We examine the link between the postponement of parenthood and fertility outcomes among highly educated women in the USA born in 1920–1986, using data from the CPS June Supplement 1979–2016. We argue that the postponement–low fertility nexus noted in demographic and biomedical research is especially relevant for women who pursue postgraduate education because of the potential overlap of education completion, early career stages, and family formation. The results show that women with postgraduate education differ from women with college education in terms of the timing of the first birth, childlessness, and completed fertility. While the postponement trend, which began with the cohorts born in the 1940s, has continued among highly educated women in the USA, its associations with childlessness and completed parity have changed considerably over subsequent cohorts. We delineate five distinct postponement phases over the 80-year observation window, consistent with variation over time in the prevalence of strategies for combining tertiary education and employment with family formation. Increasing educational attainment is one of the key factors characterizing social change and development over the course of the twentieth and early twenty-first centuries. Changes in family formation have occurred simultaneously, most notably the postponement of entry into parenthood to later stages of the life course, rising childlessness at older ages, and declines in total and completed cohort fertility rates  may reduce fertility “because it leaves little time for catching up.” : 646. ThGoldstein  proposedFertility is the complex product of a variety of biological and social processes. Differences in the postponement-completed fertility association both across societies and over time or birth cohorts are likely due to an array of factors that vary along those dimensions, such as population health and rising infertility with age, education structure and population composition, social age barriers to childbearing, changes in fertility desires over the life course, and incentives to embrace childlessness if parenthood has not occurred by a certain age, work–family compatibilities, partnering patterns, or access to assisted reproductive technology   born between 1921 and 2000. Descriptive data and sample sizes for birth cohort groups are presented in Table As a cross-sectional dataset, the CPS does not follow individuals over time, although retrospective fertility measures have been collected. Another disadvantage of the CPS is that it provides no information about educational trajectories; hence, women are classified according to their educational status at the time of survey. It is possible that some women had a different educational status at the time of their first birth or that they acquired more education after the time of the interview. The first scenario is not problematic, because we are interested in the eventual age at first birth and the likelihood of remaining childless for all women who obtained graduate education at any time in their life course, including for those women who had children first and attended graduate school thereafter. However, the second scenario might lead to bias when considering certain groups. For example, the likelihood of going back to school after the birth of their first child (and after the interview) may differ between black and white women. This would downward bias the fertility of the group of women who are more likely to attend graduate school after the birth of a child. Our strategy of pooling cohort data over multiple waves of surveys into synthetic cohorts counteracts this potential bias to some extent because we capture cohort members at different points in the life course. In addition, we carefully compare cohort-specific estimates from survivor functions with cross-sectional estimates derived from women aged 40 and older at the time of the survey, who would only very rarely increase their educational attainment level. As we did not detect downward bias of completed fertility and age at first birth, we are confident that we are able to describe fertility timing and parity of women with bachelor's degrees and postgraduate education well.The June supplement has consistently collected information on the number of live births a woman has ever had and on the timing of her last birth, although the latter item was discontinued in 2012. There are no missing values on these two variables or on other key variables  across all waves of the June CPS. In addition, some surveys  have collected full fertility histories. While surveys taken before 1998 and after 2010 also contain information on the timing of the woman’s first birth, unfortunately, the CPS omitted this question between 1998 and 2010. Thus, for the survey years 1998–2010 (11% of our pooled sample), we reconstructed the ages at first birth from household data. This “own-children method” (OCM) is common practice in demographic research, and is deemed reliable , providing us with further confidence in our estimates.Until 1990, the CPS collected education as years of schooling, from 0 to 18 + .In sum, despite their limitations, the CPS June files represent the best available data source for addressing our research questions. The only other data source of comparable scope, the available birth microdata derived from vital statistics, has many of the same disadvantages as the CPS. In particular, education is measured in ways that make the CPS a more valuable data source for the comparison of individuals with college education and with postgraduate education. The CPS introduced a measure of degree completion in 1992. As the natality data do not provide this information until 2007, they cannot be used to firmly distinguish between college and postgraduate education. In addition, the coverage of the data changed over time as the number of states joining the Vital Statistics Cooperative Program increased from six states in 1972 to 46 states in 1984. It is not until after 1985 that all states are included. Using natality data, which are available from 1969 onward, would also considerably shorten our observation window for the cohort comparison, because no retrospective births are included. Moreover, using natality data would not allow us to analyze parity at age 40–44.among all women. We present survival rates at age 44 to measure childlessness; the 50th percentile of survival time yields cohort-specific median ages at first birth, while the 25th percentile is useful for determining at what age the “fastest” quarter of a birth cohort has transitioned to motherhood. Because estimated childlessness is above 30% for some cohorts, we chose the 65th percentile to provide a rough indicator of the social and/or biological limits of fertility. While the difference between the ages at which cohorts reached the 25th and 65th percentiles is our first measure of the variation at in age at first birth, this first set of survival functions is influenced by both the quantum and the timing of motherhood. Therefore, second, we use Kaplan–Meier estimators to derive the ages at which 25%, 50%, and 75% of all births have occurred among all mothers aged 40 and older at the time of the survey. This second set of analyses estimates the cohort changes in the pure timing of motherhood. The difference between the ages at which cohorts of mothers reached the 25th and 75th percentiles is our second measure of the variation in the age at first birth across cohorts. We exclude mothers under age 40 because this would lead to a downward bias in the first birth age, given that other women who are still childless at these younger ages will likely transition to motherhood at a later point in time. We present all results for women with postgraduate education and for women with college education (without further postgraduate education) separately, and compare the estimates between these two groups. Table We conduct two different sets of survival analyses using Kaplan–Meier estimators to estimate cohort-specific first birth survival functions. First, we derive the ages at which 25%, 50%, and 65% of all births have occurred We have grouped women into birth cohorts spanning five birth years each, yielding 15 birth cohorts. The cohort born in 1976–80 is the last one for whom we can provide a childlessness measure (at age 40 instead of at age 44). This estimate may be subject to change in the future because a portion of this birth cohort had not reached age 40 at the time of the most recent surveys. We show partial Kaplan–Meier results for the cohorts born in 1981–85 and in 1986 + . Furthermore, we present completed parity measures by birth cohort and education for (a) all women (again being informed by quantum and timing of motherhood) and (b) mothers aged 40–44 only. We further show the proportions of women aged 40–44 with zero children, one child, two children, and three or more children for each birth cohort; and provide the average parity among these mothers contingent on their age at first birth. We focus on this specific age group because the number of women aged 45 and older in the sample fluctuates across cohorts due to the sampling changes in the CPS. While some women give birth in their early to mid-forties, the chances of a woman conceiving with her own oocytes appear to be rather rapidly declining after age 40 CDC . Since iTable As expected, Table Postponement is also expressed in the increases in the ages at which our cohorts reach the 25th percentile, from 22/23 to 28/29 for women with postgraduate education and from 22/23 to 26/27 for women with college education. However, unlike for the other measures, we do not see decreases after the peak postponement cohorts. Rather, we see a stabilization in this measure for both groups, with some divergence between them beginning with women born in the 1950s.Our estimates of the age at which 65% of women have had their first child are significantly higher among women with postgraduate education than among women with college education. The peak postponement cohort (1951–60) reached the 65th percentile at age 38/39 for women with postgraduate education, and at age 34 for women with college education. These values represent large increases over those of earlier cohorts, who reached the 65th percentile in their early thirties and late twenties, respectively. Women born after 1960 gradually reached these levels earlier. Accordingly, Table among mothers aged 40 or older only . Moreover, the 1971–75 birth cohort is the first to see only a small and insignificant differential in childlessness between postgraduate and college-educated women.The postponement of motherhood may lead to lower completed fertility not only via childlessness, but via lower progression rates to second or higher parity births. Figure Finally, in Fig. Table Taken together, Table before the age of 25. A “modern postponement” regime then emerged among a second generation of tertiary-educated women born after 1960. Among these “modern postponers,” first birth postponement has been linked with decreasing childlessness. Thus, among these women, both the timing of the first birth and the average parity among mothers have increased, and the variance in the timing of the first birth between postgraduate and college-educated women has been converging.In sum, the linkages between first birth postponement and completed fertility among women with college education and women with postgraduate education have changed. First birth postponement among the “pioneering postponers” born in 1940–1960 was associated with high levels of childlessness; low proportions of higher parity births; and declines in completed parity among mothers, particularly among those who had their first child First birth postponement and its association with subsequent fertility has received considerable attention, and has been attributed to educational expansion, rapidly increasing average ages at first birth, and declining fertility rates in developed countries  in their prime fertility years, seem to have had their family first and then their career. As these women had fewer children than previous cohorts, it appears that the childbearing process among highly educated women ended at somewhat younger ages in these cohorts than it did in previous birth cohorts. The 1941–1945 birth cohort seems to represent another transition cohort, as these women were the first to start postponing the first birth, albeit to a lesser extent than later cohorts. Moreover, these women tended to have fewer children, especially if they had their first child early in life. Goldin’s “career first, then family” cohorts fully overlap with our remaining “pioneering postponement” cohorts born in 1945–1959, and we may extend this strategy to describe it as “career first, then family (in terms of children) or no family at all” given the record levels of childlessness among the postgraduate women born in the 1950s. The strategy of “career and family simultaneously” dovetails with the prevailing behavior of our “modern postponers” born after 1960. However, the highly educated women born in the 1960s may have had a more diverse set of strategies for combining career and family than the women born after 1970—as our finding that the variance in ages at first birth is larger for these women than it is for our youngest birth cohorts seems to indicate. It appears that the highly educated cohorts born since 1970 are increasingly using a strategy of “career and first baby simultaneously sometime between the ages of 28 and 35.” In this context, questions remain about whether and, if so, how much new developments like ART, online dating and changing union formation processes, the adaptation of universities and workplaces to the needs of young parents, increasing involvement of men in family work, social learning from older cohorts (about when starting a family late may become too late), and increases in longevity may be related to or shape the ongoing changes in fertility behavior we observe. It is, however, clear that the changes in the family and career formation strategies over cohorts underline the deep embeddedness of fertility trajectories in greater social contexts, which may, on average, trump the biological constraints in family formation processes, at least with respect to the aggregate patterns demographers observe. As a caveat, we need to mention the changing composition of women in tertiary education over birth cohorts. In the USA, the expansion of education combined with population changes have meant that highly educated women have become more diverse over time on a variety of dimensions that may correlate with preferences regarding fertility and timing, including race/ethnicity and social background (Espinosa et al. Our results diverge somewhat from European findings in terms of the time axis of the postponement effect (Kohler et al. Thus, our finding that first birth postponement is not per se tied to declines in rates of motherhood or completed fertility underscores that what counts as “late” depends on the context, and that there is no uniform answer to the question of whether and when “late” becomes “too late.” Indeed, the outcomes of analyses that have looked at whether and, if so, to what extent first birth postponement is linked to declines in completed fertility have varied across European countries, with the postponement effect being found to be stronger in low-fertility regimes and in countries where combining work and family is most difficult (Billari and Borgoni before age 25, even among the subset of highly educated women. Complementing the findings of Morgan and Rindfuss (Finally, our results are in line with and extend the findings of Morgan and Rindfuss  on the dRindfuss , we showRindfuss . While t


Stimulation of non-crying neonates after birth can help transition to spontaneous breathing. In this study, we aim to assess the impact of intact versus clamped umbilical cord on spontaneous breathing after stimulation of non-crying neonates.This is an observational study among non-crying neonates (n=3073) born in hospitals of Nepal. Non-crying neonates born vaginally at gestational age ≥34 weeks were observed for their response to stimulation with the cord intact or clamped. Obstetric characteristics of the neonates were analysed. Association of spontaneous breathing with cord management was assessed using logistic regression.Among non-crying neonates, 2563 received stimulation. Of these, a higher proportion of the neonates were breathing in the group with cord intact as compared with the group cord clamped . The use of bag-and-mask ventilation was lower among those who were stimulated with the cord intact than those who were stimulated with cord clamped . The proportion of neonates with Apgar Score ≤3 at 1 min was lower with the cord intact than with cord clamped . In multivariate analysis, neonates with intact cord had 84% increased odds of spontaneous breathing  compared with those with cord clamped.Stimulation of non-crying neonates with intact cord was associated with more spontaneous breathing than among infants who were stimulated with cord clamped. Intact cord stimulation may help establish spontaneous breathing in apnoeic neonates, but residual confounding variables may be contributing to the findings. This study provides evidence for further controlled research to evaluate the effect of initial steps of resuscitation with cord intact. Stimulation is one of the key steps to neonatal resuscitation.Breathing prior to umbilical cord clamping has been shown to result in smoother cardiovascular transition at birth in experimental studies.figureIntact cord stimulation to breathe with the cord intact may help deliver intervention more quickly than stimulation after cord clamping and may also avoid the reflex bradycardia that can occur when the cord is clamped before the lungs are aerated. Further research is needed to define if the results are confounded by factors such as provider experience or the baby’s tone and colour influencing management decisions.Globally, among the 140 million neonates who are born every year, 10–15 million do not cry or breathe at birth.Transitioning to an extrauterine environment depends on two major physiological events, the commencement of breathing and the transition of blood flow from the umbilical to the pulmonary circulation.The International Liaison Committee on Resuscitation (ILCOR) provides guidance on neonatal resuscitation.Studies from low-income and middle-income countries have reported that neonates who are not crying or breathing at birth are immediately taken to a neonatal resuscitation area for stimulation, clearing of airways and positive-pressure ventilation.This study aims to evaluate the impact of stimulation among neonates with the cord intact versus those with cord clamped on breathing and birth outcome.This was a nested observational study within two quality improvement studies SUSTAINThis study was conducted among nine hospitals in Nepal. The hospitals are tertiary care hospitals providing referral obstetric services through comprehensive and emergency obstetric and neonatal care services. These hospitals were chosen for quality improvement studies to implement a safer birth bundle. Health workers were trained on HBB 2nd edition to resuscitate neonates with intact cord when possible as part of the safer birth bundle. The cord management was at the discretion of the individual health worker.The study was conducted between 1 June 2019 and 2 May 2020.Women in labour with gestational age ≥34 weeks and confirmed fetal heart rate during admission were approached for consent. Women who were admitted for vaginal birth were approached for consent. For this study, neonates who were crying at birth were not eligible for analysis. Non-crying neonates who received additional tactile stimulation constituted the study population. Babies who cried immediately after birth and those with birth defects were excluded from the analysis. Neonates who did not cry and were not stimulated also were excluded from the study.All non-crying neonates who received stimulation were considered for analysis.The variables considered were defined as cord status: intact and clamped; parity: no previous birth, one previous birth and two or more previous births; obstetrical complication during admission: includes pre-eclampsia, eclampsia, premature rupture of membranes, preterm labour, polyhydramnios, oligohydramnios, breech/transverse lie, decreased fetal movements, antepartum haemorrhage, chorioamnionitis, cord prolapse, meconium-stained amniotic fluid and maternal medical complications such as diabetes mellitus and pre-existing cardiovascular and renal disease; induction of labour, augmentation labour; mode of delivery: instrumental  or spontaneous; preterm birth (age of gestation less than 37 weeks); low birth weight (weight of baby less than 2500 g); immediate thorough drying after birth and breathing after stimulation (spontaneous breathing requiring no positive-pressure ventilation). Stimulation was defined as additional rubbing of the back of non-crying neonates after drying. Stillbirth was defined as no heart rate or breathing at any time after birth.The data collection was done through the existing data collection systems of the two studies REFINE and SUSTAIN. Observational data were collected by independent clinical researchers using a tablet-based application . Observa10.1136/bmjpo-2021-001207.supp1Supplementary dataThe non-crying babies included in the study were categorised as those who were stimulated with intact cord and those who were stimulated after cord clamping. Spontaneous breathing after stimulation was observed. Obstetrical and neonatal characteristics were compared between the two groups.<0.01. The variables which were significantly different by cord status during stimulation were complications during admission, mode of delivery and immediate drying.Multivariable analysis using logistic regression was done to assess the association of cord status during stimulation on breathing by adjusting for the variables which had a significance level difference of pThe main study aimed to improve the provision and experience of care of patients (mother and newborn) during childbirth. Information was provided to patients on their involvement in the main study. Results from this study will be disseminated to healthcare providers, paediatric associations and global neonatal guideline development organisations.During the study period, 41 621 women delivered in the hospitals and 34 652 women consented to the study. Among the consented women, 27 652 births were observed in the study. Among the total births observed, 24 071 babies were excluded as they cried immediately after birth and 508 births were further excluded due to birth defects; 3073 non-crying neonates were included in the analysis. Among the non-crying neonates, 2563 were stimulated. Of the neonates stimulated, 671 (26.2%) of them had their cord intact, while 1892 (73.8%) had their cord clamped .We compared the obstetric and neonatal characteristics of neonates who had cord intact versus cord clamped before stimulation. Obstetric complications during admission were lower among neonates who had cord intact than those who had the cord clamped .Neonates who had cord intact had lower proportion of breech or transverse lie during labour than those who had the cord clamped . Among neonates with cord intact, a lower proportion had meconium-stained amniotic fluid during labour as compared with those with the cord clamped . Induction of labour was lower among neonates with cord intact than clamped . The proportion of neonates born through instrumental delivery was lower among those with cord intact clamped  .The clinical outcome differed among neonates stimulated with the cord intact versus with those cord clamped. Among neonates stimulated with the cord intact, 81.1% breathed, while 68.9% breathed after stimulation with cord clamped . The use of bag-and-mask ventilation was lower among those who were stimulated with the cord intact than those who were stimulated with cord clamped . The proportion of neonates with Apgar Score 3 or less at 1 min was lower with the cord intact than clamped (7.6% vs 11.5% p=0.001). The proportion of neonates with Apgar Score 6 or less at 5 min was lower with the cord intact than clamped . The proportion of mortality was not significantly different between those with cord intact and clamped  .We compared the obstetric and neonatal characteristics of non-crying neonates who breathed after stimulation. Overall, 58.3% of neonates with a maternal complication during admission breathed after stimulation, while 73.8% of neonates without maternal complication breathed after stimulation . Overall, 66.3% of neonates born through instrumental delivery breathed after stimulation, while 72.9% of neonates who were born through spontaneous delivery breathed after stimulation . Among neonates who were not immediately dried after birth, 62.8% breathed after stimulation, while 72.7% of neonates who were immediately dried after birth breathed after additional stimulation  .In bivariate analysis, there were 1.94 higher odds of breathing if the cord was intact during stimulation compared with neonates with cord clamped (crude odds ratio (cOR), 1.94; 95% CI: 1.56 to 2.40). If the neonate’s mother had complications during admission for delivery, the odds of breathing after stimulation were 0.50 lower than neonate’s whose mother had no complication during admission . Neonates who were dried immediately after birth had 1.57 higher odds of breathing after stimulation than those who were not dried after birth . In neonates with birth weight <2500 g, the odds of breathing after stimulation was 0.63 lower than neonate’s with low birth weight  .In multivariate analysis, to assess the association of characteristics with breathing after stimulation, there was 1.84 higher odds of breathing if the cord was intact during stimulation when compared with neonates with cord clamped (adjusted OR (aOR), 1.85; 95% CI: 1.48 to 2.30) after adjusting for obstetrical complications during admission, mode of delivery, immediate drying after birth, low birth weight and preterm birth. Neonates who were dried immediately after birth had 1.49 higher odds of breathing after stimulation than those who were not dried after birth  .In this observational study, one-fourth of the non-crying neonates had stimulation performed with an intact cord. There were higher odds of spontaneous breathing if the cord was kept intact during stimulation than neonates who had their cord clamped during stimulation. The higher obstetrical complications during admission and Apgar Score less than 4 at 1 min among early cord clamped non-crying neonates indicates that these are more depressed neonates than neonates with cord intact. In line with this, a higher proportion of infants with early cord clamping received bag-and-mask ventilation. Even though there was no significant difference in mortality between the two groups, the mortality trended lower among the neonates who were stimulated with the cord intact.et al demonstrated a more stable cardiovascular adaptation if cord clamping was performed after initiation of ventilation.An experimental animal study by Bhatt Similar to our results, a single-centre randomised controlled trial (RCT) in California, USA, to evaluate the effect of delayed cord clamping in premature infants (<32 weeks) who required ventilation demonstrated that provision of gentle tactile stimulation with the cord intact may hasten the establishment of spontaneous respirations and provide a similar placental transfusion compared with positive-pressure ventilation with delayed cord clamping.A single-centre RCT in Nepal evaluated the effect on delayed versus early cord clamping in babies requiring resuscitation.Our multicentric study conducted between 2017 and 2018 showed that 9.8% of neonates do not cry at birth.A study in Tanzania showed that although the healthcare provider commonly practiced clamping the umbilical cord immediately after delivery, they were aware that delayed cord clamping has a potential benefit of oxygenation to the newborn in the event of the need for resuscitation.This study has several strengths including that observations were done by trained researchers in multiple hospitals in Nepal in a consistent way and with large sample size. Using observational methods limited recall bias. However, there are several limitations. First, this observation was only done for vaginal births and not for caesarean births. Second, cord management was at the discretion of the health workers, so there may have been a bias toward the previous practice of immediate cord clamping. The appearance of the baby at birth  may have influenced decision-making on when to cut the cord.In conclusion, our study found that non-crying neonates stimulated with the cord intact were more likely to breathe than those who were stimulated with the cord clamped. Stimulation with cord intact may help establish spontaneous breathing in apnoeic neonates, but residual confounding variables are likely contributing to the findings. Our study provides additional evidence consistent with the ILCOR recommendation on keeping the cord intact during the initial steps of resuscitation. This study highlights the importance of further controlled research to evaluate the effect of initial steps of resuscitation with cord intact.


Unfortunately, their exquisite work has since been sparsely cited in the modern literature. This work gives a modern description of many of the occipital intralobar lobe fibers described by the Dejerines. We perform a virtual dissection and reconstruct the tracts using diffusion MRI tractography. The dissection is guided by the Dejerines’ treatise, Anatomie des Centres Nerveux. As an accompaniment to this article, we provided a French-to-English translation of the treatise portion concerning five intra-occipital tracts, namely: the stratum calcarinum, the stratum proprium cunei, the vertical occipital fasciculus of Wernicke, the transverse fasciculus of the cuneus and the transverse fasciculus of the lingual lobule of Vialet. It was possible to reconstruct all but one of these tracts. For completeness, the recently described sledge runner fasciculus, although not one of the Dejerines’ tracts, was identified and successfully reconstructed.Diffusion MRI paired with tractography has facilitated a non-invasive exploration of many association, projection, and commissural fiber tracts. However, there is still a scarcity of research studies related to intralobar association fibers. The Dejerines’ (two of the most notable neurologists of 19 th century, as well as a complete translation of the original text.Bugain et al perform a virtual dissection and reconstruct the occipital intralobar tracts using diffusion MRI tractography. They provide a modern anatomical depiction of what had originally been described by the Dejerines in the 19 In humans, diffusion MRI paired with tractography permits a noninvasive three-dimensional reconstruction of large-scale white matter system organisation, which can then be compiled into an atlas4 (see reviews: refs. 7). Diffusion MRI has contributed to the verification of many association fiber pathways9, as well as to the redefinition of their boundaries and relations17. Recent success in discovering novel or forgotten association fibers has stoked interest in the less conspicuous short-range fiber connections, which can be more challenging to delineate21.The advent of in vivo magnetic resonance imaging (MRI) techniques has heightened the desire to construct a comprehensive atlas of the human brain connective network—the so-called human connectome22.Despite the rapid advancement in the technology and the connectome mapping techniques available, there is a paucity in research related to short-range association fibers in the occipital lobe. The initial focus of this new field was geared towards the more prominent, and seemingly more physiologically crucial, long-range association fibers. A more generalised issue with MRI-based tractography studies is that the findings tend to remain speculative, devoid of tangible experimental evidence and ground truth, unlike those of axonal tracer studies28. Pioneering texts have also often been an initial source of inspiration for explorative neuroanatomical studies23. Indeed, we had previously studied dissections by 19th-century neurologists Joseph and Augusta Dejerine with a view to enriching the field’s knowledge and perspectives on long-range association fiber anatomy29. It showcased the pertinence of these historical studies and prompted further examination into the Dejerines’ other work on association short-range occipital fibers.To partially overcome these inherent limitations, contemporary researchers can guide their findings through postmortem dissection studies, by consulting the tract tracing literature or historical neuroanatomy texts. The 19th-century neurologists were masterfully skilled in gross dissection and fastidious in the documentation of their composite observations. Numerous diffusion tractography studies have successfully used these classical dissections to interpret imaging results and identify false positives or false negatives30, while Wernicke defended the existence of dorsal-ventral projecting association fibres, particularly in the occipital region32. Other neurologists, like the Dejerines and Sachs, supported the school of thought of Wernicke by acknowledging the existence of the vertical occipital fasciculus of Wernicke (VOF)34 and several other intralobar tracts with a dorsal-ventral trajectory. Whereas the work of Heinrich Sachs on the anatomy of intralobar pathways has previously been explored and translated31, the equally insightful contributions and perspectives of the Dejerines have yet to be explored and made more accessible.One of the biggest divisions across the neuroanatomical field towards the end of the 19th century was the definition and categorisation of association fibers. Prominent authorities at the time, such as Meynert, postulated that true association fibres only projected in an anterior-posterior dierection36. Arguably, the Dejerines’ seminal work is their two-volume neuroanatomical treatise, Anatomie des Centres Nerveux, originally published in 1895 and 1902 and then reprinted in 1980 by Mason-Elsevier37. The Dejerines’ impressive histological sections, accompanied by beautifully intricate illustrations by H. Gillet, are relevant even in this technological era, and are reference points for anatomical findings38. Of particular interest to us, the Dejerines dedicated a portion of the first volume to occipital intralobar association fibers. The Dejerines observed five fiber bundles specific to the occipital lobe: the stratum calcarinum, the VOF, the transverse bundle of the lingual lobule of Vialet, the transverse fasciculus of the cuneus and the stratum proprium cunei. Over 100 years later and these short, intralobar, association tracts remain poorly understood and surrounded by controversies due to inconsistent classification and nomenclature39.Joseph Jules Dejerine (1849–1917) and his wife, Augusta Dejerine-Klumpke (1859–1927) frequently collaborated and are both individually celebrated as two of France’s most renowned 19th-century neurologists42. As of December 2019, a PubMed search generated thirty hits relating to the “vertical occipital fasciculus” when used as a key term. In comparison, the other intraoccipital tracts generate no results and remain overlooked, mostly being listed in passing   . The aimUsing constrained spherical deconvolution (CSD) tractography, this study successfully identified and mapped four of the five occipital intralobar white matter tracts observed by the Dejerines Fig. . The traThe following descriptions of the tracts are based on a virtual dissection derived from averaged orientation distribution functions (CSD ODFs) from 24 healthy subjects Figs. . To probWith regard to short-range association fibers arising from the occipital lobe, the Dejerines described the vertical occipital fasciculus (VOF), which spans the entirety of the occipital lobe lateral to the posterior ventricle, and four shorter association fiber tracts projecting superiorly and inferiorly from the banks of the calcarine fissure: the stratum calcarinum (SC), stratum proprium cunei (SPC), transverse fasciculus of the cuneus (TFC), and the transverse fasciculus of the lingual lobule of Vialet (TFV) Fig. .The stratum calcarinum (SC) consists of several U-shaped fibers that connect the two banks of the calcarine fissure, a major landmark that medially divides each occipital lobe into the wedge-shaped cuneus superiorly, and the lingual lobule inferiorly, and represents the boundaries of the primary visual cortex. This group of U-shaped fibers extends all along the calcarine fissure from the occipital pole to its junction with the parieto-occipital fissure at anterior border of the occipital lobe Fig. . The SC 43, however, they did not explicitly mention the SC system or distinguish it from other U-fibers.The SC fibers are composed of two superimposed layers Fig. . The firThe horizontal aspect of the SC projects away from the midline into the bank of the fissure and becomes intertwined with the other intralobar tracts that originate from the lips of the calcarine fissure: the stratum proprium cunei in the superior lip and the putative transverse fasciculus of the lingual lobule of Vialet in the inferior lip. In the anterior part of the fissure, the vertical portion of the SC is on the same plane, and slightly overlaps the sledge runner fibers (not described by the Dejerines) that travel vertically downwards, beneath the calcarine fissure, prior to continuing transversely to the anterior lingual gyrus Fig. .The stratum proprium cunei (SPC) arises from the superior bank of the anterior calcarine fissure, just posterior to the junction with the parieto-occipital sulcus Fig. . The tra46. Unfortunately, in the present study, it was not possible to identify a bundle resembling the TFC.The transverse fasciculus of the cuneus of Sachs (TFC) is described as a tight, slender bundle, consisting of relatively few fibers that initially move away from the upper fold of the calcarine fissure with a strong oblique trajectory. They course laterally and superiorly to the roof of the posterior lateral ventricle and cross the cuneus to terminate in the lateral convexities of the occipital lobeA tract resembling the many aspects of the Dejerines’ description of the transverse fasciculus of the lingual lobule of Vialet (TFV) was successfully isolated Fig. . The DejThe putative TFV has a morphology that resembles an extended U-fiber; the tract travels laterally away from the fissure prior to adopting an intense anterior-oblique trajectory that sharply curves back on itself and continues in a posterior-oblique course toward the lateral convexity of the occipital lobe. Due to the squatness of the lingual lobule, the tract appears quite flat and two ends of the fiber tract are nearly on the same coronal plane, with the lateral terminations slightly inferior to its calcarine fissure origin. The putative TFV starts superiorly and medially to the inferior longitudinal fasciculus and occipital projections of the inferior fronto-occipital fasciculus, and crosses both laterally and superior to these two major association fiber bundles, before descending just laterally to them.33, p. 779) maintaining a dorsal-ventral course lateral to the posterior ventricle. More specifically, the inferior terminations of the VOF extend from the ventral temporo-occipital cortex region, encompassing the inferior temporal gyrus and its intersection with the anterior aspects of the middle and inferior occipital gyri. The superior projections of the VOF reach the lateral gyri of the occipital lobe, including the transverse occipital sulcus, with several fibers reaching the posterior end of the intraparietal sulcus and the angular gyrus.Using the Dejerines’ classical description, we identified the vertical occipital fasciculus (VOF) Fig. , and it The ‘sheet-like’ stem of the VOF tract, that courses through the central part of the occipital lobe, is a wide bundle that has a predominantly vertical trajectory, apart from the ventral and dorsal terminations that flick out laterally and transversely to reach the convexity of the lateral occipital lobe across a wide area. Whereas the stratum calcarinum is covered laterally by the inferior longitudinal fasciculus, the VOF passes laterally to the inferior longitudinal fasciculus along with the inferior fronto-occipital fasciculus, continuing superiorly to both and coursing vertically, posterior to the arcuate fasciculus.25 were identified in both hemispheres and reconstructed successfully lly Fig. . The SRFlly Fig. . The ven50. Yet, the scope of these U-fiber studies is vast and they do not provide precise descriptions of the trajectory of the occipital U-fiber tracts. This makes it difficult to gauge to what extent pathways depicted in their figures are equivalent to our findings. As such, dedicated and focused anatomical studies are still required.The anatomical findings described in the present study suggests that the occipital lobe has at least five intrinsic white matter structures that fall between the long association fibers and the very short U-shaped fibers. These are: the stratum calcarinum, the transverse fasciculus of the lingual lobule of Vialet, the stratum proprium cunei, the vertical occipital fasciculus of Wernicke (VOF)—which were described by the Dejerines, and the recently discovered sledge runner fasciculus (SRF). Apart from the vertical occipital fasciculus of Wernicke and the sledge runner fasciculus, none have been the focus of dedicated studies since the turn of the 20th century. Certain, expansive, U-fibers studies have previously presented findings that are suggestive of some of the shorter occipital intralobar fibres identified in this current studyThis current study also highlights the persistent utility of historical studies for guidance of neuroimaging findings.51, postmortem dissections52, and it has even been identified and compared in macaques53. Yet, the boundaries of the pathway remain unclear and disputed54. Its vertical trajectory, like that of the stratum proprium cunei, distinguishes it from the other long association fibers that project into the occipital lobe, and its long dorso-ventral trajectory, located lateral to the ventricle, sets it apart from the intraoccipital tracts. The Dejerines, like other early neuroanatomists, admitted to poorly defining the anterior limits of the VOF. Their descriptions suggest that it extended anteriorly beyond the boundaries of the occipital lobe, descriptions borne out by most recent tractography studies, including this present one. Hence, it is arguable that the VOF is not strictly an autochthonous tract restricted to the occipital lobe10. Depending on how anterior the ventral terminations of the VOF were, it assumed either an oblique dorsal and posterior trajectory, or in the case of more posterior ventral terminations, a vertical trajectory to the occipital cortex. We did not find strong ventral VOF termination within the ventromedial-fusiform gyrus or the dorsomedial portion of the occipital lobe. Our findings show that the VOF extends from the dorsal to ventral aspects of the lateral parietal and occipital lobe as a thin sheet and terminates at the lateral-posterior end of the temporo-occipital region  studies24. Recent findings by Takemura et al.53 demonstrate a clear separation between the VOF and the inferior longitudinal fasciculus and optic radiations streamlines in humans through dMRI. This supports what had first been indicated in classical studies of the human and macaque by the Dejerines and Wernicke, respectively55.Studies now aim to better differentiate the VOF fibers from the neighbouring larger bundles. The VOF projects superior to the inferior longitudinal fasciculus. Their proximity once made the VOF difficult to distinguish from the terminal portions of the inferior longitudinal fasciculus, leading to its misidentification in one of the early studies on the macaque54. This has generated debate about the anatomical boundaries and distinctive functions56 of VOF and arcuate fasciculus. The proximity of the VOF to the posterior arcuate fasciculus has been seen to be dependent on species, subject variability, local model, and tractography algorithms57.Similarly, the anterior dorsal terminations of the VOF closely borders the posterior and the ventral aspect of the arcuate fasciculus58. The occipital intralobar tracts, notably the VOF, have a strong dorsal-ventral trajectory, whereas many of the major long association fiber pathways that enter the occipital lobe have an anterior-posterior trajectory. Hence, the intralobar fibers cross paths with more prominent bundles that can cancel out their signal. The Dejerines themselves remarked on the limits of even masterful brain dissection skills for identification of terminations in pathway-dense regions, limiting the extent of guidance that postmortem dissections can provide. The continuous improvement in MRI tractography angular resolution, and the development of alternative models, have made some headway59.Borders for the VOF, or any other occipital intralobar tract, can manifest small discrepancies across studies partly due to brain borders being a human construct, high subject variability, the limits of imaging resolution, and the larger number of more prominent tracts that cross the intralobar tracts16. The intermingling of U-fibers is known to obstruct the visualisation and interpretation of the deeper underlying subcortical tracts in both fiber tractography and dissections60.It is important to make these distinctions, for all association fibers, in order to generate a truly representative map—that is, one that does not include pathways that appear longer or wider than they truly are because they artificially contain subsections of adjacent tracts. Knowing the extent of a distinct white matter system is useful for future work concerning functional specialization and pathology. It has been suggested that certain U-fibers, situated between the VOF and other long association pathways, form artificial connections, or U-fiber ‘bridges’, between the pathways that can make the two tracts look like one larger tractThe difficulty that arises when studying the work of the Dejerines, like other 19th-century anatomists, relates to translating their definition of structures into the current school of thought. Inconsistent landmarks, nomenclatures, and methods were used to define and visualise structures. This discordance makes it difficult to reference a classic text and persists to the present day. Nevertheless, the congruency between the Dejerines’ dissection and modern imaging suggests that the other tracts they described should also be successfully visualised in vivo.In vivo and in vitro dissections of the calcarine fissure reveal a large continuous bundle of U-fibers, named the stratum calcarinum (SC), connecting the upper and lower edges of calcarine cortex Fig. . U-fiberThe SC system forms an atypical bundle as it consists of a long and deep layer underlying a short and more superficial layer. The superficial SC layer, as can be seen from the results Fig. , has sho46, postulated that the majority of the fibers labelled by the Dejerines, such as the SC, were actually terminal fibers of the optic radiation. Indeed, the Dejerines33 acknowledged that the histological staining method employed was insufficient to confidently evaluate the degree to which association fibers, like the SC, contribute to the projection fiber pathways that are situated along the ventricles. However, more recent studies, conducted with the improved Klingler’s technique, are congruent with the Dejerines’ description of the SC25. Unfortunately, to date, most mentions of the human SC, transverse fasciculus of the lingual lobule of Vialet, transverse fasciculus of the cuneus, and stratum proprium cunei in the literature have been in reference to historical dissections . The results show a bundle with a clear vertical projection that links the upper border of the anterior calcarine fissure to the medial aspect of the cuneus convexity. Like the stratum calcarinum, the SPC extends along the entire length of the calcarine fissure. It differs, however, by being limited to the cuneus. Schmahmann & Pandya24, speculated that the SPC bundle corresponds to fibers they identified in rhesus macaque, located in the superior parietal lobule and the dorsal occipital white matter, caudal to the dorsal component of the superior longitudinal fasciculus. The fibers connected the medial pre-occipital gyrus of the occipital lobe with the medial part of the superior parietal lobule. However, the SPC we observed does not extend past the parieto-occipital fissure and does not correspond with the observations of Schmahmann & Pandya24 who describe it as more anteriorly projecting compared to the system we have identified. The SPC shares a similar trajectory to the dorsal half of the stratum calcarinum and sledge runner fasciculus. This study specifically followed the Dejerines’ descriptions, which limits the SPC to the medial surface of the cuneus to differentiate the SPC from the stratum calcarinum and sledge runner fasciculus. In a postmortem dissection, Vergani et al.25 depict both the SPC and their discovery of the sledge runner fasciculus distinctively. Interestingly, another study examining the sledge runner fasciculus discusses its relation to the stratum calcarinum, but not the SPC. It is unclear as to whether the authors have interpreted the SPC as forming part of the sledge runner fasciculus62. Due to the limited literature on the SPC, it is not clear to what extent diffusion tractography’s limitations have affected the reconstruction.The SPC is a short and seemingly inconsequential tract that rises in the sagittal plane from the calcarine fissure at the medial border of the hemisphere Fig. . Since t44. The Dejerines were able to successfully reproduce the observations made by Vialet in their own dissection studies. Our study succeeded in reconstructing in several individual subjects a putative TFV bundle . However, Schmahmann & Pandya24 had made a similar comment in relation to the vertical occipital fasciculus and had interpreted it as part of the vertical component of the inferior longitudinal fasciculus23, which was later disputed by more focused tractography studies. Vergani et al.25, conducted a thorough postmortem exploration of the intralobar fibers of the occipital lobe, in an effort to replicate the work of Sachs34. Interestingly, like Sachs, the authors did not mention a tract that matches the morphology of the TFV as described later by Vialet, the Dejerines, and as identified in this study. A recently resurfaced photograph of a Weigert-stained histological slide of the macaque occipital lobe by von Bonin et al.63 clearly depicts the vertical occipital fasciculus and stratum calcarinum, and somewhat less clearly, the TFV and transverse fasciculus of the cuneus named the fasciculus transversus lingualis and fasciculus transversus cunei, respectively63. The brevity of the description makes it hard to ascertain in greater detail the course of the TFV in the macaque.The existence of the TFV, like the transverse fasciculus of the cuneus and vertical occipital fasciculus, as a distinct entity was heavily contested shortly after its discovery. This resulted in their omission from much of the literature, such as the neuroatlases of notable and influential neurologists like that of Constantin Von Monakow. Von Monakow described various subcortical structures with the locations and gross trajectories that match the TFV, transverse fasciculus of the cuneus and vertical occipital fasciculus, but was unable to differentiate them from neighbouring bundles and so negated their existence as distinct tractsAlthough identified in multiple subjects of this present study, limitations inherent to this study and past ones, puts into question the existence of the TFV and whether it is a misconstrued artifact formed in part by the optic radiations, or other such neighbouring pathways. Validation of the TFV will depend on future studies with higher resolution and varied methodology, and it remains putative until such a time.61. The Dejerines, with reference to Sachs’ work, described the TFC as having a trajectory that “runs slightly obliquely, anteriorly and laterally, and radiate[s] in the superior parietal lobule and in the angular gyrus” . It was specified by the Dejerines, Sachs and Vialet44 that the origin of the TFC is at the level of the calcarine fissure among the stratum calcarinum and stratum proprium cunei. This was more recently supported by Vergani et al., 2014,25 who conducted an in vitro dissection and identified segments of the TFC, which they labelled stratum transverse cunei. The cuneus is very compact with a high density of white matter fibers crossing it. Therefore, there are a large amount of fibers with an antero-posterior trajectory, crossing paths with the thinner TFC, either perpendicular or parallel to it, disrupting the fiber orientation. Indeed, a recent effort to follow the full trajectory of this bundle was unsuccessful25.Our study did not identify a consistent tract in either hemisphere that matches any previous descriptions. Yet, the Dejerines remarked that the calcarine cortex is attached to the cuneus and first occipital convolution through both the stratum proprium cunei and TFC and this observation of the TFC was also made by previous works46. It follows that if the transverse fasciculus of Vialet exists to connect the areas of the cortex involved in the superior visual fields with distal cortical regions, a similar subcortical system would need to be in place for the inferior visual fields.The transverse fasciculus of the lingual lobule of Vialet and TFC are described by the Dejerines as having opposing origins along the calcarine fissures and mirroring trajectories. This implies the possibility of complementary functions related to the upper and lower quadrants of the visual field, and integration of visual stimuli to the accessory visual integration area and the rest of the cerebrum25. The tract was initially named the ‘sledge-runner fasciculus’ to highlight its undulating shape due to its anteriorly projecting curve at the level of the calcarine fissure25. Later, in a focused tractography study, the SRF was alternatively named as the Medial Occipital Longitudinal Tract (MOLT) to better reflect its anatomy64. We continue to use the term SRF as it is the more widely known term. The SRF is a thin tract that lies within the medial aspect of the anterior calcarine fissure relaying the anterior border of the dorsal occipital lobe to the antero-superior aspect of the lingual gyrus  based virtual reconstruction of the Dejerines’ dissection in healthy subjects.Anatomie Centre Nerveux; Volume I (1895) was fully translated (MB) from its original 19th-century French to more universally accessible English and reviewed for its accuracy by the experts in this field . The complete translation is available as a The masterful description of intraoccipital fiber tracts in Chapter 5: pp. 780–784 by J.J. Dejerine and A. Dejerine-Klumpke in https://db.humanconnectome.org/). To ensure data homogeneity, the subjects selected had none of the following features/criteria: endocrine abnormalities including hyper and hypothyroidism, a handedness score below zero (people with a left-handed tendency), color vision abnormalities, illegal drug use, history of psychiatric problems, hypertensive individuals, alcohol detected by a breathalyser, data with quality control (QC) issues A or B. This study uses data collected and processed by the HCP and approved by the Washington University IRB. The additional data analysis conducted in this present study was approved by the local ethics committee of the University of Malta.A template-based, probabilistic, fiber tractography study was conducted in 24 healthy and unrelated consenting volunteers . The analysed diffusion MRI dataset was derived from the S1200 release of the publicly available WU-Minn Human Connectome Project (HCP) database  of the human brains through a customised high-resolution 3-Tesla Siemens Skyra scanner equipped with a 32-channel head coil. Structural imaging utilised an axial 3D MPRAGE pulse sequence, while the dMRI used a monopolar Sejskal-Tanner sequence79. Following the algorithm in ref. 80 DICOM image files were defaced and deidentified. For further data analysis, dcm2nii MRIcron was used to convert DICOM files to nifti81 (http://www.nitrc.org/projects/mricron).The full details of image acquisition can be found in the following articles86.Diffusion data were rectified for head motion and geometrical distortion, and preprocessed through the HCP minimally processed pipeline88. The fiber orientation distribution (FOD) functions from the diffusion signal in each voxel were computed using the multi-shell-multi-tissue CSD.All additional processing was accomplished with the fiber tractography MRtrix3 (RC_3) software toolkit and iFOD2 algorithmhttps://osf.io/5v92x/. The connectome derived from 10 million randomly seeded fibers from within it 90. Fibers traversing beyond the occipital lobe were manually assessed. Inclusion and exclusion masks are available through the osf site. Each ROI is titled in a way that reflects the order in which it was applied with a number, the name of tract it is identifying, and in which hemisphere. The first ROI selected was always an inclusion ROI to reduce the bulk of the tract and narrow it around an anatomical landmark as described in the work of the Dejerines. Within the convention of the MRtrix3, inclusion ROIs retain any tracts passing through the MRI mask regardless of their origin and termination. Inclusion ROIs were generally followed by exclusions to remove spurious fibers.The individual FODs across the 24 subjects were used to create a population template within MRtrix3. A manually defined occipital lobe mask on the template was then used to produce occipital lobe specific connectomes. The safety margins between the occipital lobe and the exclusion border were large and included posterior aspects of the temporal and parietal lobe. The mask excluded the brainstem, the cerebellum. The anterior border of the mask was defined by a coronal line at the anterior aspect of the splenium of the corpus callosum that extended straight to the lateral convexity of the cerebrum. Figures of the mask are provided in Following template space dissections, the process was repeated in all 24 individual subjects where all masks and ROIs defined in template space were warped into native space (with linear interpolation followed by a binarization with no thresholding to overestimate the native regions).Further information on research design is available in the Supplementary InformationReporting Summary


Background: Macrosomic birth weight has been implicated as a significant risk factor for developing various adult metabolic diseases such as diabetes mellitus and coronary heart diseases; it has also been associated with higher incidences of complicated births. This study aimed to examine the predictability of macrosomic births in hyperglycemic pregnant women using maternal clinical characteristics and serum biomarkers of aneuploidy screening performed in the first half of pregnancy.Methods: A retrospective observational study was performed on a cohort of 1,668 pregnant women who 1) had positive outcomes after undergoing 50-g oral glucose challenge test (OGCT) at two university-based hospitals and 2) underwent any one of the following maternal biomarker screening tests for fetal aneuploidy: triple test, quadruple test, and integrated test. Logistic regression-based models for predicting macrosomic births using maternal characteristics and serum biomarkers were developed and evaluated for prediction power. A nomogram, which is a graphical display of the best predictable model, was then generated.Results: The study cohort included 157 macrosomic birth cases defined as birth weight ≥3,820 g, which was equivalent to the top 10 percentile of the modeling cohort. Three primary models solely based on serum biomarkers achieved area under curves (AUCs) of 0.55-0.62. Expanded models, including maternal demographic and clinical factors, demonstrated an improved performance by 25% .Conclusion: Our prediction models will help to identify pregnancies with an elevated risk of macrosomic births in hyperglycemic mothers using maternal clinical factors and serum markers from routine antenatal screening tests. Prediction of macrosomic birth at mid-pregnancy may allow customized antenatal care to reduce the risk of macrosomic births. The prevalence of gestational diabetes mellitus (GDM) is steadily increasing worldwide A typical pregnancy is physiologically characterized by weight gain and insulin resistance, with 50%-70% decreased insulin sensitivity in pregnant women compared with that in non-pregnant women th percentile Predicting birth weight is an obstetrically important but difficult challenge. A reference birth weight curve has been constructed based on birth weights per gestational age (GA) Some studies have reported the potential usability of maternal biomarkers from fetal aneuploidy screening tests in predicting adverse pregnancy outcomes Therefore, we investigated the first- and second-trimester maternal biomarkers for fetal aneuploidy as well as the maternal clinical factors for their predictability of macrosomic birth hyperglycemic pregnant women. For clinical application, we used a combination of fetal and maternal data available at two antenatal visits and developed a graphical display of the best predictable model of macrosomic births.This study was a retrospective observational study. The data were obtained from pregnant women who delivered between July 1, 2007 and December 31, 2015 at two university-based hospitals in Korea, Kangnam CHA Medical Centre and Ewha Womans University Mokdong Hospital. The participants were pregnant women who had positive outcomes of 1-hour 50-g OGCT, which is equivalent to a glucose level >140 mg/dL at around 24-28 weeks' gestation. Participants were excluded if they were missing any of the early pregnancy aneuploidy screening test results and had twin pregnancy, fetal anomaly, hypertensive disorder before pregnancy, pre-existing diabetes, and missing pre-pregnancy or delivery weights. GDM was defined as two or more positive results in a 3-hour 100-g oral glucose tolerance test (OGTT): fasting ≥95 mg/dL, 1 hour ≥180 mg/dL, 2 hours ≥155 mg/dL, and 3 hours ≥140 mg/dL, or one or more positive results in a 2-hour 75-g oral glucose tolerance test (OGTT): fasting ≥92 mg/dL, 1 hour ≥180 mg/dL, and 2 hours ≥153 mg/dL. Based on the delivery date, the eligible subjects were divided into two groups: training set  and testing set .All participants underwent either of the maternal biomarker screening tests for fetal aneuploidy: triple test, quadruple test, or integrated test, comprising of pregnancy-associated plasma protein-A (PAPP-A), alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and inhibin A. Biochemical indices at sampling were adjusted for maternal weight and GA and reported as multiple of the median (MoM) values of these parameters. Study participants' demographic characteristics and risk factors, including age, pre-pregnancy BMI, parity, systolic/diastolic blood pressure (SBP/DBP), glucose, and lipid levels were obtained during their clinic visit for 50-g OGTT. GA in days was measured from the first day of the last menstrual period. If uncertain or the last menstrual period was unknown, GA was determined using sonography.Typical macrosomia is defined as a birth weight of ≥4,000 g Binary logistic regression analysis was performed to analyze the effects of each potential predictor of macrosomic birth. For constructing best-fit prediction models, multivariable binary logistic regression analysis was performed using a backward stepwise procedure as a variable selection method to minimize Akaike information criterion. Three primary models were constructed using sets of biomarkers , routine prenatal triple, quadruple, and integrated screen tests. The primary models were expanded with significant demographic and clinical factors from the univariate analysis.The discrimination power and calibration power of the constructed models were estimated using area under the curve (AUC) and Hosmer-Lemeshow test, respectively. For internal validation, leave-one-out cross-validation was performed to estimate the reliability of the constructed model. Receiver operating characteristic (ROC) curve analysis was performed to analyze potential variables to predict macrosomic birth. The cut-off values were selected to maximize the sum of sensitivity and specificity, which were used to transform potential variables to binary predictors. The prediction performance was compared among the constructed models using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses. For the practical application of the prediction model in clinical settings, we also developed a nomogram, which is a graphical display of the best performing model for the prediction of macrosomic births.N (%). Chi-square test or Fisher's exact test was performed using a contingency table to assess the association between macrosomic birth and other categorical variables as appropriate.R language version 3.3.3 , T&F program ver. 2.9 , and IBM SPSS Statistics for Windows, Version 22  were used for all statistical analyses and prediction modeling. Data are expressed as mean ± standard deviation for continuous variables. When variables were normally distributed, we performed a mean difference test between two-sample groups defined by macrosomia using a Student's t-test or Welch's t-test as appropriate. For non-normally-distributed variables, the Mann-Whitney U test was used. For categorical variables, data are expressed as simple number and percentage, The Institutional Review Boards of CHA Kangnam Medical Centre (IRB No: KNC 10-025) and Ewha Womans University Mokdong Hospital (IRB No: 2020-01-012) approved the protocol of this study.th percentile  and macrosomic birth with a birth weight ≥90th percentile.Figure 2) than in the normal group (21.02 ± 2.89 kg/m2). Obesity was also significantly associated with macrosomic birth, with approximately three times more obese subjects in the macrosomic birth group (25.5%) than in the normal group (9.0%). The levels of biomarkers  and apart from weight gain, other clinical factors  were not significantly different between the two groups until they underwent 50-g OGCT. GDM was significantly associated with macrosomic birth (P=0.039). The demographic and clinical characteristics of the subjects used for model performance evaluation are available in Table Variables were selected as potential predictors in building macrosomic birth predictive models  and S3: The models were evaluated for their prediction performance on a testing set, consisting of 328 normal birth and 47 macrosomic birth cases. Three primary models, which were constructed using sets of biomarkers , achieved marginally significant discrimination ability . The M3 P-value = 0.249). Although the overall AUC difference was not significant, the addition of serum markers significantly improved the sensitivity and specificity of our integrative model (M3-E). Both NRI and IDI demonstrated that M3-E significantly improved specificity and sensitivity compared to M-Env . This suggests that the model developed using relatively old data (2007-2009) would still be valid for applying to more recent data.The prediction performance of our model is comparable to others' models. One study used maternal serum markers of the 11-14 week screening and sonogram-based fetal size measurement to predict LGA cases th percentile of hyperglycemic mothers) compared with other studies . A cohort-specific cut-off was used in this study because different levels of metabolic risks are observed at the same BMI across different ethnic groups Pregnancies often result in adverse outcomes, and it is crucial to identify pregnancies at an elevated risk of developing adverse outcomes as early as possible. We previously reported that uE3, one of the pregnancy blood biomarkers, was highly associated with the development of GDM but not with macrosomia in a cohort from Korea Although no direct association was noted between macrosomia and uE3 level, a recent study of Chinese women reported significantly lower uE3 and AFP levels in women with GDM than in women without pregnancy-related complications; there was also a significantly over-represented proportion of macrosomia (14.29% of the GDM group) and LGA (25.82% of the GDM group) One possible mechanism is the decreased insulin sensitivities in pregnant women, which would contribute to the development of GDM There are multiple strengths in our study and the developed models. Our models primarily rely on biomarkers collected during routine aneuploidy tests; thus, there is no need to perform any additional tests. Other clinical factors used in the models are also routinely obtained during typical prenatal evaluations. Additionally, the nomograms developed in this study will allow the early estimation of macrosomic births by clinicians and consequently provide early interventions.n=1,468 with approximately 10% cases of macrosomic births), requiring caution in interpreting the results. However, recent studies have shown significant increases in obesity and GDM, but no statistically significant increases in the incidence of macrosomia and LGA have been observed in longitudinal studies This study had a few limitations. First, the study cohort was obtained from two hospitals between 2007 and 2015 in Korea; therefore, there could be a selection bias that may not represent all pregnant women. The study cohort is relatively small, and the data used were not nationwide (In conclusion, our prediction models of macrosomic birth may help to identify a substantial proportion of hyperglycemic mothers with a high risk of developing macrosomic birth using early second-trimester routine screening biomarkers for chromosomal aneuploidy without requiring additional tests. Although our models cannot completely predict macrosomic births, the models and our nomograms may be useful for customizing antenatal care to reduce the risk of developing macrosomic births.Supplementary figure and tables.Click here for additional data file.


More than one third of the neonatal deaths at Neonatal Intensive Care Unit of Debre Tabor General Hospital (DTGH) are attributable to birth asphyxia. Most of these neonates are referred from maternity ward of the hospital. However, there is no recent evidence on the prevalence and specific determinants of birth asphyxia at DTGH. Besides, public health importance of factors like birth spacing weren't addressed in the prior studies.A cross sectional study was conducted on a sample of 240 newborns at delivery ward. The collected data were cleaned, coded and entered into Epi -data version 4.2 and exported to Stata version 14. Binary logistic regression model was considered and statistical significance was declared at P< 0.05 using adjusted odds ratio.The prevalence of asphyxia neonatorum was 6.7 % based on the fifth minute APGAR score. From multi-variable logistic regression analysis, antenatal obstetric complications , fetal malpresentation , premature rupture of fetal membranes  and meconium stained amniotic fluid  were significant predictors.The prevalence of fifth minute asphyxia neonatorum was relatively low. Fortunately, its predictors are modifiable. Thus, we can mitigate the problem even with our limited resources such as enhancing the existing efforts of antenatal and intra-partum care, which could help early detection and management of any obstetric and neonatal health abnormality.” Severe degrees of birth asphyxia can cause severe neonatal multiorgan damage resulting in brain damage, lung dysfunction, cardiomyopathy, renal failure, hepatic failure and necrotizing enterocolitis Asphyxia neonatorum can be caused by factors related to the antepartum, intra partum or post partum periodThe Ethiopian neonatal mortality rate (NMR) is 29/1000 live births whilst Amhara region, a region of our study area, comprises the highest burden of the national NMR (47/1000 live births) A significant number of neonatal deaths (33.3%) at Neonatal Intensive Care Unit (NICU) of Debre Tabor General Hospital (DTGH) are attributable to birth asphyxia. Most of these neonates are referred from maternity ward of the hospital. However, there is no recent evidence on the proportion and specific determinants of birth asphyxia at DTGH A hospital-based quantitative cross sectional study was conducted from January first to April first 2019 at delivery ward of Debre Tabor General Hospital. The hospital is located in Debre Tabor town, 666 km far from Addis Ababa. It serves about 3,840 deliveries annuallyMothers who gave live birth after 28 weeks of gestational age were screened for eligibility. Newborns of unknown gestational age at birth were excluded. Furthermore, newborns with malformations incompatible to life such as hydrops and cyanotic congenital heart defects were excluded as these newborns have already been predisposed for asphyxia.A total sample of 240 mother-newborn dyads was obtained using single population proportion formula; considering a confidence level of 95%, marginal error of 5%, a reasonable estimate for the proportion of asphyxia neonatorum from a previous study (p=0.829) 38 and adding a none response rate of 10%. The average monthly delivery rate of DTGH was 320 as per DTGH'S last quarter report of 2018. Then, to ensure representativeness of the calculated sample size (n=240), every fourth eligible mother newborn dyad was selected over 3 months at maternity ward of DTGH.A pretested interviewer based questionnaire was used to collect primary data on maternal socio-demographic and ante partum related factors. For twin births, every mother was asked only once about socio-demographic and antenatal factors of her twin babies because twin neonates share similar socio-demography and antenatal history. Furthermore, a pretested structured checklist was employed to abstract secondary data from maternal chart on intra-partum  and neonatal related factors . For twin births, every mother's chart was reviewed twice for the aforementioned intrapartum and neonatal related characteristics due to variation of these factors between twin neonates.Fifth minute APGAR score was collected from direct observation by six trained BSc graduating class midwifery students both during day and night shifts in the delivery ward and operation room, which we got it feasible. Apgar score was measured using five components , body pink but bluish extremities (1 point), totally blue or pale body (0 point)); , 100 (1 point), absent (0 point)); , grimacing (1 point), no response at all (0 point));, some flexion of extremities (1 point), flaccid or limp (0 point)) and , weak or irregular and < 30 breath/minute (1 point), absent or apnea (0 point). Then, the score of each component was summed up by the data collectors and the information was documented on an Apgar score card .The diagnosis of birth asphyxia was made based on fifth minute APGAR score.. The diagnoses of birth asphyxia were further confirmed through medical interns' consultation of obstetricians and pediatricians to deal with its severity and management.The questionnaire and checklist were adapted from Ethiopian and other African studies Birth asphyxia: A newborn was considered to have birth asphyxia when its fifth minute APGAR score was <7 Prolonged labor (second stage): For nulliparous mothers, if labor exceeds 3 hours with provision of regional anesthesia, or 2 hours without regional anesthesia. For multiparous mothers, if labor exceeds 2 hours with regional anesthesia or 1 hour in the absence of regional anesthesia. We have assessed this in numbers. The collected data were coded, cleaned, edited and double entered into epidata version 4.2 after which it was exported to STATA version 14. Frequencies, proportion, summary statistics and cross tabulation were used to describe the study population. Using binary logistic regression model, bivariable analysis was first carried out to identify candidate variables (P<0.25) for multivariable analysis. Then, multivariable logistic regression analysis was performed to investigate statistically significant predictors of asphyxia neonatorum by adjusting for possible confounders. Finally, variables (P<0.05) were reported as statistically significant using AOR with 95% CI.In this study, the overall 240 respondents were involved thereby making a response rate of 100%. More than half of the respondents, 145 (60.4%) were rural residents. Moreover, 221(92.9%) of the respondents were married and concerning their educational status, about one third of them (32.4%) were unable to read and write. The mean maternal age was 28.70 (SD=± 5.86) years of whom about three quarters, 185(77%) were in the age group of (>34 years). Nearly half of the mothers, 125 (52.5%) have less than two years of birth spacing for the index newborn. Besides, about one quarter, 53 (22.1%) of the mothers had history of adverse pregnancy outcome of which prematurity 23(43.4%) accounted for the highest proportion .Nearly all the mothers, 233(95.8%) had attended antenatal care at public hospitals (59.7%) and public health center (40.3%). However, it was only about half of the mothers (52.6%) who had four and above antenatal care visits. About one tenth of the mothers (11.25%) ever used substance during their gestation of which ever alcohol users accounted for the most majority (70.4%). In the antenatal period, 87(36.3%) mothers were found to have obstetric complications. From these complications, preeclampsia/eclampsia accounted for the highest percentage (37.9%) followed by antepartum hemorrhage (23.0%), anemia (21.8%), infections (11.5%) and gestational diabetes (5.7%) .Of the total respondent mothers, 144 (60%) had spontaneous labor onset. Majority of the mothers 188(78.3%) had intrapartum rupture of fetal membranes whereas premature rupture of membrane was reported among 52 (21.7%) mothers. Following membrane rupture, meconium stained amniotic fluid was observed among 97 (40.4%) mothers and similar report was obtained to the presence of fetal distress 98 (40.8%). At labor, about one third of the fetuses 73(30.4%) were malpresented and nearly equal number of fetuses were delivered by cesarean section 71 (29.6%) .More than half of the newborns, 132 (55%) were males. There were 34 twin newborns. The mean gestational age at birth was 38.3 (±2.3) weeks and majority of the newborns (64.2%) were term. Moreover, the mean birth weight was 2674.3 (±1484.2) grams and about one third of the newborns 73(30.4%) had low birth weight. When birth weight was considered against the corresponding gestational age at birth, about one fifth of the total newborns 53(22.1%) had birth weight inappropriate for their gestational age at birth. Of those 53(22.1%) newborns with inappropriate birth weight for gestational age, 24 (10%) were small for their gestational age whereas the remaining 29 newborns (12.1%) had large birth weight for their corresponding gestational age .The prevalence of asphyxia neonatorum was found to be 16(6.7 %) . All casBesides, first minute APGAR score showed that 99 (41.3%) neonates had less than 7 APGAR score. Most of these neonates, 96 (40.0 %) hadThe bivariable logistic regression analysis showed that antenatal obstetric complications, fetal malpresentation, premature rupture of fetal membranes, meconium stained amniotic fluid, fetal distress, mode of delivery and birth spacing were crudely associated with asphyxia neonatorum. However, after statistical adjustments for the likely effects of confounding variables, only four of the aforementioned factors namely antenatal obstetric complications, fetal malpresentation, premature rupture of fetal membranes and meconium stained amniotic fluid, were significant predictors of asphyxia. In this study, the width interval for three of the adjusted point estimates  is somewhat wider, thereby indicating a relatively less precise measurement of these factors. However, the width interval for the CIs of these factors is less than 17, which is in the recommended gap as shown in The amendment to the original manuscript is included in the revised version manuscript as shown by the tracked insertions under the determinants of asphyxia neonatorum and limitation of the study on pages 9, 12 and 13.The likelihood of developing birth asphyxia among neonates born to mothers with antenatal obstetric complications was 2.63 times  more when compared to their counter-parts. Neonates born with fetal malpresentation had 3.17 times  more likelihood of being asphyxiated at birth as compared to those of vertex presentations. Neonates born to mothers with premature rupture of fetal membranes were 6.56 times  more prone to be asphyxiated at birth when compared to those with intrapartum rupture of membranes. Similarly, neonates born to mothers having meconium stained amniotic fluid were 2.73 times  as likely to have birth asphyxia as compared to those born without being meconium stained.Hypoxic-ischemic damage of neonatal vital organs mainly during the intrapartum period is the leading cause of mortality from asphyxia neonatorum. Thus, the quality of obstetric care at birth is crucial to reduce the overall newborn mortality and its long-term consequences “From this study, the prevalence of birth asphyxia was 6.7%, which was lower than a study in Iran (58.8%) In the analysis of associated factors, the likelihood of developing birth asphyxia among neonates born to mothers with antenatal obstetric complications was 2.6 times higher as compared to their counter-parts. Different prior Ethiopian studies 54Neonates born with fetal malpresentation were 3.2 times more likely of being asphyxiated as compared to those with vertex presentations. This finding was congruent with other Ethiopian studies Neonates born to mothers with premature rupture of fetal membranes were 6.6 times more prone to be asphyxiated at birth as compared to those with intrapartum rupture. A consistent finding was obtained from studies at Cameroon The risk of birth asphyxia among neonates with history of meconium stained amniotic fluid was 2.7 times higher than those born to mothers with clear amniotic fluid. This finding was consistent with other studies From bivariable analysis, it has been shown that neonates born to mothers with birth spacing of < 2 years were 1.89 times more likely to be asphyxiated as compared to those with ≥2 years of birth spacing. This may be due to the fact that narrow birth spacing (< 2 years) is a universal public health problem having association with adverse maternal, fetal and neonatal outcomes such as low birth weight The study lacks support of qualitative data. Moreover, the results may not be representative of the entire newborns in Ethiopia due to a small sample size consideration in this study. The study also shares drawbacks of a cross-sectional design.Despite the aforementioned findings, the results are limited to the diagnosis of birth asphyxia based on solely fifth minute APGAR score. However, to minimize its effect on the validity of our estimate about the prevalence of birth asphyxia, the data collectors underwent efforts of consulting senior professionals (midwives and Integrated Emergency surgery obstetricians) about the neonatal condition to confirm the diagnosis of asphyxia. The study also shares drawbacks of a cross-sectional design. Furthermore, the study lacks support of qualitative data.Compared to prior studies at other settings, the prevalence of asphyxia neonatorum in our study area was relatively low. Presence of antenatal obstetric complications, fetal malpresentation, premature rupture of fetal membranes and meconium stained amniotic fluid were significantly associated with increased odds of asphyxia neonatorum. Therefore, early antenatal screening and follow up of every mother should be given due strict emphasis for timely detection and management of any obstetric complication. Besides, mothers with fetal malpresentation should be given thorough partographic follow up of their labor to early detect any fetal abnormality for emergency actions. Mothers with PROM should be provided with prophylactic antibiotics to prevent feto-neonatal systemic infections. Besides, digital vaginal examinations of PROM mothers should be kept as minimal as possible to reduce the likelihood of chorioamnionitis. Appreciating meconium stained amniotic fluid during labor and/delivery should be regarded as a signal of birth asphyxia; hence, delivery care providers have to be ready to give immediate resuscitation for such neonates.