For those on phototherapy, duration and median irradiance were similar. F80 infants experienced reduced: feeding intolerance ; length of stay , maximum weight loss as % birth weight ; decrease in weight Z-score at 10 days . F80 infants regained birthweight earlier  and had no differences in adverse clinical outcomes. We speculate that earlier nutrient supplementation improved jaundice outcomes due to enhanced excretion/elimination of bilirubin.This study aimed to evaluate jaundice outcomes of low-birthweight premature infants commenced on earlier versus later nutrient supplementation . Demographics, feeding regimens, and clinical outcomes data were collected. Infant and maternal characteristics were similar. Earlier nutrient supplementation was associated with multiple improved jaundice outcomes: total (TSBR), unconjugated and conjugated (CSBR) serum bilirubin values (196 ± 46 vs. 228 ± 52, 184 ± 44 vs. 212 ± 50, 12 ± 4 vs. 16 ± 5, respectively, all  The basic etiology of neonatal hyperbilirubinemia is well understood. Neonatal jaundice results from an imbalance between bilirubin production soon after birth and elimination. Factors include: bilirubin formation from the breakdown of heme present in normal red blood cells; conjugation in the liver with glucuronic acid to form a water-soluble form; excretion in the bile ; some hyWhat is not so well understood, despite decades of research, are the influences contributing to hyperbilirubinemia—which, in the neonate, is a multifactorial process, associated with both biochemical and physiological immaturity. In the near term to term infant, risk factors for developing severe unconjugated hyperbilirubinemia include: haemolytic disease; gestational age 35–36 weeks; cephalohematoma; exclusive breastfeeding, particularly if nursing is problematic and weight loss significant; East Asian race; macrosomic infants of a diabetic mothers; male gender [An interrelationship between enteral feeding, the timing of feeds, nutrition and neonatal jaundice has long been recognised. In the 1960s, when 48 h fasting of newborn infants was common, studies showed that babies fed glucose in part saline or water at 4 h of life developed significantly less jaundice than fasting babies . During In our Special Care Nursery (SCN), we manage mostly moderate (32 to 34 weeks’ gestation) to late (34 to 36 weeks’ gestation), low birthweight preterm infants. Previously, we commenced the fortification of expressed breast milk (EBM) or preterm formula at a full enteral feed achievement of 160 mL/kg/day, before moving to a protocol of earlier fortification/preterm formula at 80 mL/kg/day. In a prospective, observational study, we investigated the nutritional requirements of moderate and late preterm infants—an area which has been little researched . We reviDuring the study, we found evidence to suggest a benefit of earlier nutrient supplementation at 80 mL/kg/day on jaundice outcomes—however, due to small sample size, our results did not achieve significance .The aim of this study is to explore the link between an earlier commencement of fortification of enteral feeds and the evaluation of a possible improvement in jaundice outcomes. We hoped to achieve this by retrospectively examining the records of a sufficiently large cohort of infants during the period when the earlier protocol of commencing fortification at 160 mL/kg/day was in place, with a similar sized cohort following the protocol change that commenced fortification at 80 mL/kg/day.This study’s participants were moderately preterm and late preterm LBW neonates admitted to the SCN between January 2012 to December 2018 at The Northern Hospital (TNH) in Epping, an outer suburb of Melbourne, Australia. The catchment area for TNH is a lower-socioeconomic, multicultural, multi-ethnic community with associated concerns such as obesity. We performed a retrospective chart review. Assignment into F80 or F160 groups was done on the basis of chronology. Before 2016, our feeding protocol introduced breastmilk fortification once full enteral feeds had been achieved (160 mL/kg/day). Following this date, we changed our protocol to commence fortification at 80 mL/kg/day. No other changes were made to the protocol. Otherwise, the management of F80 and F160 infants was identical.Inclusion criteria were: birthweight less than 2500 g; gestational age 31 weeks to late preterm; tolerating a total enteral fluid intake of less than 80 mL/kg/day. Infants with gastrointestinal malformations or recognized chromosomal abnormalities were excluded. Infants who did not strictly fit into the commencement criteria of 80 or 160 mL/kg/day enteral fluid intake were also excluded. Ethics approval was provided through the Northern Health Human Research Ethics Committee. (ALR No: ALR 52.2018).Maternal baseline data collected include age, gravity and para, region of birth based on United Nations country grouping, and primary language spoken at home. Maternal clinical data collected include antenatal complications such as gestational diabetes, preeclampsia, and Group B Streptococcus screening result.Baseline data collected on neonates include gestational age, sex, reason for prematurity, mode of delivery, 5-min APGAR score, and birthweight. Data on feeding regimens collected included: day of life at first enteral feed; total fluid intake at first enteral feed; total fluid intake at commencement of enteral supplementation; day of life at commencement of enteral supplementation. F80 neonates were defined as those that were commenced on human milk fortifier (or preterm formula if EBM was unavailable) at total fluid intake of 80 mL/kg/day, while F160 were defined as those that commenced on human milk fortifier (or preterm formula) at total fluid intake of 160 mL/kg/day.The primary outcome was related to hyperbilirubinemia and included: need for phototherapy; maximum number of phototherapy lights required; highest recorded bilirubin value; number of days that phototherapy was required. Anthropometric outcomes included maximum weight loss, days to regain birth weight, and discharge weight. Z-scores were calculated for birthweight, lowest weight post birth and discharge weight using the 2013 Fenton growth charts . AdverseThe use of 2013 Fenton growth charts in this study requires an explanation. Fenton growth charts are based on intrauterine data as opposed to birthweight data used for the more recently developed and internationally widely accepted Intergrowth-21st growth charts. The issue of which type of growth chart is most appropriate has become controversial. While for extremely low birth weight infants, Intergrowth 21st Project growth standards have been shown to be superior to Fenton Growth Charts . Of partDue to a policy of actively promoting and supporting breastfeeding, the majority of premature babies in our SCN are fed breastmilk. All study infants commenced feeding from day 1 at an enteral volume of 60 mL/kg and increased by 20 mL/kg daily as tolerated. The fortification/supplementation regime was standard and straightforward. Human milk fortifier  was introduced into expressed breastmilk (EBM) or preterm formula was commenced if EBM was not available  or S26 low birth weight Formula . FM85 was given at the recommended concentration of 1 g per 20 mL of EBM which boosted the protein content of EBM by 1 g of protein per 100 mL. Preterm formula provided a protein content of 2.9 g/100 mL. Prior to 2016, such fortification was commenced at an enteral volume achievement of 160 mL/kg/day (F160 group). Post 2016, due to a policy change, fortification was commenced once enteral volumes had reached 80 mL/kg/day (F80 group). Fortification or preterm formula was given to all babies up to a weight of 2500 g. Thereafter, cessation was at the discretion of the neonatal consultant and, based on such issues as appropriate weight gaining, extent of feeding intolerance and SGA .p-value. Continuous variables were analysed using the student’s t-test or the Mann—Whitney test where appropriate. A p value of <0.05 was considered significant. Statistical analyses were performed using either SPSS  or NCSS 12 statistical programme . NCSS, LLC. Kaysville, Utah, USA)Results were compared between F80 and F160 infants and differences in categorical variables were assessed using the Chi-square test or Fisher’s exact test where appropriate. Normality for continuous variables was assessed using the Shapiro-Wilk test, with Assuming an 8% change (as indicated from the raw data of our previous study ) in the A total of 215 babies were included in this study, 105 in the F80 group and 110 the F160 group. Infant gestational age ranged from 31 to 36 weeks. Between the F80 group and F160 group, there were no significant differences in birth weight, birth weight Z-scores, APGAR score at 5 min, reason for prematurity and mode of delivery see .Maternal age ranged from 16 to 44 years of age. Approximately half the mothers were born in Australia and New Zealand, with South Asia as the next largest place of maternal birth. English was the predominant language spoken at home. There were no significant differences in maternal characteristics between F80 and F160 groups see .The F80 group experienced less maximum weight loss as a percentage of birth weight compared to the F160 group. Infants commenced on earlier enteral supplementation regained birth weight before infants commenced on later enteral supplementation. Weight gain at 10 days as measured by change in Z-score from birthweight showed a significantly lower decrease in weight percentiles for F80 infants compared to F160 infants see .Multiple positive jaundice outcomes were associated with earlier supplementation of fortified breastmilk or preterm formula. For the F80 group compared with the F160 group, these outcomes significantly included lower total serum bilirubin (TSBR), unconjugated bilirubin (USBR) and conjugated bilirubin (CSBR): less infants below a phototherapy recommended cut off value for LBW infants at 36 weeks gestation of TSBR 250 µmol/L ; fewer iFeeding intolerance was lower for the F80 group. Length of stay (LOS) was significantly shorter for F80 infants than F160 infants. There were no differences in the frequencies of presumed sepsis, hypoglycaemia and respiratory distress syndrome. There was no occurrence of NEC see .As a consequence of changing our feeding protocol to an earlier commencement of fortification (at 80 mL/kg/day rather than 160 mL/kg/day), infants began supplementation of their feeds almost 5 days earlier—on average before day 3. The key finding of our study is that earlier nutrient supplementation of predominantly breastmilk fed babies (mainly by fortification) was associated with multiple beneficial jaundice outcomes such as lower TSBR, USBR and CSBR and lower phototherapy rates and consequently less exposure irradiation. As we have previously reported in some detail , althougIt could be argued that these outcomes are not surprising when viewed against the changes to infant feeding regimes that have occurred over the last half century. One reason for the abandonment of the customary 48 h fasting of newborns in the 1960s was the realization that early hypocaloric feeding, such as glucose, reduced hyperbilirubinemia . This isThere is evidence to suggest that the expression of extrahepatic UDP-glucuronosyltransferase 1A1 (UGT1A1), may play such a role. UGT1A1 is solely responsible for bilirubin conjugation and had been thought to be only present in the liver . In the At a basic level, neonatal jaundice can be thought of as an imbalance in the production and elimination of bilirubin . The proOral glucose has been shown to be an effective inducer of intestinal UGT1A1 without affecting liver UGT1A1 induction and has been suggested as a convenient way to treat neonatal jaundice while continuing the benefits of breastfeeding . The forZinc is another constituent of nutrient supplement that has been demonstrated to improve bilirubin elimination. A recent randomized, double blind trial demonstrated that neonates between 31 and 36 weeks gestation requiring phototherapy, had significantly reduced jaundice within 48 h of receiving oral zinc . These fAnother possible excretion mechanism for bilirubin is bacterial conversion. In adults, bilirubin excreted into the intestinal lumen is very efficiently converted to urobilinogen in the faeces—a natural detoxifying mechanism which aids elimination . In our Some recent studies have associated vitamin D deficiency in neonates with hyperbilirubinemia. TSBR significantly declined in vitamin D treated infants on phototherapy compared to those on phototherapy alone . NeonateWhile the focus of this paper has been on the apparent benefits to jaundice outcomes due to earlier nutrient supplementation resulting from a change in our feeding protocol that commenced supplementation at 80 mL/kg/day rather than 160 mL/kg/day, there were other clear benefits. F80 infants regained birth weight earlier, weight Z-scores were better at 10 days, the incidence of feeding intolerance was less, and LOS was almost 3 days shorter with important cost saving implication for the hospital. There was no difference in discharge weights between either group. This finding is consistent with findings that while phototherapy itself may result in a temporary weight reduction, catch up growth occurs with eventually no weight difference to infants not exposed to irradiation . The redA key limitation of this study is that being retrospective in nature, it has inferior evidence when compared to a prospective study. The convenience sampling inherent in this type of retrospective study may have led to selection bias. Of particular note is the concern of temporal relationships. This study stretched over a 6-year period, yet only a total of 215 infants were included in the study. The reason for this was the strict adherence to the criteria of only including infants commenced on fortification at 80 or 160 mL/kg/day—infants who commenced fortification at any other volume, eg 70 or 150 mL/kg/day were excluded. While this strict selection criteria improved the reliability of outcomes , it lenAnother potential limitation, as discussed in Methods, is that this study used Fenton 2013 growth charts to classify infants as SGA and to determine weight Z-scores. While this allowed a direct comparison with our previous study  and intrOur study has shown that a feeding protocol change that commenced nutrient supplementation at half enteral feed volumes (80 mL/kg/day) compared to full enteral feed volumes (160 mL/kg/day), resulted in predominately breastmilk fed infants commencing supplementation around 5 days earlier. This earlier supplementation was associated with significant clinically important benefits in reducing neonatal jaundice such as lowered levels of hyperbilirubinemia and a reduction in the frequency and extent of phototherapy. There were also additional benefits such as improved growth outcomes, reduced feeding intolerance and an almost 3-day reduction in LOS. We speculate that the improved jaundice outcomes are not related to any change in the dynamics of bilirubin liver production and conjugation, but due to mechanisms promoting more efficient elimination. The earlier nutrient supplementation occurred well before peak jaundice occurred, allowing time for fortification components to induce intestinal UGT1A1 (opposing the effects of β-glucuronidase) as well as promoting bowel motions—thus enhancing bilirubin excretion and elimination and reducing the enterohepatic recirculation of bilirubin.


The American College of Gynecology (ACOG) recommendation does not limit air travel during pregnancy, yet the evidence for air travel effect on adverse pregnancy outcomes is limited and debatable. Study objectives were to examine the association between air travel during pregnancy and preterm birth together with decreased birth weight.A retrospective cohort study.The study evaluated 628,292 women who gave birth to singleton infants from 9/2000 to 9/2016 and classified them into “air travel during pregnancy” or not, based on flight insurance as proxy. Multiple linear regression models were utilized to examine the relationship between air travel during pregnancy and newborn's gestational age and birth weight, while accounting for socioeconomic status, diabetes, high-risk pregnancies, and smoking.A total of 41,677 (6.6%) births of women who air traveled during pregnancy was included, and 586,615 (93.4%) births of women who did not. Air travel during pregnancy was associated with a statistically significant (p<0.0001) but negligible increase in birth weight (9 gr. 95% CI: 4.8 to 14.5 gr.) and gestational age (0.36 days. 95% CI: 0.24–0.48).The study results provide no evidence that air travel during pregnancy is related to adverse effects on gestational age or birth weight. These findings corroborate the current recommendations of ACOG. Worldwide, air travel has grown steadily over the years with the number of travelers mounting from one billion in 1990 to four billion in 2017[The notion that air travel may affect the course of pregnancy is based on environmental changes during the flight. In an average commercial flight at about 35,000 ft, the cabin pressure decreases from atmospheric pressure of 760 mmHg to about 560 mmHg. Consequently, oxygen saturation drops, during both long and short flights in all age groups, to a mean saturation of 90–93% in a healthy population and as low as 80% in patients with cardiopulmonary diseases,3. FibriDespite the plausible impact of environmental and physiological changes during a flight on pregnancy, and consequently on adverse pregnancy outcomes such as preterm delivery or low birth weight, data regarding this issue are scarce and controversial. A few studies found a significantly increased risk of preterm birth ,7 and loDespite the inconclusive literature, the American College of Obstetricians and Gynecologists’ (ACOG) stated in their last update, that in the absence of obstetric or medical complications, air travel is safe . This reThis study was conducted using the computerized data of Maccabi healthcare services, a 2.3 million patient integrated care organization in Israel, which covers 22–25% of the pregnant population in Israel. The stuMaccabi healthcare services’ female members, who gave birth during the study observation period—2000 through 2016, were eligible for analysis. Stillbirths, births under gestational age of 24 weeks and women who had multiple gestations were excluded, leaving 717,551 women who met eligibility criteria. Out of those, 89,259 (12.4%) were excluded due to, missing data on gestational age or birth weight, leaving 628,292 observations in the final cohort. Approximately 97% of the 20.1 million air travels per year in Israel are international. The traAdverse pregnancy outcomes, including low birth weight and low gestational age at birth, were the primary outcomes of interest. These variables were analyzed as continuous variables and also as binary variables . Data regarding date of birth, gestational week at birth and birth-weight were extracted from the Maccabi healthcare services database since this information is routinely provided to Maccabi healthcare services by the Israeli Ministry of Health.“High-risk” pregnancies were identified through “Maccabi healthcare services” computer database of women diagnosed as "high-risk” pregnancy. Women with “high-risk" pregnancies are diagnosed in ‘Maccabi Healthcare Services’ computerized database if the pregnancy threatens the health or life of the mother or her fetus. This includes women with existing health conditions, such as high blood pressure, diabetes, kidney diseases; or a history of recurrent pregnancy loss[ancy loss, pretermancy loss. The pov and preterm birth (under 37 weeks), as binary dependent variables, were also examined and analyzed by logistic regression  procedure .The threshold for statistical significance was .A total of 628,292 live births was included in the study. Among the study population, 6.6% air traveled during pregnancy. Compared to unexposed pregnancies, women who did air travel during pregnancy were older (31.8±4.8years vs. 30.1±5.4 years) and of higher SES level (7.1±1.7 vs. 5.8 ±2.0). Furthermore, women who air traveled had higher prevalence of high-risk pregnancies (10.5% vs. 7.6%) gestational diabetes mellitus (GDM) (7.7% vs. 6.3%) and fertility treatments (including IVF) (8.8% vs. 5.8%) than the unexposed group, but lower rates of smoking during pregnancy (4.4% vs. 5.9%)  and weight at birth  (see Table A in S1 Appendix).During the study period, the proportion of women who air traveled during pregnancy has increased between the years 2000 and 2014, particularly among higher SES groups (Table 2). Similarly, in the multivariable model for gestational age at birth, air travel during pregnancy was associated with a minimal increase of 0.36 days . The most significant association was calculated for high-risk pregnancies, with a decrease of more than eight days. All other variables decreased the gestational age differently (Table 3).In a multivariable model for weight at birth, air travel during pregnancy was associated with a statistically significant yet clinically neglectable increase of 9 grams . Maternal gestational diabetes mellitus and siblings were associated with increased birth weight as well, while a negative association was calculated for high-risk pregnancies, pre-eclampsia, smoking, and fertility treatments (Tables B-E in S1 Appendix).Additionally, frequency of air travels per pregnancy, timing of the flight during pregnancy , analysis for preterm birth (under 37 weeks) and low birth weight  as dependent categorial variables, and analysis of which we removed the effect of "exposure time" on pregnancy outcomes were examined by multivariable models. All analyses have shown similar results  the sample size, which is, to the best of our knowledge, the largest ever used, (2) the accurate information obtained on many risk factors that may affect gestational age and birth weight, which provided the ability to conduct appropriate statistical analysis, (3) the consistency of the results when analyses were stratified for gestational age at birth, frequency of air travel, or timing of the flight during pregnancy, (4) some of this study’s results reinforce its reliability, by demonstrating well known negative effects on gestational age and birth weight of high-risk pregnancies, pre-eclampsia, smoking during pregnancy and fertility treatments and positive effect on weight at birth in women with GDM –23.Although this study was conducted on a large and diverse database, unfortunately not all the essential information was available. For example, information about destinations and flight length. However, according to the Ben Gurion annual report, the vasGiven the raise of pregnant women air travelling, and the various factors that may adversely affect birth outcomes during flights Click here for additional data file.


Our results suggest that changes in human milk composition are associated with interactions between maternal and infant characteristics and pathophysiological factors. Future work should expand on these findings and further explore the link between hormonal profiles in human milk and infant outcomes.While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study  were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin ( Biologically active compounds in human milk (HM) include different classes of hormones, such as growth  and satiHormones mediating metabolic function and growth are of particular importance in HM, as they influence a range of infant growth and developmental outcomes. Insulin-like growth factor 1 (IGF-1) is a key mediator of growth hormone action and the most important growth factor in the infant . HoweverAs both maternal and infant characteristics, particularly maternal metabolic status before and during pregnancy and infant sex, appear to be associated with HM composition, we hypothesised that interactions between the two influence HM composition, conferring a specific profile to each milk sample. Thus, we investigated the contribution of maternal factors before and during pregnancy and infant characteristics at birth with the hormonal composition of mature HM.The present study is based on data and HM samples from 501 mothers and 507 children participating in a Finnish longitudinal cohort, Steps to healthy development of Children (the STEPS Study), which has previously been described in detail . Briefly2, normal weight 18.5–24.9 kg/m2, overweight 25–29.9 kg/m2, obese >29.9 kg/m2). Information regarding GDM (diagnosis based on the ICD-10-CM Codes O24), infant sex, birth weight and length were obtained from the Longitudinal Census Files. Birth weight Z scores were calculated using the published references specific to the Finnish population [Self-reported height and weight before pregnancy and minimum and maximum weight during pregnancy were collected at recruitment and used to determine pre-pregnancy BMI and pregnancy weight gain. Mothers were then grouped into four categories according to their pre-pregnancy BMI  kit . 150 µl of sample was centrifuged at 3000× g for 15 min and diluted 1:2 with acidified dilution buffer. After dilution, samples were centrifuged to precipitate the binding proteins and then analysed as per manufacturer’s instructions.IGF-1 was analysed using a commercially available ELISA kit . Skim HM samples were collected following centrifugation at 3000× 2 internal standard (175 mg/mL) was added to each sample. Samples were then passed through phospholipid removal cartridges  by performing an extraction with 1% (1:99 v/v) formic acid in acetonitrile. Following extraction, samples were vacuum-dried for 6 h and then reconstituted in a water-methanol solution (90:10 v/v) and injected into the machine. The mass spectrometer used a Surveyor MS pump and auto sampler followed by an Ion Max APCI source on a Finnigan TSQ Quantum Ultra AM triple quadruple mass spectrometer, all controlled by FinniganX caliber software . The column used was Kinetex® 1.7 µL EVO C18 100 Å measuring 150 × 2.1 mm . The mobile phase was constituted by methanol-water gradient set at 95:5 (v/v) at a flow of 250 μL/min. Chromatography was performed at 40 °C. Argon was used as the collision gas at 1.2 mTorr. The concentration of cGP in samples was calculated from a standard curve generated for each assay (0.14 ng/mL–265.12 ng/mL). Inter- and intra assay variability was <10%.cGP was analysed through liquid chromatography tandem mass spectrometry (LC-MS), utilising a protocol developed and optimised by our laboratory on rat milk and published previously . The pro® technology . Following dilution in 1:5 with milli-Q water, 2 µL of HM samples were transferred to the Direct Detect® Assay-free cards  and read with the Direct Detect® spectrometer as per the manufacturer’s instructions. HM total protein was quantified in order to normalise the hormone concentrations but also to investigate the associations with maternal-infant factors. The detection of total protein in the samples was carried out by infrared spectrometry using the Direct DetectThe adiponectin ELISA has previously been reported for use with HM . Leptin The power provided by the sample size of the population for linear regression and multivariate analysis of variance (MANOVA) was calculated with G*Power 3.1.9.2 as greater than 90% at the 5% significance level for the detection of 10% difference across groups for all the measured main effects. HM concentration of adipokines, IGF-1 and cGP were reported as ng or mg of the total protein concentration per ml in each sample. This was done to allow a better alignment of the results across samples and across studies, by introducing a reference biomarker (protein) that is commonly used for this purpose. Normal distribution of the data was verified through the Shapiro-Wilk test. As concentrations of bioactive components were skewed, they were normalised by log10-transformation. Relationship between pairs of compounds were investigated with bivariate analysis. Simple and multiple linear regression was used to investigate relationship between bioactives concentrations in HM and scale variables such as maternal age, infant nutrition , maternal weight gain during pregnancy, weight before pregnancy and infant gestational age, birthweight and birth length. To investigate possible predictors of HM composition amongst categorical values, we used MANOVA and tested the effect of single factors or pairs of factors on HM concentrations of all four bioactive compounds and on the ratio between IGF-1 and cGP . BecauseThe main demographics of the study population are detailed in p = 0.505, for adiponectin β = −0.019 and p = 0.667, for IGF-1 β = 0.059 and p = 0.191, for cGP β = 0.033 and p = 0.498) did not affect any of the analytes, and thus, was not included in any further analyses. Values of the five analytes across the study population are reported in Time of HM collection  in the present cohort . Finally, the concentration of total protein in the samples was associated with maternal basic education . Giving birth to twins also was associated to HM adiponectin concentrations with mothers of twins secreting higher adiponectin in their milk (p = 0.003). The IGF-1/cGP ratio displayed a positive correlation with gestational age .As shown in eir milk  as compap = 0.035, p = 0.031, p = 0.039, p = 0.05). Finally, total protein concentrations were elevated in mothers of males who underwent C-section  and infant characteristics at birth (infant sex and birth weight) and the concentration of bioactive compounds in HM collected three months after birth. In the present study, we also report, for the first time to our knowledge, the presence and concentrations of cGP in HM.The contribution of maternal BMI to HM adipokines , particuHM adiponectin was higher in mothers who delivered infants small for gestational age, as reported in previous studies  and in mp-value (0.05) still suggests an interesting associative trend. Considering that the number of GDM mothers in our cohort was limited to 44 and only constituted less than 10% of the study population, further studies with a larger GDM group should investigate this association and the impact of low adiponectin intakes for male babies, since low adiponectin is a risk factor for a range of metabolic and cardiovascular disorders [We observed that GDM mothers of males had the lowest concentration of HM adiponectin compared to GDM mothers of females and non GDM mothers of males and females, suggesting that infant sex can have a major effect on milk composition. The existing literature reports evidence that lower circulating adiponectin concentrations during pregnancy is associated with the incidence of GDM . Circulaisorders ,47.n = 39) compared to mothers who were less than 37 weeks of gestation (n = 11) and mothers who were between 37 and 40 weeks of gestation (n = 12). Only four of the infants born by C-section in our cohort were classified as small for gestational age, compared to 55 infants that were classified as appropriate for gestational age and two that were classified as large for gestational age. Taken together these observations, although of low sample size, may suggest that rather than constituting an adaptation to provide small babies with higher protein, the elevated concentrations of protein in HM of mothers who underwent C-section may be the result of altered metabolic pathways and therefore warrants further investigation.Birth-mode also displayed a sex-specific effect on HM composition, as mothers of males who underwent C-section displayed the highest amount of protein in their milk compared to all other groups. In our cohort, mothers who underwent C-section generally displayed higher protein irrespective of infant sex. However, the association between C-section and mature HM composition appears to be a novel finding in the present study. As elevated protein concentrations during early life are known to increase the risk of childhood obesity , it is cOf interest, our analysis also revealed sex-specific effects linked to socioeconomic and stress-related factors. As an example, higher concentrations of adiponectin and the IGF-1/cGP ratio were observed in male infants of mothers that experienced what would be classed as more stressful pregnancies  or were of lower socioeconomic status  although the size of some subgroups in these cases was extremely limited as discussed below. We also found that the amount of protein in HM was higher for mothers with a lower education background. While these observations are purely associative, we have previously reported that social influences, including maternal educational status, impact on HM stress hormone levels . Given tThe main strength of the present study is the large sample size, although the size of certain subgroups was limited due to the fact that the study was designed retrospectively. The lack of multiple HM collection time points from individual mothers prevented the analysis of HM compositional changes within subjects. Additionally, our samples were only representative of morning HM rather than the gold standard 24-h collection and considerable time passed between sample collection (2008–2010) and the biochemical analyses (2018) presented in this study, due to the retrospective nature of the present study design. However, the compounds analysed in the present study are known to be stable at −80 °C. Furthermore, because the HM samples were collected exclusively in the morning, collection timing and procedure was relatively standardised across all mothers. Many studies previously analysed HM composition around 3 months after birth. At this time, HM composition is more stable and thus less variable, resulting in comparable samples.Matched plasma samples and access to more detailed dietary information during pregnancy and lactation would have been useful to further delineate some of the associations detailed. Although the design of the current study does not allow any detailed mechanistic insight, previous observations in a bovine model have reported on differential programming of milk production as a function of foetal sex . The stuOverall, our findings show that maternal-infant factors, specifically maternal pregnancy and pre-pregnancy characteristics and infant sex, interact and impact upon HM compositional profiles up to three months after birth, suggesting that HM composition may be delineated during pregnancy and may have a characteristic fingerprint for every mother-baby dyad. Such a fingerprint might be used to draw maps that would serve to characterise HM composition in association with specific pathophysiological conditions. Whether the intake of HM and hormonal concentrations associated with these pathophysiological conditions impacts on postnatal outcomes and growth trajectories on the long term remains to date unknown and should be investigated in future research. This will allow a better understanding of the role played by specific nutritional and hormonal exposures during early life, in order to implement nutrition for infants who have no access to HM but also to design strategies that would help improve possibly altered HM composition due to pathological conditions. Although we had no means to investigate “cause-effect” relationships between maternal circulating hormones, dietary intakes and bioactives in HM, in the present study, the associations we observed suggest that prospective studies designed to untangle such associations and establish key determinants (and interactions therein) related to HM composition and infant outcomes are warranted.


Estimation of fetal weight (EFW) by ultrasound is useful in clinical decision-making. Numerous formulas for EFW have been published but have not been validated in pregnancies complicated by preterm premature rupture of membranes (PPROM). The purpose of this study is to compare the accuracy of EFW formulas in patients with PPROM, and to further evaluate the performance of the most commonly used formula - Hadlock IV.0/7–330/7 (n = 565). All women had an EFW within 14 days of delivery by standard biometry . The accuracy of previously published 21 estimated EFW formulas was assessed by comparing the Pearson correlation with actual birth weight, and calculating the random error, systematic error, proportion of estimates within 10% of birth weight, and Euclidean distance.A retrospective cohort study of women with singleton gestations and PPROM, admitted to a single tertiary center between 2005 and 2017 from 22p < 0.001), with 319 (56.5%) of measurements falling within 10%, 408 (72.2%) within 15% and 455 (80.5%) within 20% of actual birth weight. This correlation was unaffected by gender  or by amniotic fluid level .The mean gestational was 26.8 ± 2.4 weeks at admission, and 28.2 ± 2.6 weeks at delivery. Most formulas were strongly correlated with actual birth weight (r > 0.9 for 19/21 formulas). Mean systematic error was − 4.30% and mean random error was 14.5%. The highest performing formula, by the highest proportion of estimates and lowest Euclidean distance was Ott (1986), which uses abdominal and head circumferences, and femur length. However, there were minimal difference with all of the first 10 ranking formulas. The Pearson correlation coefficient for the Hadlock IV formula was strong at r = 0.935  formula for EFW was the most accurate, yet all of the top ten ranking formulas performed quite well. The commonly used Hadlock IV performed quite similarly to Ott’s formula, and is acceptable to use in this specific setting.The online version contains supplementary material available at 10.1186/s12884-021-03631-w. Ultrasound is one of the most useful tools for antepartum fetal surveillance. Estimation of fetal weight (EFW) by ultrasound is a key component in antepartum monitoring and management, as a means of assessing fetal growth and overall wellbeing. Yet, since ultrasound became one of the mainstays of obstetrical care, multiple formulas for calculation of EFW have been proposed –12. ThesPreterm premature rupture of membranes (PPROM) affects 2–3% of pregnancies , 22. WhiThis was a retrospective study of women with singleton gestations admitted with PPROM between 22 + 0/7 and 33 + 6/7 weeks of gestation to a university-affiliated, tertiary hospital between January 2005 and December 2017. Exclusion criteria included those with acute chorioamnionitis necessitating immediate delivery, and pregnancies with major fetal genetic or structural anomalies . The stuGestational age was determined using the last menstrual period and was confirmed by a first trimester sonogram . RupturePearson correlation coefficient (r), which represent the correlation between the EFW and the actual birth weight (BW). The closer R is to 1, the greater the linear correlation between the EFW and BW.Systematic error [SE = (EFW-BW)/BW*100], which reflects the inherent systematic deviation of a given formula from the actual BW.Random error , which reflects the random component of prediction error.Euclidean distance Proportion of estimates (POE) within ±10% of birth weight, which reflects the percentage of measurements within + 10% and − 10% of the actual BW.For small-for-gestational age , we calculated the percentage of neonates who were correctly identified by each formula as SGA (Identified as SGA by formula / SGA * 100). Birth weight percentiles were determined based on local population growth curves .The accuracy of twenty-one previously published EFW formulas was tested using the following measures:The primary objective of this study was to evaluate the accuracy of the various sonographic EFW formulas in patients with PPROM. The secondary objective was to further evaluate the performance of the Hadlock IV formula, as it is one of the most commonly formulas used to today.Statistical analysis was done using the SPSS software .There were 45,943 singleton deliveries at our institution during the study period. Of those, 845 had PPROM prior to 34 weeks of gestation, and 565 women met the inclusion criteria. Demographic data is presented in Table r = 0.940), and Hadlock [r = 0.936).The twenty-one formulas are listed in Table  Hadlock  (r = 0.9The SE ranged from 0.36% (Ott ) to − 80Yet, the Euclidean distance of the top 10 ranking formulas differed only slightly from one to another, ranging from 12.43 to 14.10%, indicating they all performed quite similarly. The formula by Hsieh  accurater = 0.935, Fig. r = 0.932 for females, r = 0.936 for males) or by level of amniotic fluid . A total of 56.5% of EFW fell within the ±10% range of the actual BW, with 72.2% of EFW within the ±15% of the actual BW and 80.5% of EFW within the ±20% margins of the actual BW.The Hadlock IV formula  is commoIn this study, we aimed to evaluate the performance of previously published EFW formulas in pregnancies complicated by PPROM.We have found that Ott’s formula  is the mOne of the earliest studies investigating EFW in pregnancies complicated by PPROM was conducted in 1990 by Valea et al. . They coA more contemporary study was performed by Esin et al.  and founBlann and Prien  studied Another study  examinedOur findings have several clinical implications. Some practitioners may choose to change the current formula they are using use in the setting of PPROM, as it ranks low among all other formulas. Others may be satisfied to realize that the formulas used by them today performs well enough for their purposes. Our findings also provide reassurance for practitioners using the Hadlock IV, regardless of fetal gender or level of amniotic fluid.EFW by an ultrasound poses many research questions including choice of formula, customized versus population growth charts, growth velocity, factors impacting EFW, and more. While our study sheds light on the performance of EFW formulas in a specific setting, additional research is needed to better characterize our use of EFW.Our study is not free from limitations, mainly its retrospective design. As a result, pertinent information, including race and body-mass index, were not available. As it was performed in a single institution this may affect the external validity. As well, although our mean interval between sonogram to delivery was 30 days, we included all patients with sonograms up to 14 days from the delivery. Nonetheless, most measurements were done within the seven-day interval from birth, and as can be seen from our results, most formulas performed quite well. Additionally, the size of our cohort and standard management protocol considerably strengthen the findings.In women with singleton gestation and PPROM, the Ott  formula Additional file 1.


The iridium‐catalysed borylation of aromatic C−H bonds has become the preferred method for the synthesis of aromatic organoboron compounds. The reaction is highly efficient, tolerant of a broad range of substituents and can be applied to both carbocyclic and heterocyclic substrates. The regioselectivity of C−H activation is dominated by steric considerations and there have been considerable efforts to develop more selective processes for less constrained substrates. However, most of these have focused on benzenoid‐type substrates and in contrast, heteroarenes remain much desired but more challenging substrates with the position and/or nature of the heteroatom(s) significantly affecting reactivity and regioselectivity. This review will survey the borylation of heteroarenes, focusing on the influence of steric and electronic effects on regiochemical outcome and, by linking to current mechanistic understandings, will provide insights to what is currently possible and where further developments are required. Which C−H bond? The iridium‐catalysed C−H borylation reaction is a powerful method for the preparation of aromatic organoboronate esters. Sterically regulated regioselectivity dominates carbocyclic aromatic C−H borylation. In contrast, heterocyclic aromatics display a much greater influence from electronic effects. In this review, examples of heterocyclic C−H borylation are surveyed, and the origins of heterocyclic C−H borylation regioselectivities discussed. A7 Scheme .[36] S7 Scheme .[37] M3.1III trisboryl complexes, respectively. , favouring greater degrees of electronic control  is exclusively borylated in the heterocyclic ring . As with other arenes, reactivity is highly dependent on both the size and electronic nature of the substituents. For example, 2,5‐dibromothiophene (84) reacts at room temperature to afford 85  and electron‐rich dimethylthiophene (86) requires more forcing conditions for efficient borylation  affords a mixture of the 2‐ and 3‐borylated products in a 76:24 ratio . In both these last two examples the “standard” dtbpy ligand exhibited poorer selectivity.As with arene borylation, regiocontrol can be attained through the use of designed ligand/additive systems. For example, enhanced 2,5‐selectivity can be observed with the L‐shaped ligand 9 Scheme .[85] A3 Scheme .[80] D4.1.2119, with limiting boron reagent, occurs at the least hindered pyrrole position minimising peri interactions, affording major monoborylated isomer 120 a alongside two minor bisborylated isomers 120 b and 120 c in a 1:1 ratio  can occur, with C−H activation occurring at, successively, C‐2, C‐7, and C‐5 . These indicate that C‐7  should be the most reactive C−H site when contrasted to other uncongested C−H sites, which range between −9.4 and 0 kcal mol−1.ortho selectivity observed in the C−H borylation of benzodioxole .Smith has suggested that the C‐7 selectivity observed with indole originates from substrate ligation to the catalyst, which may promote chelation‐controlled C−H activation. This model can potentially account for the C‐1,8 bisborylation of carbazole 0 Scheme . HoweverN‐methylindole (145), which affords a mixture of C‐2 and C‐3 functionalised products  affords the α‐borylated product via a process involving an electrostatic outer‐sphere interaction between the NBeg group and the ancillary ligand  in indoles and carbazoles, as is observed in the borylation of 151 and 154  and 4‐tert‐butylpyridine (184). The latter, lacking unhindered non‐azinyl C−H bonds, is inert, whilst the former undergoes facile C−H borylation selectively at the sterically uninhibited 4‐position  α to the azinyl nitrogen, with C‐2 functionalised pyridine 187 being detectable in 79 % GCMS yield , the 2‐pyridyl unit in 207 likely facilitates activity by functioning both as a steric blocker and an electron‐withdrawing (activating) group. Steric effects remain the dominating influence in this transformation, as the corresponding 4,4′‐dimethoxybipyridine analogue 209 gives the ortho methoxy functionalised products 210 and 211 (Scheme 200) proceeds efficiently to afford C‐3 and C‐4 boronates 201 and 202 in a 2:1 ratio (Scheme 203) shows poor conversion under comparable conditions  is ortho (to OH) selective following traceless O‐borylation with HBpin to afford C‐4 functionalised 216  borylation of the parent pyridine scaffold at room temperature. Substituted pyridines are also viable substrates for this process. Interestingly, as shown by this example, a C‐2 substituent does not seem to block complexation, giving selective access to 2,5‐disubstituted pyridine products  undergoes borylation in the carbocyclic ring mediated by B‐Si ligand L15,  and C‐5 (39.7) in 250 b provide qualitative correlation with experimental site‐selectivity. As with other arenes, congested quinolines are viable substrates but require more forcing conditions, although the preference for reaction in the heteroaromatic ring remains. For example, all C−H sites in 4,7‐disubstituted quinolines are encumbered, so borylation is completely selective for C‐3 but the reaction of 253 a bearing a chloro group at C‐4 is significantly more efficient than for the C‐4 methyl analogue . The parent unprotected imidazole is not borylated, which is perhaps due to rapid N‐borylation to form the corresponding N‐Bpin adduct, leaving all C−H sites either sterically hindered or inhibited by the azinyl nitrogen. However, N‐methylated imidazoles undergo borylation efficiently at C‐5, and this is exemplified by the borylation of 268 in the presence of 1.5 equivalents of HBpin  are selectively borylated at the α position reflecting the higher intrinsic reactivity of this C−H bond (Scheme ortho bromine substituent (280 b). C‐5 substituted pyrazoles such as 282 also undergo N‐borylation and C‐borylation is selective for C‐4  and N‐methyl‐2H‐indazole (290) show complete selectivity for the heteroaromatic moiety (Scheme H‐ or 2H‐indazoles (Scheme peri C‐4 substituent and azinyl nitrogen (Scheme ortho substituents and a lower inhibitory effect of the azinyl nitrogen which is strongly influenced by the electron‐withdrawing effect of the azole nitrogen (pKa(indazolium)=1.25).As with imidazole, the borylation of unprotected NH indazole is not effective. This is surprising, as the structurally similar heteroarene pyrazole is an active substate and is borylated at C‐4 following initial N−H borylation. The lack of indazole borylation has been suggested to be due to the inhibitory effect of the azinyl N on the catalyst.138 Altey Scheme . Moving s Scheme . This prn Scheme . This reH‐indazole isomers, which avoid this inhibitory interaction, is much more rapid and the corresponding C‐3 boronates undergo protodeborylation more slowly. The latter issue can be ameliorated through the use of the more electron‐withdrawing N‐Ms group, as in 292, which stabilises boronate 293, permitting isolation following silica gel column chromatography in 62 % yield  iteratively undergoes bisborylation, initially at C3 and then at C‐5/C‐6, to afford a 5:1 mixture of products , borylation selectively occurs at C‐7 ortho to the O atom (Scheme ortho selectivity observed in benzodioxole 36 (see Section 3.1), and correlates to the enhanced C−H acidity of this site. Mirroring the lower electronegativity of sulfur, 2‐methylbenzothiazole (303) is comparably less active towards C−H borylation and displays poorer selectivity (Scheme 305) efficiently undergoes distal borylation at C‐5 (Scheme ortho (C‐4/C‐7) reactivity can be attributed to an azinyl N effect in analogy to the inhibition of C‐8 activation in quinoline, although the contribution of an N‐Bpin adduct, which also sterically hinders the peri position, cannot be discounted. The latter possibility is supported by the requirement for increased equivalents of B2pin2 for efficient borylation of benzimidazoles.The borylation of benzoxazoles, benzothiazoles, and benzimidazoles requires a substituent at C‐2, potentially to prevent substrate ligation to the catalyst through the azinyl nitrogen. The reasons for this are not immediately obvious, as oxazole itself is an active substrate (see Section 4.5), although this may further reflect the higher reactivity of heterocyclic C−H bonds when compared with those in carbocyclic rings. In 2‐methylbenzoxazole  conversion.308 selectively  is preferentially borylated meta to the chlorine atom, as this nitrogen carries lower electron density  countered by the inhibitory effect of a proximal and or Lewis basic azinyl nitrogen.4.8.1a]pyridine (332) can be envisaged as a 1,5‐disubstituted pyrazole, with C−H borylation exhibiting C‐5 selectivity, avoiding the α azinyl position (Scheme a]pyridine (334) can be envisaged as a 1,2‐disubstituted imidazole, with C−H borylation exhibiting C‐3 selectivity α to the azole‐like N‐4 nitrogen and avoiding the C‐2 α azinyl position  is similarly C‐3 selective and affords 344, reflecting the enhanced C−H acidity of the pyrazole ring hydrogens  345 is selective for the heteroarene  in 2015. During his final year, he studied the synthesis of N‐heterocyclic carbene ligands under the supervision of Dr. Paul Davies. He then moved to the University of Durham (UK) to conduct his doctoral studies on Ir‐catalysed C−H borylation of heteroarenes under the supervision of Prof. Patrick G. Steel, graduating in 2020. Currently, he is a postdoctoral research fellow at the University of Michigan, (USA), developing new transition metal promoted radiofluorination methods under the supervision of Prof. Peter J. H. Scott.Peter Scott obtained his BSc from Loughborough University (UK) and his PhD, under the mentorship of Prof. Patrick Steel, from Durham University. He undertook postdoctoral research at SUNY Buffalo under Prof. Huw Davies, and the University of Michigan with Prof. Michael Kilbourn. He joined the faculty at Michigan in 2009 and is currently an Associate Professor of Radiology and Director of the PET Centre. He is a Fellow of the Royal Society of Chemistry and received a Distinguished Investigator Award from the Academy for Radiology & Biomedical Imaging Research in 2019.Patrick Steel undertook his undergraduate and post‐graduate training with Prof. Jim Thomas at the University of Oxford (UK). Following a NATO‐SERC postdoctoral fellowship with Prof Gilbert Stork at Columbia University (USA), he joined the staff at Durham University where he is currently a professor of organic chemistry and chemical biology. He is interested in problems in organic synthesis and chemical biology with particular focus in neglected tropical diseases and the chemical biology of plants. He was Head of the Organic Chemistry Section at Durham University 2007–2013 and was an elected council member of the Royal Society of Chemistry, Chemistry Biology Interface Division 2013–2019.


Societal determinants influence the health and well-being of the mother, the intrauterine environment and the fetal development before birth, increasing the risk of fetal loss as well as low birthweight and prematurity.The design of CIDACS Birth Cohort follows a life course perspective, using routinely collected data from Brazil. The overall objective is to research the effect of obstetric and prenatal conditions, congenital infections and other potential social and environmental determinants and the impact of social policies on birth, growth, morbidity and survival, overall and in subgroups of interest in a dynamic Brazilian birth cohort. The use of large, routinely collected, high-quality social and health databases provides a unique opportunity to examine factors that might result in long-term and rare child and mother outcomes over time without the limitations of a traditional cohort, such as limited sample sizes and expensive resources.The CIDACS Birth Cohort is housed at the Centre of Data and Knowledge Integration for Health (CIDACS), a unit of the Oswaldo Cruz Foundation in Bahia, Brazil. CIDACS also houses the 100 Million Brazilian Cohort. CIDACS works in the spectrum of data acquisition for linkage data from large Brazilian national databases, management, analysis and interpretation with ethical use and privacy issues.Ethical approval was obtained from the Federal University of Bahia’s Institute of Public Health Ethics Committee (CAAE registration number: 18022319.4.0000.5030).Brazil has about 3 million births a year. A total of 44 485 267 births were recorded in the live birth system (SINASC) over 2001–15. The CIDACS Birth Cohort population is composed of 24 695 617 (55%) children born alive in Brazil between 1 January 2001 and 31 December 2015 which linked with the baseline of the 100 Million Brazilian Cohort through common maternal information, which exists in the two datasets. All children with information recorded in the live birth system (SINASC) were eligible for linkage.,The SINASC records live births in Brazil, using a standardized form, completed by a health professional who assisted the child’s delivery. This form has information on pregnancy and delivery of newborns, including congenital anomalies, birthweight and sex. An evaluation of the birth registration system in Brazil found that over 97% of Brazilian live births are registered in this system.The baseline of the 100 Million Brazilian Cohort was created using administrative records from over 114 million individuals aged 16 years or older, whose families applied for social assistance via the Unified Register for Social Programmes (Cadastro Único para Programas Sociais: CadUnico). Since 2003, the CadUnico has become the main instrument used by the Brazilian government to assess the inclusion criteria of potential beneficiaries of social programmes. To be enrolled in CadUnico, one person in the family must provide information and required documents of all family members to an interviewer. This person must be at least 16 years old and, preferably, be a woman. The information is renewed periodically as long as the person is a candidate or enrolled in any one of the Brazilian benefits, such as Bolsa Familia (cash transfer for low-income families) and Minha Casa Minha Vida and Beneficio de Prestação Continuada (continuous benefit for people with long-term disability) among others.The characteristics of mothers and children in the CIDACS Birth Cohort were compared with the characteristics of the non-linked population of mothers and children registered in SINASC, to assess differences and similarities between our cohort populations . A higheet al. (2020).We linked SINASC live births records with the baseline of the 100 Million Brazilian Cohort using the name of the mother, maternal age at birth, maternal date of birth and the municipality of residence of the mother at the time of delivery. We excluded records with missing or implausible names and duplicates. The linkage was performed with CIDACS-RL ,At CIDACS, the processing and linking of identified databases follow legal frameworks related to ethics, privacy and data security. The study protocol was reviewed and approved by the Federal University of Bahia’s Institute of Public Health Ethics Committee (CAAE registration number: 18022319.4.0000.5030).The individuals included in CIDACS Birth Cohort will be dynamically followed from birth to death. Brazil has several mandatory national health and social registries that allow us to track a range of events throughout the individual’s life, including hospitalizations, infectious diseases occurrence, nutritional status, enrolment in social protection programmes and death . The folThe CIDACS Birth Cohort records are being linked with: SINAN [Sistema de Informação sobre Agravos de Notificação (Information System for Notifiable Diseases)]; SISVAN [Sistema de Vigilância Alimentar e Nutricional (Food and Nutrition Surveillance System)]; SIH [Sistema de Informações Hospitalares ]; and SIM [Sistema de Informação sobre Mortalidade ]. The primary data available at each phase of the CIDACS Birth cohort are listed in The Information System for Notifiable Diseases (SINAN) is the compulsory notification system for a list of infectious diseases, including dengue, zika, tuberculosis and chikungunya.The Food and Nutrition Surveillance System (SISVAN) will be used to assess child and maternal nutrition. Data from this system are available over 2008–15 and has information on anthropometric measurements, including weight and height, food consumption, breastfeeding and complementary feeding practices. The national population coverage of SISVAN ranges between 10% and 15%, mainly among children and adolescents. For those registered in the cash transfer programme Bolsa Familia, who are also enrolled in the CadUnico, the SISVAN coverage varies from 57% to 86%.All hospital admissions financed by the Brazilian National Health System  are recorded in the Information System of Hospitalizations (SIH). The hospitalization system includes personal patient information, date of hospitalization, duration, type of hospital, costs incurred, and causes of hospitalization.The Information System of Mortality (SIM) uses the death certificate, a legal document. This form collects information on the deceased individual and the conditions, place and cause of death. In the case of fetal deaths or infant mortality, it also includes maternal characteristics. In 2015, it was estimated that SIM registered more than 97% of the Brazilian deaths.The CIDACS Birth Cohort includes basic information on the mother  and her obstetric history , the pregnancy , the newborn  and the antenatal care (number of visits and when care started). In addition to birth and maternal information obtained from SINASC, socioeconomic and demographic data from the 100 Million Brazilian Cohort, such as information on family dynamics, child care arrangements, parental employment, income, housing, family formation and dissolution, are available in the baseline of the CIDACS Birth Cohort. Information on growth, breastfeeding and infectious disease has been included in the cohort follow-up. Although most variables have less than 10% missing data, there is a substantial proportion of missingness for the variables on the mother’s history of stillbirth or miscarriage (16% missing) and the employment situation of the household head (54% missing).To date, the CIDACS Birth Cohort has been used to analyse birth and mortality outcomes. Preterm births , low birthweight (<2500 g) and congenital anomalies were observed in 8.1%, 8.3% and 0.7% of the total births included in the cohort, respectively . The deaFurther linkage between CIDACS Birth Cohort baseline and other follow-up datasets are ongoing. The linkage with SINAN is being held to evaluate the impact of maternal infections, including zika and syphilis, on early outcomes  and late outcomes . In addition, the linkage with SISVAN is being conducted in order to analyse child growth curves and the effect of maternal nutrition on birth and child growth outcomes.CIDACS Birth Cohort has several strengths. First, it links health and social data coming from various government sectors, adding enormous value to already existing health data in determining both the drivers of health and the consequences of ill health. Second, its longitudinal structure makes possible to: (i) add new exposures or outcomes over time; and (ii) study outcomes at different times of exposure, including long-term outcome. Third, the large sample sizes allow analysis of small groups and rare events in ways that are not possible in projects that are dependent on the primary collection of new data. Fourth, we have included in our data information on isolated populations, such as Iindigenous people and Quilombo communities descended from AfricanBrazilian fugitive slaves. Fifth, the use of administrative data eliminates the risk of recall bias, which is a problem if data collection relies on self-reports of service use . Sixth, the linkage has been conducted with robust and accurate software developed in-house (CIDACS-RL), and a specialized team evaluates each linkage performed at CIDACS.There are some limitations that must be considered when analysing the CIDACS Birth Cohort. To measure follow-up can be a complex task in large, linked datasets where individuals have complex histories and errors can be present. The cohort baseline is the linked population of SINASC and population from the baseline of the 100 M Brazilian cohort, both routinely collected data that have not been designed for research purposes. Therefore, it brings well-known limitations relating to missing, underestimation and potential misclassification of data. For example in SINASC, the proportion of preterm births recorded was found to be underestimated by 15%, and misclassification, based on the criteria used to assess the gestational age at birth information (date of the last period), could have occurred.A limitation that must be discussed concerning each specific research question is the characteristics of people enrolled at CadUnico . There is a socioeconomic gradient that influences prevalence estimates, as reflected in higher rates of vaginal delivery that, in Brazil, is less common among wealthy families . However,The linkage process posed several challenges, such as linking different individuals (mother-baby) due to the limited numbers of identifiers that have tended to yield higher rates of linkage error, commonly due to inaccurate or incomplete provision of identifiable data. The most critical barrier to linking maternal and live birth records is the limited availability of common and complete personal identifiers, which directly impacts on sensitivity results, that tend to be lower. A validation study estimated that the overall proportion of linked people between 2001 and 2015 was 59%. However, this was not constant over the years, and from 2012 the sensitivity reached about 80%, reaching values similar to studies developed in Georgia and New Jersey, USA.Data that support the information presented are available upon request from the CIDACS and on ethical approval. The data are not publicly available due to restrictions, as they contain information that could compromise the privacy of the research population.Currently, only national and international researchers who collaborate with CIDACS, and authorized staff from government agencies, can have controlled access to de-identified linked data. These individuals and organizations must be committed to advancing scientific knowledge or generating evidence for public policy formulation. Researchers can access relevant de-identified data for their proposed study objectives exclusively via secure remote access to virtual machines.https://cidacs.bahia.fiocruz.br/] or contact us via email [cidacs@bahia.fiocruz.br].Persons who wishes to receive authorization must: (i) be affiliated to the institution or be identified as collaborators; (ii) present a detailed research project together with ethical approval by an appropriate Brazilian institutional; (iii) provide a clear data plan restricted to the objectives of the proposed study and a summary of the analyses plan intended to guide the linkage and or data extraction of the relevant set of records and variables; (iv) sign terms of responsibility regarding the access and use of data; and (v) perform the analyses of datasets provided using the CIDACS data environment, a safe and secure infrastructure that provides remote access to de-identified datasets and analyses tools. For more information, please visit the CIDACS website [The Centro de Integração de Dados e Conhecimentos para Saúde (CIDACS) Birth Cohort is a Brazilian population-based cohort derived from linked national data, developed to investigate the relationships between prenatal and early life events, and health-related outcomes.The CIDACS Birth Cohort population is composed of 24 695 617 (55%) children born alive in Brazil between 1 January 2001 and 31 December 2015, which linked with the baseline of the 100 Million Brazilian Cohort through maternal information. We have information on children from birth up to 14 years of life.Linkage was performed using a record linkage tool (CIDACS-RL) using maternal name, municipality and date of birth records or age. The link between the composite file SINASC-100 Million Brazilian Cohort with other Brazilian datasets  will provide the cohort follow-up and outcomes information.Currently, national and international researchers who collaborate with CIDACS have controlled access to de-identified linked data. Qualified investigators who wish to receive authorization to access the data must present a detailed research project together with ethical approval, provide a plan of analyses and sign terms of responsibility.CIDACS received core support from the: Health Surveillance Secretary, Ministry of Health, Brazil; Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB); Wellcome Trust (grant number 202912/Z/16/Z); Financiadora de Estudos e Projetos-FINEP; and Secretary of Science and Technology of the State of Bahia-SECTI. E.S.P. is a fellow supported by the Wellcome Trust (grant number 213589/Z/18/Z). The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report.


Urinary iodine concentration (UIC), iodine levels in amniotic fluid, and thyroid parameters  were measured in mother–baby pairs. (3) Results: There were significant differences between HR and LR groups, free thyroxine (FT4) concentration in cord blood was significantly higher in the LR group compared with HR pregnancies , meanwhile iodine concentration in amniotic fluid was significantly lower . (4) Conclusions: Our findings support the hypothesis that an adverse intrauterine environment can compromise the availability of FT4 in cord blood as well as the iodine metabolism in the fetus. These differences are more noticeable in preterm and/or small fetuses.(1) Background: The consequences of iodine deficiency and/or thyroid dysfunction during pregnancy have been extensively studied, emphasizing on infant neurodevelopment. However, the available information about the relationship between iodine, thyroid hormones, and fetal growth in high-risk pregnancies is limited. We aim to investigate if iodine metabolism and/or thyroid parameters can be affected by adverse antenatal/perinatal conditions. (2) Methods: A cross-sectional study examined differences in iodine status, thyroid function, and birthweight between high-risk (HR group;  Fetal growth is dependent upon a number of endocrine, paracrine, and autocrine events, involving interactions between the mother, placenta, and fetus, and these effects may program long-term physiology . ThyroidAlthough marked physiological differences exist between the maternal and fetal thyroids, both systems interact through the placenta and the amniotic fluid, modulating the transfer of iodine and small but biologically important amounts of thyroid hormones from the mother to the fetus . Iodine But many factors might hinder these physiological pathways, such as prematurity, severity of in utero compromise, maternal and perinatal comorbidities, complications associated with medically-induced preterm delivery. There is no exact definition of risk in pregnancy, but the tag “high-risk pregnancy” involves chronic health problems, such as diabetes or high blood pressure; infections; complications from a previous pregnancy; or other issues that might arise during pregnancy with an actual or potential hazard to the health or well-being of the mother or fetus . All of Small for gestational age (SGA) is used to describe those infants who are smaller in size than normal for their gestational age, defined as weight below the 10th percentile or 2 standard deviation (SD) for the gestational age . AlthougA recent systematic review has evaluated the association of maternal subclinical thyroid dysfunction and IUGR, demonstrating that subclinical hypothyroidism (SCH) exhibited a statistically significant association with IUGR . AnotherOur group previously investigated the effect of physiological amounts of iodine intake on the iodine concentration in amniotic fluid  as well n = 233), using as exclusion criteria any condition of obstetric and/or perinatal risk. Additionally, we recruited a new cohort of pregnant women who had been classified as high-risk pregnancies at the antenatal surveillance program of the Virgen de las Nieves University Hospital, Granada (Spain), from January 2015 to December 2018 . Factors to be considered as high-risk pregnancies were maternal chronic diseases, preterm delivery, oligoamnios, growth restriction, or preeclampsia as well as history of adverse obstetric outcomes such as recurrent miscarriages or stillbirth. Inclusion criteria for HR group were pregnant women, previously classified at high-risk, admitted to hospital, and expected to give birth within the next 24 h. Criteria for exclusion included multiple gestation, fetal malformation, a known history of endocrine disease , or exposure to iodinated agents .This study used samples and data from the aforementioned study carried out at the Regional University Hospital, Málaga (Spain) . These pAll participants from Málaga and Granada were pooled in a single database. In both groups, we analyzed maternal age, gestational age at delivery, and information regarding the consumption of supplements containing iodine during gestation, as well as timing and mode of delivery. The birthweight percentile was calculated according to customized weight curves for Spanish fetuses and newborns . The stuBlood samples and urine were collected from mothers during the active phase of delivery or just before elective caesarean section. A sample of amniotic fluid was obtained by aspiration, before amniorrhesis. At the time of birth, a sample of cord blood was obtained from the newborn and measurements were made of cord blood pH. All sample were stored at −80 °C and transferred to the laboratory of the Institute of Biomedical Research in Málaga (IBIMA) for analysis. Even though a considerable time lapse occurred between the first study  and the The plasma levels of free thyroxine  and thyroid-stimulating hormone  were measured by chemiluminescence immunoassay  at the clinical laboratory of the Regional University Hospital, Málaga. Urine and amniotic fluid iodine concentrations were measured following the Benotti technique and a modification for amniotic fluid samples ,18. The Normal distribution of quantitative variables was assessed by the Kolmogorov–Smirnov test. Quantitative variables were shown as the mean ± standard deviation and qualitative variables as percentages. The contrast hypothesis for two samples was evaluated with the Student’s t-test, and for more than two samples, with an analysis of variance (ANOVA) test. The chi-square test was applied in case of categorical variables. The correlation between variables was determined using the Spearman test, designing multiple linear regression models in those cases where it was desired to predict the variance adjusted for other variables, besides the main variable. Logistic regression was applied in the case of dichotomous outcomes.In all cases, the rejection level for a null hypothesis was alpha below 0.05. All data were analyzed using SPSS 20.0 . All the maternal and neonatal variables included in the study are shown in r = −0.009, p = 0.876), nor between maternal age and birth weight , However, there were significant correlations between gestational age and birth weight , weight percentile , and 5-min Apgar score . Birth weight correlated with 1-min Apgar , and with 5-min Apgar . Similar but a bit weaker correlations were found between weight percentile and 1-min Apgar score , and with 5-min Apgar . None of the neonatal parameters  correlated with pH values in umbilical cord .No correlation was found between maternal age and gestational age at birth , and between arterial and venous pH values in umbilical cord . There also were significant correlations between these four parameters: 1-min Apgar score correlated with arterial pH  and with venous pH in umbilical cord ; and 5-min Apgar score correlated with arterial pH  and with venous pH in umbilical cord . These correlations between Apgar and pH values remained when we consider LR and HR pregnancies separately  and 5-min Apgar scores  and higher values in arterial pH .When preterm and at term pregnancies were compared, birth weight, weight percentile, and 5-min Apgar score were significantly lower in the preterm group . Besidesr = 0.058, p = 0.312), nor neonatal parameters such as gestational age , or birth weight . Almost a third of pregnant women (28.7%) of the high-risk group did not take iodine supplements (p = 0.015). Maternal age was significantly lower in those with UIC <150 µg/L compared with pregnant women with UIC >150 µg/L .The mean urinary iodine concentration (UIC) was significantly lower in the high-risk group compared to the low-risk group . The medplements . Besidesp = 0.019 in the LR group and 30.9 ± 6.2 years, vs. 32.0 ± 4.4 years, for UIC < and UIC >150 μg/L respectively; p = 0.048 in the HR group). We did not find significant differences in gestational age, birth weight, or weight percentile according to UIC below or above 150 µg/L.This difference in maternal age according to UIC was still present when we split the sample in LR and HR groups . When only women <30 years of age who took supplements  were selected, the UIC did not show significant difference between LR and HR groups .In order to elucidate if the difference in UIC can be attributed to geographical characteristics or to adverse conditions in the HR group, we removed preterm deliveries and compared only the UIC of mothers who gave birth babies with normal weight (percentile 10–90th), there was no significant difference in UIC between LR and HR groups , and small for gestational age  (p = 0.002). However, the association between UIC <150 µg/L and preterm birth did not reach statistical significance  (p = 0.143), neither between UIC <150 µg/L and small for gestational age  (p = 0.113).In fact, the non-consumption of iodine supplements was significantly and independently associated to preterm birth   that disappeared in high-risk pregnancies . Iodine in amniotic fluid did not correlate with maternal age nor gestational age, but correlated negatively with birth weight  and with weight percentile . When we split the sample in LR and HR pregnancies, these correlations disappeared. In the group of newborns below the 10th percentile, iodine in amniotic fluid correlated with birth weight  and with weight percentile ; and in those babies born at term, iodine in amniotic fluid correlated with birth weight  and with weight percentile .On the other hand, amniotic fluid samples were obtained from 193 pregnant women of the low-risk group and 102 women with high-risk pregnancy. The iodine concentration in amniotic fluid was significantly higher in high-risk pregnancies compared with low-risk pregnancies . There wp < 0.001), FT4 . These differences were present in both groups (LR and HR). There were positive correlations between maternal and neonatal thyroid hormones: TSH , and FT4 . We did not find differences in maternal nor neonatal thyroid hormone levels according to consumption of iodine supplements, sex of the newborn, or preterm birth , neonatal TSH , and neonatal FT4 . When we considered HR and LR separately, the correlations between UIC and thyroid hormones only remained significant in the LR group (data not shown).Whereas iodine in amniotic fluid did not correlate with maternal nor neonatal thyroid parameters, UIC significantly correlated with maternal TSH , which remains in both HR pregnancies  as well as in LR pregnancies . Maternal FT4 also correlated negatively with birth weight  in the LR group, but did not in the HR group. There was no correlation between maternal FT4 and weight percentile in LR nor HR group. A significant correlation was found between neonatal FT4 and birth weight , but it was not present when the participants were separated into the LR and HR groups. When birth weight was considered as a categorical variable , it can be noticed that neonatal FT4 and iodine in amniotic fluid showed opposite behaviors (p = 0.002) and for iodine in amniotic fluid (p = 0.019).A negative correlation between maternal FT4 and gestational age was also found . No differences were found for UIC or iodine in amniotic fluid depending on the onset of labor.However, these differences can be explained by the gestational age at birth, which was substantially different among the three options: 260.65 ± 18.25 days for elective caesareans, 272.09 ± 9.98 days for spontaneous deliveries, and 275.22 ± 8.44 days for induced labor.  in women who had not taken supplements, but not in women who took them. Besides, if elective cesareans were excluded, maternal FT4 was significantly higher in the LR group  in women who took supplements, but there was not significant difference in maternal FT4 between LR and HR groups in women who did not.When preterm deliveries were excluded, maternal FT4 was significantly higher in the LR group , instrumental deliveries, and cesarean section (including elective as well as emergency cesarean sections). From this comparison, two variables showed significant differences: neonatal FT4 and iodine in amniotic fluid .p < 0.001), mode of delivery , weight percentile , and UIC  were independently associated to neonatal FT4 levels . Iodine in amniotic fluid is associated to birth weight  and mode of delivery  .Finally, linear regression models for neonatal FT4 and for iodine in amniotic fluid were developed. Maternal FT4 , THs exhibited higher levels in the LR group. Additionally, there was an inverse relationship between UIC and iodine in amniotic fluid: the LR pregnancies presented higher UIC and lower iodine in amniotic fluid in comparison with HR pregnancies. The higher values of UIC (and major consumption of iodine supplements) in the LR group might justify the higher levels of TH . In factEven after the onset of fetal thyroid secretion, human data show that maternal transfer still represents about 30–60% of fetal serum T4 and continues to have an important protective role in fetal neurodevelopment until birth . Our resAlthough the regulatory mechanisms of thyroid function at the time of birth are not fully understood, the positive TSH-FT4 correlation in maternal and cord blood have been previously reported ,25. PartThe relationship between maternal and neonatal thyroid parameters at the time of birth as well as their impact on fetal growth have been previously studied by others ,29. Our Shields et al.  inferredConcerning maternal FT4, it is important to highlight that their levels were similar for most of the comparisons , except the onset of labor, reaching the highest levels in elective caesarean and the lowest in case of induced labor. This finding, along with the inverse correlation between maternal FT4 and gestational age, support the idea that the maternal–fetal transfer of FT4 may be particularly intensified at the time of birth, being conditioned by the timing of delivery . AccordiFurthermore, when the mode of delivery is considered , we found again higher neonatal FT4 levels in eutocic deliveries in comparison with instrumental deliveries or caesarean sections. In fact, the mode of delivery appears as an influencing factor  on neonatal FT4 in the regression model, independently of gestational age or birth weight. Although other studies found higher levels of neonatal FT4 in vaginal deliveries in comparison with caesarean sections, the difference did not reach statistical significance  or was iOn the other hand, nutritional intake during pregnancy is particularly critical for directing normal fetal growth and development , so the In our study design, we included 3 different variables to estimate the nutritional iodine status in pregnant women: the consumption of iodine supplements, UIC, and iodine in amniotic fluid. The difference in UIC might be initially attributed to geographical characteristics of the two cities ; however, a national survey conducted by our group showed similar iodine status in these locations . AdditioThe lower levels of UIC in HR pregnancies, may easily be explained by a lower consumption of supplements, but those pregnant women who did not take iodine supplements also showed lower values in neonatal parameters . The fact that the risk of prematurity or small for gestational age was associated to non-consumption of iodine supplements rather than to a UIC <150 µg/L can be understood if we take into account that UIC only reflects recent intake of iodine, whereas the intake of supplements may indicate replete iodine stores . AnotherBut the most interesting contribution of our work is the study of iodine concentration in amniotic fluid. So far, we have measured iodine in amniotic fluid at mid-gestation  and at tIt is known that amniotic fluid is a complex milieu which contains nutrients and growth factors that facilitate fetal growth, and there is a rapid bi-directional diffusion between the fetus and the amniotic fluid across the not-yet-keratinized fetal skin . MoreoveOur study, as a cross-sectional study, is limited to establish cause and effect, so the correlation seen in our data could be interpreted just in the theoretical way. However, our findings suggest that the late stages of pregnancy, when the fetus significantly increases in size, is an important window of susceptibility to even narrow thyroid function deviations.According to our results, we can hypothesize that the availability of FT4 in cord blood is a sum of the effects produced by the maternal–fetal T4 transfer  and the synthesis de novo by the fetus .In summary, we can conclude that maternal and neonatal thyroid function and iodine metabolism at the time of birth is modulated by consecutive conditions: in utero environment , the onset of labor , and the mode of delivery.


Reduced global hippocampus volumes have been demonstrated in premature‐born individuals, from newborns to adults; however, it is unknown whether hippocampus subfield (HCSF) volumes are differentially affected by premature birth and how relevant they are for cognitive performance. To address these questions, we investigated magnetic resonance imaging (MRI)‐derived HCSF volumes in very premature‐born adults, and related them with general cognitive performance in adulthood. We assessed 103 very premature‐born  and 109 term‐born individuals with cognitive testing and structural MRI at 26 years of age. HCSFs were automatically segmented based on three‐dimensional T1‐ and T2‐weighted sequences and studied both individually and grouped into three functional units, namely hippocampus proper (HP), subicular complex (SC), and dentate gyrus (DG). Cognitive performance was measured using the Wechsler‐Adult‐Intelligence‐Scale  at 26 years. We observed bilateral volume reductions for almost all HCSF volumes in premature‐born adults and associations with GA and neonatal treatment intensity but not birth weight. Left‐sided HP, SC, and DG volumes were associated with adult FS‐IQ. Furthermore, left DG volume was a mediator of the association between GA and adult FS‐IQ in premature‐born individuals. Results demonstrate nonspecifically reduced HCSF volumes in premature‐born adults; but specific associations with cognitive outcome highlight the importance of the left DG. Data suggest that specific interventions toward hippocampus function might be promising to lower adverse cognitive effects of prematurity. Hedderich et al. report unspecific reductions of hippocampus subfield volumes in premature‐born adults. However, they found reduced dentate gyrus volumes to mediate the effect of low gestational age on adult full‐scale intelligence quotient suggesting functional relevance in premature‐born adults. ANOVAanalysis of varianceBLSBavarian longitudinal studyBWbirth weightCAcornu ammonisCIconfidence intervalDGdentate gyrusFS‐IQfull‐scale intelligence quotientFTfull‐termFWEfamily‐wise errorFWHMfull‐width at half‐maximumGAgestational ageGC‐ML‐DGgranule cell and molecular layer of dentate gyrusHChippocampusHCSFhippocampal subfieldHPhippocampus properINTIintensity of neonatal treatment indexMPRAGEmagnetization prepared rapid acquisition gradient echoMRImagnetic resonance imagingMSTmnemonic similarity taskROIregion of interestSCsubicular complexSEstandard errorSESsocioeconomic statusTEtime to echoTItime to inversionTRtime to repetitionVLBWvery low birth weightVP/VLBWvery preterm/very low birth‐weightVPvery pretermWAISWechsler Adults Intelligence Scale1Premature birth, that is, birth before 37 weeks of gestation, has a prevalence of around 11% worldwide . We investigated associations with perinatal variables of premature birth and with adult full‐scale intelligence quotient (FS‐IQ) as a global outcome measure of cognitive performance in order to study their specificity for premature birth and their functional relevance. Furthermore, we investigated whether functional HCSF units mediate the relationship between gestational age (GA) and adult FS‐IQ in premature‐born adults.22.1The participants examined in this study are part of the Bavarian Longitudinal Study (BLS), a geographically defined, whole‐population sample of neonatal at‐risk children and healthy full term controls who were followed from birth into adulthood  and the Department of Radiology, University Hospital of Bonn (n = 68). The study was carried out in accordance with the Declaration of Helsinki and was approved by the local institutional review boards. Written consent was obtained from all participants. All study participants received travel expenses and a small payment for attendance. A more detailed description of participants, including incidental brain MRI findings can be found in a previous publication  = 1.84, p = .11). The image protocol included a high‐resolution T1‐weighted, 3D‐MPRAGE sequence  with a reconstructed isotropic voxel size of 1 mm3 and a high resolution T2‐weighted 3D sequence based on the variable refocusing flip angle technique (sweep technique) ; 2.5http://surfer.nmr.mgh.harvard.edu/) , which is documented and freely available for download online . Statistical significance was set at p < .05; all tests are two‐sided. p‐Values of post hoc tests were FDR‐corrected for multiple comparisons according to the Benjamini–Hochberg method within every discrete set of analyses . General linear models were used to determine whether premature birth status is a significant factor for different HCSF volumes . This analysis was repeated using a similar general linear model, correcting for left/right hippocampus volumes instead of TIV. Partial correlations restricted to the VP/VLBW group and corrected for scanner, TIV, and sex were used to investigate the associations between HCSF volumes and variables of premature birth: GA, BW, and INTI. A similar partial correlation analysis was used to investigate FS‐IQ and HCSFs. Differences between VP/VLBW and FT individuals were tested using chi‐square tests  or two‐sample 33.1p = .765), sex (p = .167), SES at birth (p = .492), and maternal age (p = .889). By design, VP/VLBW subjects had significantly lower GA (p < .001), lower BW (p < .001), neonatal treatment intensity as measured by INTI, and longer duration of hospitalization after birth (p < .001). TIV was significantly lower in VP/VLBW than in FT individuals . VP/VLBW subjects had lower FS‐IQ scores in adulthood (p < .001). For detailed results and group comparison of demographic, clinical, and cognitive data, please see Table Group demographic and clinical background variables are shown in Table sex p = .67, SES a3.23, FT: 2711.6 ± 27.6 mm3; F = 12.8, p < .001; right hippocampus: VP/VLBW: 2686.8 ± 29.3 mm3, FT: 2823.5 ± 28.1 mm3; F = 10.4, p = .001. At the level of functional units, we also observed significant group differences with lower HP and SC volumes in VP/VLBW individuals: left SC: VP/VLBW: 571.1 ± 7.7 mm3, FT: 612.2 ± 7.4 mm3; p < .001; left HP: VP/VLBW: 837.6 ± 10.2 mm3, FT: 871.1 ± 9.8 mm3; p = .025; right SC: VP/VLBW: 592.1 ± 7.7 mm3, FT: 623.9 ± 7.4 mm3; p = .005; right HP: VP/VLBW: 880.7 ± 10.8 mm3, FT: 923.6 ± 10.4 mm3; p = .007). For detailed information, please see Table Using a general linear model we found lower volumes in VP/VLBW adults for all investigated HCSF presubiculum, parasubiculum, subiculum CA1, CA2‐3, CA4, DG and molecular layer, after correction for scanner, sex, and TIV  using partial correlation analyses. Significant correlations, controlled for multiple testing, were observed with GA in 9 out of 16 HCSF volumes, most notably with the subiculum bilaterally and left CA1. No significant correlations were observed between BW and HCSF. High neonatal treatment intensity showed a significant, inverse association with 8 out of 16 HCSF, most notably bilateral subiculum and CA‐1. Detailed results are given in Table Investigating functional hippocampus units , we found significant correlations between all studied volumes, namely bilateral HP, SC and DG and GA and neonatal treatment intensity. Again, no correlations were observed with BW. For detailed results, please see Table 3.3In order to investigate the relevance of HCSF volume reductions for cognitive performance, we studied the association between altered HCSF volumes and adult FS‐IQ using correlation analyses. Significant positive associations, controlled for multiple testing, were found between left‐sided CA2‐3, CA4 and DG volumes and adult FS‐IQ. For detailed results, please see Table Investigating functional hippocampus units, we found significant correlations between left‐sided volumes, namely HP, SC, and DG volumes and adult FS‐IQ. No correlations were observed between volumes of right‐sided functional hippocampus units and FS‐IQ. For detailed results, please see Table c = 1.357 ± 0.573; 95% CI: 0.220–2.494; p = .020. The direct effect of GA on adult FS‐IQ remained significant . The bootstrapped 95% CI determined that the indirect effect mediated by the left DG volume was significantly different from zero , indicating a significant mediation effect on the association between GA and adult FS‐IQ. As determined by the 95% CIs, no significant indirect effect of the other functional hippocampus units included as mediators was observed. For detailed coefficients of indirect effects, please see Table We studied a possible effect of functional hippocampus units on the association between low GA and adult FS‐IQ by use of mediation analyses. We set low GA as causal variable, FS‐IQ as outcome variable and added six mediators in the same mediation model, namely left and right volumes of HP, SC and DG  and to reject MRI assessment due to their stronger impairments and related lower level of general activity. Thus, differences in HCSF volumes between VP/VLBW and term‐born control adults reported here are conservative estimates of true differences. Classically, neurocognitive tests focusing on declarative memory are used in order to test hippocampus function clinically. However, no dedicated memory tests such as the MST were acquired in our study and we used FS‐IQ scores to correlate HCSF volumes with general cognitive performance. In our opinion, this is justified due to the large amount of hippocampus functions apart from memory encoding and retrieval such as spatial navigation or learning. It seems reasonable that especially impaired learning mechanisms might lead to impaired FS‐IQ in adulthood after premature birth. However, this rather indirect connection must be noted as a limitation. One of the strengths of our study is its large sample size (103 VP/VLBW and 109 FT adults), which enhances the generalizability of our findings. Moreover, the homogeneous and small age range of the study population in adulthood excludes effects of chronological age differences. Another strength of our study is that high‐quality brain imaging was performed so that both high‐resolution T1‐weighted and T2‐weighted input images could be used for HCSF segmentation. Advances in automated segmentation pipelines have made this study possible because the high workload of manual delineations severely limits sample size in brain imaging studies. However, several concurrent automated segmentation protocols have been published with slight differences with regard to subfield definition (Mueller et al., 4.6Our results show a general reduction of HCSF volumes in adulthood after premature birth, associated with low GA and high neonatal treatment intensity, not BW. We propose a potential dominating effect of a shifted developmental trajectory after premature birth over a special vulnerability of HCSF. Moreover, we demonstrated a significant mediation effect of left DG on the relationship between low GA and adult FS‐IQ as well as for long‐term cognitive development, underlining the functional relevance of this HCSF that is important for pattern separation and adult neurogenesis. In our opinion, this underlines that the hippocampus may constitute a potential treatment target for interventions aiming at improving long‐term cognitive outcomes after premature birth. Future studies will be needed in order to integrate several modules of impaired brain development after premature birth into a more complete framework with respect to social, biological, and psychological factors.The authors declare no conflict of interest.AppendixS1: Supporting InformationClick here for additional data file.