The birth experience of adolescents is understudied even though they are a particularly vulnerable population to experience a negative birth event, given that they exhibit many known risk factors.To ascertain whether a cesarean birth mediates the impact of infant complications on the birth experience of adolescent mothers.Using a secondary analysis of data collected from 303 postpartum adolescents previously evaluated for depression and post-traumatic stress, we employed counterfactual causal analysis to determine if delivery type mediated the birth experience at different levels of depression. Noted limitations pertain to methodological assumptions and computational feasibility as well as potential sample bias.We found that the mediating effect of delivery mode depended on the adolescent’s depression level as well as on the specific operationalization of the birth experience. At low levels of depression, the odds of a negative birth appraisal were reduced by around 30% when operationalized as a single item subjective rating. In contrast, at high levels of depression, the odds of a negative birth experience increased by 80% when operationalized as an Impact of Event Scale (IES) subconstruct.Depression level plays a pivotal role in moderating how delivery mode mediates the birth experience. The direction of impact also depends on how the birth experience is operationalized. One way of assessing the birth experience is via a conscious perceptual rating. Other methods of assessment are based on responses addressing different aspects of the experience, including detection of subjective distress and trauma impact. Adolescent mothers are a particularly vulnerable population to report a negative birth event, given an increased likelihood to experience several recognized risk factors observed among adult samples. Specific risks include depression, prior trauma, a lack of information/awareness of events taking place during labor and birth, feelings of loss of control and powerlessness, limited support, unanticipated pain levels, and infant complications. 2 More than 32% of women in the United States experience a cesarean birth (CB) annually, and rates continue to rise worldwide. 7 A common reason for a primary CB is fetal distress, but several other reasons exist. 8 Experiencing either a planned or unplanned CB can evoke negative birth feelings of varying distress levels. 10 Systematic reviews have noted the influence of type of delivery upon the development of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD). 13 Yet, contrary studies either offer no evidence supporting operative birth as an important predictor of a negative birth experience, 16 or show preference for a CB. 17Type of birth has also received attention as a factor that influences a woman’s perception of birth and distress level. 19 Symptoms reflective of PTSD are associated with poor mother-infant bonding, future infertility, an increased fear of childbirth and voluntary CBs in subsequent pregnancies. 21Despite the inconsistent findings available in the literature, a link has been identified between CB distress and birth perception, and a negative perception of birth has been recognized as an independent risk factor for the development of PTSD. 27 Demographic data such as age (younger) and race/ethnicity may also indirectly impact one’s birth experience. 19 Specifically, minority adolescents may be more prone to report a negative birth experience because of an increased prevalence of several risk factors, 28 and notably Black childbearing adult women have been shown to be at exceptional risk for a CB. 29 In the Unites States, while comparable CB rates for adolescents and adults are reported at around one in three, adolescents globally are at greater risk for a CB. 31 Yet, despite apparent risks and the high rate of CBs globally, little has been written on the birth experience of adolescent mothers, and the mediating effect of delivery type on the birth event of adolescent mothers with infant complications is unexplored.Adolescents are recognized to be more prone to experience prenatal and postpartum depression, infant complications, and prior traumas than adults. 12In this paper, we focus on a primarily minority group of adolescent mothers with infant complications and, as such, at risk for a negative birth experience. In such circumstances, infant complications may have led to an unplanned CB, which in turn may have further impacted the overall birth experience. The question we address is: Does having a CB mitigate the effect of infant complications on the adolescent’s birth experience? This question positions delivery type as a possible mediating variable through which infant complications influence the experience. We assess this possibility using counterfactual causal analysis and further leverage the potential outcome framework to ascertain whether any such effect is sensitive across levels of depression, which has been recognized to impact the experience for childbearing women. 32This secondary analysis used available data previously collected for an institutional review board-approved longitudinal study exploring the mental health of postpartum adolescents. In the parent study, initial data related to the birth experience were collected via surveys at 72 hours postpartum from 303 Spanish- and English-speaking adolescents aged 13-19 years old. Inclusion/exclusion criteria were related to language and age only. Two measures of birth experience were considered, one pertaining to the mother’s overall birth perception, and another relating to the subjective distress (or trauma impact) of birth ; the second is the birth experience of adolescents with infant complications under the counterfactual scenario that their delivery method had been – instead – a delivery method “typical” of adolescents “with no infant complications” . If the expected outcome under the latter condition is more negative than the former, then this would suggest that delivery mode – in this context, a CB – has some mitigating effect on the impact of infant complications; in short, that the experience would have been (even) worse without the CB.  Last, given the known contribution of depression upon the birth experience 12 and noted ethnic/racial disparities related to our variables of interest, 31 these two variables were identified as relevant to the analysis as potential confounders. Further, we treated depression as a moderator variable, so that the overall problem we address is one of “moderated mediation,” i.e., one in which the mediated effects vary with levels of depression.  Our previous analyses with this dataset informed our decision to exclude other potential confounders that did not show correlative relationships with the main variables in the current study.It is known that the “typical” birth experience for women with birth complications is at risk of being more negative than the birth experience of women without infant complications. 34Our research question called for an analysis of “moderated mediation,” i.e., we hypothesized that there is a mediating impact via mode of delivery type on the birth experience of adolescents with infant complications, but that this mediating effect may in turn depend on the adolescents’ level of depression. A moderator variable is one “that affects the direction and/or strength of the relation between an independent or predictor variable and a dependent or criterion variable,” while a mediator variable is one which “accounts for the relation between the predictor and the criterion.” Moderated mediation thus refers to a situation in which the “mediational effects... vary across the levels” of the moderator. 36 Indeed, various complications and ambiguities can arise if one focuses only on the reported indirect effects using traditional SEM. These issues and others have been discussed extensively, pointing to limitations of the traditional approach. 37 By now, there is a well-developed literature that integrates causal inference and counterfactual interpretation into mediation analysis. 40 In turn, the flexibility of the causal inference approach has yielded new effects to be defined that are not part of the traditional SEM approach. For our specific purposes, the main benefit of the counterfactual approach is in providing us with a means of incorporating a binary mediator (mode of delivery) into the analysis.While the idea of moderated mediation is not new, there have been various criticisms of the claim that true causal effects are being identified within the traditional structural equation modeling (SEM) approach. E) of the key variable of interest.The counterfactual causal analysis framework essentially breaks down the analysis of theorized effects into a missing data problem. In turn, given that certain basic assumptions are valid concerning the data collection process, the solution to estimating causal impacts involves inferring plausible characteristics of the missing  data. Critical to this approach is the notion of an expected outcome . Mis the observed mediator, an indicator of delivery type; in particular, whether the adolescent had a CB or not. . Zis the observed moderator, here a continuous measure for level of depression. For this, we used the Edinburgh Postnatal Depression Scale (EPDS) to screen for symptoms of depression, as well as an alternative prenatal depression rating measure which also suggests a depression baseline. The 10-item EPDS has shown adequate reliability results in multicultural and multiethnic adolescent populations. 43 The alternative prenatal score is derived from a single item measure that does not have the same established psychometric properties as EPDS but has greater causal validity in the context of our statistical model, which considers depression as moderating the causal process. Cis a set of observed covariates. In particular, the covariates here are confounders to increase the plausibility of certain assumptions required for causal analysis. Two confounders are of note: 1) ethnic/racial background and 2) a history of prior trauma. Published reports suggest that women of diverse ethnic/racial backgrounds are at increased risk for depression symptoms, prior trauma, infant complications, and CB, 44 all of which have been associated with a negative birth experience. 12 We note that both these confounders come temporally before the birth experience, which adds to the plausibility of their causal role. E[Y)] is the expected value of the birth experience for an adolescent with infant complications and whose mode of delivery type is typical of a mother with infant complications. E[Y)] is the expected value of the birth experience for an adolescent with infant complications whose mode of delivery type is typical of a mother without infant complications. supplementary material.A full description of all variables used in the analysis can be found in the online-only Yi (x), which denotes the potential outcome that would have been observed for subjectihad the treatment variableXbeen set to the valuex, where a value of 0 or 1 denotes respectively the control and treatment groups. In our case, the “treatment” group refers to adolescent mothers with infant complications. The counterfactual concept inherent here is due to the fact that only one ofx= 1 or 0 will be observed for any one individual; i.e., we only observe an adolescent in one of the two states (infant complications or no infant complications). Since we wish to consider the same individual at both values, we focused on average effects (denoted by theE operator). Thus, while the effect of treatment expressed asYi (1) –Yi (0) cannot be identified, the average effectE[Y(1) –Y(0)] can.This analysis centers on the “counterfactual,” or “potential outcome,”Y(birth experience) and mediatorM(delivery type), but only showing the actual values observed for each adolescent (indexed byi). As such, the first adolescent listed was observed in the treatment group (had infant complications) and was also observed to have a CB (M= 1) with a birth appraisal rating of 10, while the third adolescent was not in the treatment group  but, similarly to the first adolescent, also had a CB – in her case, the birth appraisal rating was 4. Since the counterfactual approach to mediation analysis is central to our purpose of modeling a binary mediator, we provide a brief review of its theoretical underpinnings.An example dataset is provided inThe underlying mediation model which is the foundation for estimating the effects of interest is defined by Equation 1 and Equation 2.Equation 1:Equation 2:Ydepends on how the mediatorMvaries under the specified conditions, which implies an integration overM, as shown in Equation 3.As such, the expectation ofEquation 3:45While there are various direct and indirect effects capable of being defined under the potential outcome framework, our specific interest here was in the conditional total natural indirect effect (TNIE), shown in Equation 4. Equation 4:X= 1) in the expected value of birth appraisal (Y), based on the adolescents’ typical mode of delivery type under these circumstances (M(1)) compared to the expected value of birth appraisal based on the typical mode of delivery type had there been no infant complications (M(0)), conditional over a range of moderator,Z(depression), values.In the context of our study, this translates to the difference between those who had infant complications .The case in which the mediator is itself binary, as is the case here, has also been extensively discussed in the mediation literature. Equation 5:FM (x) denotesP(M= 1 |X=x), withFrepresenting either the standard normal or logistic distribution function corresponding to using probit or logistic regression, respectively. 45whereE[Y] =P(Y= 1)]. LettingFY  denoteP, the version of the expression above for a binary outcome is as follows (Equation 6).If the outcome is also binary, thenEquation 6:The TNIE can also be expressed in terms of an odds ratio (Equation 7).Equation 7:34 As such, we obtained bootstrap confidence intervals using 1,000 bootstrap draws with maximum-likelihood estimation in the analysis to follow.The estimated indirect effect and direct effects for a binary outcome usually have non-normal sampling distributions so that a non-symmetric confidence is needed. 49 The second aspect of birth is based on the Impact of Event Scale (IES). 50 The 15-item IES was developed to determine subjective distress/trauma impact, with numerous researchers emphasizing the IES’s two-factor structure (intrusion and avoidance) as stable over different types of events. 51 With this recognized utility as a research tool, the IES was one of the first instruments used among childbearing populations to measure PTSD following birth. 53Here we consider two different aspects of the birth experience measured as birth perception and subjective distress. The first is a straightforward single indicator variable (0 to 10) of the adolescent’s overall appraisal (rating) of the experience from 1 (great) to 10 (awful). Appraisal of the birth experience has been assessed using a one-item measure in several previous studies, with a suggested cutoff of > 6 as indicative of a traumatic birth appraisal. 54Since the IES is a multi-item scale, we assessed its construct validity and found that the 8-item avoidance subscale exhibited stable statistical properties ; however, neither the 7-item intrusion subscale , nor the overall 15-item construct did so . As such, we used only the avoidance scale from the IES instrument, juxtaposed as an alternative outcome measure to the single-item birth appraisal rating. By definition, avoidance refers to numb feelings relating to birth, or denial of feelings about the birth experience with efforts not to think or talk about the birth. The results for the two estimated models are shown in Tables It is not obvious from these estimates that there was any mediation effect of delivery type on either of the outcome variables, nor whether any such mediation effect varied according to depression level. This requires computation of our main causal effects of interest, specifically the conditional TNIE as defined above, across different levels of depression. These results are depicted inThe second feature of note is that the effect sizes are low to moderate in either case, which is suggestive of additional research. For example, in the first case, a CB for an adolescent with no depression may reduce the probability of a negative birth appraisal by 2-16 percentage points, which translates to an odds ratio (as defined above) of around 0.7. In the second case, a CB for an adolescent with infant complications and with the highest depression score in our sample was more likely to report a higher level of avoidance by 2-26 percentage points, which translates to an odds ratio of around 1.8. These results were replicated using the prenatal rating measure of depression as the moderator. As with the case above, where birth appraisal was the outcome variable, only for the adolescents who indicated they were “usually happy” did a CB mitigate the impact of infant complications on the birth appraisal evaluation. Likewise, in the case of the avoidance outcome measure, adolescents who were more depressed during pregnancy  indicated higher avoidance scores after a CB.55 These mostly pertain to the need to control for variables that simultaneously affect any pair among the treatment, mediator and outcome variables. We sought to address these issues by the inclusion of confounder variables in our analysis. In addition, these confounders, (prior trauma and ethnicity/race) must not be affected by the exposure (infant complications), which in our case is assured by the natural temporal ordering of these variables. We do, however, acknowledge a potential issue concerning endogeneity, given that our preferred measure of depression  was contemporaneous with the outcome variables. However, as noted earlier, we replicated our results using a prenatal rating measure of depression, albeit this was a measurement tool of less content validity.The main assumptions and limitations here are of two types; the first pertaining to the causal effect methodology and the second pertaining to our specific research design and sample. Assumptions of the counterfactual approach were summarized by VanderWeele & Vansteelandt. 56 Baseline depression was not established via a strong measure; however, it has been reported that the occurrence of depression in the last trimester of pregnancy and in the immediate postpartum period is similar. 57 Further, given our use of available data, all potential confounders could not be examined, including reason for CB. However, our assumption is that all the CBs reported in our sample were for medical reasons and unplanned, given age and knowledge of birth options by the typical adolescent. Last, sample biases may include age and ethnic characteristics among small samples, especially for white adolescents.Additional limitations reflect the use of secondary analysis. Measurement choices and procedures for data collection were preset within the parent study. However, the choice of tools to assess birth experience in general represents a challenge, as available instruments range widely in purpose, content, and psychometric properties. 19 In addition, the methodology employed is limited in terms of identifying true causal effects and the role of CB as a mediator of birth outcomes. Our study is unique in several respects: 1) we examined a population, specifically adolescent mothers, for which CBs are most likely to be experienced due to medical reasons, and not pre-planned (elective); 2) we considered various aspects of the birth experience, recognizing that a plethora of different measuring instruments is currently being used; and 3) we assessed the role of CB using modern counterfactual analysis, which allows one to identify true causal effects.The role of CB on the mental state of women has been investigated by various scholars, often finding a negative impact. Available literature, however, notably considers primarily adults and often overlooks confounders such as race/ethncitiy. The non-parametric nature of the counterfactual analysis formulation enables consideration of outcome and mediator variables that are not necessarily normally distributed. This was crucial for our purposes in being able to treat CB as a mediator, as it is inherently a binary variable. With regard to the outcome variable, while we only presented results using binary measures of the birth appraisal and avoidance outcome variables, we also performed the same analysis with the continuous versions of these variables and obtained the same substantive results. Our choice of presenting the results for the binary outcome variables also lent more naturally to expressing effect sizes in terms of probabilities and odds ratios.58 the role of depression as a contributor to a negative birth experience and potential PTSD is important to acknowledge to guide assessments and treatment. Adolescent depression rates both prenatally and after birth are higher than reported rates among adults and draws attention to the possible increased vulnerability of childbearing adolescents. 59Results of the study also provided several clinical insights relevant to the childbearing adolescent which lend support to existing literature but also expand current thought. Infant complications were found to predict both CB and a negative birth experience. However, birth appraisal varied according to level of depression. Adolescents with infant complications but without reported depression who experienced a CB appraised their birth experience better than in a scenario with no CB. This finding may suggest that adolescents without depression are better able to perceive the value/need of a CB to save her own or her infant’s life than the depressed teen. While adolescents, more likely than adults, may rate both vaginal and CBs as positive, 19 Risk factors related to a negative birth experience among primarily adults have been found to often characterize the Black woman, including higher rates of CB and infant complications. 60 Additional patient-level health factors, quality of physician-provider interaction, and patient preferences are also recognized as linked to infant complications and higher rates of CB among Black women. 31 Therefore, a combination of factors may have increased the likelihood for the Black adolescent to experience a negative birth event. Side analyses did indicate a significantly higher percentage of infant complications and CB rates among the Black adolescents; however, additional research is needed to further assess the vulnerability of the Black adolescent to a negative birth experience.Black race/ethnicity also contributed to a negative birth appraisal. Race/ethnicity and age are frequently overlooked as potential contributors to birth trauma, and when examined, findings are inconsistent. 61 While shock and disbelief due to unexpected infant complications or CB is not an unlikely reaction by any age woman, a younger adolescent may have more difficulties in managing the situation, especially if depressed. A high rate of CB has been recognized and studies are being conducted to aid in its reduction 7 ; yet, minimal advance has been seen related to hospital policy and state legislation supporting mandatory education and/or routine assessment of depression for childbearing women. 63 Given the fact that the present findings illustrate an interaction between depression and delivery mode as an influence on both birth appraisal and avoidance, and given a recognized possibility of subsequent mental health concerns from additional works, suggested research and clinical practice actions could be informed by this study as well as by future research adopting the counterfactual approach.Neither race/ethnicity nor infant complications showed a direct effect on the avoidance outcome measure; yet, depressed adolescents with infant complications and CB had higher avoidance scores than they would have had without a CB, suggesting that, if the adolescent is highly depressed, a CB will tend to accentuate feelings and actions associated with avoidance . While perhaps such actions may be within the nature of depression itself, other factors for these young mothers can also exist. While already facing multiple challenges above and beyond the transition to motherhood, a CB may bring additional distress due to unexpected birth consequences such as an adverse infant condition and admission to neonatal intensive care unit (NICU), as well as increased postpartum pain and longer hospitalization and recovery time following birth. Studies have described maternal mental health consequences to preterm birth and NICU admissions. Using counterfactual causal analysis, we found evidence that delivery type does indeed exhibit a mediating impact on the birth experience of adolescent mothers with infant complications, but that the size and direction of this effect depends in turn on how the birth experience is operationalized as well as on existing levels of depression. Specifically, we found opposite effects when the outcome was measured in terms of a conscious appraisal of the overall birth experience as compared to a subjective distress “avoidance” reaction. For adolescent women with low levels of depression, a CB leads to a better birth appraisal than it would without a CB. Yet for adolescent women with moderate to high levels of depression, a CB leads to a higher avoidance reaction than would without a CB. In summary, both potential positive and negative perceptions emerge from giving birth by CB, depending on depression levels, and essential assessments of high-risk adolescents can guide immediate and future assessments and treatment.


Preterm birth accounts for over 15 million global births per year. Perinatal interventions introduced since the early 1980s, such as antenatal glucocorticoids, surfactant, and invasive ventilation strategies, have dramatically improved survival of even the smallest, most vulnerable neonates. As a result, a new generation of preterm-born individuals has now reached early adulthood, and they are at increased risk of cardiovascular diseases. To better understand the sequelae of preterm birth, cardiovascular follow-up studies in adolescents and young adults born preterm have focused on characterizing changes in cardiac, vascular, and pulmonary structure and function. Being born preterm associates with a reduced cardiac reserve and smaller left and right ventricular volumes, as well as decreased vascularity, increased vascular stiffness, and higher pressure of both the pulmonary and systemic vasculature. The purpose of this review is to present major epidemiological evidence linking preterm birth with cardiovascular disease; to discuss findings from clinical studies showing a long-term impact of preterm birth on cardiac remodeling, as well as the systemic and pulmonary vascular systems; to discuss differences across gestational ages; and to consider possible driving mechanisms and therapeutic approaches for reducing cardiovascular burden in individuals born preterm. In spite of improvements in medical care, preterm-born individuals are at greater risk of all-cause mortality in young adulthood,3 as well as cardiometabolic diseases, including type 1 and 2 diabetes mellitus,4 hypertension,5 pulmonary vascular disease,8 early heart failure,9 and ischemic heart disease.10Preterm birth (<37 weeks’ gestation) affects over 10% of live births, with rates ranging from 5% to 18% worldwide.Preterm birth occurs during a key period of cardiovascular development, leading to an early physiological shift to a relatively hyperoxic environment with increased systemic and decreased pulmonary vascular resistance. As a result, animal and clinical studies across developmental stages have focused on observational and mechanistic insights into cardiovascular changes related to prematurity that may contribute to short- and long-term risk of disease Figure . In this9 published a register-based cohort study of 2 665 542 individuals born in Sweden from 1987 to 2012 to determine the association between preterm birth and the risk of incident heart failure. Individuals were followed up from 1 year of age until December 31, 2013, with a total follow-up time of 34.8 million person-years and 501 cases of heart failure. After individuals born with potentially confounding malformations were excluded, there were 305 heart failure cases and a follow-up of 34.2 million person-years. Incidence rates of heart failure were inversely related to gestational age at birth, with a 17-fold increased risk in those born extremely preterm compared with those born at term even after adjustment for maternal characteristics, subject sex, birth period, and birth weight for gestational age. While the adjusted risk of incident heart failure was 3.6× higher in subjects born very preterm compared with term, there was no significant increase in the risk of heart failure for subjects born moderate-to-late preterm.In 2017, Carr et al10 published a similar register-based cohort study in 2019 to investigate the association between prematurity and increased risk of ischemic heart disease in adulthood. A total of 2 141 709 individuals born in Sweden as singleton live births between 1973 and 1994 were included, with follow-up until the end of 2015. The total follow-up time was 30.9 million person-years, with 1921 individuals receiving a diagnosis of ischemic heart disease. Gestational age was inversely associated with ischemic heart disease risk across ages 18 to 43 years, including a strong association among individuals born late preterm. The strength of this relationship was higher in those individuals currently 30 to 43 years of age; interestingly, both preterm birth and early-term birth (37–38 weeks’ gestation) were associated with increased relative risks of ischemic heart disease  compared with individuals born full term between 39 to 41 weeks’ gestation.Crump et al11 A recent meta-analysis investigating cardiac differences between preterm-born and term-born individuals demonstrated that individuals born preterm have morphological and cardiac functional impairments across all developmental stages including neonatal life, infancy, childhood, and into young adulthood.12 These underlying cardiac differences in structure and function that are apparent as early as neonatal life may make the preterm heart more susceptible to heart failure and ischemic heart disease.13The third trimester is a period of rapid cardiac growth, primarily driven by cardiomyocyte hyperplasia. Birth results in a switch in cardiomyocyte growth from a fetal hyperplastic to a neonatal hypertrophic response.14 Preterm-born individuals had smaller left ventricular (LV) end-diastolic volumes, smaller internal LV cavity dimensions and lengths, as well as greater LV wall thickness and mass. These cardiac changes were independent of differences in body size and blood pressure between groups. Through the use of a novel computational atlas created from CMR images, it was found that the primary morphological feature contributing to the lower LV end-diastolic volumes was the reduction in LV length. Though the preterm-born young adults had no differences in LV ejection fraction, LV longitudinal systolic strain and strain rate, as well as diastolic strain rate, were reduced. In the same cohort of participants, right ventricular (RV) end-diastolic volumes were also lower and RV mass higher in preterm-born compared with term-born young adults, which could not be accounted for by differences in body size.15 Unlike in the LV, RV ejection fraction was lower in the preterm group, with 6% of young adults having values below the clinical normal range (<45%). Preterm-born young adults also had lower RV systolic strain and strain rates, as well as diastolic strain rate.The first study to investigate the cardiac impact of being born preterm in young adulthood was done using cardiovascular magnetic resonance (CMR) in 234 individuals, of whom 102 were born preterm with an average gestational age of 30 weeks.16 Using echocardiography, the study showed that preterm-born young adults had smaller LV end-diastolic volumes and dimensions and increased LV mass indexed to body size, as well as impaired longitudinal systolic strain. In the same cohort, body size indexed RV end-diastolic areas and volumes for echocardiography and CMR were lower in preterm-born individuals,17 with RV CMR revealing higher RV mass, lower RV ejection fraction, and a unique 3-dimensional geometry by computational atlas formation in those born preterm. Measurements of RV function by echocardiography, including RV fractional area of change and tricuspid annular plane systolic excursion, were lower in preterm-born compared with term-born young adults, with RV changes remaining significant when adjusting for pulmonary function parameters by spirometry.Similar findings have been reported in an independent cohort of 101 normotensive young adults, of whom 47 were born preterm with an average gestational age of 33 weeks.20 differences in mass are less consistent. While some studies using both CMR17 and echocardiography18 have reported higher LV and RV mass in preterm-born young adults compared with term-born controls, others have reported lower mass in those born preterm.21 A recent study using CMR in a group of 40 normotensive adolescents, of which 20 were born preterm with an average gestational age of 28 weeks, and 70 normotensive young adults, of which 38 were born preterm with an average gestational age of 29 weeks, showed that both LV and RV end-diastolic and stroke volumes were lower in the preterm groups, as was LV mass when indexed to body size.20 Interestingly, LV longitudinal systolic strain was higher in the preterm-born young adults in this study, as were RV longitudinal systolic and diastolic strain parameters. Further work is needed to explore these differences, taking into account variability in perinatal characteristics and interventions, as well as lifestyle factors throughout development, such as exercise activity level, socioeconomic status, and diet. How the heart will remodel with the development of other risk factors associated with preterm birth, such as pulmonary and systemic hypertension and obesity,22 remains to be determined and may account for some of the variability in results. Part of this variability in hypertrophic response may also be due to changes in perinatal clinical management, which have rapidly evolved in the 1980s and 1990s. Moreover, the most premature individuals, such as those born at <28 weeks’ gestation, may have the lowest cardiac endowment and thus the fewest overall number of cardiomyocytes. As such, cardiac mass may remain lower even if the individual cardiomyocytes are hypertrophied. Individuals born less premature, such as those born around 32 weeks’ gestation, may have the same early hypertrophic stimuli to increase cardiomyocyte size but are also more likely to have a greater total number of cardiomyocytes due to longer in utero development, which may ultimately drive higher mass relative to term-born controls , Kowalski et al19 reported similar carotid-radial PWV and augmentation index compared with term-born controls, despite smaller aortic diameters, higher blood pressures, and no difference in body mass index between groups. However, in a recent study by Barnard et al,45 aortic PWV was increased in 10 very preterm-born young adults compared with 12 term-born blood pressure and body mass index–matched controls.Arterial stiffness has been investigated in preterm-born individuals using surrogate indices such as pulse wave velocity , augmentation index (the reflection pressure wave modulated by vessel stiffness and blood pressure), and other measures of vascular elasticity. Arterial distensibility and elasticity depend largely on the ratio of elastin and the more rigid collagen in arterial walls. In humans, elastin synthesis peaks toward the end of gestation and continues into early childhood, declining rapidly thereafter, with minimal synthesis by adulthood.46 the majority of studies performed in adolescents and young adults born very or extremely preterm have not shown any alteration in endothelial function associated with preterm birth evaluated using brachial artery flow–mediated dilation or reactive hyperemia index.36 Studies reporting carotid intima-media thickness—an early marker of atherosclerosis and nonatherosclerotic remodeling—in preterm-born adolescents and adults have consistently shown no differences compared with term-born controls.36 In line with this, Hovi et al36 found that carotid intima-media thickness did not differ between very preterm and term-born adults, but because lumen diameter was much smaller in the preterm group, carotid intima-media thickness was increased relative to lumen diameter.Although a single study suggests diminished endothelial function in 32 young adults born extremely preterm,47 reported that, independent of retinopathy of prematurity, retinal vascular caliber and density were decreased in children and young adults born very preterm on average at 30 weeks. Furthermore, skin microvascular perfusion and density have been shown to be reduced and to correlate with higher blood pressure and circulating antiangiogenic factors.48 Reduced systemic angiogenic capacity could underlie impaired vascular growth. Neonatal exposure to high oxygen, which mimics preterm birth–related physiological conditions, reduced in vitro angiogenic capacity and systemic microvascular density in adult rats.50 Supporting this possibility, endothelial colony–forming cells collected from venous blood had altered in vitro proliferation and angiogenic capacity in young adults born extremely preterm, which correlated with increased blood pressure.51 Further work is needed to clarify the role of defective vascular tree development or repair and related mechanisms, such as epigenetic changes and accelerated senescence of progenitor cells,52 contributing to the development of cardiovascular diseases in individuals born preterm.At the microvascular level, Kistner et al53 Studies have also shown higher hemoglobin,54 evidence of sympathetic nervous autonomic system activation,55 and hypothalamus-pituitary-adrenal dysregulation56 in preterm-born adults, which all potentially contribute to higher blood pressure. A recent study of 101 young adults born on average at 27 weeks’ gestation compared with 105 young adults born at term found no association between preterm birth and markers of inflammation and oxidative stress, as well as no association between high blood pressure and other cardiovascular risk factors , suggesting a unique mechanism to hypertension and disease development.57 Perinatal interventions and complications that are common in preterm infants, including perinatal infection, accelerated postnatal weight gain, parenteral nutrition, and antenatal and postnatal steroids, have been shown to relate to increased vascular stiffness and may contribute to long-term cardiovascular remodeling.58 Further work is needed to look at the long-term effects of these early life interventions. In addition, the hereditary component of hypertension among individuals born preterm has not yet been fully investigated. Indeed, women who had preeclamptic pregnancies (an antecedent to 20%–30% of preterm births) or who had spontaneous preterm deliveries were recently shown to be at increased risk of future cardiovascular diseases.59 Whether genetically inherited factors add to the risk of systemic hypertension related to altered organ and vascular development and function as a result of being born preterm is plausible but remains to be addressed.Beyond altered vascular structure and growth, other elements may contribute to the etiology of hypertension in the preterm-born population. Studies of children and adults born very or extremely preterm have shown that preterm birth is associated with altered nephrogenesis and smaller kidneys, with the reduction in kidney size correlating with higher blood pressure in adults.6 This relationship persisted after adjusting for known risk factors such as congenital heart disease and bronchopulmonary dysplasia. Further, the association was even stronger in children and adolescents , likely reflecting improved neonatal survival of the most at-risk individuals.8In addition to the direct cardiac and systemic vascular effects of premature birth, individuals born preterm are at increased risk for pulmonary vascular disease as evidenced by both epidemiological and clinical data. The initial epidemiological data supporting prematurity as a risk factor for adult pulmonary hypertension come from a case-control study of adults in the Swedish pulmonary arterial hypertension registry. When compared with controls from the birth register, matched by birth year and hospital, premature birth was associated with an odds ratio of 3.08 for adult pulmonary arterial hypertension.60 Additional echocardiogram-based studies in adolescents and adults born preterm have reported an elevated tricuspid regurgitation velocity and lower pulmonary artery acceleration times in those born preterm, indicating increased pulmonary vascular resistance relative to term-born age-matched controls.61 The only right heart catheterization study conducted to date enrolled 11 young adults born preterm with an average gestational age of 28 weeks, of whom 5 of 11 satisfied criteria for pulmonary hypertension as defined by a mean pulmonary artery pressure >20 mm Hg. Furthermore, pulmonary vascular resistance and arterial elastance were significantly elevated among preterm adults, suggesting a stiffer pulmonary vascular bed overall.25 Among these subjects, RV-pulmonary vascular coupling was impaired in preterm-born relative to term-born subjects.62 In contrast, an echocardiography-based study of ventriculo-vascular coupling in young adults born preterm with an average gestational age of 33 weeks demonstrated preserved RV coupling relative to term-born adults.16 The lower gestational age in the catheter-based study further suggests that early RV-pulmonary artery uncoupling may be gestational age dependent. Further, the degree of uncoupling was unexpected for the mild elevation in afterload and supports the concept of prematurity serving as a direct insult to the RV as well. In summary, changes in RV function and pulmonary vascular resistance are present across gestational ages, and it is possible that RV-pulmonary vascular uncoupling will occur sooner even in those born moderate-to-late preterm, warranting further follow-up into mid and late adulthood.Recent clinical studies demonstrate the presence of mild pulmonary hypertension in a significant percentage of adolescents and young adults born moderately to extremely premature. Among 193 adolescents with an average gestational age of 27 weeks, nearly half had a mean pulmonary artery pressure by echocardiogram >20 mm Hg.63 These findings, however, were not confirmed in the aforementioned right heart catheterization–based study, possibly due to smaller sample size.25 Among the studies that have assessed the response to hypoxia, the hypoxic vasoconstrictor response appears intact and similar between term- and preterm-born subjects.63 Some of these studies have identified bronchopulmonary dysplasia as one of the possible key drivers of overt late pulmonary vascular disease, though it is unlikely to be the sole contributor.60Several studies have assessed the pulmonary vascular response to exercise or hypoxia. In an echocardiography-based exercise study, adults born premature demonstrated an exaggerated increase in estimated pulmonary pressure.65 Therefore, the lifetime impact may be significant even in relatively healthy individuals with a history of preterm birth.Finally, although the overall severity of pulmonary vascular disease appears mild in childhood and adult studies, a subset of premature infants develop more severe pulmonary vascular disease. Additional studies are needed to understand the natural history of pulmonary vascular-RV development in these high-risk individuals. In the meantime, even small elevations in mean pulmonary artery pressure are associated with a significant increase in all-cause mortality in adults.Mechanistic studies of the cardiac and vascular sequelae of premature birth are somewhat constrained due to limitations of available animal models. Whereas both small and large animal models can be delivered prematurely, there is limited-to-no ability to support the degree of prematurity that is encountered and survivable in humans. However, both may be informative regarding specific aspects of cardiovascular development and will be discussed here.66 The application of oxygen exposure in this model aims to mimic the relative hyperoxic environment common to premature birth. Birth results in an immediate transition to normoxia, which is relatively hyperoxic compared with normal fetal life. Although hyperoxic animal models do not recapitulate prematurity per se, they do mimic the developmentally inappropriate relative hyperoxia that a preterm infant experiences and is highly relevant to the developing heart. Specifically, at birth, the rodent heart is predominantly mononucleated, with terminal cell cycle arrest and transition from hyperplasia to hypertrophy for cellular growth occurring during the first week postnatally.67 When hyperoxia is applied, cell cycle arrest is accelerated through activation of DNA damage responses.68Rodent models have been used for decades to study the sequelae of premature birth, specifically as related to the development of bronchopulmonary dysplasia. Although models differ in the duration and severity, most utilize postnatal hyperoxia exposure to recapitulate the alveolar and vascular oversimplification characteristic of bronchopulmonary dysplasia.69 There appears to be some degree of pulmonary revascularization, only to have accelerated vascular pruning with aging.70 Pulmonary vascular disease is associated with bimodal RV dysfunction, with early uncoupling and RV dysfunction due to the severity of the vascular disease. There is a period of cardiac recovery, as the pulmonary hypertension improves, followed by late RV failure related to emergence of mitochondrial dysfunction and accumulation of mitochondrial DNA damage.71 Mitochondrial oxidation also drives cardiomyocyte loss beginning in the neonatal time period and may be rescued with administration of antioxidants such as mitoTEMP.72 Therefore, a diminished cardiomyocyte endowment may further contribute to cardiac dysfunction. In the LV, postnatal hyperoxia results in remodeling and impaired systolic function even before systemic blood pressure elevation, including an increase in LV cardiomyocyte hypertrophy, fibrosis, and in markers of premature senescence.73 Moreover, these early cardiac alterations increased the susceptibility of rodents to develop heart failure following pressure overload induced by angiotensin II infusion. Development of cardiac alterations in adulthood, including fibrosis and hypertrophy, was linked to upregulation of angiotension II receptors type 1 and 2 in the LV, signifying increased renin-angiotensin system activation, which was prevented with early treatment with the AT1 (angiotensin II type 1) receptor antagonist losartan and with an antagonist of the Toll-like receptor-4 proinflammatory pathway.75 This indicates that a number of deleterious mechanisms for myocardial development are triggered by preterm birth–related conditions along with neonatal oxidative injury.Postnatal hyperoxia exposure in rodents has been utilized to recapitulate both the late RV-pulmonary vascular and LV-systemic vascular complications of premature birth. Animals develop moderate-to-severe pulmonary hypertension in the neonatal period, with some ability to recover in adolescence and adulthood.76 It is noteworthy that preterm-born sheep also had an ≈7-fold increase in interstitial collagen deposition, even without the normal inflammatory and stress-related conditions that are commonly associated with preterm birth in humans.77 Nucleation and ploidy of the cardiomyocytes were also shown to be altered, supporting the argument that there are irreversible myocardial stress–related changes in DNA in the preterm-born lambs. At 14.5 months postnatal age follow-up, preterm-born sheep had thinner RV walls, a higher reserve of immature undifferentiated cardiomyocytes, lower cardiomyocyte numbers, and smaller cardiomyocyte areas with reductions in RV functional and adaptive capacity.In an ovine model of preterm birth (14 days premature), LV and RV cardiomyocytes were hypertrophied in the preterm-born lambs compared with controls at 9 weeks postnatal age.78 There is evidence that neonatal risk factors do appear to be modifiable. For example, exclusive human milk feeding during infancy, as compared with formula, was associated with larger LV and RV end-diastolic and stroke volumes and smaller pulmonary artery to aortic diameter ratios in adulthood.79 Ultimately, further study is needed to understand the role of intervention strategies throughout the life span, including lifestyle modifications such as exercise and pharmacological interventions, on improving cardiac remodeling and decreasing long-term cardiovascular risk.Currently, there are limited data to suggest specific therapeutic strategies in adults born preterm to treat hypertension or modify heart failure risk. Elevated plasma levels of angiotensin I and the presence of autonomic dysfunction and impaired heart rate recovery may suggest a potential role for angiotensin or adrenergic blockade, but these have not been specifically evaluated in preterm subjects.It is now clear that preterm birth is associated with increased risk of cardiovascular diseases including ischemic heart disease and hypertension, as well as increased risk of heart failure. The mechanisms are not completely understood, and current evidence indicates that the disruption of heart, vessels, and overall organ development associated with preterm birth contributes to disease risk, most likely in addition to hereditary components. While much remains to be unraveled regarding mechanisms, attention should now also be directed on how to effectively prevent hypertension and disease occurrence, from the neonatal period through adult life. Subclinical diseases, including high blood pressure and mild cardiac dysfunction, are detectable in young adulthood and might not be accompanied by classically associated risk factors such as obesity. Thus, recognition of preterm birth as a significant risk factor for cardiovascular disease becomes imperative for clinicians, parents, and the preterm-born adults. Birth history should be included in best practice guidelines from childhood to adulthood to permit healthy lifestyle counseling and appropriate screening. Among those symptomatic or at the highest risk, clinicians should consider that symptoms may be multifactorial, including a compilation of cardiac, pulmonary, and vascular sequelae of prematurity, and may require more nuanced testing and clinical evaluation, such as early utilization of exercise testing Figure . ModifyiA.J. Lewandowski is funded by a British Heart Foundation Intermediate Basic Science Research Fellowship (BHF FS/18/3/33292). A.M. Nuyt is funded by the Canadian Institutes of Health Research (CIHR 399001 and 313082), the Heart and Stroke Foundation of Canada, the Canadian Foundation for Innovation, and the Cercle Sainte-Justine Developmental Origins of Health and Diseases Research Chair. K.N. Goss is funded by a Parker B. Francis Fellowship Award and American Heart Association Career Development Award .None.


The rate of multiple pregnancies in IVF/ICSI ranges from 20 to 30%. The incidence of preterm birth in multiple pregnancies is as high as 60% and is even higher in pregnancies conceived after IVF & ICSI. The effect of progesterone on prevention of preterm birth in twins is controversial. Our group has proven a positive effect in reduction of preterm birth, by starting progesterone from the mid-trimester, in exclusively IVF/ICSI singleton pregnancies but not twins. The purpose of our current study was to explore the effect of earlier administration of natural progesterone, in IVF/ICSI twin pregnancies starting at 11–14 weeks for prevention of preterm birth.This is a double-blind, placebo controlled, single center, randomized clinical trial. Women with dichorionic twin gestations, having an IVF/ICSI trial were randomized to receive natural rectal progesterone (800 mg daily) vs placebo, starting early from 11 to 14 weeks. They also received oral and vaginal antimicrobial agents as part of our routine treatment for vaginitis and urinary tract infection. They were randomized regardless of cervical length and had no previous history of preterm birth or known Mullerian anomalies. The primary outcome was spontaneous preterm birth rate before 37 weeks. The secondary outcome was; spontaneous preterm birth before 34, 32, 28 weeks and neonatal outcome.P = 0.626). Progesterone administration was not associated with a significant decrease in the spontaneous preterm birth rates before 37 weeks , before 34 , before 32  & before 28  weeks.A total of 203 women were randomized to both groups, final analysis included 199 women as 4 were lost to follow up. The base line characteristics as well as gestational age at delivery were not significantly different between the study and the placebo group (34.7 ± 3.6 vs 34.5 ± 4.5, Rectal natural progesterone starting from the first trimester in IVF/ICSI twin pregnancies did not reduce spontaneous preterm birth.69810120.The trial was registered on 31 January 2014 at www.ISRCTN.com, number  Multiple pregnancy remains one of the major complications of assisted reproductive techniques. A large percentage of ART-conceived babies are twin pregnancies, and multiple pregnancies are associated with a high rate of preterm birth, perinatal morbidity and mortality , 2 and hThe incidence of spontaneous preterm birth is higher for ART-conceived infants when compared to spontaneous pregnancies  and in a more recent study 10.1% vs 5.5% before 37 weeks and 3.6% vs 2.2% before 34 weeks [Prevention of spontaneous preterm birth in ART pregnancies is prioritized in an attempt to decrease prematurity complications. It was previously reported in several large randomized studies and meta-analysis that administration of progesterone resulted in a significant reduction in the rate of spontaneous preterm births in singleton pregnancies, when administered starting at mid trimester to all women, including those with a previous history of preterm birth as well as women with a short cervix –12. SimiControversy surrounds the use of progesterone in the prevention of preterm birth in twin gestation. Two large randomized controlled studies , 14 founOur present study aimed to explore the effect of earlier administration of natural rectal progesterone in IVF/ICSI twin pregnancies, starting at 11–14 weeks up to 37 weeks’ gestation, on spontaneous preterm birth rates.All pregnant women with dichorionic twins, who had not undergone cerclage, following an IVF/ICSI trial performed at the Egyptian IVF Center, Maadi, Cairo, Egypt, from January 2014 to July 2017 were counseled to participate in this study. They performed a first trimester scan and randomized women fulfilled the following Inclusion Criteria:1) Non-smokers, 2) Normal fetal anatomy, 3) No uterine anomalies, 4) Dichorionic twins only, 5) No previous history of preterm birth, 6) Healthy pregnant women not suffering from medical disorders e.g. diabetes and hypertension, 7) No known allergy to progesterone.Participants received 100 mg IM Progesterone injections (IBSA Egypt) daily for luteal phase support starting on the day of oocyte retrieval until the first viability ultrasound was performed at 7 weeks. Once fetal heart beats were confirmed they were advised to stop intake of progesterone. This was based on a previous study by our group which showed no significant difference in miscarriage rates in patients who stopped progesterone early as compared to those who continued to 10 weeks gestations .To ensure eligibility of participants, all women enrolled in the study had a first trimester scan for risk assessment of Down syndrome in addition to an anomaly scan at 11–14 weeks of pregnancy. Dating was performed by calculation from the date of embryo transfer.After the supervising obstetrician counseled the patient about the protocol and its aim and design, women who agreed to join the study signed a consent form. They were then randomized and began the suppositories immediately.Randomization was done into either the Progesterone Group or the Placebo Group. This was performed by opening a numbered, sealed, opaque envelope, with an indication of either group (Progesterone and Placebo) at a ratio of 1: 1. The randomization was hand generated using the Microsoft Excel software which was executed by a third party (nurse) not involved in the trial. Progesterone and placebo suppositories were provided by the manufacturer (IBSA Egypt) in indistinguishable packaging, labeled with the patient’s code and the study name. The manufacturer was not involved in the writing of the protocol, study design or writing of the paper nor its submission. Suppositories were provided to the patient by the supervising nurse in sealed packages given once a month to cover the period before her next antenatal visit. On the next visit she returned the empty packages for confirmation of compliance.The study group received natural progesterone suppositories of 400 mg, while the Placebo was composed of 126 mg hard fat, 36 mg Gelucire pellets, 0.2 mg Sorbic acid, 300 mg cocoa butter, and 195 mg purified water (Supplied by IBSA Egypt). They appeared identical. All suppositories were administered rectally twice daily starting from the time of randomization at 11–14 weeks until 37 weeks or delivery. Rectal administration was chosen as the social and cultural background of participating women showed that they have a great fear of repeated vaginal administration. In addition, we chose this route to minimize possible risks of vaginal infections from repeated prolonged periods of twice daily administration of vaginal suppositories.Participants, supervising doctors, and nurses were unaware of the randomization and group allocation of the women. Only an independent secretary had the key code but had no access to the data nor to the participants. The blinding code was not broken until all data was collected from all participants, which took place a few weeks following delivery of the last patient. A long term follow up of the infants was not performed in this study.Participants in both study and control groups received our routine antimicrobial agents given to twin pregnancy, for prophylactic and curative treatment of vaginitis and urinary tract infections. It is known that preterm premature rupture of membranes (PPROM) is the cause of approximately one third of preterm deliveries, and this rate is higher in our group of lower socioeconomic status patients .All Patients received Clindamycin vaginal cream (2%) for 7 days each month as well as oral Amoxicillin as a single dose of 3 g once every month –20.All women were followed up according to the routine antenatal care protocol of our institution. Every visit we confirmed adequate intake of the suppositories and took note of any reported side effects or adverse outcomes. Phone calls were also made to the patients to confirm compliance and monitor their condition. Collection of data was done following delivery by direct contact with the patient’s obstetrician and neonatologist. This included gestational age at delivery, neonatal condition, reporting of neonatal intensive care unit (NICU) admission, birth weight and congenital anomalies undetected during pregnancy.Primary outcome measures: Spontaneous preterm birth before 37 weeks’ gestation.Secondary outcome measures: Spontaneous preterm births before 34, 32 and 28 weeks.Neonatal outcome; including: NICU admission, neonatal death.Early fetal loss: fetal death between 11 and 22 weeks of gestational age Late fetal loss: fetal death between 22 and 28 weeks of gestational age Stillbirth: Fetal death after 28 weeks gestational age NICU admission; neonatal admission to Intensive care for any reason other than neonatal jaundiceNeonatal death; death up to 30 days after delivery. Calculation was done based on comparing 2 proportions from independent samples using Chi-square test wherein the α-error level was fixed at 0.05 and the power was set at 80%. Accordingly, the sample size was calculated to be 96 cases in each arm. Sample size calculation was done using PS Power and Sample Size Calculations software, version 3.0.11 for MS Windows .Sample size calculation was based on a 20% reduction of the previously reported 65% preterm birth rate in twin pregnancies before 37 weeks of gestation [www.ISRCTN.com, number 69810120. There was no specific funding, the suppositories trial drug and placebo were provided by IBSA Egypt free of charge.All women read and signed an informed consent after full explanation of the study design and procedure. The study protocol was designed according to the CONSORT statement. Ethical approval was obtained on 15/11/2013 by our local Ethics Committee ‘Ethics and Research Committee of the Egyptian IVF Center’ headed by Professor Ibrahim Fahmy, (imfahmy@gmail.com) and received an IRB number of 3/2013. The trial was registered on 31 January 2014 at t test for independent samples. The Chi-square test was used to compare categorical data between groups. A two-tailed P value < 0.05 was considered statistically significant. All statistical calculations were done using computer program SPSS  release 20 for Microsoft Windows (2006).Data was statistically described in terms of mean ± standard deviation (± SD), or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables was done using Student We counseled 250 women to join the study: 215 were enrolled, and finally 203 signed the consent and were randomized  in the latest ICMART  report was 20.9% . The mosThe outcome of preterm neonates depends on the gestational age at birth and available resources of the Neonatology Unit caring for those infants .It is of course noteworthy that care of premature neonates adds a huge financial burden on the health care provider and on the parents, especially when medical care is privately funded . The objThis randomized placebo controlled double blind study did not show any benefit of giving natural rectal progesterone starting early on in pregnancy for prevention of preterm birth before 37 weeks in IVF/ ICSI twins. It is worth noting that the mean gestational age at delivery in both groups was +/− 34 weeks. This is earlier than that reported in most literature, which could be attributed to the different ethnicity of our studied group , 28. In The results of this study align with several previous publications , 13, 14.Furthermore, this study used the rectal route instead of the vaginal route while all previously published studies used the vaginal route , 13, 14.We have previously proven that progesterone is effective in reducing preterm birth  rates inNumerous trials have been published , 37–47 oA recent meta-analysis showed that administration of vaginal progesterone to asymptomatic women with twin gestations and a sonographic short cervix in the mid trimester reduces the risk of preterm birth occurring before 30 to 35 weeks’ gestation . FurtherIn the latest report by the ICMART  includinRectal progesterone starting from the first trimester is ineffective in reducing spontaneous preterm birth in IVF/ICSI twin pregnancies. As the risk of preterm birth is known to be high in twin pregnancies, the best approach in the management would be preventive. This can be achieved to a great extent by routine single embryo transfer after IVF/ICSI.


Background: Iron supplementation in pregnancy is recommended by the WHO to prevent a major public health problem, namely, maternal iron deficiency and its consequences. There are gaps in the existing evidence regarding maternal and neonatal benefits and harms of universal iron supplementation.Objective: To evaluate the association between maternal iron status during pregnancy and infant size at birth (birth weight and length).Method: This present prospective cohort study was nested in a food and micronutrient supplementation trial conducted in Matlab (MINIMat study), rural Bangladesh. We randomly selected 573 women recruited into the MINIMat study from January – December 2002 who delivered singletons with available birth anthropometric information. The plasma ferritin of each mother was measured at gestational week 14  and at week 30 (GW30).Results: Multivariable linear regression revealed no association between plasma ferritin at GW14 and birth weight. However, newborns of women in the highest tertile of plasma ferritin at GW30 (median = 29 µg/L) had on average a 93-gm lower birth weight  than the newborns of women in the lowest tertile (median = 8 µg/L). Logistic regression showed that odds of low birth weight were approximately two times higher  among those with mothers in the highest ferritin tertile than in the lowest tertile at GW30. No association was found between maternal plasma ferritin and birth length.Conclusion: We observed an inverse association between high plasma ferritin in the last trimester (GW30) and birth weight but not birth length. The results suggested that elevated plasma ferritin in pregnancy could have an untoward effect on birth weight. Iron (Fe) is essential for physiological functions, including hemoglobin (Hb) synthesis, and cell growth and development . Iron deSeveral studies have evaluated the associations between maternal iron status and fetal iron status  and growMost of the previous studies evaluating the iron status and birth outcome used hemoglobin level as an indicator of iron status, and few studies have evaluated serum ferritin as an indicator of iron status ,12. AddiThis study was carried out in Matlab, a rural subdistrict of Bangladesh, where the International Centre for Diarrhoeal Disease Research in Bangladesh  has been operating a Health and Demographic Surveillance System (HDSS) since 1966. The study was nested into a larger study named Maternal and Infant Nutrition Intervention in Matlab  that recruited 4,436 pregnant women from November 2001 to October 2003. The design and procedures of the MINIMat trial have been reported elsewhere [th-95th percentiles = 12–17) and 30 . Participating women were prescheduled to visit health centers, and their venous blood samples were collected. The blood samples were centrifuged, followed by separation of plasma and then stored at −70°C in freezers in Matlab. Then, they were shipped on dry ice to the University of California, Davis, where radioimmunoassays  were used to analyze the samples for plasma ferritin [We measured plasma ferritin, an established biomarker of body iron , to asseferritin .The outcome variables were neonatal birth weight and length. Approximately 40% had anthropometric assessment at the health clinics where delivery took place . In case2) was calculated based on the woman’s weight and height recorded at the time of enrollment (at ~9 weeks gestation). Pregnancy weight gain (in kg) was calculated by subtracting the weight measured at enrollment from the weight measured at GW30. The gestational age (weeks) was calculated by subtracting the date of the last menstrual period (LMP) from the date of the pregnancy outcome. The LMP dates were obtained by interviewing the women during the process of pregnancy identification. Gestational age was also assessed by ultrasonography. Parity was defined as the number of live- or stillborn children before the current pregnancy. Maternal education was categorized according to the number of completed years of formal schooling: no education, 1–5 years, and ≥6 years. SES was based on wealth scores, derived mainly from ownership of a number of durable household assets by using principal component analysis [Information on maternal age, weight, height, parity, education, socioeconomic status (SES), and date of delivery and on newborn sex were obtained from the MINIMat databases. The maternal body mass index , Kruskal–Wallis test, or χ2 tests, depending on the type of data. The associations of serum ferritin in tertiles with size at birth were assessed by multivariable-adjusted linear regression. The models were adjusted for variables that were significantly associated with exposure and outcome (p < 0.05), that changed the effect size estimates by 10% or more, or that are known or proposed to affect size at birth. We tested for collinearity between covariates, and those that were strongly associated (rs>0.60) were not included in the same model. There were strong correlations between maternal age and parity, as well as between SES and maternal education. Therefore, only parity and education were included in the models, as they had the largest influence on the estimates. Furthermore, we estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of low birth weight (LBW)  and preterm birth  in relation to tertiles of maternal plasma ferritin at GW14 and GW30.We assessed the bivariate associations using Spearman’s rank correlation coefficient . The statistical analyses were conducted using SPSS  and STATA .Statistical significance was considered when a 95% CI did not include zero or at a Our analysis involved pregnant women enrolled in the MINIMat trial during one calendar year from January to December 2002 , and 53% of the newborns were boys. The mean birth weight was 2,670 g , approximately 33% of the newborns weighed <2500 g , and 9.4% were preterm (<37 weeks). There were no significant differences in background characteristics  between those included (n = 573) and those excluded (n = 427). Additionally, we compared the background characteristics of the women included in the analysis (n = 573) and the women excluded due to discarded samples (n = 129). We did not find any significant difference between the two groups.The sociodemographic characteristics of the participating mother-newborn dyads are presented in The mean plasma ferritin concentration was 43 µg/L (range 2.4–201 µg/L) at GW14 and 20 µg/L (range 1.0–96 µg/L) at GW30. Of the 573 women, 29% were anemic , and only 7% (n = 41) had iron deficiency (plasma ferritin <12 µg/L) at 14 weeks. Although the proportions of anemia were similar between GW14 and GW30 (34%), iron deficiency was higher  at GW30. However, only 68 women (12%) had both Hb <110 g/l and plasma ferritin <12 µg/L, and 125 (22%) women had anemia at GW30. The proportions of LBW babies were significantly higher among women in the highest ferritin tertile at GW30 .p = 0.077) among the newborns of women in the highest tertile of plasma ferritin at GW14 (median = 64 µg/L) compared to women in the lowest tertile (median = 17 µg/L). There was no association between plasma ferritin at GW14 and birth length  than the newborns of women in the lowest tertile of plasma ferritin level (median = 8 µg/L). When plasma ferritin concentration was analyzed as a continuous variable , in the multivariable-adjusted model, plasma ferritin at GW30 was inversely associated with birth weight . There was no association between plasma ferritin at GW30 and birth length  or GW30  with LBW.In this prospective cohort study, we found a negative association between maternal plasma ferritin at GW30 and birth weight. The women in the highest tertile of plasma ferritin had babies weighing on average 93 g less than those born to women in the lowest tertile. This reduction has significant public health implications, as reflected by the two times higher odds of LBW at the same level of ferritin exposure. We did not find a similar, significant association between plasma ferritin at GW14 and birth weight.Our findings are consistent with previous studies reporting the associations between high maternal ferritin, measured between GW26 and GW36, and preterm birth ,21, fetaThe inverse association between plasma ferritin concentration in the highest tertile median = 29 µg/L) and birth weight was evident in late pregnancy, and the explanation may be multifold. Placental oxidative stress due to a systemic inflammatory response during the third trimester and activation of maternal endothelial cells all produce high amounts of circulating reactive oxygen species (ROS) which may cause intrauterine growth retardation of the fetus ,26. Iron µg/L andSeveral studies indicated that a high ferritin concentration in the third trimester correlates with preterm delivery, probably due to subclinical maternal infection ,22,32. MNevertheless, elevated plasma ferritin in our participants was not influenced by acute infection or inflammation, which was confirmed by C-reactive protein (CRP) levels in early and late pregnancy. Only 4% of the MINIMat women had elevated CRP levels (10 mg/L) at GW14 and 7% at GW30 .CRP was It is noteworthy that for mothers in the highest ferritin tertile, the median plasma ferritin at GW30 was less than half of that at GW14 (29 µg/L versus 64 µg/L). This finding was in line with Goldenberg et al. who reported a decline in the mean plasma ferritin level from 41 pg/L at 19 weeks to 18 pg/L at 36 weeks . We beliThe main strengths of this study include its prospective, population-based design with a cohort of pregnant women who did not smoke or consume alcohol. We considered multiple potential confounders, including maternal age, parity, BMI, education, SES, and child sex. All data were collected by trained health workers and technicians. We used plasma ferritin as an indicator of iron status, which is more specific than Hb, albeit sensitive to concurrent infection. One limitation was the lack of data on plasma ferritin for a considerable proportion of participants (n = 427), which would have strengthened our evaluation of the association between ferritin and size at birth. To address the natural dip in birth weight after the first day , we adjuIn the current study, we observed an inverse association between higher maternal ferritin in late pregnancy and infant birth weight. The magnitude of the reduction in birth weight  corresponds to approximately 25% of the standard deviation of the mean birth weight and reflects a similar effect of tobacco smoking  or inter


Pelvic growth may be sensitive to early‐life nutrition, with implications for maternal risk of obstructed labor. However, the “developmental origins” of adult pelvic variability require further investigation. We tested whether adult pelvic dimensions are associated with two components of height, indexing different periods of linear growth: tibia length, a proxy for early postnatal growth, and height‐residual (height regressed on tibia length), a proxy for later growth. We also tested whether adult pelvic dimensions are associated with birth weight, a marker of nutritional investment in utero.In this cross‐sectional study, data were obtained on 68 nulliparous young women of South Asian ancestry. Pelvic dimensions  were measured using magnetic resonance imaging. Height and tibia length were measured manually. Birth weight and gestational age were obtained by recall. Multivariable regression models were fitted with a given pelvic dimension regressed on height‐residual, tibia, and birth weight, with the latter adjusted for gestational age.Controlling for birth weight, height‐residual was predictive of bi‐acetabular breadth, bi‐iliac breadth, and the pelvic inlet, while tibia length significantly predicted all dimensions except interspinous diameter. Controlling for the linear growth variables, birth weight was predictive of bi‐iliac breadth only.Markers of linear growth during both early and later development were associated with adult pelvic dimensions, whereas size at birth was poorly predictive. Efforts to reduce stunting in early life may facilitate the attainment of maximum potential growth for both height and the pelvis. ShorterGlobal variation in the incidence of feto‐maternal disproportion is likely influenced by maternal and fetal nutrition and growth, both within and across generations  are associated with adult height, and with markers of three specific growth periods. Birth weight served to index nutritional investment in fetal life. Tibia length and height‐residual (height minus tibia length) were used to index linear growth in the first 2 to 3 years of life, and linear growth from ~3 years to its cessation, respectively. We used tibia length following previous authors  in the range 17 to 28 kg/mMethods of recruitment included posters, online advertisements, and word‐of‐mouth. Data collection took place from March 2015 to May 2016 at the UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust. All participants attended 1 to 2 appointments to complete measurements. The larger study of body composition and metabolic variability from which the current data were derived received ethical approval from a Research Ethics Committee of the NHS Health Research Authority. All participants gave written, informed consent.Height was measured in duplicate to the nearest 0.1 cm using a wall‐mounted stadiometer (Holtain). Weight was measured in duplicate to the nearest 0.01 kg using a scale integral to the BodPod air‐displacement plethysmography system . Large sliding calipers (Harpenden) were used to measure in duplicate, to the nearest millimeter, tibia length as the distance from the medial tibial plateau to the inferior edge of the medial malleolus on the left leg only, following standard protocols .High‐resolution 3D body imaging was undertaken using a 3T Siemens Magnetom Prisma scanner. We performed a volumetric 3D TSix pelvic dimensions  were measured from raw DICOM images using OsiriX open‐source software  on different days and averaged for analysis. A small number of measurements were considered unreliable due to reduced image quality and were thus excluded. The anteroposterior pelvic outlet measure was particularly affected. This is reflected in the table containing descriptive statistics and sample size for each measure (see below).3Birth weight SD scores (SDS) were derived from birth weight and gestational age using UK‐WHO reference birth centiles  and interspinous diameter (1.6%). Table % and intCorrelations among pelvic measurements, total height, and growth‐period proxy variables  are shown in Table r = 0.20, P = .1) and tibia .The ability of birth weight, tibia, and height‐residual to act as markers of distinct growth periods depended on their mutual independence. Height‐residual was by definition unrelated to tibia, while birth weight SDS was unrelated to both height‐residual , which is a transverse measure of the outlet. It is possible that the anteroposterior outlet's relatively high variability in our sample is related to variation in sacral/coccygeal length Tague, , howeverSeveral variables could have served as linear growth proxies. Because tibia and femur lengths are likely highly correlated, height‐residual may include some tibia information via the femur. If we used leg length (tibia + femur) as our proxy of early linear growth, however, height‐residual would represent sitting height, and be far less predictive without the femur component. Authors have often used relative leg length (leg length/height) to index early childhood environmental experience  is useful for predicting obstructed labor or operative delivery at the individual level has been assessed by a number of authors, with mixed results  on adult pelvis size and shape. It will be important to focus efforts on reversing negative secular trends in height, especially in populations where maternal BMI is increasing (Wells et al., MKS and JCKW codesigned the study. MKS collected and analyzed the data and wrote the first draft of the manuscript. OJA assisted with data collection, data processing, and analysis. TJC served as statistician for the study. JCKW and CAC contributed to data acquisition and served as principal investigators. All authors provided critical comments on the manuscript and approved the final version.


N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder . In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS;  Classifying psychiatric disorders into distinct diagnoses remains challenging, although Kraepelin dissociated schizophrenia and bipolar disorder more than a century ago. While psychiatric disorders, such as schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder, display specific symptoms, many of their symptoms are shared by multiple disorders. Although studies show common genetic abnormalities across psychiatric disorders, the pathophysiological characteristics, such as regional brain abnormalities in gray matter or white matter across psychiatric disorders, are not fully understood –6. IdentPrevious diffusion tensor imaging (DTI) studies have predominantly reported lower white matter fractional anisotropy (FA) in psychiatric disorders –32. Lowehttp://enigma.usc.edu/ongoing/dti-working-group/), and identified white matter microstructural alterations along with atlas-defined regions of interest (ROIs) in patients with schizophrenia [To address variation in analysis methods and boost statistical power, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Schizophrenia Working Group performed the first worldwide meta-analysis pooling schizophrenia-control effect sizes based on results from multiple sites generated using the same DTI, quality assurance, and statistical analysis methods. Thus, Kelly et al. performed a large-scale meta-analysis using the established ENIGMA-DTI protocol, which harmonized the processing of diffusion data from multiple sites  consortium, conducts a large, multisite, cross-sectional investigation of white matter microstructural differences among healthy comparison subjects (HCS) and individuals with schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder by using mega-analytic methods similar to those of the study by Kelly et al., which has already shown differences in white matter microstructural alterations in the patients with schizophrenia compared with the HCS . As a neA total of 2937 individuals assessed at 12 sites participated in the current cross-sectional COCORO cohort project. The cohort included data from 1506 HCS, 696 individuals with schizophrenia, 211 with bipolar disorder, 126 with autism spectrum disorder, and 398 with major depressive disorder (Table https://fsl.fmrib.ox.ac.uk/fsl) tract-based spatial statistics (TBSS). Furthermore, we excluded protocols with fewer than five participants in either diagnostic group in the mega-analysis for investigating group differences, and we excluded protocols with fewer than 15 participants in each diagnostic group in the mega-analysis for investigating correlations of the DTI indices with duration of illness or medication to minimize very small sample effects.Multisite raw DTI data were pooled at the University of Tokyo where mega-analyses were performed. Detailed imaging parameters for each protocol are shown in Supplementary Method http://enigma.ini.usc.edu/protocols/dti-protocols/). FA is thought to indicate the underlying characteristics of white matter microstructure, such as the directionality of axonal fibers, diameter, density, and myelin sheath thickness. FA is derived from the degree of anisotropy of the following eigenvalues of the diffusion tensor: λ1, λ2, and λ3. The largest eigenvalue (λ1), i.e., the AD, is a possible marker for axonal injury. The average of the two smaller eigenvalues λ2 and λ3, i.e., the RD, is considered an indicator of myelin damage. The MD is the average of all three eigenvalues [DTI image processing steps included head motion and eddy current correction using eddy_correct (FSL 5.0). Estimation of the following DTI indices were performed using dti_fit (FSL 5.0): FA, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). TBSS, using the ENIGMA-DTI template and JHU ROIs, was applied to extract local values of the DTI indices based on ENIGMA-DTI protocols . Wolfers et al. noted that group-level differences disguised biological heterogeneity and interindividual differences among patients . To addrd effect sizes in each of the 25 ROIs for FA, MD, AD, and RD (four DTI indices) differences in HCS versus individuals with schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder after including age, sex, age × sex, age2 and age2 × sex as covariates for each cohort same as previous studies [d effect sizes using Metasoft software (http://genetics.cs.ucla.edu/meta) similar to Kelly et al. [For comparison of the DTI indices, we calculated Cohen’s  studies , 47. Nexy et al. . In addiβ coefficients for associations of DTI metrics with duration of illness, considering sex as a covariate in regression analyses in patients with schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder for each cohort. For the individuals with autism spectrum disorder, we employed age instead of the duration of illness. Then, we performed mega-analyses across cohorts with the β coefficients using the metacor package in R (https://cran.r-project.org/web/packages/metacor/), which is suitable for meta-analyses with the β coefficients.We evaluated the effect of duration of illness on the four DTI indices. We calculated the β coefficients of the chlorpromazine equivalent dose, considering age, sex, age × sex, age2, and age2 × sex as covariates in individuals with schizophrenia for each sample. We calculated β coefficients of lithium dose, considering age, sex, age × sex, age2, and age2 × sex as covariates in patients with bipolar disorder for each sample. We calculated β coefficients of the imipramine equivalent dose, considering age, sex, age × sex, age2, and age2 × sex as covariates in individuals with major depressive disorder for each sample. Next, we performed mega-analyses across samples with the β coefficients using the metacor package in R (https://cran.r-project.org/web/packages/metacor/). The significance level was set at a Bonferroni corrected p value of 0.002 (0.05/25). We conducted a power analysis to estimate the sample sizes required to detect an effect size with a previous study at a power of 0.80 and a one-tailed significance level of 0.002 (0.05/25), with G*Power version 3.1.9.2 [Furthermore, we evaluated medication effects on all four DTI indices. We calculated  3.1.9.2 , 48.I2 was in the upper 90% for almost all DTI indices in all groups, and the heterogeneity in each protocol was large; it was difficult to interpret the results.The number of DTI indices that the variability ratio was significantly higher compared with HCS was larger in the order of schizophrenia, major depressive disorder, bipolar disorder, and autism spectrum disorder , which was published in 2013, originally aimed to use biological indicators for the diagnosis of psychiatric disorders; however, this goal had not been reached, and therefore, the DSM-5 still relies on symptomatic diagnosis . Our resRelationships between duration of illness and white matter indices were widespread in patients with schizophrenia and present in those with bipolar disorder, autism spectrum disorder, and major depressive disorder. Our findings of those significant relationships in white matter tracts, such as the anterior corona radiata and corpus callosum in individuals with schizophrenia, were similar to those reported by the ENIGMA-Schizophrenia meta-analysis . BecauseSome limitations of our study must be noted. First, the effects of MRI scanner differences on our findings cannot be completely ruled out; however, we minimized this effect using the mega-analysis method. It may be desirable for classification analyses to be performed using the DTI indices among the patient groups; however, there are methodological limitations due to the large effect of MRI scanner differences. Second, although the medication effect on the DTI indices cannot be completely ruled out, we found no significant medication dose-related effects on the DTI indices using regression analysis. Third, associations between symptom severity and effect sizes of DTI indices were not investigated in this study. Investigating relationships of DTI indices with cognitive function, depressive state, manic state, and psychotic syndrome will be fruitful for understanding common or unique pathologies across psychotic disorders in the future. Fourth, genetic or environmental effects on the DTI indices were not investigated in the current study. It is known that lower birth weight among individuals who later develop schizophrenia than among HCS, and a previous study has shown that birth weight influences the white matter volume in patients with schizophrenia –64. FutuIn conclusion, we have shown white matter microstructural alterations across psychiatric disorders. The widespread white matter microstructural alterations in limbic and cortical regions in schizophrenia reported by Kelly et al. were successfully replicated in the present study . FurtherSupplementary text


To observe prevalence, characteristics and outcomes associated with operative vaginal birth (OVB).We compared spontaneous vaginal birth with OVB.p = 0.04) and integrated emergency surgical officers  were more likely to attend. Women experiencing OVB were more likely to receive local anesthesia .Of 993 women, 759 (76.4%) experienced vaginal birth; 716 were spontaneous (94.3%), 14 (1.8%) underwent forceps-assisted birth and 29 (3.8%) had vacuum assistance. In a multivariable model of OVB (forceps and vacuum), compared with a midwife, general practitioners (OR 5.6, OVB is used sparingly but safely at Mizan-Tepi University Teaching Hospital. We followed a convenience sample of 1000 women (those who conveniently presented to the facility to give birth after 28 completed weeks of gestation) at MTUTH between 6 May and 21 October 2019. Through a combination of chart review and structured interview at admission, delivery and discharge, three physicians collected de-identified data on paper forms, which was then entered into REDCap (an electronic data capture system) after quality checking of the paper forms was complete. The rationale for performing this work at MTUTH is that it is the only major referral facility in the Bench Maji Zone and, given a catchment area of 2.5 million people, we wanted to ensure that high-quality care is being delivered.2 and Kruskal-Wallis tests were performed depending on the variables. All covariates significant to p < 0.05 were included in a multivariable logistic regression to determine which covariates were independently associated with cesarean birth. Subsequently, individual logistic regressions, adjusted for covariates significant in the first multivariable model to p < 0.05, were executed to observe the association of OVB with a number of maternal and neonatal outcomes.Bivariate comparisons of sociodemographic, obstetric, birth and pregnancy outcomes of women experiencing vaginal vs OVB were performed using STATA software version 15.2 . Fisher's exact, χp = 0.03, χ2 test), to have been transferred to MTUTH from another facility , to have had greater cervical dilation on admission , to receive local or spinal anesthesia  and to be delivered by a physician or integrated emergency and surgical officer than a midwife . Adverse outcomes that were more likely to result after a woman delivered by OVB included: a lower 5-min Apgar score  and a higher prevalence of neonatal demise . All tests were performed on available data and missing data were excluded from the comparison.Women who delivered by OVB were more likely to be from an urban area .To analyze if there was any association of OVB and adverse pregnancy outcomes, we then performed individual logistic regressions of OVB to test the association with various maternal and neonatal outcomes, adjusted for delivery attendant and anesthesia use. As shown in 3 The obstetric skill is provided by higher level providers  and is often associated with the use of local anesthesia, presumably for perineal tear repair, but is not associated with advanced tearing in this setting.2 No other adverse maternal and neonatal outcomes were found to be more prevalent after OVB compared with routine vaginal birth, suggesting that the procedure is being performed without undue harm. The implication of this analysis is that with global cesarean birth rates rising, OVB may be an alternative mode of delivery that can reduce unnecessary cesarean birth.4 The experience at MTUTH, a low-resource setting, suggests that the procedure can be used by mid-level non-physician providers without undue harm to women and infants, which is a reassuring finding related to OVB.The overall prevalence of OVB at MTUTH is 5.7%, which is consistent with usage globally, regardless of development index.


Urachus is an embryonic organ related to the bladder that degenerates after birth. Defective obliteration of the urachus leads to urachal malformations, the most common of which is a urachal cyst. A urachal cyst is often misdiagnosed due to its myriad presentations. Delay in diagnosis can lead to complications such as sepsis, fistula formation, and rupture of the cyst mimicking peritonitis. Hence, a high index of suspicion is required for the timely diagnosis and management of urachal cysts presenting in the emergency room. We report the case of a 32-year-old woman who presented with clinical features suggestive of an acute abdomen. The judicious use of imaging confirmed the diagnosis of an infected urachal cyst, which was surgically managed. Urachal cyst is an uncommon congenital anomaly that typically presents in older children. It very rarely presents in adults and the incidence is largely unknown in this age group. It arises from the incomplete obliteration of urachus, which is a primitive structure that connects the umbilical cord to the fetal bladder . The incA 32-year-old woman presented to the emergency department with acute onset of suprapubic pain of six-hour duration and low-grade fever of 38 °C. The pain was neither radiating nor migrating to other regions of the abdomen. She denied any history of trauma or comorbid illness. She had delivered two children through a lower segment cesarean section and had not undergone any other surgery. On examination, her vital signs were stable. Her abdomen was soft with a 5-cm sized tender swelling over the suprapubic region. A subcutaneous abscess was suspected based on the initial clinical findings.The laboratory results including renal parameters, electrolytes, blood counts, and urine analysis were normal except for leucocytosis of 13,000 cells per ml . Ultrasonography revealed a 5*5*5-cm sized hypoechoic lesion in the suprapubic region closely related to the dome of the bladder with internal echoes. CT of the abdomen and pelvis showed a 5*4*5-cm sized hypodense homogenous collection in the anterior abdominal wall close to the bladder (Figure Escherichia coli and appropriate antibiotics were started. Histological examination showed the cyst wall lined by stratified columnar epithelium, suggestive of a urachal cyst. The postoperative course was uneventful and the patient was discharged on the seventh postoperative day.Given the above findings and the acute presentation, the patient underwent emergency exploration after informed consent. A transverse skin incision was made over the swelling and exploration was done, which revealed a 5-cm sized pus-filled cavity connected to the bladder dome by a fibrotic band. The abscess with its wall and the entire tract extending to skin and bladder were excised, and the skin was closed primarily after leaving a drain. Culture of the pus revealed The urachus is a midline structure arising from the anterior aspect of the fetal bladder which in turn is derived from the ventral part of urogenital sinus . During The urachal cyst is the most common urachal anomaly and is caused when both the proximal and distal portions of the urachus obliterate leaving a cystic cavity in the middle . The incEscherichia coli, Enterococcus faecium, and Klebsiella pneumonia being the common organisms isolated [Imaging techniques such as ultrasonography, CT, and MRI are the main modalities employed for the diagnosis of a urachal cyst . The uraisolated . Imagingisolated . The uraisolated . Endoscoisolated . In the isolated -11.The optimal management of the urachal cyst in adults is not standardized. Excision of the cyst can be done under antibiotic cover in one sitting or a two-staged procedure can be performed, which involves incision and drainage followed by delayed excision of the urachal remnant . In the Urachal anomalies are rare in adults and are often misdiagnosed due to the heterogeneous clinical presentation. Acute presentation of urachal cyst in adults is seldom encountered in clinical practice. Early diagnosis can help in planning appropriate surgical interventions, thereby reducing the morbidity. A high index of suspicion is of paramount importance for the timely diagnosis of this uncommon congenital anomaly.