Maternal B cell signaling orchestrates fetal development in mice.

B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19-/-) mice, females with B cell-specific MyD88 (BMyD88-/-) or IL10 (BIL10-/-) deficiency as well as wild-type and MyD88-/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88-/- and MyD88-/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL10 resulted in decreased implantation areas at gestational day (gd) 5, gd8 and gd10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL10-/- dams at gd10. Challenge with 0.4 mg lipopolysaccharide/kg bodyweight at gd16 revealed that BMyD88-/-, BIL10-/- and CD19-/- mothers delivered preterm, whereas controls maintained their pregnancy. B cell-specific MyD88 and IL10 expression is essential for appropriate in utero development. IL10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL10 expression influences susceptibility towards preterm birth.

Does PM1 exposure during pregnancy impact the gut microbiota of mothers and neonates?

BACKGROUND: Ambient air pollutant exposure can change the composition of gut microbiota at 6-months of age, but there is no epidemiological evidence on the impacts of exposure to particulate matter with an aerodynamic diameter ≤1 µm (PM1) during pregnancy on gut microbiota in mothers and neonates. We aimed to determine if gestational PM1 exposure is associated with the gut microbiota of mothers and neonates. METHODS: Leveraging a mother-infant cohort from the central region of China, we estimated the exposure concentrations of PM1 during pregnancy based on residential address records. The gut microbiota of mothers and neonates was analyzed using 16 S rRNA V3-V4 gene sequences. Functional pathway analyses of 16 S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The impact of PM1 exposure on α-diversity, composition, and function of gut microbiota in mothers and neonates was evaluated using multiple linear regression, controlling for nitrogen dioxide (NO2) and ozone (O3). Permutation multivariate analysis of variance (PERMANOVA) was used to analyze the interpretation degree of PM1 on the sample differences at the OTU level using the Bray-Curtis distance algorithm. RESULTS: Gestational PM1 exposure was positively associated with the α-diversity of gut microbiota in neonates and explained 14.8% (adj. P = 0.026) of the differences in community composition among neonatal samples. In contrast, gestational PM1 exposure had no impact on the α- and ß-diversity of gut microbiota in mothers. Gestational PM1 exposure was positively associated with phylum Actinobacteria of gut microbiota in mothers, and genera Clostridium_sensu_stricto_1, Streptococcus, Faecalibacterium of gut microbiota in neonates. At Kyoto Encyclopedia of Genes and Genomes pathway level 3, the functional analysis results showed that gestational PM1 exposure significantly down-regulated Nitrogen metabolism in mothers, as well as Two-component system and Pyruvate metabolism in neonates. While Purine metabolism, Aminoacyl-tRNA biosynthesis, Pyrimidine metabolism, and Ribosome in neonates were significantly up-regulated. CONCLUSIONS: Our study provides the first evidence that exposure to PM1 has a significant impact on the gut microbiota of mothers and neonates, especially on the diversity, composition, and function of neonatal meconium microbiota, which may have important significance for maternal health management in the future.

Gaps in the knowledge of thyroid hormones and placental biology†.

Thyroid hormones (THs) are required for the growth and development of the fetus, stimulating anabolism, and oxygen consumption from the early stages of pregnancy to the period of fetal differentiation close to delivery. Maternal changes in the hypothalamic-pituitary-thyroid axis are also well known. In contrast, several open questions remain regarding the relationships between the placenta and the maternal and fetal TH systems. The exact mechanism by which the placenta participates in regulating the TH concentration in the fetus and mother and the role of TH in the placenta are still poorly studied. In this review, we aim to summarize the available data in the area and highlight significant gaps in our understanding of the ontogeny and cell-specific localization of TH transporters, TH receptors, and TH metabolic enzymes in the placenta in both human and rodent models. Significant deficiencies also exist in the knowledge of the contribution of genomic and nongenomic effects of TH on the placenta and finally, how the placenta reacts during pregnancy when the mother has thyroid disease. By addressing these key knowledge gaps, improved pregnancy outcomes and management of women with thyroid alterations may be possible.

Maternal lipid profile in pregnancy and embryonic size: a population-based prospective cohort study.

BACKGROUND: Lipids are crucial for fetal growth and development. Maternal lipid concentrations are associated with fetal growth in the second and third trimester of pregnancy and with birth outcomes. However, it is unknown if this association starts early in pregnancy or arises later during fetal development. The aim of this study was to investigate the association between the maternal lipid profile in early pregnancy and embryonic size. METHODS: We included 1474 women from the Generation R Study, a population based prospective birth cohort. Both embryonic size and the maternal lipid profile were measured between 10 weeks + 1 day and 13 weeks + 6 days gestational age. The maternal lipid profile was defined as total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), remnant cholesterol, non-high-density (non-HDL-c) lipoprotein cholesterol concentrations and the triglycerides/high-density lipoprotein (TG/HDL-c) ratio. Additionally, maternal glucose concentrations were assessed. Embryonic size was assessed using crown-rump length (CRL) measurements. Associations were studied with linear regression models, adjusted for confounding factors: maternal age, pre-pregnancy body mass index (BMI), parity, educational level, ethnicity, smoking and folic acid supplement use. RESULTS: Triglycerides and remnant cholesterol concentrations are positively associated with embryonic size (fully adjusted models, 0.17 SDS CRL: 95% CI 0.03; 0.30, and 0.17 SDS: 95% CI 0.04; 0.31 per 1 MoM increase, respectively). These associations were not present in women with normal weight (triglycerides and remnant cholesterol: fully adjusted model, 0.44 SDS: 95% CI 0.15; 0.72). Associations between maternal lipid concentrations and embryonic size were not attenuated after adjustment for glucose concentrations. Total cholesterol, HDL-c, LDL-c, non-HDL-c concentrations and the TG/HDL-c ratio were not associated with embryonic size. CONCLUSIONS: Higher triglycerides and remnant cholesterol concentrations in early pregnancy are associated with increased embryonic size, most notably in overweight women. TRIAL REGISTRATION: The study protocol has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (Erasmus MC), Rotterdam (MEC-2007-413). Written informed consent was obtained from all participants.

Prenatal oestrogen-testosterone balance as a risk factor of migraine in adults.

BACKGROUND: Migraine is a common neurological disease with extremely debilitating, but fully reversible symptoms. Women suffer from migraine more often than men. It was assumed that fluctuation of oestrogen level during menstrual cycle is one of many factors responsible for more frequent migraine attacks. The second-to-fourth digit ratio (2D:4D) is considered as an indicator of prenatal sex steroids. Balance of prenatal androgens (testosterone) and oestrogen has been studied in numerous diseases that are affected by hormones. However, the relationship between migraine and the sex steroids balance in prenatal development is still unexplained. The aim of this paper is to provide an evidence of relationship between prenatal oestrogen and testosterone exposure following 2D:4D digit ratio, and migraine prevalence in adults. METHODS: We examined a group of 151 adults (33 males, 118 females) with migraine and a control group of 111 adults (45 males, 66 females). 2D:4D digit ratio of both hands was measured using sliding Vernier calliper. RESULTS: Significant differences were found in the right hand. Female migraineurs had lower value of 2D:4D ratio than the control group and the right 2D:4D was lower than left 2D:4D (Δ2D:4D), suggesting prenatal testosterone dominance. The opposite relationship was observed in males. Male migraineurs had higher value of 2D:4D ratio and Δ2D:4D was greater than the control group, suggesting prenatal oestrogen dominance. CONCLUSIONS: Our results suggest that depending on sex, different proportion of prenatal sex steroids might be a risk factor of migraine in adults. Women with migraine were presumably exposed in prenatal life to higher testosterone levels relative to oestrogen, while men with migraine were probably exposed in prenatal life to higher levels of oestrogen relative to testosterone.

Transcriptional and translational dynamics during maternal-to-zygotic transition in early chicken development.

Maternal-to-zygotic transition (MZT) is the critical process for the establishment of embryonic identity across vertebrates. During this period, the massive transcriptional activation, called zygotic genome activation (ZGA), is mediated by maternally stored factors, and maternal mRNA clearance by conserved zygotic microRNAs (miRNAs) occurs; however, the important transition in avian species was identified by morphologic perspectives only. In this study, we performed transcriptome analysis to examine the molecular transitions of intrauterine development in chickens. On the basis of coexpression analyses on RNA sequencing data, 2 waves of ZGA-mediated MZT were observed across the early embryonic stages and were associated with transcriptional and translational dynamics. Furthermore, definite transitions were observed according to the distinct developmental characteristics between cleavage and the area pellucida formation period in the functional analysis. Finally, epigenetic modification and the evolutionarily conserved miRNA expression suggest that certain MZT proceeds from Eyal-Giladi and Kochav stage VIII in early chicken development. We expect our study to provide an evolutionary link among vertebrates from the perspective of MZT regulation.-Hwang, Y. S., Seo, M., Bang, S., Kim, H., Han, J. Y. Transcriptional and translational dynamics during maternal-to-zygotic transition in early chicken development.

Fetal Smoke Exposure and Kidney Outcomes in School-Aged Children.

BACKGROUND: Fetal smoke exposure may result in developmental adaptations that permanently affect the developing kidney. In this study, the associations of maternal and paternal smoking during pregnancy with childhood kidney size and function were assessed. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: This study was conducted in a group of 5,622 children in Rotterdam, the Netherlands. PREDICTORS: Maternal and paternal smoking were assessed during pregnancy by questionnaires. OUTCOMES & MEASUREMENTS: At a median age of 6.0 (5th-95th percentile, 5.6-7.9) years, we measured childhood kidney volumes, estimated glomerular filtration rate (eGFR), and albumin-creatinine ratio. RESULTS: The confounder model, which included size at birth, shows that compared with children from mothers who did not smoke during pregnancy, those from mothers who continued smoking during pregnancy had smaller combined kidney volumes at the age of 6 years. The strongest effect estimate was observed for mothers who smoked 5 or more cigarettes per day during pregnancy (difference for combined kidney volume, -2.80 [95% CI, -5.15 to -0.45] cm(3)). Similarly, continued maternal smoking during pregnancy also was associated with a lower eGFR in childhood (difference, -2.25 [95% CI, -3.70 to -0.79] mL/min/1.73 m(2)). First-trimester-only smoking was associated with a higher risk of increased albumin-creatinine ratio (OR, 1.45; 95% CI, 1.05-2.01). Among mothers who did not smoke during pregnancy, paternal smoking was associated with smaller childhood combined kidney volume (difference, -1.78 [95% CI, -3.48 to -0.07] cm(3)), but not with childhood kidney function measures. LIMITATIONS: Smoking behavior was measured with questionnaires. Follow-up measurements were available for only 70% of the children. CONCLUSIONS: Continued maternal smoking during pregnancy is associated with smaller combined kidney volume and lower eGFR in school-aged children. Stronger effect estimates for maternal versus paternal smoking suggest that intrauterine adaptive responses may play a role as underlying mechanisms.

Day-1 chick development.

The first day of chick development takes place inside the mother hen (in utero), during which the embryo progresses from fertilization to late blastula/early gastrula formation. The salient features of developmental anatomy in this period are conserved among the sauropsids (birds and reptiles). Many of these features are also shared in prototherian (monotreme) embryos, whereas metatherian (marsupial) and eutherian (placental) embryos display significant variations. Important for understanding the evolution of early development in amniotes, the knowledge of cellular and molecular mechanisms regulating in utero chick development may also offer valuable insight into early lineage specification in prototherians and conserved features in mammalian early development. This commentary provides a snapshot of what is currently known about intrauterine chick development and identifies key issues that await further clarification, including the process of cellularization, allocation of maternal determinants, zygotic gene activation, mid-blastula transition, cell layer increase and reduction, radial symmetry breaking, early lineage segregation, and role of yolk syncytium in early patterning.

Diabetes Mellitus and Pregnancy: An Insight into the Effects on the Epigenome.

Worldwide, diabetes mellitus represents a growing health problem. If it occurs during pregnancy, it can increase the risk of various abnormalities in early and advanced life stages of exposed individuals due to fetal programming occurring in utero. Studies have determined that maternal conditions interfere with the genotypes and phenotypes of offspring. Researchers are now uncovering the mechanisms by which epigenetic alterations caused by diabetes affect the expression of genes and, therefore, the development of various diseases. Among the numerous possible epigenetic changes in this regard, the most studied to date are DNA methylation and hydroxymethylation, as well as histone acetylation and methylation. This review article addresses critical findings in epigenetic studies involving diabetes mellitus, including variations reported in the expression of specific genes and their transgenerational effects.

Heat Stress-Induced Fetal Intrauterine Growth Restriction Is Associated with Elevated LPS Levels Along the Maternal Intestine-Placenta-Fetus Axis in Pregnant Mice.

The exacerbation of the greenhouse effect has made heat stress (HS) an important risk factor for the occurrence of intrauterine growth restriction (IUGR). The experiment aims to uncover the effects of maternal HS on IUGR and its mechanisms. The results showed that HS leads to decreased maternal and fetal birth weights, accompanied by increased serum oxidative stress and cortisol levels. Moreover, HS inflicted significant damage to both the intestinal and placental barriers, altering maternal gut microbiota and increasing intestinal LPS levels. As a result, LPS levels increased in maternal serum, placenta, and fetus. Furthermore, HS damaged the intestinal structure, intensifying inflammation and disrupting the redox balance. The placenta exposed to HS exhibited changes in the placental structure along with disrupted angiogenesis and decreased levels of nutritional transporters. Additionally, the leakage of LPS triggered placental JNK and ERK phosphorylation, ultimately inducing severe placental inflammation and oxidative stress. This study suggests that LPS translocation from the maternal intestine to the fetus, due to a disrupted gut microbiota balance and compromised intestinal and placental barrier integrity, may be the primary cause of HS-induced IUGR. Furthermore, increased LPS leakage leads to placental inflammation, redox imbalance, and impaired nutrient transport, further restricting fetal growth.

Perinatal Stressors as a Factor in Impairments to Nervous System Development and Functions: Review of In Vivo Models.

The human body is faced with stress throughout ontogeny. At the stage of intrauterine development, the mother's body serves as a source of resources and most of the humoral factors supporting the development of the fetus. In normal conditions, maternal stress-related humoral signals (e.g., cortisol) regulate fetal development; however, distress (excessive pathological stress) in the perinatal period leads to serious and sometimes irreversible changes in the developing brain. The mother being in an unfavorable psychoemotional state, toxins and teratogens, environmental conditions, and severe infectious diseases are the most common risk factors for the development of perinatal nervous system pathology in the modern world. In this regard, the challenge of modeling situations in which prenatal or early postnatal stresses lead to serious impairments to brain development and functioning is extremely relevant. This review addresses the various models of perinatal pathology used in our studies (hypoxia, exposure to valproate, hyperserotoninemia, alcoholization), and assesses the commonality of the mechanisms of the resulting disorders and behavioral phenotypes forming in these models, as well as their relationship with models of perinatal pathology based on the impact of psychoemotional stressors.

Associations of maternal dietary patterns during pregnancy and fetal intrauterine development.

Dietary pattern is excellent in reflecting an individual's eating conditions. Longitudinal data on fetal growth can reflect the process of intrauterine growth. We aimed to evaluate the associations between maternal dietary patterns and intrauterine parameters in middle and late pregnancy. The present study was conducted within Jiangsu Birth Cohort (JBC) study. Dietary information was assessed with a food frequency questionnaire (FFQ) in the second and third trimester of gestation. B-ultrasound scans were performed to obtain fetal intrauterine parameters, including head circumference (HC), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW). Exploratory factor analysis was used to extract dietary patterns. Multiple linear regression and linear mixed-effects model (LMM) were used to investigate the association between maternal dietary patterns and fetal growth. A total of 1,936 pregnant women were eligible for the study. We observed inverse associations of maternal "Vegetables and fish" and "Snack and less eggs" patterns during mid-pregnancy with fetal HC Z-score, respectively ("Vegetables and fish": ß = -0.09, 95% CI -0.12, -0.06; "Snack and less eggs": ß = -0.05, 95% CI -0.08, -0.02). On the contrary, "Animal internal organs, thallophyte and shellfish" pattern in the second trimester was associated with increased HC Z-scores (ß = 0.04, 95% CI 0.02, 0.06). Consistently, score increase in "Vegetables and fish" pattern in the third trimester was inversely associated with the Z-scores of HC (ß = -0.05, 95% CI -0.09, -0.02), while "Meat and less nuts" pattern was positively correlated with the Z-scores of HC (ß = 0.04, 95% CI 0.02, 0.07). As compared to the fetus whose mothers at the lowest tertile of "Snack and less eggs" pattern in both trimesters, those whose mothers at the highest tertile demonstrated 1.08 fold (RR = 2.10, 95% CI 1.34-3.28) increased risk of small HC for gestational age (GA). No correlation was observed between maternal dietary patterns and other intrauterine parameters. Our results suggested the effects of maternal dietary patterns on fetal growth, particularly HC. These findings highlighted the adverse impact of unhealthy dietary pattern on fetal growth, might provide evidence for strategies to prevent intrauterine dysplasia and dietary guidelines during pregnancy.

The influence of litter birth weight phenotype on embryonic and placental development at day 30 of gestation in multiparous purebred Large White sows.

The aim of this study was to understand the intrauterine biological processes associated with the low litter birth weight phenotype in pigs. Analyses were conducted on reproductive data from a purebred Large White maternal line to identify sows (>2 parities) with repeatable high or low litter birth weight phenotype (HLBWP or LLBWP). A total of 40 sows were selected (n = 20 HLBWP and n = 20 LLBWP) and bred with semen from purebred Large White boars of proven fertility. Sows were euthanized on day 28-30 of gestation (day 29.5 ± 0.6) and samples of placenta and embryos collected. Total number of embryos (TNE), embryonic weight (EW), embryonic viability, and crown-rump (CRL) measurements were recorded, along with the ovulation rate (OR) and allantochorionic fluid volume (AFV). No significant difference was detected (P > 0.05) in OR, TNE, and number of viable embryos on day 30 of gestation between the two groups. There was no significant difference in EW (LLBWP: 0.80 ± 0.05 g; HLBWP: 0.88 ± 0.04 g, P = 0.18) or CRL (LLBWP: 21.5 ± 0.7 mm; HLBWP: 21.9 ± 0.68 mm, P = 0.46). Placental development represented by the average AFV was significantly lower in the LLBWP compared to HLBWP (LLBWP: 131 ± 9.82 mL; HLBWP: 149 ± 9.39 mL, P = 0.03). In conclusion, placental development may be the main factor causing lower BW of entire litters in LLBWP sows.

Intrauterine exposure to metformin: Evaluation of endothelial and perivascular adipose tissue function in abdominal aorta of adult offspring.

The biguanide metformin (MET) has been used during pregnancy for treatment of polycystic ovary syndrome and gestational diabetes. MET crosses the placenta and maternal treatment can expose the progeny to this drug during important phases of body development. Direct vascular protective effects have been described with the treatment of metformin. Nevertheless, it is unclear whether intrauterine exposure to metformin is safe for the vascular system of offspring. Thus, the present study aimed to investigate the intrinsic effects of metformin exposure in utero in the offspring abdominal aorta reactivity, in the presence and absence of perivascular adipose tissue (PVAT) and endothelium. For this, Wistar rats were treated with metformin 293 mg/kg/day (MET) or water (CTR) by gavage during the gestational period. The abdominal aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in male adult offspring. It was observed that abdominal aorta relaxation was similar between MET and CTR groups in the presence or absence of PVAT. In addition, the contraction to phenylephrine was similar between MET and CTR groups in the presence and absence of PVAT and endothelium. Therefore, metformin exposure during pregnancy had no intrinsic effect on the offspring abdominal aorta PVAT and endothelial function, demonstrating it to be safe to the vascular system of the offspring.

Epigenetics and type II diabetes mellitus: underlying mechanisms of prenatal predisposition.

Type II diabetes mellitus (T2DM) is a widespread metabolic disorder characterized by insulin resistance precipitating abnormally high blood glucose levels. While the onset of T2DM is known to be the consequence of a multifactorial interplay with a strong genetic component, emerging research has demonstrated the additional role of a variety of epigenetic mechanisms in the development of this disorder. Heritable epigenetic modifications, such as DNA methylation and histone modifications, play a vital role in many important cellular processes, including pancreatic cellular differentiation and maintenance of normal ß-cell function. Recent studies have found possible epigenetic mechanisms to explain observed risk factors, such as altered atherogenic lipid profiles, elevated body mass index (BMI), and impaired glucose tolerance (IGT), for later development of T2DM in children born to mothers experiencing both famine and hyperglycemic conditions. It is suggested that these epigenetic influences happen early during gestation and are less susceptible to the effects of postnatal environmental modification as was previously thought, highlighting the importance of early preventative measures in minimizing the global burden of T2DM.

Effect of feeding level of pregnant dairy heifers sired by one bull on maternal metabolism, placental parameters and birth weight of their female calves.

This study aimed to evaluate the effect of different phases of feed restriction on the metabolism and placental indices of growing heifers inseminated with sexed semen of one bull and on the birth weights of their calves. Red-Holstein heifers were randomly divided into three groups. C-group animals (N=17) daily received recommended energy and crude protein (standard diet). ER-Group animals (N=14) were fed 60% of recommended energy and crude protein for the first two pregnancy months followed by the standard diet. LR-group animals (N=13) were provided with the standard diet throughout the first seven months and with 60% energy and crude protein for the last two months of pregnancy. Blood metabolites and weights of dams were assessed regularly during pregnancy. Placenta weight, area of placentomes and calves' birth weights were examined directly after birth. The physiological levels of blood metabolites varied in C-group animals during the different pregnancy stages. Both restriction periods resulted in reduced weight gain of the dams. ER-group animals showed a marked compensatory growth during mid-pregnancy. Serum glucose, cholesterol and beta-hydroxybutyrate were lower in ER-group animals compared with C-group animals during early restriction. During late restriction, only non-esterified fatty acids increased in LR-group animals. Placental parameter and calves' birth weights did not differ between groups. Results indicate only minor effects of a 40% energy and protein restriction during early or late pregnancy in growing heifers on maternal metabolic and placental indices as well as on foetal development, but further studies might show long-term consequences of offspring.

Efecto de la infección congénita por Trypanosoma cruzi sobre el desarrollo intrauterino y la respuesta inmune fetal-neonatal / Effect of congenital infection by Trypanosoma cruzi on intrauterine development and the fetal-neonatal immune response

En la infección congénita por Trypanosoma cruzi la morbilidad y mortalidad varían desde casos asintomáticos hasta severos cuadros clínicos de la enfermedad. En recién nacidos infectados por T. cruzi se ha encontrado que no existe un perfil clínico determinado, puesto que durante el desarrollo intrauterino se producen diversas alteraciones, presentándose cambios en el perfil serológico y parasitológico. Algunos factores intrínsecos del hospedador, tales como: la barrera placentaria y la capacidad tanto de la madre como del feto de desarrollar una respuesta inmune específica capaz de controlar la multiplicación parasitaria podrían estar involucrados en tales diferencias. Otra posibilidad incluye el polimorfismo genético de T. cruzi, pues se considera que las cepas de mayor virulencia pueden atravesar con mayor facilidad la placenta y son más patógenas para el feto y/o neonato.

In congenital infection by Trypanosoma cruzi, morbidity and mortality vary from asymptomatic cases to severe clinical forms of the disease. It has been found that there is no specific clinical profile in newborns infected by T. cruzi, since during intrauterine development diverse pathological changes take place, causing alterations in the serological and parasitological profiles. Some intrinsic factors of the host, such as: the placental barrier and the ability of both, mother and fetus, to develop a specific immune response to control parasite multiplication, could be involved in such differences. Another possibility includes the genetic polymorphism of T. cruzi, since it is considered that strains of greater virulence can cross the placenta more easily and are more pathogenic to the fetus and/or the neonate.

[The effectiveness and safety of use of a soluble recombinant growth hormone formulation in the treatment of shortness in children with retarded intrauterine development].

The study was undertaken to investigate the effectiveness and safety of 12-week use of the recombinant growth hormone (rGH) Nor-dithropin-Simplex (NovoNordisk, Denmark) in children with retarded intrauterine development (RIUD) and significant postnatal shortness. A group of examinees comprised 15 prepubescent children with RIUD without hormone growth hormone deficiency. The evaluation criteria were growth (absolute and SDS), the rate of growth (absolute and SDS), and the time course of changes in bone maturation, hormonal and biochemical parameters. Treatment included subcutaneous daily injections of Nordithropin-Simplex, 0.067 mg/kg, at night. Control examinations were made every 3 months. Intragroup birth height SDS averaged 3.61±1.15; body mass SDS was 3.65±0.71. Before treatment, the mean chronological age was 5.46+1.65years; the bone age averaged 1.42±0.70years less than the chronological one; growth SDS was 3.24+0.81; and growth rate SDS was -1.24±1.10. After 12-month rGH treatment, growth rate SDS increased up to 4.98±2.65 (p <0.0005), growth ∆ SDS for chronological age averaged 1.02±0.39 with variations from -3.24±0.81 to -2.22+0.78 (p < 0.0005). During 12-month therapy, bone age increase by, on the average, 0.91±0.42years. Two-fold dose rGH therapy, as compared with replacement therapy, was well tolerated and produced no serious side effects. It is concluded that 12-month therapy with Nordithropin-Simplex in a dose of 0.067 mg/kg/day in children with RIUD and significant postnatal growth retardation can induce acceleration of growth rates without causing a significant adverse reactions. Long-term multicenter centers are required to analyze the impact of rGH therapy on final growth, metabolic effects and to evaluate the safety of its long-term use.