To compare neonatal mortality in English hospitals by time of day and day of the week according to care pathway.Retrospective cohort linking birth registration, birth notification and hospital episode data.National Health Service (NHS) hospitals in England.6 054 536 liveborn singleton births from 2005 to 2014 in NHS maternity units in England.Neonatal mortality.After adjustment for confounders, there was no significant difference in the odds of neonatal mortality attributed to asphyxia, anoxia or trauma outside of working hours compared with working hours for spontaneous births or instrumental births. Stratification of emergency caesareans by onset of labour showed no difference in mortality by birth timing for emergency caesareans with spontaneous or induced onset of labour. Higher odds of neonatal mortality attributed to asphyxia, anoxia or trauma out of hours for emergency caesareans without labour translated to a small absolute difference in mortality risk.The apparent ‘weekend effect’ may result from deaths among the relatively small numbers of babies who were coded as born by emergency caesarean section without labour outside normal working hours. Further research should investigate the potential contribution of care-seeking and community-based factors as well as the adequacy of staffing for managing these relatively unusual emergencies. This analysis used a large linked data set bringing together data for over 6 million births over 10 years which enabled stratification by mode of onset of labour and mode of birth, and by time of day as well as day of birth.Stillbirths: Stillbirths were excluded as around 90% of fetal deaths occur before the onset of labour so the timing of death is unknown.Adjustment for covariates: The large number of variables available made it possible to adjust for covariates including obstetric risk factors and the seasonal and temporal nature of birth.The subdivision of caesarean births by timing of decision into elective and emergency used in the UK has enabled the identification of a group which would not have been visible using the subdivision of caesareans into ‘before labour’ and ‘in labour’ used in many other countries.Variables were all derived from anonymised hospital administrative data, so there were no data available about events in the community before admission to hospital or after discharge.Since 2001, a considerable number of analyses have shown higher mortality rates among patients admitted to hospital at weekends compared with weekdays. There has been considerable debate about how to interpret these rates, with differences in quality of care and differences in case mix being frequently citedIn the perinatal field, studies have investigated pregnancy outcomes by day of the week, time of the year and time of day, particularly from the 1970s onwards. Analyses of perinatal mortality in England and Wales among births in the years 1970–1976The 2021 systematic reviewThis study uses linked data from birth registration, birth notification and maternity hospital episode statistics.Information about births in England and Wales is recorded in several systems. Socio-demographic information is recorded at birth registration. Further information, including gestational age and time of birth, is recorded at birth notification when each baby is issued with an NHS number. Information about care at birth in NHS hospitals in England is recorded in Maternity Hospital Episode Statistics (HES) within the mother-based HES deliveries file. Further information about the health of the baby and level of care required after birth is recorded in the baby-based HES baby file.Following a series of pilot projects in collaboration with City, University of London, the Office for National Statistics (ONS) now routinely links birth registration and birth notification data. City, University of London has linked these data to HES and also to corresponding data for Wales to form the City Birth Cohort.This study uses a source data set derived from the City Birth Cohort and consisting of all 6 054 536 singleton births occurring in NHS maternity units in England from 2005 to 2014 and with good links to HES. Derivation and analysis of linkage bias for this cohort has been described elsewhere.From this population, we removed live births occurring before 22 weeks of gestational age and births registered as stillborn. Nearly 90% of stillbirths in England are recorded as antepartum, with fetal death occurring before the onset of labour.By contrast, virtually all neonatal deaths are identified unambiguously so we have higher confidence in the completeness of that population. We used the ONS’ modified Wigglesworth classification system2 test for comparisons between groups.We used the mean and SD to summarise continuous variables and t-test for comparisons between groups. We used percentages to summarise categorical variables and χThe primary outcome was cause-specific neonatal mortality attributed to asphyxia, anoxia or trauma using the ONS’s modified Wigglesworth categories,We used an 8-day categorisation for day of birth which included Monday to Sunday and public holidays. Time of birth was categorised into daytime hours from 07:00 to 19:00 and night-time hours. A combination of day of birth and time of birth was used to classify births as occurring during ‘working hours’, defined as weekday daytime hours and ‘out of hours’, defined as all other times of the week and including all nights, weekends and holidays. In breaking down out-of-hours further, the hours from midnight to 07:00 on a Monday were classified as a weekend/holiday night to reflect the fact that people giving birth in that period would have had access to weekend staffing only in the preceding 48 hours.The data set was stratified by mode of birth and later analysed by mode of onset of labour. To determine the mode of birth we used the Office of Population Censuses and Surveys (OPCS) procedure codes recorded in the standard HES record, supplemented by the HES ‘maternity tail’ variable DELMETH, as previously described.We used the HES maternity tail variable DELONSET to determine the mode of onset of labour. Models were constructed for each mode of birth with onset of labour as a covariate.We identified candidate covariates and confounders fitting univariable and multivariable logistic regression models and used a combination of forwards and backwards selection to determine inclusion of covariates in the models. Models were compared using the likelihood ratio test and the Bayesian information criterion (BIC).Long-term trends, and mother’s age were characterised using natural cubic splines with the amount of smoothing chosen by minimising BIC as a function of df. Day of birth in the year was modelled using yearly and semestral harmonic terms. Binary contrasts referred to sex of the baby and changes between Greenwich Mean Time and British Summer Time. Birth attendants notifying births are instructed to notify gestational age in completed weeks from last menstrual period but some may have used gestational age as recorded by ultrasound as this has become routine. Birth weight was measured in grams and categorised into five levels for modelling. Ethnicity as recorded at birth notification was coded using 17 categories based on the ethnicity question in the 2001 Census of England and Wales. Parity was defined as nulliparous or multiparous by combining information from ONS and HES and by reviewing linked HES records’ Mother IDs to determine whether there had been previous births.We accounted for geographical variation by adjusting for the former Strategic Health Authority Region of England where the birth took place. Random effects terms were included in the models to allow for clustering of providers within the NHS trust where the birth took place. As the constituent hospitals making up some trusts varied over the 10-year time period, maternity units were allocated to a single trust (the ‘Assigned Trust’) for the entire period, even if they were not part of this Trust for the whole time, as described in the project report.During exploratory analyses we found associations between missing information for some variables and neonatal mortality. We also found non-random missingness patterns for key variables including gestational age and birth weight which were not suitable for imputation. For this reason, predictors were included in the models as categorical variables with a category for missing information. Data completeness, particularly for HES, has improved over time. We also observed this pattern in birth weight and gestational age data recorded at birth notification and registration; the percentage of births for which either birth weight or gestational age were missing was under 1%, well below the extent to which data were missing from HES. For around 15% of births the mode of onset of labour was unknown. They were included in the analyses that did not stratify by mode of onset, and we included them in models as an unknown category rather than considering them as missing data.Following a suggestion from our patient and public involvement group, we calculated an absolute measure of risk—the number needed to harm (NNH)—as well as the relative measure presented by the OR. The NNH was calculated as:where the patient expected event rate (PEER) was the rate of neonatal death attributed to asphyxia, anoxia or trauma in the unexposed timing category and the OR was that from the adjusted logistic regression model.Coding of all variables is shown in 10.1136/bmjopen-2022-067630.supp1Supplementary dataPublic involvement and engagement (PI&E) have been at the core of the work undertaken to develop and analyse the City Birth Cohort using a documented ‘three-tier’ approach.The source data set consisted of 6 054 536 singleton births taking place in NHS maternity units in England between 1 January 2005 and 31 December 2014. We excluded 25 748 births recorded as stillborn (4.25 per 1000 births) and 1782 births recorded as occurring at less than 22 weeks gestational age (0.03%).We further excluded 6494 births recorded as infant deaths  attributed to congenital anomalies (0.11%), leaving a descriptive population of 6 020 512 births .2 p=0.75) or neonatal mortality attributed to asphyxia, anoxia or trauma (χ2 p=1).To derive the analysis population, we then excluded 55 864 births that had missing information about time of birth as we could not categorise these as exposed or unexposed. We did not find any evidence that missing time of birth was associated with either neonatal mortality  were stratified by whether births took place inside weekday working hours (weekdays 07:00 to 19:00) or outside working hours  . The proCrude rates of cause-specific neonatal mortality attributed to asphyxia, anoxia or trauma were higher for births out of hours than for births during working hours . The crude mortality rate ratio was not significantly different from 1 for spontaneous, instrumental or emergency caesarean births. The elevated rate in the overall population was driven by a large rate ratio among births recorded as planned caesareans but occurring out of hours , an estiWe fitted multivariable mixed-effects logistic regression models to isolate the effect of working hours from potential confounding by other factors associated with neonatal mortality attributed to asphyxia, anoxia or trauma. Our final models were adjusted for baby’s sex, gestational age, birth weight, mode of onset of labour, geographical region, NHS trust, baby’s ethnicity, baby’s date of birth, mother’s age and parity, as well as yearly harmonic terms for day of year of the birth. After adjustment, there was no significant difference in the odds of mortality out of hours compared with working hours for spontaneous or instrumental births. The odds of neonatal mortality attributed to asphyxia, anoxia or trauma for emergency caesareans was significantly higher out of hours compared with during working hours  . For allWe further stratified emergency caesareans by mode of onset of labour. The largest group of emergency caesareans occurred after spontaneous onset, followed by induced onset, and fewer than one-fifth are emergency caesareans before the start of labour. These emergency caesarean births without labour constituted 2.2% of all births in the data set. The rates of neonatal mortality were highest among the group with no labour, and that is also the only group for which the rate of neonatal mortality was significantly higher out of hours compared with during working hours .The odds of neonatal mortality attributed to asphyxia, anoxia or trauma for emergency caesareans without labour were two-thirds higher for births out of hours compared with births during working hours, unaffected by adjustment for characteristics of the mother, baby and birth  . No signBabies born by emergency caesarean without labour are a group at inherently high risk, so to estimate the effect of out-of-hours care we further adjusted the model for this group of births for obstetrical risk factors. We compared obstetrical risk factor characteristics during and out of working hours  and inclTo understand better the circumstances in which births were at higher risk of neonatal mortality we disaggregated the ‘out of hours’ category to allow us to distinguish evenings from weekends and holidays. Among emergency caesarean births without labour, being born during daytime hours of 07:00 to 19:00 at the weekend or on a holiday held no greater risk of mortality attributed to asphyxia, anoxia or trauma than being born during daytime hours on a working weekday. By contrast, emergency caesarean birth without labour in the night-time held an increased risk both during weeknights  and night-time at weekends and holidays  . There sWe further investigated whether risk of death out of hours was significantly associated with gestational age, local-area deprivation (using deciles of the Index of Multiple Deprivation) or year of birth (data not shown). We found that the only gestational age category where birth out of hours had a significant crude rate ratio for death attributed to asphyxia, anoxia or trauma compared with working hours was among term births (37–42 weeks). We found no evidence that the association of birth timing with mortality differed by epoch of birth (characterised in 2-year epochs and in 5-year epochs across the period 2005–2014). Lower local-area deprivation appeared to have had a small protective effect but this was not significant.We calculated how many emergency caesareans without labour would have to occur out of hours to be associated with a neonatal death attributed to asphyxia, anoxia or trauma beyond those expected if all emergency caesareans without labour happened during working hours. The PEER was taken as the rate of neonatal death attributed to asphyxia, anoxia or trauma among emergency caesareans without labour during weekday working hours, 1.43 per 1000 live births , and theOverall, this study did not find evidence of a higher risk of all-cause or cause-specific neonatal mortality for spontaneous or instrumental births, or for births by emergency caesarean after spontaneous or induced onset, when born outside of working hours.Among babies coded as born by emergency caesarean without labour, which accounted for 2% of births in our analysis population, those born at night-time during the week had 56% higher odds of neonatal death attributed to asphyxia, anoxia or trauma when compared with those born during weekday working hours (defined as between 07:00 and 19:00 Monday to Friday); those born at night-time during the weekend or on a holiday had 75% higher odds compared with those born in weekday working hours. In our data set, with 71 700 births coded as emergency caesareans without labour outside working hours, we estimate that 46 excess deaths are likely to be associated with being born outside of working hours across the 10 years.This study used a large, linked data set which brings together information on birth registration, birth notification and hospital maternity data for over 6 million births over 10 years. To date, a cohort of this size has not been used to analyse birth outcomes based on timing in the NHS. The large cohort allowed for stratification by distinct care pathways based on both onset of labour and mode of birth, and for the opportunity to examine mortality attributed to asphyxia, anoxia or trauma, most likely to be affected by care at birth but comprising approximately 11% of neonatal deaths. A study in Scotland found a raised risk of mortality attributed to anoxia in term birthsMoreover, the analysis of Scottish data included only term births whereas our large data set allowed for adjustment by gestational age. Our findings confirm those of this Scottish report but further identify a specific cohort of births at risk: the subset of births born by emergency caesarean without labour.The nations of the UK are unusual in stratifying caesarean sections into elective/planned and emergency, while in many other countries the subdivision is into whether they take place before or in labour.Given the large number of variables available in the linked data sets, we were able to adjust for relevant covariates including obstetrical risk factors, unlike the Scottish study. We have also adjusted for the seasonal and temporal nature of births and neonatal mortality over the study period, reported in our previous analyses of this data set.A study using data from Maternity HES to analyse perinatal mortality by day of the week concluded that mortality was higher at weekends.Our classification of caesareans requires decision-making based on how births are coded, which may not always reflect clinical practice and, particularly for planned caesareans, may be influenced by clinical decisions made at earlier ‘booking’ antenatal appointments. For births recorded as planned caesareans, we found evidence of an inflated rate ratio for all-cause and cause-specific mortality outside of working hours which may be related to data recording and requires further consideration. Only 29 873 of the 582 990 planned caesareans in our analysis population (5%) took place outside of working hours. Among ‘planned caesareans’, the underlying population differed according to working hours: planned caesareans usually occur in working hours, and those ‘planned caesareans’ that occur out of hours are likely to involve complications. An audit of caesarean section in Scotland in 1994/1995 found that elective caesareans outside the hours of 09:00 to 18:00 occurred mainly where women were booked for an elective caesarean but went into labour before the planned date.We suspect that the crude findings related to planned caesareans were due to misclassification of actual emergency caesareans as ‘planned’, but there is little way to verify this without booking information and this requires further investigation by other means. There could be an important subgroup of women who are identified as at risk at booking but then progress to become emergencies. The limitations of the administrative data in this study meant we were unable to assess whether this is related to any differences in care in and out of hours.Studies have used 09:00 to 17:00 to represent working hours, but are unlikely to reflect typical working hours in the NHS. We used a wider definition of working hours 07:00 to 19:00 to capture this and to reduce the potential for misclassification.A key strength is our patient engagement—we have presented the number needed to harm through recommendations from maternity service users who felt that ORs and relative risks were not accessible for all to understand and did not fully capture rarity of events and absolute risk. This is also important for planning and strategies. To our knowledge, this is the first time that the NNH has been estimated for neonatal mortality in relation to hospital working hours and birth type.As with all observational studies, there is a potential for unmeasured confounding despite adjustment for multiple covariates. There is also potential for variation in reporting which can vary between trusts and over time, although the quality and completeness of HES improved over the period covered by this study. Future analyses are needed to confirm if these results persisted after the study period as the introduction in 2015 of a second national system, the Maternity Services Data set may have competed for staff time available for data recording. Investigations of the ‘weekend effect’ assume that timing of birth is associated with availability of specialist care, but we did not have any data to directly measure that availability. The size and completeness of our data set gives us confidence in the accuracy of our findings for NHS births in England as a whole, although variation within England will not be captured in this estimate.Overall, out of hours care is not associated with a raised risk of neonatal mortality. Policy should focus on making arrangements for the small subset of emergencies where there may be an association rather than regarding all births out of hours as dangerous. Such arrangements may regard antenatal monitoring of or advice on healthcare-seeking behaviour for parents of particularly vulnerable babies.Our NNH finds that over a 10-year period there were approximately 46 excess neonatal deaths attributed to asphyxia, anoxia or trauma among babies born out of hours by emergency caesarean without labour.Emergency caesareans without labour make up approximately 2% of all births over the study period. Compared with other care pathways, they have by far the highest crude rates of neonatal mortality both overall and of mortality attributed to asphyxia, anoxia or trauma, both in and out of working hours.As such, these births represent a cohort of mothers and babies with high risk, emergent conditions that are, by nature, likely to be unpredictable. The 2017 MBRRACE report on term, singleton, intrapartum stillbirth and intrapartum-related neonatal deaths reported that many of the deaths they reviewed followed pregnancies classified as low-risk.We have found that women facing an emergency requiring caesarean birth without labour have a small increased risk of neonatal mortality when giving birth at night. However, the reasons behind this remain unclear, particularly whether the increased risk has its origins in hospital or community care.Future research should focus on characterising the cohort of women who have an emergency caesarean without labour, whether there are aspects of their care pathways or care-seeking behaviour that would be amenable to intervention and whether a planned caesarean would have been an option.Analyses by NHS trust would not include sufficient numbers of deaths to look at mortality outcomes but could provide useful information on rates of emergency caesareans in and out of hours and ideally could link to information on staff-to-patient ratios. We had hoped to do this in our earlier project using NHS workforce statistics, but found that they were too inconsistent.The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to (1) publish, reproduce, distribute, display and store the Contribution, (2) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, (3) create any other derivative work(s) based on the Contribution, (4) to exploit all subsidiary rights in the Contribution, (5) the inclusion of electronic links from the Contribution to third party material wherever it may be located; and, (6) licence any third party to do any or all of the above.The Submitting Author has the right to grant and does grant on behalf of all authors of the Work an exclusive licence on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (‘BMJ’) and its licensees.The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to the Submitting Author unless you are acting as an employee on behalf of your employer or a postgraduate student of an affiliated institution which is paying any applicable article publishing charge (‘APC’) for Open Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative Commons licence—details of these licences and which licence will apply to this Work are set out in our licence referred to above.The manuscript’s guarantor affirms that this manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.


Preterm birth is the leading cause of neonatal and under-five mortality worldwide. It is a complex syndrome characterized by numerous etiologic pathways shaped by both maternal and fetal factors. To better understand preterm birth trends, the Global Alliance to Prevent Prematurity and Stillbirth published the preterm birth phenotyping framework in 2012 followed by an application of the model to a global dataset in 2015 by Barros, et al. Our objective was to adapt the preterm birth phenotyping framework to retrospective data from a low-resource, rural setting and then apply the adapted framework to a cohort of women from Migori, Kenya.This was a single centre, observational, retrospective chart review of eligible births from November 2015 – March 2017 at Migori County Referral Hospital. Adaptations were made to accommodate limited diagnostic capabilities and data accuracy concerns. Prevalence of the phenotyping conditions were calculated as well as odds of adverse outcomes.Three hundred eighty-seven eligible births were included in our study. The largest phenotype group was none , followed by extrauterine infection (25.1%), and antepartum stillbirth (16.7%). Extrauterine infections included HIV (75.3%), urinary tract infections (24.7%), malaria (4.1%), syphilis (3.1%), and general infection (3.1%). Severe maternal condition was ranked fourth (15.6%) and included anaemia (69.5%), chronic respiratory distress (22.0%), chronic hypertension prior to pregnancy (5.1%), diabetes (3.4%), epilepsy (3.4%), and sickle cell disease (1.7%). Fetal anaemia cases were the most likely to transfer to the newborn unit  and fetal anomaly cases were the most likely to result in a pre-discharge mortality .Using routine data sources allowed for a retrospective analysis of an existing dataset, requiring less time and fewer resources than a prospective study and demonstrating a feasible approach to preterm phenotyping for use in low-resource settings to inform local prevention strategies. Preterm birth is a complex syndrome, yet it is the leading cause of death in children worldwide. To help unravel the clinical complexities, preterm birth phenotyping is a framework that considers multiple diagnoses in the mother, helping to evaluate trends in causes of preterm birth in a given region. In our study, we adapted this international phenotyping framework to accommodate a rural, low-resource setting where obstetrical and neonatal technologies were limited, but preterm birth rates were high. We evaluated data from the patient records of a large hospital in Migori, Kenya, in the southwestern region of the country. By lowering the threshold of diagnostic criteria, we were able to apply this framework to our dataset and see that maternal infection and maternal chronic illness appear to be a significant driving forces of preterm birth. Given high rates of HIV and malaria in the region, this is not a surprising finding, but one that can inform antenatal care practices, mainly the need to test and treat for common infections , and to increase the frequency of antenatal care interactions per the World Health Organization recommendations. Resulting in the death of one million children per year, preterm birthis the leading cause of both neonatal and under-five mortality worldwide . PretermIn 2012, the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) released a classification system for preterm birth based on “clinical phenotypes” to consider multiple causal factors that may lead to a preterm delivery. Their preterm birth phenotypes were defined as “one or more significant conditions related to the mother, the foetus, and/or the placenta that are present before initiation of parturition” . The GAPstdataset and through a 2-step cluster analysis identified twelve preterm birth phenotypic clusters and their prevalence across eight countries [In 2015, Barros et al. applied the GAPPS system to preterm births from the INTERGROWTH-21ountries . The stuThis study was nested in the University of California, San Francisco (UCSF) East Africa Preterm Birth Initiative’s (PTBi-EA) intrapartum quality improvement cluster-randomized control trial . It was Migori County is in the southwestern region of Kenya, on the border with Tanzania. MCRH is a level IV government referral hospital with approximately 4,000 births per year and receives most of the region’s complicated maternal and neonatal cases.The Barros et al. definitions were adapted to allow for missed diagnoses, limited data availability, and variations in the completeness and accuracy of data in a low-resource setting. From the available data, we were able to adapt nine of the twelve phenotyping conditions used in Barros et al. HELLP syndrome, IUGR suspicion, and early pregnancy bleeding were unable to be identified in this setting due to limited laboratory data, low and late antenatal care (ANC) engagement, inconsistent recording of ANC data, and variable gestational age (GA) accuracy. We added fetal anaemia as a phenotype, due to the high prevalence of this condition in our study population which was not included in Barros et al. as a phenotype but was listed as a fetal condition with a causal relationship to preterm birth. Finally, sickle cell anemia and other documented severe anemia not related to the presence of malaria infection were added to the phenotype “severe maternal condition” due to the high prevalence of these conditions in our sample population. Table Due to a lack of early pregnancy ultrasounds, inconsistent recording of GA data , and unlikely GA and birth weight combinations (i.e. 4000 g and 28 weeks), GA accuracy was determined to be limited in this setting. As such, eligibility criteria were based on a combination of listed GA and birthweight, including: 1) all babies with a birth weight less than 2500 g, and 2) and babies with a birth weight between 2500 to 3000 g only if the GA recorded in the MR was < 37 weeks. As babies greater than 3000 g were most likely term and those less than 2500 g were most likely preterm, recorded GA was used only for babies who fell within the more uncertain 2500-3000 g range. These definitions are consistent with the eligibility criteria defined by the PTBi-EA parent study and are explained in greater detail elsewhere [Eligible births were identified in the MCRH maternity register (MR), a Ministry of Health logbook where maternity demographic and outcomes data are hand-recorded for each birth by the attending healthcare provider. The inpatient number associated with each eligible MR record was recorded, and the corresponding Maternity Unit inpatient record (IPR) was retrieved from the on-site health records office. If an IPR could not be found, the birth was excluded from the analysis.Data were extracted from the MR and IPR by PTBi-EA research staff and entered into an Open Data Kit (ODK) tool. The variables extracted were predetermined in consultation with obstetricians and paediatricians from UCSF and KEMRI and modelled on the Barros et al. phenotypic cluster diagnostic criteria. If data between the MR and IPR contradicted one another, preference was given to the IPR.The clinical data for each birth were reviewed and classified into one or more of the phenotypes by two independent researchers (LM and CS). For each phenotype, births were categorized as having either a single condition or multiple conditions. Extrauterine infection and severe maternal condition were further disaggregated to report the breakdown of infections and conditions. The frequency of each phenotype within the study population was calculated, as well as the frequency of corresponding conditions within each phenotypic subgroup.To evaluate outcomes associated with each phenotype, the mean birthweights, GAs, parity, maternal age, and antenatal care (ANC) visits were calculated, as well as the proportion and odds ratios of babies who were transferred to the special care newborn unit (NBU), or died before hospital discharge . All data were analysed in Microsoft Excel (version 16.16.3) and RStudio (Version 1.0.136).All data were extracted from routine data sources collected from patients by healthcare providers. No personally identifiable data were collected, and all data were stored on encrypted computers and servers. Permission to access the data was sought and granted by the leadership of MCRH.From November 2015 to May 2017 there were 5,641 births at MCRH of which 621 (11.0%) met the eligibility criteria. Of eligible births, 234 (37.7%) IPRs could not be traced, resulting in a dataset of 387 , antepartum stillbirth, and severe maternal conditions (most commonly anaemia) as the leading identifiable phenotypes of preterm birth. These findings are consistent with a recent systematic review of determinants of preterm birth in East Africa, can inform future prevention interventions in the region, and demonstrate the feasibility and utility of an adapted phenotyping framework applicable to lower-resource clinical settings in which the availability of clinical data is often limited .The MCRH preterm rate of 11% is comparable to the burden across high-income and low-income settings with the recent Born Too Soon 2023 report showing a global preterm birth estimate of 9.9% . With raThe high percentage of unclassified preterm births (41%) was in line with the global trends and other phenotyping studies , 11. In Women in Migori County are at high risk for infection given HIV and malaria endemicity, lack of adequate sanitation in most households, and limited general healthcare accessibility . DespiteFor women living with HIV in our dataset, viral load and antiretroviral therapy (ART) regimen information were unavailable, so it is impossible to know if active infection or the ART regimens themselves, as recent studies suggest, contributed to early onset of labor –21. WomeSexually transmitted and reproductive tract infections, including UTIs, are known to be highly correlated with preterm birth , 23. Of The high incidence of maternal anaemia in our dataset may have multiple explanations. For one, anaemia is often associated with malaria or other parasitic infections and may indicate a higher incidence of malaria than reported –32. For The preterm birth phenotypes identified suggest the need for greater infection management in the antepartum and intrapartum periods for women in Migori County particularly malaria, UTIs, STIs, and HIV. Extrauterine infection was not only the largest identifiable phenotype but was the largest corresponding phenotype with both antepartum stillbirth and fetal distress. High rates of anaemia also suggest a need for increased routine monitoring and nutritional counselling and assistance.These recommendations imply increased frequency and quality of ANC visits. In our MCRH dataset the mean number of ANC visits was only 3 compared to the WHO recommendation that all pregnant women receive at least 8 ANC visits . It can From a data perspective, enhanced linkage opportunities between maternity files and files from other departments  would give maternity healthcare workers critical information needed in the intrapartum period and could allow for a more comprehensive clinical picture to be documented in the chart. This would be most efficiently accomplished through the introduction of electronic medical record systems, but also through more consistent patient identification numerical systems in the interim.Concessions were made in diagnostic precision to allow this model to be applied to births from facilities with limited infrastructure and data accuracy and completion concerns. As we were not diagnosing individuals for treatment but rather assigning phenotypes to look for facility trends our threshold for assigning a phenotype to a preterm birth was lowered. In a region in which necessary confirmatory tests are often missing and documentation in the medical record may be more limited, this approach allowed for greater inclusion of likely cases. With GA quality concerns, an adapted definition of preterm birth was used which may have under or over counted preterm babies (but was consistent with the definition used in the larger PTBi-EA study). Additionally, retrieving patient files for all eligible mothers was not possible due to poor filing systems. Only including births in which the IPR could be traced may have led to a level of selection bias, in that patients with complications may have been more likely to have proper documentation than those without. It is important to note, however, that the filing system at MCRH, is stronger than many others in the region; the high rates of IPRs that could be traced is a strength of this study. Finally, being unable to diagnose HELLP syndrome, IUGR, and early pregnancy bleeding is certainly a limitation. However, as the Barros et. al dataset reported no instances of HELLP syndrome and only a few cases of early pregnancy bleeding, we feel that the exclusion of IUGR was the biggest limitation in our analysis.Adapting the Barros et. al phenotyping framework allowed for an evaluation of preterm birth trends at MCRH that can inform future clinical and intervention strategies. This analysis highlighted the need for maternal extrauterine infection prevention and management in the antenatal and intrapartum periods for women in Migori. Even in regions where data is limited, our investigation demonstrates that adaptations can be made to the preterm phenotyping framework to accommodate a range in data accuracy and completeness. Indeed, areas with the highest preterm birth rates tend to also have the lowest availability of quality data, reinforcing the importance of adapting valuable methods to meet the needs of highly impacted communities.


Assisted Reproductive Technology (ART) has made great strides in the pastforty-years, but no medical treatment comes without side effects. Despiteseveral studies reporting high incidences of perinatal complications, theassociation is inconclusive. Also, the effect of racially and ethnicallydistinguished Asian population undergoing ART on perinatal outcomes is notwell studied. Therefore, this study attempts to compare various perinataloutcome parameters in ART, and spontaneously conceived singleton pregnanciesfrom a single high-volume tertiary care center.This is a retrospective cohort study from a single tertiary infertilitycenter, carried out from January 2011 to September 2020. The study included1,125 IVF conceived babies (AB group) and 7,193 spontaneous conceived babies(SB group). The groups were compared using the Pearson Chi-square test andadjusted odds ratio, calculated using the multivariate analysis.Most of the perinatal complications, such as preterm birth (PTB), earlypreterm birth, low birth weight (LBW), extremely low birth weight, small forgestational age, large for gestational age babies, neonatal intensive careunit (NICU) admission, need for surfactant, meconium aspiration syndrome,neonatal seizures, intraventricular hemorrhage, hypoxic-ischemicencephalopathy, and patent ductus arteriosus was significantly increased inthe AB group when compared to the SB group (p<0.05). In-vitrofertilization (IVF) independently increases the risk of LBW , PTB , NICU admission  and neonatal seizures .Conclusions: All ART-conceived pregnant patients should receiveantenatal counselling regarding perinatal complications and should deliverat a tertiary care center with appropriate NICU support. The field has made incredible advancements and expanded its knowledge,resulting in more than six million babies born worldwide through ART (Assisted Reproductive Technology (ART) has made great strides in the forty yearssince the birth of the first ough ART .Just like a coin has two sides, no medical treatment comes without side effects.There has been caution among clinicians while offering ART because of controversialevidence regarding the increased risk of perinatal complications in IVF conceivedbabies , Perinatal outcome measures included: gestation at delivery, the newborn weight, Apgarscores, mode of delivery, the requirement of NICU admission, oxygen requirement (ifany), need for resuscitation/ventilatory support/surfactant administration, anycongenital malformation, and neonatal mortality.Low birth weight was defined as baby weight at birth less than 2500 gr  and pretp-value<0.05 was considered statistically significant. Multivariate analysis wasperformed; adjusted odds ratios (aORs), 95% confidence intervals (CIs), and2-sided p values were calculated. Differences were consideredstatistically significant if the effect estimate excluded 1.0 from the 95% CIand the 2-sided p-value was <0.05.The data was compiled on an excel spreadsheet and analyzed using SPSS.v.23software. The data were divided into two groups: (a) Babies conceived via ART(AB) and (b) Spontaneously conceived babies (SB). Variables amongst the groupswere compared using the Pearson Chi square test and a versus 26 years), which was statisticallysignificant (p<0.001). The distribution of maternal age in thetwo groups is shown in Out of the 8,318 females included in the study, 1,125 females conceived through ART.The mean age of ART conceived females was higher than spontaneously conceivedfemales (31 years p<0.05). Whereas the incidence of transient tachypnoeaof new-born (TTN), hyaline membrane disease (HMD), congenital malformations andneonatal death was similar in the two groups , earlypreterm birth, low birth weight (LBW), extremely low birth weight, small forgestational age (SGA), large for gestational age (LGA) babies, neonatalintensive care unit (NICU) admission, need for surfactant, meconium aspirationsyndrome (MAS), neonatal seizures, intraventricular hemorrhage (IVH),hypoxic-ischemic encephalopathy (HIE) and patent ductus arteriosus (PDA) wassignificantly increased in AB group as compared to the SB group andhad statistically significantly lower birth weight compared to spontaneously conceived babies. There are various independent riskfactors of LBW and PTB like pre-eclampsia, gestational hypertension, maternalage, and antepartum hemorrhage. IVF also independently increases the risk of LBWand PTB by 2.5 times (p<0.001) and 4 times(p<0.001), respectively  than in the SB group.But on eliminating the covariates like APH, maternal age, and placenta previa,IVF has slightly increased risk for SGA, but not statistically significant(p=0.058) (Babies of the AB group were more prone to be diagnosed with SGA (7.2%p=0.058) .vs. 8.3%,p<0.001). Contributing factors like PTB, LBW, SGA,congenital anomalies, and PDA independently increase the risk of NICU admission.IVF itself is an independent predictor of NICU admission, and it doubles therisk as compared to the SB group , these high rates of PTB and LBW can beaccounted for, due to an increased rate of induction of labor due to raisedincidences of PIH, GDM, APH and other pregnancy induced co-morbidities in IVFconceived pregnancies. Also, an increased frequency of spontaneous PTB before 34weeks was observed in IVF conceived pregnancies. Subsequently, this led to anincrease in detection of patent ductus arteriosus (PDA), in concordance with theresults observed in other studies too  and transient tachypnoea of new-born wassimilar between the two groups, as per observed by In tandem with our study, IVF has been considered an independent risk factor forintraventricular hemorrhage (IVH) in neonates , and this risk further elevated whencomparison was made with respect to major birth defects , but onlThe previous literature reported an increased risk of perinatal mortality in ARTconceived babies, but there is marked heterogeneity since it includes stillbirthsand neonatal deaths. Similarly, singletons conceived through ART had an increasedrisk of infant mortality from birth up to 1 year of life, predominantly in the earlyneonatal period (This study assessed IVF-conception outcomes from a high volume tertiary care centerin a country that has the second largest population and houses more than a millionIVF, facilities providing infertility services at a much lower cost compared to thewestern world . The comART births are strongly associated with poor perinatal outcomes. Thus, all infertilepatients scheduled for high technology infertility treatments should be informed andprognosticated regarding increased perinatal risk in case of a successful IVF cycle.Careful pre-conceptional counselling and delivering at a tertiary care center withappropriate NICU support are keystones to optimize perinatal outcomes.


The worldwide rate of preterm birth (PTB) has been increasing over the last two decades. COVID-19 lockdowns provide a unique opportunity to assess the effects of socioenvironmental and lifestyle factors on premature birth and birth weight. We explored the effects of COVID-19 lockdowns on the PTB rate and birth weight at a nationwide scale in France until one year after their occurrence.Programme Médicalisé des Systèmes d'Information database. The rates of global and sub-categories of PTB were tested. The birth weight was studied before and after lockdown for all live births, for term and premature neonates, and for each category of low birth weight (LBW) by a stratified analysis.This national retrospective observational study evaluated the rate of PTB and birth weight in France from January 2016 to December 2020. Data were obtained from the national p < 0.0001). The proportion of children with LBW also decreased 2 months after lockdown . For VLBW, the difference only appeared over the 6-month post-lockdown period .Data from 2,949,372 births from January 2016 to December 2019, including 228,857 PTB, were compared to those of 699,344 births and 51,886 PTB from January to December 2020. The national rate of PTB decreased significantly from 7.7% to 7.3%, when compared with the 2016–2019 period. This decrease was persistent up to 9 months later. It was observed only for moderate PTB, whereas very PTB and extremely PTB remained stable. The national mean birth weight for full-term babies increased after the lockdown and was still observable up to 8 months later (+0.16%, This nationwide study shows a significant reduction in prematurity and a significant increase in birth weight in France after the lockdown for a period of time not limited to the lockdown itself. A more in-depth study of the factors determining these variations may help to drive PTB prevention policies. The frequency of preterm birth (PTB) varies according to the geographical area, from 5%–9% in Europe to 10.6% in North America and 11.9% in Africa . Beyond The exact etiopathogenesis of PTB is unknown, but it may be at the crossroads of genetic, epigenetic, biological, behavioral, environmental and maternal factors . Fetal gDuring the SARS-CoV-2 health crisis, three national lockdowns were decreed in France . The first lockdown was the most restrictive: nearly all travel was prohibited, school and universities were closed, teleworking for all non-emergency workers became mandatory, and industrial production was stopped. Between the lockdowns, the harshness of the restrictions varied with, for example, limitations on the number of people who could gather in one place, the promotion of remote working with limited transportation, and the reduction of non-essential economic activities. Overall, these restrictions reduced the anthropogenic emission of air pollution, with possible health benefits –14. The Previous studies have provided contrasting results. A national study in Denmark and a study in the Netherlands found a decrease in PTB compared to earlier periods , 16. AnoProgramme Médicalisé des Systèmes d'Information (PMSI) database, which contains medical-economic information on admissions to French public and private hospitals, based on the International Classification of Diseases (ICD-10).This national retrospective observational study evaluated the evolution of the rate of PTB and birth weight in all of metropolitan France from January 2016 to December 2020, particularly focusing on the effects of the first and most restrictive lockdown from 16 March to 11 May, 2020. Data were obtained from the exhaustive standardized data of the national PTB categories were defined according to the WHO definition as a live birth before 37 weeks of gestation, with subcategories as follows: moderate PTB: from 32 to 36 + 6 weeks of gestation, very PTB: from 27 + 6 to 31 + 6 weeks of gestation, and extremely PTB: before 28 weeks of gestation. Birth weight was defined as follows: low birth weight: <2,500 g, very low birth weight: <1,500 g, and extremely low birth weight: <1,000 g.A comparative analysis between the rate of PTB during the 2016–2019 period and the lockdown period was performed using a score test. We tested various periods from the lockdown itself to the whole year following it. Each comparison was based on similar months of previous years to avoid bias due to seasonal variations. Global PTB and the PTB subcategories were tested separately. We then studied the birth weight before and after lockdown at three levels: birth weight of all live births, separate analyses for term and premature neonates , and stratified analyses for low, very low and extremely low birth weight . Statistical analysis was performed using R (version 4.0.3) software.Overall, 3,648,716 live births were included between January 2016 and December 2020, out of a population of 66.99 million inhabitants. Data from 2,949,372 births from January 2016 to December 2019, including 228,857 PTB, were compared to those of 699,344 births and 51,886 PTB from January to December 2020 .The national rate of PTB from March to December 2020 decreased significantly from 7.7% to 7.3%, when compared with the 2016–2019 period . Two poip < 0.0001). This increase was detectable 2 months after the start of lockdown  and was observable up to 8 months later. To further explain this increase in birth weight in full-term babies, we explored the evolution of gestational age and the proportion of SGA infants among these full-term infants. We found no significant difference in the gestational age in full-term infants before (39.3 weeks of gestation) and during and after lockdown (39.3 weeks of gestation). Regarding the rate of SGA, it decreased from 8.98% before lockdown to 8.73% during and after lockdown (p = 3.10–10) (p = 0.02) (p = 0.006). For ELBW, there was no difference between the lockdown period and previous years. This increase in birth weight was also observable for premature babies   . This ob3.10–10) . The pro = 0.02) . For VLB = 0.03) .To evaluate a particular pattern of these changes in metropolitan cities, additional analyses were carried out in the three largest cities of France: Paris, Lyon and Marseille. No difference was found for overall prematurity or mean weight in full-term infants in these areas. The increase in the birth weight of preterm infants was observed only during lockdown.The study found that, at the nationwide scale, the COVID-19 lockdown was associated with a reduction in PTB beyond the time of lockdown and a concomitant increase in mean birth weight. Regarding prematurity, these data are consistent with previous studies. For instance, a national study in the Netherlands found a decrease in the incidence of PTB across various time windows around the implementation of COVID-19 mitigation measures . A studyInterestingly, the lockdown had differential effects on PTB according to the severity of the prematurity. In France, we and others  have shop = 0.001). This trend then accelerated after lockdown (7.32%). Our results also showed that the reduction in prematurity was not limited to the initial period of lockdown and persisted for at least up to 9 months post-lockdown. Several factors may explain this lasting mid-term effect: the gradual lifting of the measures, the continuation of teleworking for most people, the protection of pregnant women against other viral infections, and the long-lasting effects of the lockdown measures at the start of pregnancy on later placenta function.A trend toward a decrease in PTB was observed in 2019 compared to previous years (7.55% vs. 7.77% To further confirm the effect of the lockdown on fetal maturation and growth, we explored the data on birth weight in France. We reported an early reduction in the incidence of LBW and a later reduction in VLBW with no significant effect on ELBW. The effects of lockdowns on LBW have also been suspected by others , 32, butIt remains unclear why the variations observed at the national level were largely unobservable in France’s three main metropolitan cities. Urban migration has been described during the lockdowns, in France as in other countries, which may have had a variable impact on the rate of prematurity, depending on the characteristics of the population that left these areas . These dSome limitations should be acknowledged, but they are inherent to observational and retrospective studies at a country scale. First, daily living habits changed during the lockdown, but details about these changes were not accessible. For instance, the diets of pregnant women were probably different , as was Overall, this nationwide study shows a significant reduction in prematurity and a significant increase in birth weight in France after the lockdown for a period of time not limited to the lockdown itself. A more in-depth study of the factors determining these variations may help to drive PTB prevention policies.


The largest poverty alleviation program in the US is the earned income tax credit (EITC), providing $60 billion to over 25 million families annually. While research has shown positive impacts of EITC receipt in pregnancy, there is little evidence on whether the timing of receipt may lead to differences in pregnancy outcomes. We used a quasi-experimental difference-in-differences design, taking advantage of EITC tax disbursement each spring to examine whether trimester of receipt was associated with perinatal outcomes.N = 2,740,707). To predict eligibility, we created a probabilistic algorithm in the Panel Study of Income Dynamics and applied it to the CA data. Primary outcome measures included preterm birth, small-for-gestational age (SGA), gestational diabetes, and gestational hypertension/preeclampsia.We conducted a difference-in-differences analysis of California linked birth certificate and hospital discharge records. The sample was drawn from the linked CA birth certificate and discharge records from 2007–2012 (Eligibility for EITC receipt during the third trimester was associated with a lower risk of preterm birth compared with preconception. Eligibility for receipt in the preconception period resulted in improved gestational hypertension and SGA.This analysis offers a novel method to impute EITC eligibility using a probabilistic algorithm in a data set with richer sociodemographic information relative to the clinical and administrative data sets from which outcomes are drawn. These results could be used to determine the optimal intervention time point for future income supplementation policies. Future work should examine frequent income supplementation such as the minimum wage or basic income programs.The online version contains supplementary material available at 10.1186/s12889-023-16920-0. Socioeconomic status during pregnancy is an increasingly recognized determinant of adverse birth outcomes and later life health for both the birthing person and child , 2. ReseThere is limited work that examines the effects of poverty reduction interventions on birth outcomes, and little evidence on whether the timing of such interventions may lead to differences in health outcomes. In the U.S., the earned income tax credit (EITC) is the largest poverty alleviation program, providing income supplementation to working families in the form of tax rebate contingent their employment. The size of the credit increases with increasing earned income, eventually plateauing followed by a phase-out of benefits . InitiatThe EITC may impact birth outcomes of interest through several hypothesized pathways, including reductions in stress associated with financial insecurity, or increases in material resources such as housing, nutrition, healthcare access, and transportation.A handful of studies have evaluated the effects of the EITC on birth outcomes, most demonstrating improvements –20. The We estimated the effects of the trimester of eligibility for EITC income receipt on perinatal outcomes, using data from more than 2 million births in California. Leveraging the fact that EITC income is received after taxes are filed in the spring and that timing of receipt is unlikely to be associated with individual characteristics, we used a quasi-experimental difference-in-differences (DID) design. DID compares perinatal outcomes 1) among pregnant people who receive EITC during first, second, and third trimester compared to preconception and 2) and between pregnant people who were likely to receive EITC and those who were not. This second comparison “differences out” any seasonal variation in birth outcomes by trimester among non-EITC eligible pregnant people. Given racial inequities in birth outcomes, we also conducted subgroup analyses by race/ethnicity.The sample was drawn from all live births between 2007 and 2012 using the California Office of State Health Planning and Development database, containing birth and death certificates linked to hospital discharge records. It included information on maternal and infant characteristics, discharge diagnoses, and procedures recorded as early as one year prior to birth for the birthing person and as late as one-year post-birth for the birthing person and infant. The data set was restricted to singleton live-born infants with a gestational age between 26 and 42 weeks at birth, to allow exposure to all trimesters of pregnancy. The final sample size was 2,740,707 births to 2,321,353 people. Prior work has validated the use of outcome and covariate data from birth certificates and hospital discharge records . The stuN = 3,672 people who reported giving birth in the past year). PSID includes self-reported information on income, household size, marital status, and age, which we used to calculate each individual’s EITC eligibility using Internal Revenue Service (IRS) formulas implemented as part of the taxsim package for Stata [The primary exposure was eligibility for an EITC refund in the preconception period, compared to the first, second, or third trimester of pregnancy. As with most administrative data, the records do not contain information on EITC receipt. We therefore used a probabilistic algorithm to create a proxy measure of EITC eligibility using the 2001–2015 waves of the Panel Study of Income Dynamics . We examined two maternal outcomes from hospital discharge records: whether the mother developed gestational diabetes mellitus (GDM) in pregnancy and whether she developed gestational hypertension or preeclampsia. Pregnant people with preexisting diabetes were excluded from the GDM analysis. Pregnant people with preexisting hypertension that did not develop preeclampsia were coded as part of the non-outcome group.Infant outcomes included variables abstracted from birth certificates and hospital discharge records, which are known to be associated with maternal stress or material resources during pregnancy: preterm birth  and small for gestational age , education , Medicaid insurance, parity, infant sex assigned at birth, and indicator variables for year of birth.Patients were not directly involved in this study, as it uses birth records and hospital discharge data.We tabulated sample characteristics among those classified as EITC-eligible and ineligible. We then used a difference-in-differences (DID) approach –41 to essupplement.DID models included an interaction term between a binary variable for EITC eligibility  and trimester of exposure. Both continuous and binary outcomes were modeled using linear regression models. This is standard for DID analyses, because of differences in the interpretation of interaction terms in non-linear models , 43. CoeWe ran our primary models stratified by race/ethnicity, to estimate any differences in the associations.We conducted several sensitivity analyses to test differences in the EITC receipt probability threshold and to address potential bias in the timing of the cohort selection see .n = 1,256,199)  (Fig. Stratified models revealed differences in the association of the trimester of EITC receipt with birth outcomes by maternal race/ethnicity Fig. , althougAnalyses in which EITC eligibility was determined based on a probability threshold of 0.6 yielded similar results to the main analysis eTable , althougIn this study, we leveraged the timing of EITC disbursement in February of each year as a natural experiment to examine whether there is a sensitive period in pregnancy in which receipt of additional income could differentially affect perinatal outcomes. EITC receipt in the third trimester of pregnancy was associated with a 6 percent reduction in preterm birth relative to receipt during the preconception period. In contrast, receipt in the second or third trimester was associated with a 3 percent and 4 percent increase in SGA risk compared to receipt during preconception. There were no differences in maternal gestational diabetes based on trimester of EITC receipt, and a reverse pattern for was noted gestational hypertension and preeclampsia, in which receipt in the second and third trimesters was associated with increased risk compared to preconception.EITC refunds may impact the outcomes of interest through several hypothesized pathways, including reductions in stress associated with financial insecurity, or increases in material resources such as housing, nutrition, and transportation. Our findings suggest that there may be different windows of opportunity for these mechanisms to impact health, depending on the outcome. For example, the stronger association for preterm birth for income received during the third trimester suggest that interventions to reduce stress and improve material resources in the period immediately before birth may have a substantial impact on outcomes related to gestational age at birth. While assessing a different exposure, this work is consistent with seminal work from the Dutch Famine Birth Cohort Study finding that exposure to famine in the third trimester resulted in lower birthweights compared with exposure in earlier trimesters . MeanwhiRacial/ethnic inequities in birth outcomes led us to test for heterogeneity by race/ethnicity. We found that reductions in preterm birth among those receiving the EITC in the third trimester were greatest among Black pregnant people, the racialized group at highest risk for preterm birth. This result mirrors findings of stronger birthweight improvements for Black pregnant people following food stamp receipt in the third trimester . Wealth Our study has several strengths. First, we used a quasi-experimental design and a large population of births to provide rigorous evidence of the association of timing of income supplementation on a range of birth outcomes. Second, we used a novel method to impute EITC eligibility using a probabilistic algorithm in a data set with richer sociodemographic information relative to the clinical and administrative data sets from which outcomes are drawn.This study also has several limitations. First, the linked birth certificate data do not include information on EITC receipt, EITC eligibility, or income, increasing likelihood of exposure misclassification. This is a common drawback in survey and administrative data, and our use of a probabilistic algorithm is an improvement over prior studies that used educational attainment or state EITC policies as crude proxies for eligibility , 34, 35.Importantly this analysis is not directly testing whether EITC receipt in pregnancy impacts birth outcomes, which has been demonstrated in other analyses , 18, 38,In this study, we provide some of the first evidence on how timing of receipt of income during pregnancy affects a range of perinatal health outcomes. These findings have important implications for understanding the effects of economic policy on early life health. These findings for EITC policies extend to international contexts, where cash transfer programs have been found to have small, but potentially important population-level effects on birthweight . As the Additional file 1:Supplementary Online Content, Supplementary Tables 1, 2 and 3.


The relationship between body size and metabolism of goats remains poorly studied. The study evaluated the neonatal metabolic adjustments and elucidated the relationship between serum metabolites and body size in 39 single-born dwarf and normal-sized goat kids. Body weight, length and height of kids were recorded at birth and blood samples were collected from the dwarf and normal-sized (Red Sokoto and Sahel) goats on Days 0 (birth), 3, 10 and 20, postnatal. Also, the body mass index (BMI) was calculated and the concentration of metabolic markers was determined. Results revealed that values of BMI, body weight, length and height were lowest (P < 0.01) in the dwarf, followed by values in Red Sokoto kids, while the Sahel kids had the highest (P < 0.01) values. Conversely, the concentration of triglyceride at birth was highest (P < 0.05) in the dwarf, moderate in Red Sokoto and lowest in Sahel goats. Similarly, the Sahel goat kids had the lowest neonatal (P < 0.05) concentration of serum cholesterol. Neonatal concentrations of serum albumin and urea were higher in Sahel than Red Sokoto (P < 0.05) and the dwarf (P > 0.05) goats. Concentration of serum albumin was lower (P < 0.05) at birth, but significantly increased later, while values of serum urea concentration were higher (P < 0.05) at birth, but significantly decreased in subsequent postnatal days. Unlike the BMI, birth weight showed significant negative (P < 0.05) correlation with the concentration of most serum metabolites, especially triglyceride, which showed negative correlation at birth and in subsequent postnatal days. We concluded that dwarfism or small body size is associated with high serum triglyceride in single-born neonatal goats, and this is probably due to the accumulation of body energy reserve in the form of body fat to compensate for lower body tissue mass. Domestic goats are subdivided into three categories based on body size, namely: dwarf, small and large breeds . CaprineNeonatal goats seem anatomically complete at the kidding point, but are physiologically immature; needing maturation in metabolism, immunity and thermoregulation . BiomarkLipid homeostasis in higher organisms is controlled via an integrated system capable of prompt response to metabolic changes . TriglycIn rodents and humans, dwarfism is associated with growth hormone deficiency and obesity , 18. TheThe adopted study protocol and experimental design followed the international guidelines for animal welfare and got the approval of the Animal Use and Welfare Committee of Ahmadu Bello University: ABUCAUC/2019/13. Efforts were made to reduce suffering of the kids during the experiment; no kid was sacrificed or anesthetized. The animals used for the study were housed in the National Animal Production Research Institute (NAPRI), Ahmadu Bello University, Shika, Zaria, Nigeria (latitudes 11 and 12° N and longitudes 7 and 8° E). Each well-ventilated pen had a maximum stocking density of 20 does and dimensions of 6.1, 6.1 and 2.2 m for length, width and height, respectively.®; half the manufacturer’s recommended dose for a cow) into the thigh muscle. Does that showed signs of oestrus 24 h post-treatment, were housed in separate pens of 5 does per pen and a proven buck was introduced to each pen.More than 200 does with parity ranging between 1 and 2 were used for the study. The does in three breeds were balanced for parity. They were synchronized by injecting 1 mL of cloprostenol  were used for the study. A total of 39 single-born kids, belonging to Red Sokoto (n = 12), Sahel (n = 12) and WAD (n = 12) goats were used for the study. Eighteen (n = 17) of the kids were buck-kids and 19 were doelings. After commencement of suckling, the kids were allowed with their dams for 10 minutes to strengthen maternal-kid bonding. Then, they were restrained gently by experienced personnel, using a gloved-hand to collect blood samples on the day of birth. Subsequently, blood sample collection was repeated on Days 3, 10 and 20, postnatal. Blood samples were collected in the morning (08:00 h GMT + 1) by jugular veni-puncture. The birth weight and morphometric variables were determined using a weighing scale  and measuring tape. Body length was measured as the length from the external occipital protuberance to the base of the tail and body height was measured as the length from the surface of a platform to the withers .® reagents, spectrophotometer was used to determine the concentration of serum total proteins, albumin, urea [The blood samples were gently transferred into anticoagulant-free tubes and allowed to clot, followed by centrifugation at 3,000 revolutions per minute for 15 minutes. The serum was decanted into serum sample bottles, capped and stored at -20°C until analysed for serum total proteins, albumin, urea, triglyceride and cholesterol. Using Randoxin, urea , triglycin, urea  and cholin, urea . The gloin, urea  and recein, urea .The Statistical Package for Social Science (SPSS) version 21 was used for the analysis. Descriptive statistics was performed on all variables and values were expressed as mean ± standard error of the mean. The effects of age, breed and sex on concentration of serum metabolites were evaluated for significance using repeated measures analysis of variance (ANOVA) in a general linear model (GLM) with Greenhouse–Geisser correction. Effect of breed on BMI, body weight, length and height were evaluated for significance using one-way ANOVA. Multiple comparison of experimental groups was performed using Tukey honestly significant difference (HDS) test to separate the means. Interactions between experimental groups and time (age) were assessed to evaluate the effect of advancing age in the neonates. Pearson’s correlation was used to compare the relationship between values of serum metabolites and birth weight or BMI. Discriminant analysis was performed to identify variables with greater discriminatory power between the three breeds and was followed by discriminant analysis option of variable classification. Boxplot was constructed to show the centrality, spread and symmetry of the outcome variables in each experimental group. Comparisons in all cases were done at the 5% level of significance.The mean values of variables showing body size were presented in Age-dependent changes in metabolic parameters in the dwarf and normal-size breeds of goats during neonatal life is presented in Figs The values of serum protein profiles  showed tKids of the three breeds had a significant increase (P < 0.05) in concentration of circulating immunoglobulins .The relationship between serum metabolites and both body weight and BMI at birth are presented on Tables Generally, the boxplot  shows thAlthough the discriminant function classification shows some levels of metabolic homogeneity in the response of the three breeds to the novelty of neonatal life, the breed with hereditary dwarfism (WAD goat kids)  generallTo our knowledge, the cause of the negative association between birth weight and serum triglyceride concentration is yet to be elucidated. It is possibly due to metabolic dependence of low birth weight neonates on lipid metabolites for cellular energy supply, due to small body mass that may lower the amount of glucose and amino acid stores in liver and muscles , 14, 30.Similarly, variation in serum lipid based on birth weight in the three breeds explains the higher discriminant power of serum cholesterol and triglyceride in differentiating the response of the three breeds during neonatal life. Higher serum lipid in the dwarf goat kids may be associated with previously reported higher body and milk fats in the breed , 34. TheThe low total cholesterol levels in Sahel goats as compared to other breeds in the current study agrees with the studies of Okonkwo et al.  and NjidAccording to O’Brien and Sherman , a totalThe lower concentrations of serum total protein and albumin in Red Sokoto than Sahel and WAD goat kids in the current study, agrees with the finding of Njidda et al. , which dHigher serum urea concentrations in Sahel and WAD goat kids, unlike in Red Sokoto goat kids, in the first 3 day of life, may reflect marked protein degradation and deamination of amino acids as well as high rate of tissue remodelling after birth . The negSerum urea is strongly linked to supply, synthesis and degradation of proteins , 49 and The Sahel goat breed which had the highest body weight, length and height as well as BMI during neonatal life seems to have a more efficient protein metabolism; indicated by the higher levels of serum albumin as well as the relatively higher serum total proteins and immunoglobulin at birth with no significant fluctuation after the increase at birth. However, the higher levels of serum urea may suggest that Sahel goats relied more on protein catabolism  to compensate for the low the gluconeogenic energy supply due to low serum lipids in the Sahel goats. The gluconeogenic supply of energy is important in neonatal ruminants and needs to be compensated for, as it provides about 75% of their total glucose needs , 52. ThiThe significant increase in the concentration of immunoglobulins on Day 3 in the three breeds of goat kids suggests an efficient intestinal uptake before gut closure , 43. TheA marked negative association exists between birth weight and serum triglyceride concentration during neonatal life in single-born neonatal goat kids. Dwarfism or small body size is associated with higher serum lipid profiles in goat kids. The Sahel goat kids which had larger body size at birth demonstrated lower lipid profiles, but higher profile of serum urea. Goat kids with higher birth weight may have elevated immunoglobulin concentration in late neonatal life. Thus, the birth weight could be useful in predicting the expected metabolic adjustments in neonatal tropical goat kids, and this information may serve as a valuable tool in manipulating maternal and neonatal diets to enhance survival. We recommend high dietary protein supplementation in Red Sokoto goat kids through provision of concentrate feed to the kids and their does.S1 Data(XLSX)Click here for additional data file.


N = 947, total pregnancies = 1338). Data were collected on demographics, pregnancy and birth outcomes and complications. Participants reported pregnancies in the UK (N = 771), USA (N = 364), Australia (N = 106), Canada (N = 60), New Zealand (N = 23) and Ireland (N = 14). Incidences were higher in people with hEDS/HSD than typically found in the general population for pre-eclampsia, eclampsia, pre-term rupture of membranes, pre-term birth, antepartum haemorrhage, postpartum haemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitate labour and being born before arrival at place of birth. This potential for increased risk related to maternal and neonatal outcomes and complications highlights the importance of diagnosis and appropriate care considerations for childbearing people with hEDS/HSD. Recommendations include updating healthcare guidance to include awareness of these possible complications and outcomes and including hEDS/HSD in initial screening questionnaires of perinatal care to ensure appropriate consultation and monitoring can take place from the start.One in 20 births could be affected by hypermobile Ehlers–Danlos syndrome or Hypermobility Spectrum Disorders (hEDS/HSD); however, these are under-diagnosed and lacking research. This study aimed to examine outcomes and complications in people childbearing with hEDS/HSD. A large online international survey was completed by women with experience in childbearing and a diagnosis of hEDS/HSD ( When thinking about starting a family, people with long-term medical conditions have an additional layer of considerations around health and risk to themselves and their baby. The Ehlers–Danlos syndromes (EDS) are a heterogenous group of genetic disorders affecting the structure, processing and functioning of collagen ,2 with fBox 1Although hEDS is inherited in an autosomal dominant fashion, work to identify the genetic cause is ongoing . DiagnosThe first study of the diagnosed prevalence of hEDS/HSD found that 1 in 500 people in Wales had a diagnosis of either EDS or Joint Hypermobility Syndrome (JHS) on their medical records  and 1 inGuidance recommends that an individual assessment is carried out for planning birth with a connective tissue disorder . It is tExisting research is inconsistent about the rates of obstetric complications among people with hEDS/EDS. Increased rates of miscarriages  , pretermAn online international survey was carried out predominantly collecting quantitative data with additional open-ended qualitative questions to allow participants to clarify responses. Five third-party organisations  were involved in the development of this project, as partners in the funding application and supported recruitment. This was the first part of a larger project that also explored childbearing women and healthcare professionals’ experiences of perinatal care, followed by the co-creation of useful tools for implementation in practice .Participants recruited were women over the age of 18 years who had given birth after 24 weeks of pregnancy at least once from 2007 onwards . The timeframe chosen was to ensure that birthing experiences were after the publication of the World Health Organisation recommended interventions for improving maternal and newborn health . ParticiThe survey questions were developed following a review of the available literature in relation to childbearing with hEDS/HSD and modified following piloting and ethical review . Patient and public involvement (PPI) was conducted via an online poll and led to the inclusion of certain complications—for example, premature birth, abnormal length of labour/birth, poor anaesthetic coverage and haemorrhage . To facData were analysed with SPSS 28 software using descriptive statistics to two decimal places. Data were reviewed to ensure all responses met eligibility criteria, and descriptive statistics were calculated for participant demographics. Percentage incidences were calculated for outcomes and complications . Where responses were binary, i.e., experienced or not experienced, 95% confidence intervals for proportions were calculated. Survey data are presented alongside relevant published general population incidences, collated where available following literature review, to aid interpretation in the context of the study design.All qualitative responses were read for familiarity and analysed using conventional content analysis to compliment the quantitative focus and capture additional complications not asked about quantitatively. This approach is appropriate when limited literature exists and to analyse alongside descriptive statistics ,44. To iN = 194, 20.49%), further education , higher education , professional qualifications  or equivalent other . Just under half (47.94%) of the participants had received a diagnosis based on the more recent 2017 criteria , while the remainder had diagnoses from older criteria for these conditions . At least 65% of participants conceived their first pregnancy before receiving a diagnosis. Most pregnancies took place in the UK , with the rest in the USA , Australia , Canada , New Zealand  and Ireland . The majority (77.20%) were planned pregnancies, with 787 out of 1033 conceived in less than 12 months.The number of surveys completed was 955. Data for outcomes and complications are based on 947 responses, because eight respondents appeared to enter data on four separate pregnancies in one single round of the survey and so were excluded from analysis. A total of 1338 pregnancies were reported with outcomes as reported in N = 946, 77.67%). The remaining births were reported as being in maternity units led by midwives , home births  or births before arriving at the intended place of birth .Most were singleton pregnancies (98.01%) with the remainder being twins . The majN = 1230), 190 (15.45%) were pre-term (occurring before 37 weeks) including 7 stillbirths. Of the 183 pre-term live births, 149 were singleton pregnancies  and 34 were twins . There were 44.80%  births at term before the due date (between ≥37 weeks and <40 weeks) and 39.76%  births after the due date (≥40 weeks) (In relation to babies born after 24 weeks (0 weeks) . These d, 190 15.% were pr, 190 15.% were prOut of the 1041 pregnancies with live or stillborn vaginal births and emergency caesareans , induction of labour, described to participants as inserting a tablet (pessary) or gel into the vagina, was reported in 153 (14.70%). Augmentation of labour, defined as drugs to speed up the birth of the baby after contractions had started, was reported by 135 (12.97%). A quick or abnormally rapid labour was reported in 357 (34.29%) births, defined to participants as the birth of a baby within less than 3 h of the start of regular contractions.N = 1209)—for example, where the births of twins vaginally would be counted as one pregnancy. Outcomes and complications that have been highlighted in bold in the table indicate where confidence interval findings from this study sit outside of the general population incidences.N = 528) reported their latent phase of labour length. The data on latent labour were not normally distributed, as indicated on a histogram, with reports of occurrences that lasted weeks, and 148 (12.24%) reporting latent labours longer than 24 h. For those that did not report a latent phase, some added statements to explain that they did not know how long it was, were not aware of their latent phase, could not remember the change from latent to active labour or it was not applicable to them because they had a caesarean section. Some participants added qualitative text further describing long latent phases and quick births that were not always in their planned place, for example “2 days [latent phase]. 3 min from 4cm to birth though”. and “Onset of labour was so quick the baby was born 7 min after I was discovered to be in active labour. Almost was born in the elevator between the inpatient and birthing floor”.Out of the 1209 pregnancies, 43.67% , Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome , obstetric cholestasis , retained placenta  and placenta previa . There were five themed areas from the qualitative analysis: joints moving out of place and pain; issues from epidural; bruising, tearing and poor wound healing; blood pressure and syncope issues; and infections and unexplained allergic reactions.Where participants selected ‘other’, listed complications included gestational diabetes ((1)[sacroiliac] joint issues, headaches” and “induced labour caused hip dislocations”.Joints moving out of place and pain: “hip dislocation in labour”, “sporadic pelvic displacement, wheelchair from 5 months until 2 weeks after”, “widespread post-partum joint pain and weakness”, “hip subluxation from stirrups (wasn’t aware of hypermobility)”, “severe looseness of shoulders and hips”, “pain, pain, pain”, “pelvic separation leading to bad post-partum pain”, “abdominal divarication, torn ligaments, stretched ligaments, pubis symphysis”; “Pubic Bone Separated at 20 weeks gestation”, “subluxed hips”, “costochondritis as baby moved from under ribs—misdiagnosed as indigestion at the time (EDS not diagnosed at that time)”, “pelvic displacement”, “SI (2)[cerebral spinal fluid] leak”, “post-dural puncture headache from a ‘technically difficult’ epidural (x3) requiring a blood patch [sic]”, “CSF leak from epidural and have continued pain there since”, “extreme hypotension from epidural”; “hypotension with epidural. Prolonged effects of epidural”, and three people said “broken” or “dislocated coccyx”.Issues from epidural anaesthesia: “CSF (3)Bruising, tearing and poor wound healing: “very significant bruising”, “bruising on the baby from fast birth”, “site of vaginal tear never fully healed”, “previous Caesarean scar ruptured during this labour”; “polyps in birth canal from tearing”, “torn hip labrum from long labour” and “bilateral femoral nerve damage and bilateral hip labral tears”.(4)Blood pressure and syncope issues: “blood pressure dropped severely (PoTS) [Postural (orthostatic) Tachycardia Syndrome]”, “tachycardia”, “syncope several hours following birth”, “low blood pressure” and “high blood pressure after delivery”.(5)sic]”, “chorioamnionitis”, “systemic infection”, “baby born with group B strep”, “infection due to time between waters breaking and giving birth”, “bladder infection”, and four people said “uterine infection”.Infections and unexplained allergic reactions: “unexplained anaphylaxis 7 days and 8 days postpartum respectively [The aim of this study was to explore the outcomes and complications of pregnancy and birth for people with hEDS/HSD. A large number of participants completed the survey in a short space of time, highlighting the desire for people with hEDS/HSD to extend the knowledge base for these conditions via research. In summary, the results confirmed higher incidences of certain childbearing complications than are typically found in the general population and reports others for the first time. These include preterm birth, pre-eclampsia, eclampsia, Pre-term Rupture of Membranes, antepartum haemorrhage, postpartum haemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, PTSD, precipitate labour and being born before arrival at intended place of birth. Higher incidences are concluded whereby ranges for population incidences fall entirely outside of the confidence intervals found in this study. The meaning and implications of these findings are subsequently discussed.This study corroborates previous findings with roughly twice the population incidence of preterm birth among people with hEDS/HSD . In addiAntepartum haemorrhage, sometimes caused by placental abruption, was higher than would be expected based on population incidences . BleedinA much higher than typical number of participants reported a precipitate labour ,40, consShoulder dystocia was reported at a much higher incidence than the population average . The knoPostpartum haemorrhage was reported to be three times more common among surveyed participants than the general population incidence . This haAlthough nausea and vomiting are estimated to occur in 50–90% of pregnancies, a much higher incidence of hyperemesis gravidarum was reported in this hEDS/HSD population (25.48%) compared to the general population (3%) . hEDS/HSSeveral studies have reported that people with hEDS/HSD do not feel listened to, contributing to traumatic experiences in maternity  and healN = 1338) in over six countries and three continents, inclusive of up-to-date diagnostic criteria for hEDS/HSD. Population health surveys are useful for estimating condition prevalence [These data cover a large number of pregnancies  that may impact fertility were not measured . The majThe word ‘woman’ was used during recruitment, which led to us being contacted by people who have experienced childbearing but do not identify as cisgender women and therefore felt excluded from the research. We did not collect gender demographics within this survey and so cannot say that all who took part were cisgender women, but this potential lack of representation for childbearing people as a whole group should be considered. Following this feedback, further research was carried out to examine perinatal care for trans and non-binary birthing people .www.hEDStogether.com).The majority of reported births occurred in obstetric units. This can typically be because of planned or emergency caesareans, or to manage birth complications or high-risk pregnancies. It is important to note, however, that people with hEDS/HSD should not automatically be considered to have a high-risk pregnancy, because of the wide heterogeneity in clinical presentation  with posN = 1338) over six countries and three continents, inclusive of up-to-date diagnostic criteria for hEDS/HSD. This research draws us closer to understanding how pregnancy and birth complications may be linked to hEDS/HSD. This is within the context of the recent understanding that 1 in 20 births could be affected, with many people with hEDS/HSD being undiagnosed. The findings from this study have highlighted that the following incidences were higher in people with hEDS/HSD than the general population: preterm birth, pre-eclampsia, eclampsia, PROM, antepartum haemorrhage, postpartum haemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, PTSD, precipitate labour and being born before arrival at intended place of birth. These can have profound impacts on perinatal and neonatal outcomes. Recommendations include updating healthcare guidance to include awareness of these possible complications and outcomes and including hEDS/HSD in initial screening questionnaires of perinatal care to ensure that appropriate consultation and monitoring can take place from the start. These findings also raise new questions about the aetiology of certain perinatal complications, which could lead us to a better understanding of causes and therefore treatment options for some serious and even life-threatening pregnancy-related conditions.These data cover a large number of pregnancies (


Objective: To evaluate the effectiveness of vaginal progesterone in preventing preterm birth in women with a singleton gestation and short cervical length and to determine which of the two formulations, micronized progesterone vaginal capsule versus vaginal gel containing micronized progesterone, is more effective for preventing preterm birth.Data sources: A systematic search was performed in the following databases: EMBASE, PubMed (MEDLINE), The Cochrane Library, and the Clinical Trials Registry .Study eligibility criteria: Randomized controlled trials (RCTs), prospective and retrospective observational studies were included. We searched for progesterone administration to prevent preterm birth in asymptomatic women with a shortened cervix (<25 mm) measured by ultrasound in the second trimester of singleton pregnancy.Study appraisal and synthesis methods: Assessments of the risk of bias of RCTs were performed by applying the Cochrane Collaboration’s Risk of Bias Tool; non-randomized control trials were evaluated with the Newcastle–Ottawa Scale (NOS). The primary outcome was preterm birth ≤33 weeks of gestation. Pooled relative risks (RR) and 95% CI’s were calculated for dichotomous outcomes. Heterogeneity of treatment effect was assessed with the I2 statistic. We pooled results of the primary outcome for individual studies using a random-effect model. We then performed a network meta-analysis to pool indirect comparisons between the two formulations (gel vs capsule). This analysis was performed using the network meta-analysis package within the R environment.Results: Five studies met the inclusion criteria  including 1,048 women. The meta-analysis demonstrated that vaginal micronized progesterone significantly reduces preterm birth risk, Risk Ratio = 0.63; 95% CI, 0.48–0.82; p = 0.0006; with no heterogeneity between the studies: I2 = 0%. In the network meta-analysis, no significant difference was demonstrated  between the effect of the two formulations of vaginal micronized progesterone  on the risk of PTB.Conclusion: Vaginal progesterone is associated with a decreased risk of premature birth in women with a shortened cervix in the second trimester of pregnancy. No differences were found between vaginal micronized progesterone in gel or capsule formulations. Systematic Review Registration: PROSPERO, identifier CRD42020165198.  Prematurity is the leading cause of death in children under 5 years of age. The prevalence of premature births varies from 5% to 18%, with approximately 15 million babies being born preterm every year. Prematurity is associated with short-term and long-term complications . The higCervical shortening, particularly between 14 and 28 weeks of gestation, is associated with an increased risk for spontaneous preterm birth. A short cervix is generally defined as a transvaginal sonographic cervical length (CL) of 25 mm or less in the mid-trimester of pregnancy. An inverse relationship exists between the cervical length measured by ultrasonography during pregnancy and preterm delivery frequency .Progesterone increases the arterial blood supply to the fetus and glycogen production and prevents bacteria from entering the uterus by thickening the cervix. Its role in the second and third trimesters of pregnancy is less clear. However, its effects on the uterus, myometrium and cervix explain the logic of using it to prevent spontaneous preterm birth. Progesterone exerts an inhibitory effect on the expression of contraction-associated protein genes in the myometrium and hinders the production of stimulatory prostaglandins (PG). Cervical remodeling  occurs with loss of progesterone’s tissue effects, usually starting several days or weeks before the onset of regular uterine contractions, a late step in the parturition process. Decreased local progesterone responsiveness, termed “functional withdrawal,” probably instigates cervical remodeling . The intInterventions to reduce the risk of preterm birth in cases of cervical shortening, including progesterone, cervical cerclage, and cervical pessary, have been extensively investigated as treatment options for women with varying risk factors. Guidelines have been developed, matched to the most effective treatment for each case.The present review and meta-analysis will focus on the management of asymptomatic women with a singleton gestation with short cervical length at mid-trimester, and the comparative effectiveness of vaginal micronized progesterone delivered via gel or capsule.Natural micronized progesterone is chemically identical to ovarian progesterone. Its micronization decreases particle size, increases surface area, improves absorption and bioavailability, and decreases metabolic and vascular side effects. The advantage of vaginal progesterone is its high uterine bioavailability since uterine exposure occurs before the liver’s first-pass effect. The term ‘first uterine pass effect’ refers to the phenomenon where progestational effects on the endometrium persist, even in the presence of low plasma levels . In addip = 0.0006]. Moreover, the administration of vaginal progesterone resulted in improvements in several neonatal outcomes, including respiratory distress syndrome, composite neonatal morbidity and mortality, birthweight <1500 and <2500 g, and admission to the neonatal intensive care unit, with relative risks ranging from 0.47–0.82.In 2018, a meta-analysis of patient-level data from randomized clinical trials was performed to determine whether vaginal progesterone administration prevents preterm birth and improves neonatal outcomes in asymptomatic women with a singleton gestation with a short cervix. The analysis comprised of 974 women , who had a cervical length ≤25 mm and were enrolled in five high-quality clinical trials. The results demonstrated that vaginal progesterone administration was significantly associated with a reduced risk of preterm birth before 33 weeks of gestation . No sigOur study has several strengths. First, the method of searching, extracting, collecting, and evaluating the data, analyzing and reporting the findings were conducted systematically according to PRISM guidelines. We included all available data without language restriction. Second, the included studies’ quality was evaluated, and all the studies were found to be of good quality. Third, we added another study to the latest meta-analysis conducted on the subject that, in our opinion, despite not being an extensive study and being methodologically inferior (cohort rather than RCT), is relevant and important as it includes information on a different ethnic group and risk factors, and thus expands the external validity of the study. Another strength lies in the absence of statistical heterogeneity. Therefore, it can be determined that the effect found is indeed due to intervention, vaginal progesterone, and not to any bias.This meta-analysis also has limitations. The main limitation in this meta-analysis lies in the source of the data. As mentioned above, since in some studies the primary outcome (rate of preterm births), was determined for a different gestational week, it was necessary to take the outcome we extracted (PTB<33 weeks) from Romero’s meta-analysis of individual patient data . We assuThe studies selected for our meta-analysis investigated the effect of progesterone on preterm birth in women with various risk factors, including asymptomatic women with shortened cervix at mid-trimester.p = 0.014). In the same year, p = 0.02). In 2011, p = 0.01). Each study defined the primary outcome and number of preterm births at different gestational weeks. p = 0.0005) and PTB ≤33 weeks  respectively. In 2016 p = 0.02). However, in cervical length between 20 mm and 25 mm there were no significant differences in their rate of spontaneous PTB<33 . When the two groups’ data are combined , the odds ratio for progesterone administration in prevention of PTB<33 weeks is OR = 0.53; 95% CL, 0.14–1.96 (In 2007, .14–1.96 .Using Romero’s meta-analysis data  and inclIn this study, we aimed to re-examine progesterone’s effectiveness in preventing preterm birth and to determine which of the two formulations, micronized progesterone vaginal capsule versus vaginal gel containing micronized progesterone, is more effective. This network meta-analysis demonstrates that vaginal gel and vaginal capsule of micronized progesterone equally reduce the risk of preterm birth in women with a singleton gestation with short cervical length in the mid-trimester.