Negative childbirth experiences may result in negative emotions that may lead to negative outcomes, such as post-traumatic stress disorder. We aimed to examine the differences in emotions between primiparous and multiparous women and mode of birth. We used a retrospective cross-sectional study design with three hundred and fifty women. Primiparous women reported higher levels of fear, lack of control, and dissociation emotions compared to multiparous women. The EmCs (emergency cesarean section) group experienced the most fear, lack of control, anger, and conflict emotions. It is important to conduct follow up work with women who underwent unplanned birth procedures since negative childbirth experiences may lead to further negative effects on women’s psychosocial health and well-being. Giving birth to a child is a process that is accompanied by both happiness and pain . Labor aPrevious research has shown that a high percentage of women (between 20% to 48%) who perceived their childbirth to be traumatic later reported symptoms of PTSD ,5. In orPrimiparity refers to giving birth for the first time, which often translates into feelings of inexperience and an inability to assess the childbirth experience. Thus, primiparous women are more likely to feel uncertainty and fear related to childbirth than multiparous women  . Among mThis study refers to VB as the natural and most common mode of birth. Other modes of birth may involve intensive obstetric intervention, including vacuum extraction (VE) and elective (ElCs) or emergency cesarean section (EmCs). Studies have shown that the lower the number of obstetric interventions, the greater the odds for women’s positive birth experiences and vice versa ,20. ObstWomen who underwent planned birth procedures (VB or ElCs) reported significantly more positive emotions during childbirth than those who underwent unplanned birth procedures (VE or EmCs) . AnotherTo compare the negative emotions of primiparous and multiparous women during their last birth;To compare the differences between the negative emotions during birth based on the mode of birth: VB, VE, ElCs, and EmCs;To compare the negative emotions between women that experienced ‘planned’ birth procedures compared to ‘unplanned’ birth procedures.Accordingly, it is important to examine factors such as primiparous and multiparous women, mode of birth, and planned’ birth versus ‘unplanned’ birth procedures and their potential to be associates with negative emotions in birth. Since negative emotions during birth may cause negative consequences, such as PTSD and depression, in the short and long term ,3. It maWe applied a retrospective, cross-sectional comparison study. The study was conducted in the State of Israel. We contacted online social networks with potential volunteers through a massage requesting to complete the questionnaire through the internet. Those who wanted to volunteer for the research sent their email address to receive a link to the questionnaire. The questionnaire was then delivered and took an estimated time of approximately 10 min to fill out. The participants did not receive any compensation for participation in the research. The e-mail was sent to approximately 1493 potential applicants, and 325 expressed interest and participated in the study. The overall response rate for research participation was 22%, which is a good response rate.Three hundred and twenty-five women participated in the research. The inclusion criterion included having given birth in the two previous years, being free from pregnancy and obstetric complications , and multiple pregnancy. The exclusion criterion was women who never gave birth. The University Institutional Review Board approved this research . The participants enrolled voluntarily, were informed of the research aims, and signed electronic informed consent before filling out the questionnaire. The participants were also informed about the option to withdraw from the study at any point, that their questionnaire responses would remain confidential, and that the data would be analyzed discretely. To assess women’s emotions and their relation to birth details and mode of birth, the questionnaire was comprised of three sections. The first section referred to participants’ background characteristics . The second section included obstetric background . The third part of the questionnaire included categories describing personal cognitions and emotions of intrapartum hotspots, referring to moments of extreme distress during traumatizing events. The categories contained several emotions: fear and lack of control (example of item: during the last birth you felt out of control of what was going on), which included six items ; anger and conflict (example of item: during the last birth you felt angry), which included five items ; intrapartum dissociation, (example of item: during the last birth you felt detached as if in a dream), which included five items ; and failure and fault (example of item: during the last birth you felt guilty), which included three items . The total responses ranged from 0 = “not at all” to 3 = “extremely” . The surA statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS TM), 25.0 version, Chicago, IL, USA. A parameters analysis test was performed since the groups were not equal in size. In addition, we conducted the Cronbach’s alpha, descriptive statistics, Mann-Whitney non-parametric analysis as an independent sample test, Spearman correlation, and Kruskal-Wallis one-way analysis of variance.n = 325) was 28.79 ± 5.39 years. Most of the women were religious , married , had a higher education , and had one child . The participant characteristics are presented in For examining research aim 1, we conducted a Mann-Whitney non-parametric analysis as an independent sample test and found that primiparous women reported higher levels of fear, lack of control, and intrapartum dissociation emotions than multiparous women during their previous birth. Regarding anger and conflict and failure and fault, no differences were found between the groups . p < 0.00). Hence, the higher the number of children, the less the woman felt intrapartum dissociation. The other two relationships of number of children birthed with fear and lack of control  and failure and fault  were very weak and, thus, insignificant . In addition, one meaningful negative correlation was found between the number of children birthed and the emotion of intrapartum dissociation  = 33.27, p < 0.00; χ2 (3) = 12.16, p < 0.00; χ2 (3) = 11.22, p < 0.01; χ2 (3) = 56.56, p < 0.00, respectively). The group that felt the most fear and lack of control and anger and conflict emotions was the EmCs group, as compared to the VB group. The group that felt the most intrapartum dissociation emotions was the VE group; the VB group experienced these emotions the least. The group that felt the most failure and fault emotions was the ElCs group; the VB group experienced these emotions the least , anger and conflict , and fault and failure  than women who underwent planned procedures , and to compare negative emotions between women that experienced ‘planned’ birth versus ‘unplanned’ birth procedures. According to the results of the present study, primiparous women reported higher levels of fear, lack of control, and intrapartum dissociation emotions than multiparous women during their previous birth. Additionally, the group that felt the most fear, lack of control and anger, and conflict emotions was the EmCs group, as compared to the VB group. The group that felt the most intrapartum dissociation emotions was the VE group; the VB group experienced these emotions the least. The group that felt the most failure and fault emotions was the ElCs group; the VB group experienced these emotions the least. Furthermore, significant differences between the two groups regarding planned vs. unplanned birth procedures were found. Women who experienced unplanned birth procedures reported higher levels of fear and lack of control, anger and conflict, and fault and failure than women who underwent planned birth procedures.Like other studies, we found that primiparous women feared more for their health and life than multiparous women. One study demonstrated that primiparous women, as compared to multiparous women, felt more fear during birth. Additionally, primiparous women had significantly lower self-efficacy compared to multiparous women during childbirth . MoreoveThe group that felt the most fear, lack of control, anger, and conflicting emotions was the EmCs group. These findings are in line with another study that found that EmCs was a strong predictor of negative birth experiences . An addiWomen who went through unplanned birth procedures, such as VE or EmCs, reported higher levels of fear, lack of control, anger, conflict, fault, and failure than women who underwent planned birth procedures, such as VB or ELSC. It is noteworthy that negative emotions, including a lack of control or involvement in decision making, are strongly associated with negative birth experiences . SimilarThis study strives to assess women’s emotions during birth based on the mode of birth: VB, VE, ELSC, and EmCs. Furthermore, the study aims to evaluate if there were different emotions between primiparous and multiparous women’s during birth. Israel is a country that encourages having multiple children, so the social pressure on women is increasing, especially among primiparous women. It is important to be aware that during birth risk factors such as fear, lack of control, and dissociation might cause long-term damage. The early recognition of women at risk of negative emotions towards childbirth in clinical settings is important in order to help improve women’s healthcare during the pregnancy and after childbirth. Intrapartum interventions that emphasize communication, information sharing, and emotional and practical support during birth  may be helpful. Women who underwent interventions, including EmCs, VE, and ELSC, might have experienced negative emotions during birth, such as fear, lack of control, and dissociation. Enhanced knowledge and understanding among caregivers would provide a vital step towards implementing effective plans to improve pregnant and postpartum women’s health. It is worth mentioning that postpartum women who demonstrated signs of mental stress, such as intrapartum dissociation, especially during birth with medical intervention, should provide postnatal support to prevent the development of PTSD. We conclude that particular attention to personal well-being must be given to women during childbirth, especially those who undergo unplanned birth procedures, as many who endure negative birth experiences later feel negative health-related consequences.There are three limitations to this research. First, our findings are based on a self-reporting survey, for which women with negative birth experiences are less likely to volunteer to fill out a questionnaire than those with more neutral or positive birth experiences. Therefore, a prospective study might be beneficial to neutralize this bias. Second, the study was conducted through the convenience sample method in Israel and has limited research sample representativeness. Therefore, it is recommended to investigate women with negative birth experiences in a large probability sample and in different countries. The third limitation is the applicate single tool (questionnaire) in this research. Therefore, further research should combine some tools, such as interviews, which might be helpful for identifying complex perceptions of women with negative birth experiences.


To describe the feeding profile of low birthweight (LBW) infants in the first half of infancy; and to examine growth patterns and early risk factors of poor 6-month growth outcomes.Prospective observational cohort study.Stable, moderately LBW (1.50 to <2.50 kg) infants were enrolled at birth from 12 secondary/tertiary facilities in India, Malawi and Tanzania and visited nine times over 6 months.Key variables of interest included birth weight, LBW type , lactation practices and support, feeding profile, birthweight regain by 2 weeks of age and poor 6-month growth outcomes.Between 13 September 2019 and 27 January 2021, 1114 infants were enrolled, comprising 4 LBW types. 363 (37.3%) infants initiated early breast feeding and 425 (43.8%) were exclusively breastfed to 6 months. 231 (22.3%) did not regain birthweight by 2 weeks; at 6 months, 280 (32.6%) were stunted, 222 (25.8%) underweight and 88 (10.2%) wasted. Preterm-small-for-gestational age (SGA) infants had 1.89 (95% CI 1.37 to 2.62) and 2.32 (95% CI 1.48 to 3.62) times greater risks of being stunted and underweight at 6 months compared with preterm-appropriate-for-gestational age (AGA) infants. Term-SGA infants had 2.33 (95% CI 1.77 to 3.08), 2.89 (95% CI 1.97 to 4.24) and 1.99 (95% CI 1.13 to 3.51) times higher risks of being stunted, underweight and wasted compared with preterm-AGA infants. Those not regaining their birthweight by 2 weeks had 1.51 (95% CI 1.23 to 1.85) and 1.55 (95% CI 1.21 to 1.99) times greater risks of being stunted and underweight compared with infants regaining.LBW type, particularly SGA regardless of preterm or term status, and lack of birthweight regain by 2 weeks are important risk identification parameters. Early interventions are needed that include optimal feeding support, action-oriented growth monitoring and understanding of the needs and growth patterns of SGA infants to enable appropriate weight gain and proactive management of vulnerable infants.NCT04002908. This study collects 6-month longitudinal data on feeding and growth patterns among moderately low birthweight infants (1.50 to <2.50 kg) in resource-limited settings.Linear mixed-effects models were used to assess differences in growth by low birthweight type.A quasi-likelihood estimation approach specifying a generalised linear model with a log link, a Poisson distribution and robust SEs was used to estimate relative risks.When determining generalisability of the findings, it should be noted that our cohort had ready access to secondary/tertiary health facilities; and the majority of preterm infants were late-preterm, thus influencing feeding patterns/abilities.Low birthweight  infants account for nearly 15% of births, yet make up 80% of neonatal deaths.There is little evidence on the standard of care, feeding practices, growth patterns and associated health outcomes among LBW infants in low-income and middle-income countries (LMICs). Available literature is concentrated on very LBW (<1.50 kg) or preterm infants and in high-income settings.There is renewed interest and investment in efforts to improve quality of care provision, and to prevent and manage poor outcomes among LBW infants.The LIFE study is a formative, multisite, prospective, observational cohort study using a convergent parallel, mixed-methods design to establish foundational knowledge needed to design feeding interventions for nutritionally at-risk LBW infants.Inclusion criteria were birthweight from 1.50 to <2.50 kg and residence within 50 km of the enrolment facility. Infants were excluded if born with congenital abnormalities impacting feeding, had a twin who died prior to screening, had mothers younger than 16–18 years of age (dependent on site) or had mothers who died after screening but prior to consent for data collection. Further exclusions from analysis included infant death <72 hours of birth or administrative withdrawal from the study.Mother–infant dyads were screened for eligibility at study facilities within 72 hours of birth using a checklist based on chart data and maternal interviews. If the dyad met inclusion criteria, they were enrolled, and a baseline assessment was conducted via chart checks, maternal interviews and examinations. The assessment captured demographic characteristics, pregnancy history, feeding since birth, anthropometrics and Dubowitz assessment of gestational age (GA). Dyads were visited at nine time points  in the facility or community via maternal interviews, observations and examinations. Detailed descriptions of follow-up assessments have been published in the protocol.Prior to data collection, site investigators conducted training that covered standard operating procedures, surveys, anthropometric measurement and calibration of equipment. Refresher training and data quality assurance were conducted throughout to ensure consistency and accuracy of data collection. Surveys were translated into local languages. Infant anthropometric measurements included weight, length, head circumference and mid-upper arm circumference. In this paper, we focus on reporting findings related to weight and length, common indicators of attained size; results related to other measures will be shared in a separate publication. Anthropometrics were collected in triplicate at each of the nine study visits using standardised equipment  and calibration protocols.We employed a safety net standard operating procedure, including the completion of a safety net module by data collectors at all study visits. The indicators that we assessed included: malnutrition/severe growth faltering  z-score <−3, oedema in both feet and visible wasting), danger signs or severe illness among the mother or infant. When study staff encountered a mother–infant dyad with any indication, a subsequent referral for advanced care was completed.Birthweight, used for eligibility assessment and all relevant analyses, was measured by facility staff using local equipment prior to baseline assessment and recorded from patient charts. Birthweight was adjusted based on the time between birth and weighing using an established algorithm to account for weight loss .Chronological age is the time in weeks since birth. Postmenstrual age (PMA) is chronological age plus GA at birth in weeks. Unlike chronological age, PMA accounts for the maturity of an infant  and allows for consideration of biological differences given GA at birth.Infants were stratified into four LBW types at birth based on GA (<37 weeks or ≥37 weeks) and size-for-GA , 10–90th percentile of weight for GA; and large-for-GA (LGA), >90th percentile): (1) preterm-SGA, (2) preterm-AGA, (3) preterm-LGA and (4) term-SGA.Feeding profile was based on 7-day recall of feeding patterns at each visit: human milk only, mixed milk feeding , no human milk and not yet fed.Six-month stunted, underweight and wasted were defined by <−2 z-scores for length-for-age (LAZ), weight-for-age (WAZ) and WLZ, respectively. WHO growth standards were used for term infants and INTERGROWTH-21st standards were used for preterm infants to calculate z-scores and size-for-GA; at 6 months, we used WHO standards corrected for GA for preterm infants.We calculated the sample size for precision of estimates based on the percent of LBW infants whose mean LAZ at 6 months was <−2 z-scores; with 300 dyads per site, we had precision of at least ±3.6% for a true proportion of 10% of infants.http://ctri.nic.in).The study is registered with ClinicalTrials.gov (NCT04002908) and CTRI/2019/02/017475  to ensure that research questions were culturally appropriate, understandable and relevant to the study population. The study team involved personnel familiar with each of the respective settings and populations.After screening 1982 mothers and 2152 infants for eligibility, 1114 infants and their mothers (n=1070) were enrolled and analysed .20 Six-mThe pooled cohort included 151 (13.6%) preterm-SGA, 327 (29.4%) preterm-AGA, 37 (3.3%) preterm-LGA and 597 (53.7%) term-SGA infants. African infants were predominantly preterm compared with term-SGA in India. The mean GA was 36.6 weeks (SD 2.7). The majority of preterm infants (465 (90.3%)) were late-preterm. Mean birthweight was 2112 g (246), slightly lower in African compared with Indian sites .Infants not discharged within the first week of life were not included in this analysis, thus resulting in smaller denominators.Overall, 363 (37.3%) infants initiated breast feeding within 1 hour of birth (299 (43.4%) delivered vaginally, 65 (22.7%) via caesarean section); more term-SGA infants initiated early breast feeding compared with the other LBW types, with large site differences (India-Karnataka 144 (52.4%), India-Odisha 144 (75.0%), Malawi 64 (24.5%) and Tanzania 12 (4.9%)) . At base10.1136/bmjopen-2022-067316.supp1Supplementary dataDuring the first 6 months, 493 (44.3%) mothers reported feeding difficulties . Among tOverall, 231 (22.3%) infants did not regain their birth weight by 2 weeks, slightly more pervasive among preterm (131 (27.6%)) compared with term (100 (17.8%)) infants. Stunted was the most prevalent poor growth indicator at 6 months (280 (32.6%)), followed by underweight (222 (25.8%)) and wasted (88 (10.2%)). Stunted prevalence was higher in African sites while underweight and wasted were more common in Indian sites.Poor 6-month growth outcomes differed by LBW type and were most prevalent among term-SGA infants , table 210.1136/bmjopen-2022-067316.supp2Supplementary dataMother–infant dyads who reported feeding difficulties over the first 6 months were more likely to have infants who were underweight at 6 months  compared with those never reporting feeding difficulties; no significant associations were observed with 6-month stunted and wasted outcomes . Being sFinally, we found no evidence of a relationship between EBF to 6 months and 6 month poor growth outcomes in the multivariable models (stunted 1.08 (95% CI 0.88 to 1.31), underweight 1.08 (95% CI 0.86 to 1.36) and wasted 1.30 (95% CI 0.86 to 1.95)) . FurtherWe found that LBW type and early growth deficits were significant risk factors for poor 6-month growth outcomes. Our LBW infant cohort was heterogeneous with nutritional risks varying by setting and birth outcome. Preterm-SGA and term-SGA infants exhibited greater risks for being stunted and underweight at 6 months compared with preterm-AGA infants. Similarly, infants who failed to regain their birth weight by 2 weeks were more likely to be stunted and underweight at 6 months than those who successfully regained. These findings emphasise the need for early growth monitoring and proactive intervention for small and/or nutritionally at-risk infants. While human milk feeding was the predominant feeding profile among this cohort, 567 (58%) infants were not EBF to 6 months as advised by WHO. Additionally, nearly half of mother–infant dyads reported feeding difficulties in the first 6 months, which reinforces the need for universal and consistent lactation support and management targeted to the needs of LBW infants in low-resource settings. The MAMI Care Pathway Package highlights reported feeding difficulties as criteria for further assessment and enrolment in support at the population level.While a major objective of this study was to fill the gap in evidence regarding moderately LBW infant feeding patterns and their relationship with growth and other health outcomes, we recognise that numerous factors besides feeding impact infant growth including maternal nutritional status, maternal health and well-being, infant illness, intrinsic causes of intrauterine growth restriction, kangaroo mother care/thermal care and supplements given to infants.In order to improve growth patterns and outcomes, early indicators are needed to identify infants in need of close monitoring and timely intervention. In general, growth faltering indicators are not standardised in their definition or use.EBF is an optimal source of nutrition for child health and survival, supported by strong evidence of its protective impact on morbidity and mortality.This study had numerous limitations. While the COVID-19 pandemic led to some changes in study activities, study timelines were only slightly impacted and visit attendance remained high. Despite a lack of unified guidance on the application, harmonisation and interpretation of existing child growth standards for this LBW population, we were able to recommend and apply an approach to assess infants against an appropriate standard. We note known difficulties of GA measurement in LMIC and acknowledge the possibility of some misclassification. To identify the best estimate of GA, we used an algorithm based on multiple sources documented in patients’ charts. Regardless of possible imprecisions in birth weight measurements, we felt this measure taken within minutes/hours of birth was more accurate than using enrolment weight  as a proxy of birth weight; a sensitivity analysis was conducted using enrolment weight in the models and similar trends were observed. Possible response bias was minimised through data collection by research staff not known to respondents rather than their care providers. As in every longitudinal study, missing data and lost to follow-up was present; we tried to minimise this by conducting phone interviews or extending visit windows where in-person visits were not possible. Exclusion of LBW infants with congenital abnormalities that interfere with feeding at the screening stage of the study means that the particular needs and likely poorer health outcomes associated with early life disability are not captured in this paper. Finally, when determining generalisability of the findings, it should be noted that our cohort had ready access to secondary/tertiary health facilities; and the majority of preterm infants were late-preterm, thus influencing feeding patterns/abilities.This study examined the feeding and growth patterns of moderately LBW infants in the first half of infancy. Our LBW infant cohort was heterogeneous, comprising four LBW types that differed in prevalence by region. LBW type, particularly those born SGA regardless of preterm or term status, and lack of birthweight regain by 2 weeks may be important parameters that could be used to identify and proactively manage nutritionally at-risk infants early in life. Additionally, utilisation of these indicators could facilitate the prioritisation of scarce resources  and services  to infants at highest risk. Research is needed to support optimal feeding strategies for LBW infants, understand the needs and growth patterns of SGA infants and evaluate the role of human milk volume, nutrient composition and feeding frequency on infant growth.10.1136/bmjopen-2022-067316.supp3Supplementary data


Although some studies have highlighted short birth interval as a risk factor for adverse child nutrition outcomes, the question of whether and to what extent long birth interval affects better nutritional outcomes in children remains unclear.In this quantitative meta-analysis, we evaluate the relationship between different birth interval groups and child nutrition outcomes, including underweight, wasting, and stunting.Forty-six studies with a total of 898,860 children were included in the study. Compared with a short birth interval of <24 months, birth interval of ≥24 months and risk of being underweight showed a U-shape that the optimum birth interval group of 36–48 months yielded the most protective effect . Moreover, a birth interval of ≥24 months was significantly associated with decreased risk of stunting  and wasting  when compared with the birth interval of <24 months.The findings of this study show that longer birth intervals (≥24 months) are significantly associated with decreased risk of childhood undernutrition and that an optimum birth interval of 36–48 months might be appropriate to reduce the prevalence of poor nutritional outcomes in children, especially underweight. This information would be useful to government policymakers and development partners in maternal and child health programs, especially those involved in family planning and childhood nutritional programs. Despite significant progress in reducing child mortality attributed to undernutrition, childhood undernutrition remains a major public health concern in developing countries. Undernutrition is most often measured by anthropometry and evaluated in terms of underweight, stunting, and wasting . These uThe WHO 2025 global nutrition target is to reduce the prevalence of stunting by 40% and wasting to <5% . The UniAdequate nutrition is essential for the healthy growth and development of children. The consumption of nutrients by children begins long before birth. Undernutrition during pregnancy stunts fetal growth and can lead to poor brain development, resulting in irreversible damage . During Various studies have identified that low dietary intake, low birth weight, higher birth order, low parental education level, exclusive breastfeeding more than 6 months of age, illnesses such as diarrhea, and sex of child  are contributing factors to childhood undernutrition –18. HoweThis is a meta-analysis study and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Guideline to examine the pooled odds ratio of the birth interval and its association with child undernutrition. A comprehensive literature search of research studies published before 30 June 2022 was conducted. Different search engines including PubMed, Web of Science, Science Direct, Google scholar, and Cochrane library were methodically searched. We tried to search for studies in different languages, but only English articles appeared to have relevant data about birth intervals and undernutrition, so we only used a single language for the search.A further computerized search was conducted using a combination of medical subject headings or keyword terms for birth interval and child undernutrition and was used separately in combination using Boolean operators such as “OR” or “AND.” Terms for birth intervals included birth interval, birth spacing, interpregnancy interval, interbirth interval, preceding birth interval, and subsequent birth interval, and for the child undernutrition, these terms were also used: undernutrition, malnutrition, nutrition status, nutrition outcomes, child growth, stunting, wasting, and underweight.Studies included in this review had to meet the following criteria: “(1) cross-sectional, case–control, or cohort studies that evaluated the relationship between birth interval and any of the child undernutrition indicators, namely underweight, stunting, and wasting; and (2) original data were available. Studies were excluded if they were case series or reports, editorials, and reviews and if original data to calculate the association were unavailable.Two authors independently extracted all necessary data. The full text of these potentially eligible studies was retrieved and assessed for eligibility by two review team members. Any discrepancies were resolved jointly. The data extraction format included the first author's name, publication year, country, region, sample size, study design, interval group, undernutrition indicators measured, and the quality score of each study.Two authors independently assessed the quality of the eligible studies and controlled for possible bias by adapting specific protocol/sample characteristics. The criteria proposed in the Newcastle–Ottawa Scale quality assessment tool were adapted and used to assess the quality of each study. Two authors independently assessed the quality of each original study using the tool. Discrepancies between the two authors were resolved jointly.The effect size of the meta-analysis was an odds ratio of underweight, stunting, and wasting reported in each study about the birth interval applied, the pooled odds ratio with a confidence interval of underweight, stunting, and wasting, according to the birth intervals grouped into <24 and ≥24) were estimated. When heterogeneity between studies was absent, we merged the results using fixed effect models. Otherwise, a random-effects model was chosen. Subgroup analyses were conducted for the studies according to regions and by considering the birth intervals, which were classified into 24–48 against <24 and ≥48 against <24 to determine the extent to which a certain birth interval used is considered a risk factor or protective according to the nutrition outcomes . To determine the extent of publication bias, funnel plots were scattered and tested for asymmetry, and Begg's tests were computed. The analysis was performed using STATA version 15 statistical software .We then utilized the funnel plot and Begg's test to evaluate potential publication bias in the literature. The funnel plots were symmetrical in all the studied undernutrition outcomes . MoreoveThe results of our study show that a longer birth interval (≥24 months) is significantly associated with a reduced risk of childhood undernutrition. Moreover, birth interval of ≥24 months and risk of underweight showed a U-shape that the optimum birth interval group of 36–48 months had the most protective effect compared with the birth interval of <24 months.The most important risk factors for child undernutrition have been proven to occur early in life, including inadequate breastfeeding and maternal undernutrition during pregnancy . If longSome researchers have stipulated that having short birth intervals are caused by socioeconomic status, poorer lifestyles, failure to or inadequate use of healthcare services such as healthcare advice provided by healthcare advisers at community health centers, and other behavioral or physiological determinants, which will, in turn, lead to poorer pregnancy outcomes leading poor child nutrition outcomes , 72.However, the effect of short birth intervals on children's nutritional status was not attenuated when socioeconomic and maternal characteristics were controlled , 73. ThiThis study had several strengths. First, our study presented a comparison between birth interval and all three undernutrition indicators: underweight, stunting, and wasting. Second, over 85% of the studies included in our meta-analysis were conducted in low-income and middle-income countries, which are mainly found in Africa and Asia, where the burden of child undernutrition is high. Therefore, this study supports the call to address the underlying causes of acute and chronic childhood undernutrition. Third, this study has identified areas where fellow researchers can design appropriate and strategic interventions to help the community to have healthy birth spacing based on our recommended birth interval.There were some limitations to this study. First, there were few studies in developed countries, even though undernutrition is more prevalent in developing countries, so the results cannot be easily generalized. In addition, in many studies, assessing the relationship between birth interval and child nutritional outcomes was not a primary objective because birth interval was only one of the many variables examined. Most studies often lacked an assessment of all three nutritional indicators, namely, stunting, wasting, and underweight in their analysis. For three categories of child nutritional outcomes, further studies including a more comprehensive assessment of potentially confounding variables are needed to extract the complex factors involved in the relationship between birth interval and child nutritional outcomes.Our study reveals that a longer birth interval (≥24 months) is significantly associated with decreased risk of childhood undernutrition including underweight, stunting, and wasting. More importantly, the optimum birth interval of 36–48 months yielded the most protective effect for underweight, and this would allow for repletion prior to the next conception and conserves required nutrients for the baby's growth during and after the delivery, hence boosting further child nutrition status while reducing unacceptably high burden of child undernutrition.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.JN, WZ, AQ, and ZC contributed to the literature search and painting of all figures. JN wrote the manuscript. WZ contributed to the critical revision of the manuscript. MC designed the study and had full access to all data in the study and take full responsibility for the accuracy of the analyses and their interpretation. All authors read and approved the final manuscript.


Moreover, the risk of macrosomia, premature birth and being born large for gestational age (LGA) increased by 2.01 , 1.35  and 1.80  times, respectively. Additionally, for every 1 mmol/L increase in FPG associated with a decrease in gestational age , the risk of SGA decreased by 0.70  times. Every 1 mmol/L increase in 1/2-h PG had similar outcomes as FPG, besides premature birth and SGA. Conclusions: Higher blood glucose in pregnant women may increase neonatal birth weight, decrease gestational age and lead to a higher risk of macrosomia, premature birth and LGA. Mothers should actively prevent and control hyperglycemia to promote maternal and infant health.Objective: This study aimed to investigate the relationship between maternal blood glucose levels during pregnancy and neonatal birth outcomes in Northwest China. Methods: This population-based cohort study included 10,010 first-trimester pregnant women who joined the birth cohort of the Northwest Women’s and Children’s Hospital from July 2018 to July 2020. Basic demographic characteristics, lifestyle and behavior patterns were collected. Oral glucose tolerance test (OGTT) results during the second trimester and pregnancy outcomes after childbirth were also collected. A generalized linear model was constructed to analyze the effects of blood glucose levels on neonatal birth outcomes. Results: We found that every 1 mmol/L increase in fasting plasma glucose (FPG) was associated with an increase in birth weight ( Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy and is defined as glucose intolerance that results in hyperglycemia initiated or first diagnosed during pregnancy. The prevalence of GDM differs widely depending on the diagnostic criteria used and population characteristics. The estimated global standardized prevalence of GDM was 14.0% in 2021, with the highest GDM prevalence in the Middle East and North Africa 27.6%), followed by Southeast Asia 20.8%), Western Pacific (14.7%) and Africa (14.2%) . Some st%, follow%, WesterSince the human fetus is highly dependent on glucose from the maternal circulation, glucose homeostasis transferred from the mother to the placenta is thought to be a major determinant of fetal development . SubstanTherefore, we analyzed 10,010 pregnant women who delivered at the Northwest Women’s and Children’s Hospital of Shaanxi Province from January 2018 to December 2020. We specifically assessed the relationship between maternal blood glucose levels during pregnancy and neonatal birth outcomes in Northwest China. The data presented herein provide insights on the early prevention of GDM, reducing the risk of maternal and neonatal complications caused by hyperglycemia, and reducing the medical burden to both countries and individuals.Data were collected from a population-based prospective cohort study  on neona+6 gestational weeks; (3) pregnancy care and delivery performed at Northwest Women’s and Children’s Hospital. The exclusion criteria were as follows: (1) under 20 years old; (2) presence of at least one of the following diseases before pregnancy: hypertension, GDM, hyperthyroidism, heart disease, chronic kidney disease or tuberculosis; (3) unable to answer questions accurately due to psychiatric symptoms or other serious illnesses. Termination or withdrawal criteria were as follows: (1) the subject developed serious diseases or died due to uncontrollable factors during the observation period; (2) the subject requested to be withdrawn or was lost to follow-up.The following inclusion criteria were used to select patients for the study: (1) pregnant women who voluntarily joined the birth cohort and signed informed consent from January 2018 to December 2020; (2) 1 to 13We excluded subjects with miscarriage or pregnancy induction (248 cases), twins (144 cases) and incomplete information (72 cases). This study only included pregnant women of singleton live births with well-defined pregnancy outcomes .This study was divided into three main stages. (1) Enrollment: After being recommended by doctors from the outpatient clinic, pregnant women voluntarily joined the birth cohort and completed the “Early Pregnancy Information Questionnaire” available at the EDC (Enterprise Data Center) cloud platform online system to collect general demographic characteristics and early pregnancy life behaviors. (2) Maternal medical examinations and complications during pregnancy were recorded during the second and third trimesters of pregnancy through the online EDC cloud platform and the hospital outpatient system. (3) Data on pregnancy outcome  were gathered through the hospital’s inpatient medical record system.The birth weight Z score was calculated according to the INTERGROWTH-21st standard : birth wAll pregnant women were subjected to a 75 g oral glucose tolerance test (OGTT) at 24 - 28 weeks of gestation. Abnormal blood glucose levels were diagnosed according to American Diabetes Association criteria: fasting plasma glucose (FPG) ≥ 5.1 mmol/L, 1-h plasma glucose (PG) ≥ 10.0 mmol/L or 2-h PG ≥ 8.5 mmol/L.2, normal: 18.5 ~ 23.9 kg/m2, overweight: 24.0 ~ 27.9 kg/m2, obesity: ≥ 28.0 kg/m2), gestational weight gain (GWG) , first pregnancy , complications in previous pregnancies , fetal sex , smoking or passive smoking , fever or cold  and the use of multidimensional nutrients or folic acid supplements . “Pregnancy period” refers to the period from 3 months before pregnancy to the end of pregnancy. “Smoking or passive smoking” refers to smoking at least one cigarette or passive inhalation of smoke for more than 15 min at least 1 day per week during pregnancy. “Maternal fever or cold” refers to having a fever or cold at least 1 time during pregnancy. “Supplementation of folic acid or multidimensional nutrients” refers to mothers taking folic acid or multidimensional nutrients for more than 30 days during pregnancy. “Complications in previous pregnancy” refers to mothers who developed gestational hypertension, GDM or thyroid disease during a previous pregnancy. BMI was obtained by dividing the mother’s pre-pregnancy weight by the square of their height (kg/m2). GWG was classified as insufficient, appropriate or excessive based on pre-gestational BMI according to 2009 Institute of Medicine (IOM) criteria. Specifically, for underweight women, appropriate GWG ranges from 12.5 to 18 kg; for normal women, 11.5 to 15.9 kg; for overweight women, 7 to 11.5 kg; and for obese women, 5 to 9 kg.Considering data from previous studies ,17, we c2 test. A t-test or analysis of variance (ANOVA) was used to compare values between groups for continuous variables. We constructed a generalized linear model (GLM) to explore the association between blood glucose levels during pregnancy and neonatal birth outcomes. Continuous outcome variables, such as neonatal gestational age, selected the connection function as identity: g−1(μ) = μ. Binary outcome variables, such as low birth weight, selected the connection function as logit: η = ln (μ/1 − μ), where μ is the conditional probability of the offspring outcome variable. Possible confounding variables were included in the multivariate analysis. We drew the trend for macrosomia risk and neonatal birth weight, and gestational age despite elevated blood glucose levels by restricted cubic spline and smoothing spline, respectively. Moreover, we used the GLM to evaluate the effects of changes in blood glucose levels on neonatal birth outcomes. As shown in p < 0.05 indicated a significant difference.Categorical variables are expressed as frequency and percentages, while continuous variables are expressed as mean and standard deviation (SD). In univariate comparisons, categorical variables were compared between groups using the χp < 0.05).β = 59.21 g, 95%CI: 40.86, 77.56), birth weight Z score , birth weight Z centile , decrease the gestational age  and lead to a higher risk of macrosomia  and LGA  in the adjusted model. β > 0 or OR  >  1). The association between maternal high blood glucose and birth weight and macrosomia was relatively stable, although some effects were not statistically significant.As shown in β = 100.22 g, 95%CI: 81.91, 118.52), birth weight Z score  and birth weight Z centile , and increase the risk of macrosomia, premature birth and LGA by 2.01 , 1.35  and 1.80  times, respectively. Moreover, every 1 mmol/L increase in FPG decreased gestational age  and decreased the risk of SGA by 0.70  times. Every 1 mmol/L increase in 1-h PG and 2-h PG had similar outcomes as FPG, besides premature birth and SGA  and 1-h PG  could increase maternal weight before delivery , weight Z score , macrosomia  and LGA  [p = 0.004) [This study found that mothers with high blood glucose during pregnancy had babies with increased birth weight and risk of macrosomia and LGA, which is consistent with conclusions of previous studies. Indeed, a prospective cohort study conducted in Zhou Shan (Zhejiang Province) found that abnormal blood glucose was positively correlated with neonatal birth weight  . Materna1, 2.89) ,20, the = 0.004) . A retro= 0.004) .95%CI: 0.4, 11.5) percentage-point increase in birth weight percentile [95%CI: 1.54, 5.88) and 2.74 , respectively [95%CI: 0.39, 0.57) and the odds ratio of LGA increased by 2.61 times . Higher early FPG levels were associated with restricted fetal growth in the second trimester, followed by a compensatory growth starting in the third trimester that culminated in a significant weight gain and an increased risk of LGA [Another cohort study continuously measured maternal glucose levels and found that a 1-unit increase in maternal mean nighttime glycemia was associated with a 6.0 , stillbirth  and neonatal respiratory distress syndrome  [95%CI: 1.15, 1.77) [Some studies have found that maternal hyperglycemia during pregnancy increase the risk of preterm birth ,32. Spec< 0.001) . Indeed,5, 1.77) . Here, wOR, β) of blood glucose levels on birth outcomes in this study seem to be lower than in developed countries and economically developed areas such as the coastal provinces in China. It is well known that regional variations in the prevalence of GDM, due to diagnostic criteria, ethnicity, lifestyle and environmental factors [Overall, the effect values ( factors , and inf factors ,39,40,41 factors . Hypergl factors . Thus, a factors . In para factors .Some studies have shown that increased protein in poultry, fish, nuts and soy foods in the diet of pregnant women may reduce the risk of GDM ,47,48. IThis was a large, population-based, prospective study that investigated the impact of maternal hyperglycemia during pregnancy on birth outcomes and provided high-quality data in an underexplored population using statistics. We introduced indicators that comprehensively reflect neonatal developmental status, such as birth weight Z score, birth weight Z centile and blood glucose changes to comprehensively analyze the influence of blood glucose levels on birth outcomes. Overall, the data contained in this study might enlighten policy makers and help guide strategies to prevent hyperglycemia in pregnant women. However, some limitations should be acknowledged. First, the research subjects were all from Northwest Women’s and Children’s Hospital, which might induce a selection bias. Second, some confounding factors in this study, such as cold or fever before pregnancy and early pregnancy, were obtained through recall, and we cannot exclude a recall bias. Third, we did not obtain maternal ambulatory information on gestational blood glucose levels and glycosylated hemoglobin, which might influence the effect of blood glucose on neonatal birth outcomes.In conclusion, higher blood glucose during pregnancy has adverse effects on both the mother and the newborn. This study found that every 1 mmol/L increase in maternal PG levels during pregnancy was associated with increased birth weight, decreased gestational age and higher risk of macrosomia and LGA. Additionally, elevated FPG was also associated with a higher risk of premature birth and a lower risk of SGA. Health education and pregnancy care for women of childbearing age should be strengthened, and corresponding measures should be actively taken to prevent and treat hyperglycemia to promote prenatal and postnatal care.


To assess deviations in longitudinally measured cytokines with preterm birth (PTB).Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T) intervals: first trimester (T1: 8–14 weeks’ gestation), second trimester (T2: 18–22 weeks’ gestation), and third trimester (T3: 28–32 weeks’ gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: “Uncomplicated” (delivered ≥37 weeks) or “Preterm Birth” (<37 weeks). Generalized Linear Modeling determined rate of change T1–T3 by outcome.Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1β), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1β, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancyWomen delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy. Shifts in immune parameters in pregnancy have been implicated in pregnancy outcomes. A number of adverse pregnancy outcomes like preeclampsia, preterm premature rupture of membranes, and miscarriage have all been hypothesized to have a strong association with increases in systemic inflammation as demonstrated by various serum markers. A number of environmental factors  and health conditions  are known to both increase systemic inflammation and in turn increase risk for preterm delivery , 2], , . While mMaternal immune responses are modified during pregnancy. Prior data indicate a trend over gestation toward a dampened T helper type 1 (Th1)-associated and pleiotrophic cytokine expression; such data implicate enhanced counter regulatory cytokine expression as instrumental in decreasing inflammatory responses and, in effect, tolerance to fetal tissues . Other dT cells have often been the focus of many reproductive studies given their role in signaling and coordination of immune responses via cytokine signaling , 9], , . Given tWhile prior data on cytokine response in pregnancy suggest immune modulation plays an important role in normal pregnancy , completMoreover, the trajectory of cytokine expression over the course of pregnancy in term vs. preterm is not well characterized. A number of questions surround whether cytokine profiles differ at time of preterm delivery only or if trajectory from early and mid-trimesters vary as well . Such gaA number of biological fluids have been sampled for assessing inflammation as it pertains to preterm birth; these have included amniotic fluid, cervical secretions, urine, saliva, serum, plasma, vaginal secretions, and periodontal fluid. Each type of fluid has both strengths and limitations with respect to knowledge that can be gained. Preterm birth is an endpoint in many respects that which multiple pathways may lead to triggering inflammation, upregulation of oxytocin receptors and downregulation of progesterone receptors whether the inflammation originates from the gingiva or the vagina for example. Arguably, the best clinical marker for the prediction of spontaneous preterm birth to date has been fetal fibronectin in the cervix and/or vagina .However, cervicovaginal fluids are only one pathway that leads to preterm birth. Evidence continues to mount that periodontal disease creates local inflammation in the oral cavity that spreads systemically and affects other organ systems. Such harm is not limited to increased incidence of cardiovascular disease and myocardial infarction but joint periodontal and obstetrical investigators have demonstrated a strong association of periodontal disease when untreated leads to increased systemic inflammation that in turn seeds the cervix with inflammatory changes leading to early shortening and in turn preterm delivery. Like cervicovaginal lavages, saliva is the ultrafiltrate of the plasma and facilitates assessment of a number of inflammatory markers from C-reactive protein (CRP) to cytokines. However, both cervicovaginal and saliva fluid samples are limited by patient activity  and Drexel University. Institutional Review Board (IRB) approval was obtained from both universities . We initiated a prospective, longitudinal investigation of immune and neuroendocrine parameters associated with stress, infection, and preterm birth.For this study, all women attending their first prenatal visit at a hospital-based clinic in Philadelphia, Pennsylvania between March 2001 and November 2002 were screened for eligibility. Women were considered eligible for participation if they were, (1) English or Spanish speaking, (2) had a singleton intrauterine pregnancy, (3) <15 weeks’ gestation, and (4) ≥17 years of age.Conversely, women were excluded from participating if they had any immunologic disorder /Acquired Immunodeficiency Syndrome (AIDS), Systemic Lupus Erythematosis (SLE), sarcoidosis, taken systemic corticosteroids six months prior to enrollment, or taken antibiotics for infection in the 15 days prior to enrollment. All eligible women were approached for consent, and those who provided written informed consent were enrolled. Women became ineligible at the second or third trimester visits if they were no longer pregnant, developed an excluding medical condition, or if they moved out-of-state and could no longer take part in the study.Trained interviewers collected demographics, medical history, behavioral history, and psychosocial data from study participants upon enrollment. Study participants were followed at regularly scheduled prenatal appointments with updated data. Phlebotomy specimens were obtained at three intervals: first trimester (T1: 8–14 weeks’ gestation), second trimester (T2: 18–22 weeks’ gestation), and third trimester (T3: 28–32 weeks’ gestation). These intervals were carefully selected to accomplish the following: (1) avoid early immune shifts and variation during the initial phase of implantation; (2) ensure enrollment after well-established viability and diagnosis of singleton intrauterine pregnancy; (3) assess phlebotomy and urine at times that coincided with usual standard of care visits; (4) be representative time points within all three trimesters in well-dated pregnancies; and (5) avoid drop out and bias due to preterm delivery to facilitate comparison across the two groups that would either deliver preterm or term.Upon enrollment, all women completed a face-to-face interview with trained study personnel to assess: (1) socio-demographic history, (2) psychosocial history, (3) health behavior history, and (4) medical history. Maternal variables abstracted by research staff were those having pertinent effects on preterm birth; these included the following: age, race, substance abuse , education level, and income. Alcohol use was qualified by patient self-report during the face-to-face interview. Criteria for being classified as positive for pregnancy complicated by illicit/recreational drug use was qualified by a positive urine drug screen or positive patient report of drug use during pregnancy of any one or more of the following: cocaine, marijuana, phencyclidine (PCP), amphetamines, opiates, benzodiazepines, barbiturates, methadone, propoxyphene, and/or quaaludes. Likewise, as part of the consent process for the study, our physician panel had the opportunity to review all prenatal care records, including outpatient clinic visits, hospitalization records, delivery records, neonatal records during initial hospitalization, and postpartum care to review for any positive report or test result of any substance use, including tobacco, alcohol and all illicit/recreationally used drugs or prescribed substance dependency. These results were abstracted into the data sheets for each patient accordingly for demographics and outcomes as either positive/negative for substance use or likewise either positive/negative for smoking.Anthropometric measurements  were obtained. All participants had their body mass index (BMI) calculated. Standard cutoffs for BMI were used as follows: overweight (>25), obese (>30), morbidly obese (>35).Medical records were reviewed to obtain and verify antepartum, intrapartum, and post-partum information about the study participant’s demographics, history and medical conditions as well as documentation of a live birth from available medical records. To ensure accuracy of the medical record information, medical records were abstracted by trained personnel and collectively verified by a physician panel. Obstetrical complications included abruption/previa, intrauterine growth restriction (IUGR) as demonstrated by low birth weight (LBW) on Fenton index chart, gestational hypertension (GHTN)/pre-eclampsia, or fetal distress. Abruption was the coded indication for delivery when maternal hemorrhage suggestive of abruption was the documented reason for delivery by cesarean. When placenta previa was documented in the chart as due to ultrasound findings, the indication for delivery by cesarean was coded as previa. Fetal distress was defined as non-reassuring fetal heart tracing (NRFHT), repetitive fetal heart rate decelerations prompting an indicated delivery, or if a Category III fetal heart tracing was noted. Low birth weight was defined by birth weight less than the 10th percentile for the assigned gestational age per Fenton growth chart. Gestational hypertension (GHTN) was defined as at least two maternal blood pressures ≥140/90 in the absence of proteinuria. Criteria for pre-eclampsia were defined as at least two maternal blood pressures over a 4 h interval of ≥140/90 with proteinuria  was the indication for delivery, we examined six individual variables: (1) maximum recorded intrapartum temperature, (2) maternal leukocytosis , (3) maternal tachycardia  for 20 min), (4) fetal tachycardia , (5) malodorous amniotic fluid (when documented by labor and delivery nurse/physician), and (6) uterine tenderness . Those identified as having infection .in vitro cytokine release assays. For the cytokine release assay, the sample of anti-coagulated maternal blood was collected and transported on ice within 30 min to the on-site laboratory for processing as follows: the cytokine release analysis was performed on incubated supernatants from stimulated whole blood. For the cytokine release assay, 24-well plates were prepared in advance with 1.5 mL of media consisting of Roswell Park Memorial Institute’s RPMI 1640  containing 10% fetal bovine serum  and penicillin/streptomycin  at 1:100 dilution added to individual wells. Plates were stored at −20 °C, thawed and brought to room temperature immediately before use. Heparin anti-coagulated blood samples were distributed, 0.5 mL of whole blood, into four individual wells of the previously prepared 24-well plate containing one of the three conditions: (1) supplemented with phytohemagglutinin (PHA)  at a final concentration of 5 μg/mL, (2) supplemented with lipopolysaccharide (LPS) −2  at a final concentration of 1 μg/mL, or (3) not supplemented as the control.At each of three time points, phlebotomy samples were collected by standard antecubital venipuncture with vacutainer collection in sodium heparin anticoagulant, for 2. At the conclusion of this period, plates were placed on ice and the contents of the four wells for each condition were transferred to 15 mL conical tubes. Samples were centrifuged at 4 °C for 10 min at 300 × g followed by distribution of the supernatant into 500 µL aliquots that were immediately frozen at −80 °C and maintained frozen until analysis in triplicate by Luminex-100 MAP® methods using commercially available kits  according to manufacturer’s instructions and as previously reported , , . We alsoWe selected the following cytokines for analysis: IFN-γ, the prototypical Th1-associated cytokine; IL-4, a Th2-associated cytokine; the less specific pro-inflammatory cytokines TNF-α, IL-10, and IL-6; and IL-10, a predominant counter-regulatory cytokine associated with suppression of T cell maturation. An extensive literature search and experience by the investigators led to selection of these cytokines as representative for the Th1-associated, Th2-associated, pro-inflammatory, and counter-regulatory cytokine assays to represent the profile or inflammatory status of each of the subjects and by birth outcome stratification. A power calculation indicated that assuming a 15% preterm birth rate in our higher risk inner city population that 30 women would be needed in total to detect a 30% variance in cytokine trajectory between preterm and term birth outcomes. Knowing that additional pregnancy outcomes in the targeted sample would inevitable occur in those completing the three phlebotomies.in vivo interactions between monocytes/dendritic cells and T cells). However, mitogen use has been validated and is a widely-accepted approach for the study of the immune response , , , 31], , , 33], , . Cervicoin vivo ratios with other cell types and non-cellular components; (4) retention of all blood components including serum; and, (5) ability to assess systemic inflammatory alterations in pregnancy that result from other portals of entry .Our project was designed to assess and analyze cytokine milieu via ELISA on phlebotomy specimens. Ex vivo analysis offers the important advantages of (1) ease of handling; (2) low or negligible risk on pregnancy outcome for the patient; (3) maintaining target cell types at their Our study design further adds to knowledge of immune modulation as expressed systemically and moreover longitudinally over the course of both gestations that result in uncomplicated term deliveries vs. otherwise uncomplicated spontaneous preterm deliveries. We additionally include data on how smoking affects longitudinal expression of a broad panel of cytokines over the course of gestation. Our group of investigators has experience in evaluating systemic inflammation in pregnancy and the Luminex assay methodology has been validated . FurtherOur study has a number of other strengths. Both key clinical data and maternal biological samples were collected prospectively. Our group of includes statistical expertise as well as substantial experience in measurement and interpretation of cytokine levels using Luminex ELISA assays. Additionally, our study is unique in that we performed a longitudinal study in pregnant women on cytokine profiles across pregnancy ending in either uncomplicated term delivery or spontaneous preterm delivery.Prior data demonstrate that IL-1β plays a key role in mediating the inflammatory response to bacterial vaginosis. Such response underpins the association of bacterial vaginosis with preterm birth. The response to the bacteria or lack thereof until inflammatory colonization sets in is likely rooted in polymorphisms in the host or gravid female’s immune system . IL-1β iFuture studies in this area may prove useful in the care of the obstetrical patient by (1) identifying deviations from normal longitudinal patterns and (2) potentially identifying interventions to modify outcomes for at risk populations. Studies on the effect of interventions  on cytokine trajectories may likewise shed light on mechanisms of action by known treatments for those at risk of delivering preterm.Notably, the population studied is that of predominantly African-American community and may limit generalizability to other populations and their respective outcomes and immune responses in pregnancy. Given disparities in healthcare resources and research funding alike as they pertain to the underserved poor African-American population, our data are critical for the scientific and clinical community to add to the growing knowledge of our understanding of pregnancy biology in these underserved women. Better understanding of environmental triggers and underlying maternal immune response longitudinally over pregnancy may enable physician-scientists to identify modifiable variables that may ultimately impact pregnancy outcomes which are notably worse in the poor, underserved African American communities.Analyses of cytokine trajectories associated with environmental insults like stress and smoking along with other adverse outcomes such as preeclampsia and stillbirth may be useful in better understanding mechanisms leading to their occurrence.


A pessary is a device made of synthetic material that is placed in the vagina and has been used for prevention of preterm birth. It has been suggested that a potential mechanism of the pessary is alteration of the cervico‐uterine angle to a more posterior position, which reduces cervical compression in women with a singleton pregnancy and a short cervical length. Pessaries should not be used in routine clinical care to reduce the frequency of preterm birth or to improve outcomes  related to preterm birth. In women with a twin pregnancy—regardless of cervical length—pessaries should not be used in routine clinical care to reduce the frequency of preterm birth or to improve outcomes  related to preterm birth. Presently there is no sufficient evidence suggesting that pessaries should be used as a standard treatment to prevent preterm birth; their use should be reserved for study populations. Pessary for prevention of preterm delivery is presently not recommended and should only be used for study populations. One potential application of the pessary has been preventing preterm birth in high‐risk groups, such as women with a singleton pregnancy with a shortened cervix in the mid‐gestation, or those with a twin gestation. One hypothesis is that the pessary alters the cervico‐uterine angle to a more posterior position, which reduces cervical compression and other changes. Nevertheless, the exact physiologic mechanism by which a more posterior cervix would lead to a lower preterm birth rate has not been demonstrated.There have been several randomized trials within the last decade (and many more ongoing) that have evaluated whether pessary is a beneficial strategy for preterm birth prevention in a variety of different populations . These trials have yielded inconsistent results even among women with similar risk factors for preterm birth. Some showed benefit among those who received a pessary, and others showed statistically similar results regardless of whether a pessary was used.22.1As two examples of conflicting studies among women with singleton pregnancies and a short cervix, Goya et al. randomized those with a singleton pregnancy and a cervix ≤25 mm to an Arabin pessary vs no pessary, and found that those who received the pessary had an 82% reduction in the relative risk of spontaneous preterm birth and an 86% reduction in a composite of perinatal morbidity.Recommendation: In women with a singleton pregnancy and a short cervical length, a pessary should not be used in routine clinical care to reduce the frequency of preterm birth or to improve outcomes  related to preterm birth.2.2+0 weeks . Other investigators similarly have shown no difference in preterm birth rates among women with twins who received a pessary. However, some of these trials were smaller, with a corresponding greater chance of type II error.Among a general population of women with twins, Liem et al.Recommendation: In women with a twin pregnancy—regardless of cervical length—pessaries should not be used in routine clinical care to reduce the frequency of preterm birth or to improve outcomes  related to preterm birth.3While some studies have shown benefits from pessary, those benefits have often not been related to the a priori primary outcome or have been seen only after subgroup analysis in women with different cervical lengths. Other studies have shown statistically similar effects among women at risk of preterm birth regardless of whether they received a pessary. In some cases, the size of the trial has been small enough, and the confidence interval around the point estimate of the effect size sufficiently wide, that a clinically significant benefit remains possible. Interpretation of the results is further complicated because studies have varied concerning management among those enrolled, including whether or not vaginal progesterone was used. This inconsistency in findings and lack of clear delineation of a specific group of individuals among whom pessary is efficacious is the basis upon which to conclude that, at this time, there is not sufficient evidence to suggest that pessary should be used as a standard treatment to prevent preterm birth, and that its use should be reserved for study populations.William A. Grobman reports no conflicts of interest. Jane Norman reports receipt of grants from government and charitable bodies for research into understanding the mechanism of term and preterm labour and understanding treatments; participation in a Data Safety and Monitoring Board for a study involving a preterm birth therapeutic agent for GlaxoSmithKline; and consultancy for Dilafor on drugs to alter labour progress. Bo Jacobbson reports research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund and the US National Institute of Health; clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed) and Hologic (ongoing) with expendidures reimbused per patient; clinical probiotic studies with product provided by FukoPharma  and BioGaia ; collaboration in IMPACT study where Roche, Perkin Elmer and Thermo Fisher provided reagents to PLGF analyses; coordination of scientific conferences and meetings with commercial partners as such as NNFM 2015, ESPBC 2016 and a Nordic educational meeting about NIPT and preeclampsia screening. Bo Jacobbson is also Chair of the FIGO Working Group for Preterm Birth and the European Association of Perinatal Medicine's special interest group of preterm delivery; steering group member of Genomic Medicine Sweden; chairs the Genomic Medicine Sweden complex diseases group; and is Swedish representative in the Nordic Society of Precision Medicine.All authors and the FIGO Working Group for Preterm Birth drafted the concept and idea of the paper. WAG wrote the first version of the manuscript. JN and BJ revised various versions of the manuscript. All authors and working group members commented on the manuscript and approved the final version.Bo Jacobsson (Chair), Joe Leigh Simpson, Jane Norman, William A. Grobman, Ana Bianchi, Stephen Munjanja, Catalina María Valencia González, Ben W. Mol, Andrew Shennan.


Higher levels of thyroid autoantibodies in follicular fluid (FF) of thyroid autoimmunity (TAI) positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development. Literature highlights that levothyroxine (LT4) treatment may attenuate the risk of adverse pregnancy outcomes. The aim of the study was to estimate the pregnancy and newborn outcomes in women with FF thyroid autoantibodies undergoing assisted reproductive technology (ART).The study population included 24 women with confirmed clinical pregnancy, 8 TAI positive and 16 TAI negative women. LT4 supplementation was applied in 20.8% patients, TAI positive.3 was lower in the group with TAI (p = 0.047). Serum P4 was higher in LT4 treated group (p = 0.005), with TAI, and newborns in this group had higher birth weight (p = 0.001) and height (p = 0.008). Maternal complications occurred in 23.8% of patients. No congenital malformations in newborns were noted.Pregnancy outcomes were: twin pregnancy rate 41.7%, early miscarriage rate 8.3%, late miscarriage rate 4.2%, preterm birth rate 16.7%, term birth rate 70.8%, live birth rate 96.0%. There was significant difference in serum and in FF TgAbs (p< 0.001)between the groups according to TAI, while serum fTThyroid autoantibodies present in FF may have an effect on the post-implantation embryo development, but have no effect on further course of pregnancy. The special benefit of LT4 treatment for successful ART outcome was demonstrated for newborn anthropometric parameters. Among fifty-two patients undergoing ART enrolled in our study, pregnancies rates count both per initiated cycle and per embryo transfer (ET) cycle were significantly different between TAI positive and TAI negative group Hence, in order to estimate the pregnancy and newborn outcomes in women with FF thyroid autoantibodies undergoing ART, we established primary aim of the study as live birth rate, and secondary aims: late miscarriage rate, preterm and term birth rate, gestational length, delivery method, newborn gender, newborn weight and height.This prospective study included 24 women as study population in whom clinical pregnancy was confirmed. Initially 52 women, 26 TAI positive and the same number of TAI negative  underwent ART, in study conducted during the period from November 2014 to July 2016, in Clinic for Gynecology and Obstetrics »Narodni front«, Belgrade, Serbia. Among 26 TAI positive patients in 8 of them clinical pregnancy was confirmed, and in 16 patients of TAI negative group Confirmed pregnancy was the only inclusion criteria for this study, but all these patients when underwent ART procedure had to fulfill the criteria predefined by the National Expert Commission of the Ministry of Health for biomedical assisted fertilization procedures 3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) levels were measured in serum by Cobas 6000 ROCHE, using immunochemiluminescent method. Referent values for the analyses were: TSH 0.40–4.00 mIU/mL, fT4 12.00–22.00 pmol/L, fT3 3.10–6.80 pmol/L, TgAbs 0.0–25.3 IU/mL, upper limit of TPOAbs reference range 19 IU/mL (95 % CI 17–26 IU/mL), adapted for the local population in Serbia Before the initiation of protocol for the COH, TSH, free triiodothyronine  levels were measured, by automatic analyzer Cobas 6000 ROCHE, using commercial tests of the same company based on the principleof immunochemiluminescent method. No specific cutoffs are known for these parameters in FF. ET was carried out second or third day after the oocyte aspiration. For the luteal support P4 was administered.In the following text the ART protocol is described th to the 20th week of gestation; preterm birth defined by the birth of a live-born or still-born newborn in the period after 20 weeks of gestation, and before 37 completed weeks of gestation; term birth defined as live-born or stillborn-born newborn born between 37 and 42 weeks of gestation; gestational length; delivery method; live birth rate; birth weight, height and gender.We analyzed late miscarriage defined as spontaneous loss of pregnancy from the 12Results were presented as frequency (percent), median (range) and mean±SD. For parametric data independent samples t-test was used to test differences between groups. For numeric data with nonnormal distribution and ordinal data Mann-Whitney U test was used. Fisher’s exact test was used to test differences between nominal data (frequences).All p values less than 0.05 were considered significant. Statistical data analysis was performed using IBM SPSS Statistics 22 .Study population included 24 pregnant women, 8 (33.3%) in TAI positive study group and 16(66.67%) in TAI negative control group. LT4 supplementation was applied in 5 of 24 patients (20.8%), all of them TAI positive, in order to maintain TSH under 2.5 mIU/mL before IVF treatment. Twin pregnancy was initially confirmed in 10 patients (41.7%). Early miscarriage occured in 2 , late miscarriage in 1 , and preterm birth in 4 patients , others (70.8%) gave birth in term. Of 10 twin pregnancies in initial ultrasound control, 4 of them (40%) ended by the birth of two children, and the same number by the birth of one child, while one pregnancy finished by early and other one by late miscarriage. Maternal complications, such as gestational diabetes mellitus or pregnancy induced hypertension, were present in 23.8% (5/21).We analyzed the outcomes, pregnancy characteristics, hormonal and immunological parameters according to either presence of TAI, or LT4 treatment, and divided patients in the same manner in groups.Different etiologies, male, female , combined male and female, as well as unkown causeof infertility had no impact on pregnancy outcomes, p=0.228 Characteristics of the study group according to presence of thyroid autoimmunity TAI are listed in Characteristics of the study group according to presence of LT4 treatment are listed in Among newborns 11 (45.8%) were male, and 13 (54.2%) female. No congenital malformations in newborns were found. Live birth rate was 96.0% (24/25). Mean birth weight 2997.5±607.4 kg, height 49.7±3.2 cm.3 was lower in the group with TAI.As was expected, serum fT4 was higher in LT4 treated group, with TAI, and newborns in this group had higher birth weight and height. The limitation of the study was small sample size, with a power sample less than 80% for statistically insignificant variables, but it was available number of all consecutively involved patients in the study for the abovementioned period. It is an preliminary study, and further confirmation of the results is needed.The present study included 24 women with confirmed clinical pregnancy achieved by ART. Live birth rate was 96.0%. Analizing hormonal and immunological parameters it could be noted that TgAbs showed significant difference in serum as well as in FF between the groups according to TAI, while serum fTA significant causal association was demonstrated between most preexisting or concomitant diseases presented at the starting time of the first intended oocyte retrieval cycle and lower odds of cumulative live birth 3 in the group with TAI. Hence, T3 is considered a biological amplifier of the stimulatory action of gonadotrophins on granulosa cell function LT4 supplementation should be recommended to improve clinical pregnancy outcomes in women with thyroid dysfunction, and in infertile women with SCH and/or TAI who are undergoing IVF, mostly to reduce the miscarriage rate In a cohort study of 2497 Dutch women without overt thyroid dysfunction, the risk of miscarriage, fetal, and neonatal death increased with higher levels of maternal TSH, i.e. by 60%  for every doubling in TSH concentration 4 and TSH levels, higher maternal fT4 levels were associated with lower birth weight, as well as with an increased risk of small size for gestational age at birth newborns 4 level was higher in TAI positive group and in the group on LT4 supplementation, but with higher birth weight and height of newborns in these groups.Increased likelihood of low birth weight infants born to TPO+ mothers and an increased likelihood of large-for-gestational age infants born to TPO+ women were reported Treating SCH women remains controversial. Most studies published to date, initiated treatment after the end of the first trimester, which may have been too late to derive benefit, on contrary of those reported an overall reduction in pregnancy complication rate in women treated in the first trimester, but not in those treated in the second trimester Although, TPO Abs are more frequently determined in the blood in the sense of TAI, it seems that Tg Abs could play an important role on neonatal outcomes of TAI positive women, and measuring thyroid antibodies in FF in these women could be used to predict the outcomes. Even though, there is still a debate on LT4 treatment pregnancy outcome, a positive effect on neonatal characteristics should not be neglected. Further analysis of thyroid autoantibodies in the FF of women undergoing IVF and their association with adverse pregnancy and neonatal outcomes could help elucidate the mechanisms of TAI impact on the maternal and neonatal complications, all with the aim of achieving a higher birth rate.In conclusion, thyroid autoantibodies present in FF, in women with TAI undergoing ART, may have an effect on the post-implantation embryo development, but have no effect on further course of pregnancy. Women with TAI and on LT4 supplementation are related to higher newborns weight and height, indicating the special benefit of LT4 treatment for newborn anthropometric parameters.Ethical committee of Faculty of Medicine, University of Belgrade and Ethical committee of Clinic for Gynecology and Obstetrics »Narodni front«, granted approval for the study and written informed consents were obtained from all subjects.This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.Conceptualization: Sanja Medenica, Eliana Garalejic, Dzihan Abazovic, Milos Zarkovic.Investigation: Sanja Medenica, Eliana Garalejic, Biljana Arsic, Dzihan Abazovic, Milos Zarkovic.Methodology: Sanja Medenica, Eliana Garalejic, Zoran Bukumiric, Dzihan Abazovic, Milos Zarkovic.Resources: Sanja Medenica, Eliana Garalejic, Biljana Arsic, Milos ZarkovicSupervision: Eliana Garalejic, Stavroula A. Paschou, Snezana Vujosevic, Milos Zarkovic.Validation: Sanja Medenica, Eliana Garalejic, Dzihan Abazovic, Zoran Bukumiric, Stavroula A. Paschou, Biljana Arsic, Snezana Vujosevic, Biljana Medjo, Milos Zarkovic.Visualization: Sanja Medenica, Eliana Garalejic, Zoran Bukumiric, Dzihan Abazovic, Biljana Medjo, Milos Zarkovic.Writing – original draft: Sanja Medenica.Writing – review & editing: Sanja Medenica, Eliana Garalejic, Stavroula A. Paschou, Milos Zarkovic.All the authors declare that they have no conflict of interest in this work.FF, follicular fluid;
TAI, thyroid autoimmunity;
LT4, levo -thyroxine;
ART, assisted reproductive techonology;
SCH, subclinical hypothyroidism;
IVF, in vitro fertilization;
COH, controlled ovarian hyperstimulation;
TSH, thyrotropin;
ET, embryo transfer;
FT4, free thryoxine;
FT3, free triiodothyronine;
TPOAbs, thyroid peroxidase antibodies;
TgAbs, thyroglobulin antibodies;
GnRH-a, gonadotropin-releasing hormone agonist;
GnRH-ant, gonadotropin-releasing hormone antagonist;
hMG, human menopausal gonadotrophin;
FSH, follicle-stimulating hormone;
hCG, human horionic gonadotropin;
E2, estradiol; P4, progesterone;
PCOS, polycystic ovary syndrome