes associated with inflammation and macrophage differentiation, which showed increased levels in patients with extended disease at 1 year, and genes associated with immune regulation, which showed increased levels in patients with persistent disease at 1 year. CONCLUSION: Analyses of the proportions of synovial lymphocytes, levels of CCL5, and differential gene expression yielded potential biomarkers with which to predict the likelihood of extension of oligoarticular JIA to a more severe disease phenotype.

BCL6b mediates the enhanced magnitude of the secondary response of memory CD8+ T lymphocytes.

A characteristic of the secondary response of CD8(+) T cells that distinguishes it from the primary response is the generation of greater numbers of effector cells. Because effector CD8(+) T cells are derived from a pool of less differentiated, replicating cells in secondary lymphoid organs, and because IL-2 mediates effector differentiation, the enhanced secondary response may reflect the enlargement of this generative pool by the transient repression of IL-2-mediated differentiation. We have examined for this function the transcriptional repressor BCL6b, a homologue of BCL6 that represses IL-2-induced B cell differentiation. BCL6b is expressed in a small subset of antigen-experienced CD8(+) T cells. Ectopic expression of BCL6b in CD8(+) T cells diminishes their growth in response to IL-2 in vitro. Female mice in which the BCL6b gene has been interrupted have normal primary responses of CD8(+) T cells to infection with vaccinia expressing the H-Y epitope, Uty, but Uty-specific, BCL6b(-/-), memory CD8(+) T cells have diminished recall proliferative responses to this epitope in vitro. BCL6b(-/-) mice also have normal primary CD8(+) T cell responses to influenza infection, but nucleoprotein peptide-specific, BCL6b(-/-), memory CD8(+) T cells have a cell autonomous defect in the number of effector cells generated in response to reinfection. Therefore, BCL6b is required for the enhanced magnitude of the secondary response of memory CD8(+) T cells.

Alcohol elimination at low blood concentrations among women taking combined oral contraceptives.

OBJECTIVE: Evidence implicating a role of natural and synthetic estrogens and/or progestin on ethanol pharmacokinetics can be traced back to the mid-1970s when reports of large metabolic differences were found suggesting that sex hormones interfered with the efficient clearance of alcohol at the liver microsomal level. Research teams in this area manipulate sex hormone levels by either examining natural-cycling women at different phases of their menstrual cycle or others taking oral contraceptives that synthetically regulate the hormonal fluctuations. These collective studies (over a dozen to date involving over 200 participants) have all been similar in focus and outcome. With one important exception, the published laboratory research since 1976 has failed to replicate the earliest research suggesting sex hormone effects. One well-controlled study in 1987 did generate renewed interest in the area with the paradoxical finding that progesterone actually enhanced alcohol elimination at low blood concentrations (<.025%). The present study represented the most direct attempt to replicate this particular finding using 5-minute breath alcohol readings that extended below blood alcohol concentrations of .025%. METHOD: A total of 17 women taking combined oral contraceptives were tested during both menstruation and the luteal phase (Days 16-22) of their cycle in counterbalanced sequence. RESULTS: Pharmacokinetics differences were not found. CONCLUSION: These results contribute further to a literature base demonstrating the limited effects of both natural and synthetic sex hormones on alcohol metabolism in women.