Fetal brain development in diabetic guinea pigs

Fetal brain development was investigated near term in guinea pigs rendered diabetic with streptozotocin. The liver and the placenta were used as reference organs. Compared to controls, those fetuses from diabetic animals had normal cerebrum and cerebellum weights, but higher liver and placenta weights in relation to fetal weights. Although liver and placenta cell number (DNA content) was unchanged, it was significantly increased in the fetal cerebrum and cerebellum of diabetics. Although the tissue protein concentration was decreased in the liver and the placenta, it was unchanged and even increased in the cerebrum and cerebellum, respectively. The concentration of myelin (cerebroside-sulfatide) was unchanged in the cerebrum, but it was increased in the cerebellum of diabetic animals. These data suggest that diabetes has a growth-promoting effect on the fetal brain cell number. Furthermore, differences in the protein content between fetal organs may reflect abnormalities in protein metabolism which do not affect the brain during diabetic pregnancies.     

Human fetal hand size and hand maturity in the first half of the prenatal period

The purpose of the present study has been to establish radiographic standards of hand length and finger bone size in the first half of the prenatal period, and to relate these measurements to general fetal size (CRL) and foot length (FL), as well as to the skeletal maturity assessed from a Composite Number of Ossified bones in hand and foot radiographs (CNO). The right hand and foot of each of 251 normal human fetuses (CRL 47–194 mm) were radiographed. From each hand radiograph hand length (DM), third proximal phalangeal bone length (PP) and third metacarpal bone length (MC) were measured. The study showed that third proximal phalangeal and metacarpal bone lengths both provide a valuable basis for estimating hand length. Both hand length and the length of the third metacarpal bone were found to be good predictors of general fetal size (CRL). The study provides standards for the relationships between hand and finger bone sizes, general fetal length and foot length. By combining third metacarpal bone size and skeletal maturity of the hand and foot general fetal development (age and crown-rump length) can be estimated. Insight into normal hand size and finger bone size at different stages of normal development including skeletal maturation is useful in future evaluation of handsize under pathological conditions.     

Dynamics of gyrification in the human cerebral cortex during development

This study quantitatively characterized cortical gyrus folding over human neocortical development by calculating the gyrification index (GI) in 22 human fetal specimens from 16 to 40 weeks with magnetic resonance imaging data. GI values remained constant at approximately 1.0 until the fetal specimens reached 500 g body weight and 200 mm crown‐rump length (CRL), respectively, and then increased in correlation with the body weight and CRL. The rostrocaudal GI distribution in the cerebral cortex revealed a correspondence of GI peaks with indentations of early‐generated primary sulci at 21 weeks of gestation and more frequently increased GI values in the parieto‐occipital region than in the fronto‐temporal region at 31 and 40 weeks of gestation. These results provide a quantitative reference set for gyrification in normal human cortical development, which may help reveal the mechanism of neurodevelopmental disorders.     

Morphological features and length measurements of fetal lateral ventricles at 16–25 weeks of gestation by magnetic resonance imaging

Normal growth of the lateral ventricles (LVs) was characterized three‐dimensionally using magnetic resonance imaging (MRI) data from 16 human fetuses at 16–25 weeks of gestation. The LV was differentiated into four primary regions, the anterior horn, central parts, posterior horn, and inferior horn, at 16 weeks of gestation. The LV changed shape mainly by elongation and narrowing, which corresponded to the external and internal growth of the surrounding cerebrum. Six length parameters measured in the LV correlated with biparietal diameter by simple regression analysis (R² range, 0.56–0.93), which may be valuable for establishing a standardized prenatal protocol to assess fetal well‐being and development across intrauterine periods. No correlation was found between biparietal diameter and LV volume (R² = 0.13).     

Development of olfactory epithelium in the human fetus: Scanning electron microscopic observations

Aims:  Human olfactory epithelium becomes functional at birth, but prenatal development remains unclear. In the present study, we aimed to clarify the development of human olfactory epithelium using scanning electron microscopy (SEM).
Methods:  The development of human olfactory epithelium was observed in 24 externally normal fetuses, which were formalin-fixed and long-preserved, with a crown-rump length (CRL) of 102–336 mm (gestational week 14–38). The olfactory mucosa in the superior wall of the nasal septum near the choana were dissected and observed under SEM. We examined the number of olfactory vesicles per unit area, diameter of olfactory vesicles, and number and length of cilia on olfactory vesicles.
Results:  At circa (ca) CRL 100 mm (ca 14 weeks), olfactory epithelium displayed several olfactory vesicles with 1–2 short cilia per unit area. At ca CRL 150 mm (ca 18 weeks), olfactory vesicles were present in small clusters, and cilia were longer. At CRL lager than 225 mm (ca 26 weeks), olfactory vesicles became located separately from each other, while length and number of cilia per olfactory vesicle were further increased.
Conclusion:  The present findings suggest that fetal olfactory epithelium becomes morphologically almost the same as that in adults in late gestation, much later than previously thought.     

Individual variation in organ histogenesis as a causative factor in the developmental origins of health and disease: Unnoticed congenital anomalies?

Morphological studies of congenital anomalies have mainly focused on abnormal shape (i.e. malformation) and thus on disturbed organogenesis. However, in regard to postnatal functions of organs that develop through branching mechanisms, organ size is another important morphological feature. These organs consist of a large number of structural and functional units, such as nephrons in the kidney, and the total number of these units, that is approximately proportional to the organ size, has been shown to vary widely among individuals. Organ‐specific cells are differentiated and organized to form structural units and realize organ‐specific functions during the histogenetic period (i.e. from mid‐gestation to the early postnatal period). The total number of units is attained at the end of histogenesis and determines the total functional capacity, including the functional reserve of the organ, and thus may be related to predispositions to postnatal organ‐based diseases, because the functional reserve decreases during the course of life and eventually become short of the minimum requirement of each organ. Therefore, it may be hypothesized that a smaller number of units of organs at the end of histogenesis is one of the predisposing factors for postnatal diseases (i.e. a form of unnoticed but late‐manifested congenital anomalies), in this era of extended longevity. However, the mechanisms that control the total number of units in each organ during histogenesis and the possible relationship among the numbers of units in different organs remain unknown. Here, we review our trials based on the above hypothesis in order to (1) mathematically analyze the morphometric data of the different organs in fetuses to elucidate relationship among developing organs, (2) analyze the developing neuro‐immuno‐endocrine network as a series of mechanisms to systemically correlate the histogenesis of multiple organs, and (3) examine the maternal environment, including dietary fat, as a factor to influence histogenesis and thus the predisposition to type 1 diabetes.     

Effect of a micronutrient‐rich snack taken preconceptionally and throughout pregnancy on ultrasound measures of fetal growth: The Mumbai Maternal Nutrition Project (MMNP)

Improving micronutrient intakes of under‐nourished mothers in low‐ and middle‐income countries increases birth weight, but there is little data on the nature and timing during gestation of any effects on fetal growth. Ultrasound measures of fetal size were used to determine whether and when a food‐based supplement affected fetal growth. Non‐pregnant women living in Mumbai slums, India (N = 6,513), were randomly assigned to receive either a daily micronutrient‐rich snack containing green leafy vegetables, fruit, and milk (treatment) or a snack made from lower‐micronutrient vegetables (control) in addition to their usual diet from before pregnancy until delivery. From 2,291 pregnancies, the analysis sample comprised 1,677 fetuses (1,335 fetuses of women supplemented for ≥3 months before conception). First‐trimester (median: 10 weeks, interquartile range: 9–12 weeks) fetal crown‐rump length was measured. Fetal head circumference, biparietal diameter, femur length, and abdominal circumference were measured during the second (19, 19–20 weeks) and third trimesters (29, 28–30 weeks). The intervention had no effect on fetal size or growth at any stage of pregnancy. In the second trimester, there were interactions between parity and allocation group for biparietal diameter (p = .02) and femur length (p = .04) with both being smaller among fetuses of primiparous women and larger among those of multiparous women, in the treatment group compared with the controls. Overall, a micronutrient‐rich supplement did not increase standard ultrasound measures of fetal size and growth at any stage of pregnancy. Additional ultrasound measures of fetal soft tissues (fat and muscle) may be informative.     

Nasal bone length in human fetuses by X-ray

BACKGROUND: To construct a normal range for the prenatal nasal bone length (NBL) in Brazilians irrespective to the knowledge of the ethnic genetic background. STUDY DESIGN: We studied 35 human fetuses (20 males, 15 females) ranging from 14 to 22 weeks of gestation. Gestational age (GA), crown-rump length (CRL), foot length (FL) and body mass (BM) were measured. The X-ray of the head lateral view was made with the specimens placed directly on the film and the NBL was measured. The NBL was correlated with the GA, the CRL, the FL, and the BM using log-transformed data and the allometric model log y=log a+b log x. RESULTS: Correlations of the NBL growth with GA, CRL, FL, and BM were positive and significant (P<0.05), but NBL vs. BM showed the smallest R indicating this correlation as of little practical use. No sexual dimorphism in the NBL growth in the second trimester fetuses was observed. The NBL grew with positive allometry relative to GA, CRL and BM, but it was allometrically slightly negative relative to the FL in both genders. The NBL be allometrically positive against GA, CRL and BM means the bone grew with growth rates higher than those indices in the period analyzed, but not against FL. CONCLUSION: NBL could be considered an auxiliary measurement in the assessment of the 2nd trimester fetal development because its strong correlation with GA, CRL and FL, even when nothing is known about the ethnicity of the population.     

A 5‐HT2A/2C receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane,mitigates developmental neurotoxicity of ethanol to serotonergic neurons

Prenatal ethanol exposure causes the reduction of serotonergic (5‐HTergic) neurons in the midbrain raphe nuclei. In the present study, we examined whether an activation of signaling via 5‐HT_2A and 5‐HT_2C receptors during the fetal period is able to prevent the reduction of 5‐HTergic neurons induced by prenatal ethanol exposure. Pregnant Sprague–Dawley rats were given a liquid diet containing 2.5 to 5.0% (w/v) ethanol on gestational days (GDs) 10 to 20 (Et). As a pair‐fed control, other pregnant rats were fed the same liquid diet except that the ethanol was replaced by isocaloric sucrose (Pf). Each Et and Pf group was subdivided into two groups; one of the groups was treated with 1 mg/kg (i.p.) of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), an agonist for 5‐HT_2A/2C receptors, during GDs 13 to 19 (Et‐DOI or Pf‐DOI), and another was injected with saline vehicle only (Et‐Sal or Pf‐Sal). Their fetuses were removed by cesarean section on GD 19 or 20, and fetal brains were collected. An immunohistological examination of 5‐HTergic neurons in the fetuses on embryonic day 20 using an antibody against tryptophan hydroxylase revealed that the number of 5‐HTergic neurons in the midbrain raphe nuclei was significantly reduced in the Et‐Sal fetuses compared to that of the Pf‐Sal and Pf‐DOI fetuses, whereas there were no significant differences between Et‐DOI and each Pf control. Thus, we concluded that the reduction of 5‐HTergic neurons that resulted in prenatal ethanol exposure could be alleviated by the enhancement of signaling via 5‐HT_2A/2C receptors during the fetal period.     

宫内生长受限新生儿多系统器官损害与临床管理

胎儿时期是各系统器官发育形成的关键时期,宫内生长环境的改变可导致胎儿-新生儿多系统器官损害,并与成人期疾病密切相关,包括神经系统损害(如脑发育障碍、功能异常及脑瘫等)、心血管系统损害(如冠心病、高血压等)、生长障碍与代谢性疾病(如胰岛素抵抗、2型糖尿病、肥胖症、生长发育障碍等)、泌尿系统损害(如肾间质性疾病、肾性高血压等)、呼吸系统损害(如呼吸窘迫综合征、支气管肺发育不良等)等,本文对此予以介绍,以助于临床医师对胎儿生长受限的认识及加强相关干预措施,提高其生存质量.     

Assessment of the Fetal Heart at 12–14 Weeks of Pregnancy Using B-Mode, Color Doppler, and Spatiotemporal Image Correlation via Abdominal and Vaginal Ultrasonography

This study aimed to evaluate the effect that combining multiple ultrasonographic imaging methods has on the proportion of tests with a satisfactory fetal heart assessment at 12–14 weeks of pregnancy using B-mode, color Doppler, and spatiotemporal image correlation software (STIC) via both the abdominal and vaginal routes. This cross-sectional prospective study involved healthy pregnant women at 12–14 weeks of pregnancy with a crown-rump length (CRL) of 84 mm or shorter. The following four cardiac views were assessed: four-chamber, left and right ventricular outflow tract, and aortic arch views. The same examiner sought to identify these four views using B-mode, color Doppler, and STIC via both the vaginal and abdominal routes. The study determined the proportion of cases and the respective 95 % confidence intervals (CIs) in which all four views were identified. The presence of significant differences in comparisons between methods was analyzed using McNemar’s test. Although 57 pregnant women at 12–14 weeks of pregnancy agreed to participate in the study, 4 were not included because they presented with a CRL longer than 84 mm. Thus, 53 pregnant women were thoroughly assessed and included in the analysis. The combination of B-mode, color Doppler, and STIC via both the abdominal and vaginal routes enabled the highest proportion of identification of the four views (90.6 %; 95 % CI, 79.8–95.9 %). The lowest proportions were observed when B-mode was used alone via both the vaginal route (30.2 %; 95 % CI, 19.5–43.5 %) and the abdominal route (37.7 %; 95 % CI, 25.9–51.2 %). The abdominal route showed results slightly better than those of the vaginal route with all the methods, but the differences were not statistically significant. In the vast majority of the cases, the fetal hearts were properly assessed at 12–14 weeks of pregnancy when several methods were combined using both the abdominal and vaginal routes. However, only one-third of them would have had adequate heart assessment if the B-mode via either the abdominal or the vaginal route had been used alone.     

Growth and motor development in fetuses of women with type-1 diabetes. I. Early growth patterns

Early embryonic and fetal growth were followed longitudinally in 23 women with type-1 diabetes to investigate whether there was any evidence of early growth delay and, if so, when it originated and when catch-up growth occurred. Weekly crown-rump length (CRL) measurements were taken between 7 and 14 weeks of gestation; the biparietal diameter (BPD) of the fetal head was measured once every 2-4 weeks from 13 to 30 weeks of gestation. Data were compared to those of a control group and to control data published in the literature. The CRL of the fetuses in the diabetic group was generally shorter than that observed normally. Six out of the 23 (26%) fetuses showed true early growth delay (a size smaller than normal by 6 days or more). Growth delay was present from the first recording onwards and must therefore have occurred before the seventh gestational week. Fetal growth (BPD) was found to be normal at around 20 weeks and there was evidence of accelerated growth of the BPD during the second trimester in fetuses that became macrosomic. Early embryonic growth delay was most profound in the women whose periconceptional quality of glucose control was poor, although the relationship with the HbAlc values was not statistically significant. It is concluded that fetuses of women with type-1 diabetes, as a group, have a significantly different growth pattern than control fetuses throughout the first 30 weeks of pregnancy.     

Factors associated with catch‐up growth in early infancy in rural Pakistan: A longitudinal analysis of the women's work and nutrition study

The adverse health impacts of early infant stunting can be partially ameliorated by early catch‐up growth. Few studies have examined predictors of and barriers to catch‐up growth to identify intervention points for improving linear growth during infancy. This study aimed to estimate the prevalence of, and factors associated with, catch‐up growth among infants in Pakistan. A longitudinal study of mother–infant dyads (n = 1,161) was conducted in rural Sindh province, with enrolment between December 2015 and February 2016 (infants aged 0.5–3 months), and follow‐up (n = 1035) between November 2016 and January 2017 (infants aged 9–15 months). The outcome was catch‐up growth (change in conditional length‐for‐age z‐scores >0.67 between baseline and endline). Associated factors were examined using multivariable logistic regression analyses. The prevalence of stunting was 45.3% at baseline and 60.7% at follow‐up. 22.8% of infants exhibited catch‐up growth over this period. Factors positively associated with catch‐up growth included maternal height (odds ratio (OR) = 1.08 [1.05–1.11]), household wealth (OR = 3.61 [1.90–6.84]), maternal (OR = 2.43 [1.30–4.56]) or paternal (OR = 1.46 [1.05–2.03]) education, and households with two or more adult females (OR = 1.91 [1.26–2.88]). Factors negatively associated with catch‐up growth were two (OR = 0.64 [0.45–0.89]) or three or more (OR = 0.44 [0.29–0.66]) preschool children in the household and the infant being currently breastfed (OR = 0.59 [0.41–0.88]). Catch‐up growth was exhibited among approximately a quarter of infants despite living in challenging environments associated with extremely high rates of early infant stunting. Several modifiable factors were identified that might represent suitable programme intervention points to off‐set early infant stunting in rural Pakistan.     

Alterations in the rate of fetal and placental development as a consequence of early maternal protein/calorie restriction.

The in utero growth rates have been determined for the body, brain, and the placenta in the rat. The accumulation of cell number (DNA content) and protein content in the cerebrum and the placenta were investigated during normal development. When rats were exposed to a severe reduction in protein/calorie intake during the first 10 days of pregnancy and the fetal growth rates were compared to those of the normal control animals, highly significant differences were observed. Pregnant rats, which were restricted in their protein/calorie intake during the early part of pregnancy, significantly prolonged the gestation time. When this increase of in utero time is taken into consideration and the offspring are compared at the time of natural birth, the data presented demonstrate the possibility of in utero catch up growth. The variations, in fetal development within the same litter and across litters, demonstrate a considerable plasticity during normal development in utero.     

新生儿窒息多器官功能损害的危险因素分析

目的：探讨新生儿窒息多器官功能损害的危险因素,为预防窒息后新生儿多器官功能损害提供理论依据。方法：2009年1月至2010年12月窒息患儿共397例,其中合并多器官功能损害患儿179例作为观察组,无多器官损害患儿218例为对照组,回顾性分析影响新生儿窒息后多器官功能损害的危险因素。 结果：多因素logistic 回归分析显示：重度窒息、宫内窘迫、异常分娩、羊水减少为新生儿窒息后多器官功能损害的独立危险因素。经Spearman秩相关发现,受累器官个数随入院日龄的增加而增多（P<0.05）,随胎龄、出生体重的降低而增多（均P<0.05）。结论：临床上应加强围产期监护,特别要重视对早产儿和低出生体重儿的监护,从而降低多器官功能损害的发生率。     

Organ weight/bodyweight ratios: Growth rates of fetal organs in the latter half of pregnancy with a simple method for calculating mean organ weights

Ratios for major organ weights compared with bodyweights of 1023 stillborn and liveborn babies who lived less than 72 h are presented. The ratios were calculated for 2 week increments of gestational age from 20 to 43 weeks and clearly depict the relative growth of fetal organs during the last half of pregnancy. The ratios for heart and for kidneys were virtually constant for the whole period of gestation examined. The ratios for thymus and spleen increased between 20 and 30 weeks gestation and then became constant, although the ratio for the spleen dropped slightly during the last 6 weeks. The ratios for liver, lungs and adrenals decreased between 20 and 30 weeks gestation, and then steadied. The ratio for brain declined very slowly throughout the period examined. An observation of practical importance was that all organ weight/bodyweight ratios were virtually constant after 30 weeks gestation. Approximate mean organ weight/bodyweight ratios between 30 and 43 weeks gestation were: heart 0.007, lungs 0.02, spleen 0.003, liver 0.04, kidneys 0.01, adrenals 0.003, thymus 0.004 and brain 0.13. By multiplying the mean ratio by the total bodyweight, the approximate mean weight for a particular fetal organ can be calculated in situations where charts of normal organ weights are not at hand.     

Organ-specific maturation of the major histocompatibility antigens in rats

The essential role of major histocompatibility complex (MHC) class I and II in the process of rejection has been documented, and some studies suggest that fetal transplants could enjoy an organ-specific immunologic privilege. However, little is known as to when these antigens develop in fetal organs and which tissues mainly present them. This study investigated the dynamics of immunogenicity in the developing transplant organs of rats. The study focused on the classic transplant organs including lung, heart, liver, pancreas, intestine, and kidney. Fetal organs (14th and 20th day of gestation), organs at the 3rd, 7th, 10th, 14th and 28th days postpartum (pp), 2 and 3 months pp, and adult organs were taken and snap-frozen in liquid nitrogen. MHC expression was analyzed applying the APAAP technique on serial cryosections by two well-defined monoclonal antibodies (mAb) generated against rat MHC class I (Ox 18) and class II (Ox 6). Immunoreactivities were compared to those of different monoclonal markers against endothelial cells (HIS52, CD 31), histiocytes (ED 1, ED 2), dendritic cells (Ox-62), granulocytes (HIS48), B-cells (RLN-9D3), T-cells (Ox-52), CD 4 (Ox-35), CD 8 (Ox-8a), natural killer cells (10/78), and CD 45 (Ox-1, leukocyte common antigen). A non specific mAb (MR 12/53) served as a negative control. In all stages of organ maturation, MHC I expression was found predominantly on immunocompetent cells, endothelial cells, and certain parenchymal cells, whereas MHC II was almost entirely restricted to dendritic cells. In organ development, the onset of MHC I expression and the number of MHC II-positive cells varied in a time-dependent manner. However, between the 2nd and 3rd month pp the expression pattern was comparable to adult organs. The study indicates that each organ carries a variable immunologic burden, that matures heterogeneously. Consequently, the variable content of MHC I/II in organ maturation needs to be considered for any transplantation model.     

The placenta, PGE2 and parturition.

It is proposed that prostaglandin E2 (PGE2), secreted by the fetal placenta of the sheep, acts as a circulating regulator of the physiological function of many fetal organs (tissue) in a way analogous to catecholamines in the adult. The specificity of PGE2 action in different tissues is determined by three different receptor subtypes which regulate intracellular calcium concentrations via the IP3 pathway, or cyclic AMP concentrations via the adenylcyclase system. The placenta, by secreting PGE2 (and possibly other factors such as adenosine), modifies the function of key organ systems allowing the fetus to survive and develop in the aqueous environment of the uterus. During fetal development, fetal organs and metabolic pathways can mature while their function is suppressed by placental PGE2. At birth, by ligating the cord and removing the placenta as the source of these inhibitory substances, the newborn is able to adapt readily to its new environment with fully-functional, mature organ systems. This paper discusses how placental PGE2 may regulate fetal breathing movements, whether the removal of placental PGE2 is involved in the initiation of continuous breathing at birth, and whether it suppresses the activity of the peripheral chemoreceptors during fetal life. The ability of PGE2 to maintain a widely patent ductus arteriosus, to suppress non-shivering thermogenesis, to stimulate fetal insulin secretion and to suppress the hepatic gluconeogenic pathway in the fetus is also discussed. Finally, the ability of PGE2 to activate the fetal hypothalamo-pituitary-adrenal axis is discussed, raising the possibility that the placenta also plays a key role in the initiation of birth in this species.