Human Fetal Growth Research Articles

Basic fibroblast growth factor expression is regulated by corticotropin in the human fetal adrenal: a model for adrenal growth regulation.

Human fetal adrenal growth after midgestation is very rapid and appears to be dependent upon pituitary adrenocorticotropin (ACTH) in vivo. We hypothesized that the regulation of fetal adrenal growth by ACTH is mediated by ACTH-stimulated local growth factor production. As we have found basic fibroblast growth factor (bFGF) to be a potent mitogen for human fetal adrenal cells in culture, we conducted studies to determine whether bFGF is synthesized by the human fetal adrenal gland and whether bFGF gene expression in primary cultures of human fetal adrenal cells is regulated by ACTH. Bioassayable bFGF-like activity was detected in extracts of whole human fetal adrenal glands and primary cultures of human fetal adrenal cells. Northern blot analysis of total RNA from whole human fetal adrenal glands revealed a characteristic 7-kilobase bFGF mRNA, indicating that the fetal adrenal bFGF bioactivity was most likely due to local synthesis. Slot blot and ribonuclease protection analysis showed that bFGF mRNA was present in very low amounts in total RNA from primary cultures of unstimulated human fetal adrenal cells but was increased 2- to 3-fold in cells exposed to 10 nM ACTH-(1-24) or 1 mM 8-bromoadenosine 3',5'-cyclic monophosphate for 24 hr. bFGF mRNA was localized to adrenocortical cells and not fibroblasts by in situ hybridization. bFGF mRNA was barely detectable in unstimulated cells, whereas it was markedly increased in cells exposed to either ACTH or 8-bromoadenosine 3',5'-cyclic monophosphate. These data support our hypothesis that the regulation of human fetal adrenal growth by ACTH at midgestation may be mediated by the stimulation of local growth factor production, and we suggest that bFGF may play a major role in this process.

Human Fetal Thyroid Cell Growth in Vitro: System Characterization and Cytokine Inhibition*

We have studied primary human fetal thyroid cell monolayers as an in vitro model for thyroid cell growth and function. Fetal thyroid cells grew slowly in a serum-free medium under basal conditions (i.e. without insulin and TSH), with a doubling time of 112 +/- 7 h (mean +/- SEM), indicating autonomous growth capacity. Addition of insulin (10 micrograms/ml) lead to increased growth, with a doubling time of 43.0 +/- 2.5 h, and TSH further reduced the doubling time in a dose-dependent manner, with the highest growth rate at 1-10 mU/ml (doubling time, 27 +/- 0.5 h). These growth rates were only observed when cells were subjected to a short culture time (12 h) before investigation, whereas after 96 h of culture the fetal thyroid cell growth rate was reduced by up to 50%. Addition of more than 5% serum completely inhibited the growth stimulation initiated by insulin and TSH. The accumulation of extracellular cAMP by the fetal cell monolayer was induced by TSH in a dose-dependent manner and reached a maximum effect at 10 mU/ml (4.8 +/- 0.6 pmol cAMP). Basal thyroglobulin (Tg) release was 26.9 +/- 0.5 ng/10(5) cells.day. Insulin decreased Tg release to 16.7 +/- 0.5 ng/10(5) cells,day, whereas TSH increased it up to 52.5 +/- 1.0 ng/10(5) cells.day. The T cell cytokine gamma-interferon, a product of the lymphocytic infiltrate in autoimmune thyroid disease, significantly reduced both insulin and TSH-stimulated cellular growth as well as accumulation of Tg. In conclusion, human fetal thyroid cell monolayers grew at high velocity under defined experimental conditions in vitro. These conditions included a low serum concentration, short culture time before investigation, and insulin/TSH supplementation. Furthermore, this human thyroid model confirms our earlier observations on the influence of cytokines in thyroid cell growth regulation.

Fetal growth signals.

Human fetal growth is not uniform. Tissue patterns and organ primordia are established during embryogenesis, then from the end of the first trimester and throughout the second the fetus undergoes massive hyperplasia. In the third trimester further organ modelling and functional maturation occur in preparation for extrauterine life. Each aspect ofdevelopment requires orchestrated intercellular signalling at two levels. The release of peptide growth factors and the modulation of an extracellular matrix are paracrine actions that occur within cell populations and between adjacent germ layers. In contrast, endocrine hormones may stimulate growth nonspecifically or promote specific maturational events. The interactions between paracrinology, endocrinology, and environmental constraints to growth during normal and abnormal fetal development have been reviewed in detail recently.1 2 In this commentary emphasis has been placed on new concepts of embryonic and fetal growth control.

Placental lactogen and growth hormone receptors in human fetal tissues: relationship to fetal plasma human placental lactogen concentrations and fetal growth.

The specific binding of human placental lactogen (hPL) and human GH (hGH) to particulate cell membranes from human fetal liver and skeletal muscle at 12-19 weeks gestation was examined. Fetal liver and muscle specifically bound [125I]hPL. This binding was inhibited by increasing concentrations of unlabeled hPL (half-maximal concentrations, 2.2 and 3.4 nmol/L, respectively). Scatchard analysis of the hepatic membrane binding revealed curvilinear plots with higher (Kd, 2.2 nmol/L) and lower (Kd, 24 nmol/L) affinity sites, while binding to muscle involved a single receptor class of Kd 5.6 nmol/L. The binding capacities for the two hepatic sites correlated positively with fetal body weight. [125I]hGH specifically bound to liver, but not muscle, with higher (Kd, 1.6 nmol/L) and lower (Kd, 8.6 nmol/L) affinity sites. [125I]PRL bound to hepatic membranes, but was preferentially displaced by hPL or hGH. Between 4 and 500 micrograms/L (mean, 82 micrograms/L, 3.8 nmol/L) hPL were present in fetal plasma. The findings identify distinct hPL receptors in human fetal liver and skeletal muscle and a hepatic hGH receptor in midgestation.

Studies on the roles of insulin-like growth factor-1 (IGF-1)/somatomedin C (SMC) during pregnancy

Studies in human as well as animal experiments have proved that IGF-1/SMC, which shows mitogenic activities in a wide variety of cell types, stimulates growth in vitro and in vivo. The aim of this study was to investigate the roles of IGF-1/SMC on fetal growth during pregnancy by measuring IGF-1/SMC, insulin, C-peptide, human placental lactogen (hPL), and GH and PRL concentrations in maternal and fetal plasma, and by clarifying the changes of IGF receptor in human fetal liver microsomal membranes during pregnancy. Maternal plasma IGF-1/SMC concentrations were not distinguishable from those of nonpregnant women (9.2 +/- 1.7 nmol/l) in the 1st and 2nd trimester of gestation; however, they showed a gradual increase after the 30th week of gestation, reaching 12.7 +/- 5.4 at term. They possessed a significant positive correlation with hPL (r = 0.45, p less than 0.05) and PRL (r = 0.38, p less than 0.05) but not with GH (r = 0.39, NS). On the other hand, IGF-1/SMC in cord plasma could be first detected in the 30th week of gestation, and it increased gradually until term but had no significant correlation with that in maternal plasma. Furthermore, it possessed an intimate correlation with C-peptide (r = 0.30, p less than 0.05) but not with GH or PRL. Additionally, IGF-1/SMC in cord plasma had a positive correlation with birth weight (r = 0.60, p less than 0.005). On the other hand, specific binding of 125I-IGF-1 and -II to liver microsomal membranes which was also displaced by nonlabeled insulin could be detected in human fetuses at various gestational ages. Scatchard analyses indicated that the binding affinity, which was 0.14 +/- 0.05(x 10(9)M-1) in the fetal liver before the 19th week of gestation, increased after the 19th week of gestation (0.58 +/- 0.12); conversely, the binding capacity was lower after the 19th week of gestation (0.15 +/- 0.08 x 10(-12) moles/mg protein) compared with that before the 19th week (0.51 +/- 0.25). These results suggest that (1) plasma IGF-1/SMC might be produced in fetal sites and its regulating mechanism is different from that in maternal sites, and that (2) IGFs might play an important role in human fetal growth and development by its affect via IGF or insulin receptors on the human fetal liver.

Fitting growth curves to head and abdomen measurements of the fetus: a multicentric study.

Three different mathematical models were fitted to ultrasonic measurements of the biparietal diameter, head circumference, and abdomen circumference obtained from 1,426 healthy fetuses. The linear cubic function gives coefficients comparable with most previous studies, but it does not thoroughly explain fetal growth throughout pregnancy. Both the exponential-power function and the logistic-logarithmic function fit the raw data well and theoretically reflect the biological phenomena of human fetal growth. The characteristics of each model are discussed.

Human fetal epiphyseal chondrocytes in culture: an "in vitro" model for studying human fetal growth.

Human fetal epiphyseal chondrocytes in culture: an "in vitro" model for studying human fetal growth.

Proliferation of human embryonic and fetal epidermal cells in organ culture.

The morphology of human embryonic and fetal skin growth in organ culture at the air-medium interface was examined, and the labeling indices of the epidermal cells in such cultures were determined. The two-layered epidermis of embryonic specimens increased to five or six cell layers after 21 days in culture, and the periderm in such cultures changed from a flat cell type to one with many blebs. The organelles in the epidermal cells remained unchanged. Fetal epidermis, however, differentiated when grown in this organ culture system from three layers (basal, intermediate, and periderm) to an adult-type epidermis with basal, spinous, granular, and cornified cell layers. Keratohyalin granules, lamellar granules, and bundles of keratin filaments, organelles associated with epidermal cell differentiation, were observed in the suprabasal cells of such cultures. The periderm in these fetal cultures formed blebs early but was sloughed with the stratum corneum in older cultures. The rate of differentiation of the fetal epidermis in organ culture was related to the initial age of the specimen cultured, with the older specimens differentiating at a faster rate than the younger specimens. Labeling indices (LIs) of embryonic and fetal epidermis and periderm were determined. The LI for embryonic basal cells was 8.5% and for periderm was 8%. The fetal LIs were 7% for basal cells, 1% for intermediate cells, and 3% for periderm. The ability to maintain viable pieces of skin in organ culture affords a model for studying normal and abnormal human epidermal differentiation from fetal biopsies and for investigating proliferative diseases.

Fetal α-melanocyte-stimulating hormone levels: No correlation with late fetal growth but increased with diabetes mellitus

The pars intermedia of the fetal pituitary produces α-melanocyte-stimulating hormone. Previous reports suggest that α-melanocyte-stimulating hormone may be a determinant of early fetal growth in animal models. Based on anencephalic fetuses, a similar role was suggested in humans. To examine its relationship to late human fetal growth, α-melanocyte-stimulating hormone levels were measured by radioimmunoassay in 185 umbilical cord blood samples from anatomically normal fetuses of 28 to 42 weeks' gestation. With use of stepwise multiple regression analysis, no significant relationship was demonstrated between α-melanocyte-stimulating hormone levels and fetal growth. However, significantly higher levels were found in infants of diabetic mothers (p < 0.05) independent of birth weight, gestational age, or both. No significant relationship with other maternal factors related to fetal growth, labor, and delivery was demonstrated. We conclude that fetal plasma α-melanocyte-stimulating hormone levels do not correlate with late human fetal growth. It is speculated that increased α-melanocyte-stimulating hormone levels among infants of diabetic mothers might be related to altered neurological maturation.

Fetal growth from 12 to 26 weeks of gestation

175 freshly aborted fetuses (including three pairs of twins), 12-26 weeks postmenstrual age and products of induced expulsion from 172 Kashmiri women, were observed for 12 anthropometric measurements, namely, crown-heel length, crown-rump length, trunk height, head length, head circumference upper-arm length, fore-arm length, hand length, thigh length, leg length, foot length and weight. The general pattern of age changes in various body dimensions conforms to the sigmoid nature of human fetal growth. Comparison of the present findings with those from other studies reveals no definite population trends. The mean values for various anthropometric variables of Kashmiri fetuses lie within the overall range of observations made by various authors.

Transmission through the female line of a mechanism constraining human fetal growth.

Cross-breeding experiments between large and small strains of mammals have shown the powerful influence of the maternal organism on the control of fetal growth. The prepotency of a maternal regulator has also been demonstrated in humans. Our earlier studies indicated that this regulator acts by means of constraint; there is no equivalent accelerating mechanism. Data on 1092 siblings and 5207 paternal and maternal relatives of 986 probands show different patterns of birthweight among families ascertained, respectively, through very large and very small babies. When constraint is relaxed the Mendelian laws of inheritance are clearly followed. At the lower extreme there is evidence for the transmission of constraint through the female line only. This could be due to the maternal genotype, but our data suggest that a non-Mendelian path might also be involved. Such a process would be adaptive, facilitating fairly fast changes in fetal growth rate as the conditions under which a population lives deteriorate or improve.

Insulin-related genes expressed in human placenta from normal and diabetic pregnancies.

Rapid growth of human fetal tissues requires insulin or insulin-like growth factors. A high rate of human fetal growth occurs between implantation and about 14 weeks of gestation. Fetal pancreatic insulin secretion begins much later. Since maternal insulin does not cross the blood/placental barrier, other sources of insulin or insulin-like growth factors may be provided for fetal development. We report here that placental polyadenylylated RNAs from the first and third trimester of normal pregnancy as well as from term pregnancies of diabetic mothers hybridize to a 32P-labeled cloned cDNA of an insulin-related sequence expressed in fetal pancreas. Moreover, placentas from diabetic women express much more of these sequences. These results suggest that insulin-related genes are expressed in placental tissue during fetal development and may be a source of growth-promoting hormones for the human fetus. Fetuses developing in diabetic women receive a large influx of glucose. This in turn may stimulate the expression of insulin-related sequences, which may result in higher utilization of glucose, thus bringing about the macrosomia and high incidence of malformation and still-births known to result from pregnancies in diabetics.

The relationship between differences in regional growth rates and changes in shape during human fetal craniofacial growth

Large differences in growth rates between various craniofacial regions have been reported but have not distinguished between absolute and relative rates. Measurements on 60 fetuses, 49–212 mm crown-rump length, showed that absolute growth rates correlated highly with size of the craniofacial region measured ( r = 0.9996, p < 0.001) but were unrelated to changes in shape and relative proportion. By standardizing for size, absolute growth rates were converted into relative growth rates which correlated with changes in relative proportion and thus shape ( r = 0.785, p < 0.001).

Human fetal weight and placental weight growth curves. A mathematical analysis from a population at sea level.

A mathematical analysis of human fetal and placental growth curves was made on data collected prospectively from a population at sea level. Both the fetal and placental growth curves can best be described by a form of the logistic equation inhibited growth model. The fetal growth rate reaches its maximum approximately 4 weeks after the placental growth rate has reached its maximum. Growth rate constants were calculated for several populations at various altitudes.

Use of DNA estimation for growth assessment in normal and hypoplastic fetal lungs.

Total DNA was estimated in the lungs of 80 fetuses and newborn infants varying in gestation from 14 weeks to term. In fetuses of appropriate weight for gestational age total lung DNA increased at a constant rate from about 35 mg at 17 weeks' gestation to 480 mg at term. The lungs of immature fetuses were heavier and contained more DNA relative to body weight than did those of mature infants. Small-for-dates infants had lower lung DNA levels for gestation than infants with weights appropriate for gestational age, but there was no difference when lung DNA was corrected for body weight. Lung hypoplasia defined in terms of lung/body weight ratio was associated with low lung DNA content for gestation, even when corrected for body weight. The total lung DNA at 34-40 weeks' gestation in infants with lung hypoplasia associated with fetal anuria or urinary outflow obstruction was equivalent to that seen in normal fetuses at 20-22 weeks' gestation. We conclude that the early second trimester is a critical period for human fetal lung growth.

The effect of genital mycoplasmas on human fetal growth.

The relation between maternal genital colonization by mycoplasmas and fetal growth was examined in a study of 195 women. Swabs were taken from the endocervix on three occasions during pregnancy and once post partum. Ureaplasma urealyticum organisms (ureaplasmas) were recovered from 42.7 per cent of Caucasian women and from 34.6 per cent of Asian women at their first antenatal visit. These isolation rates remained similar throughout pregnancy, although there was a decrease in isolation after delivery. Mycoplasma hominis was recovered from 6.5 per cent of Caucasians and from 11.5 per cent of Asians at their first antenatal visit and these rates remained fairly constant during pregnancy and after delivery. Caucasian women colonized by ureaplasmas had a longer mean length of gestation (p less than 0.025) than non-colonized women. Furthermore, the colonized women gave birth to infants who had a statistically significant greater mean birth weight and a greater mean birth weight-for-dates than those of the non-colonized Caucasians. There was no correlation between gestational length, birth weight, or birth weight-for-dates and genital colonization of Asian mothers by ureaplasmas or M. hominis. It is clear the ureaplasmas are not associated with low birth weight in our population.

Maternal nutrition and fetal outcome

important regulator of human fetal growth. Two major steps are required to test this hypothesis: 1) to identify a predictable relationship between fetal growth and maternal nutrition and 2) to design and test an intervention to prevent predicted fetal malnutrition. This paper deals primarily with the first step and with several elements which must be considered to achieve it successfully. Five points will be emphasized: first, that extraneous nonnutntional factors which influence fetal growth must be taken into account; second, that the leukocyte cell model is related to the nutritional status of the mother; third, that cell bioactivities are associated with the interactions between some nutrients; fourth, that a nutritional profile, rather than deficiency or excess of a single nutrient, is associated with fetal growth in the Oklahoma women of our sample; and fifth, that it is feasible to use maternal nutritional status, measured once at midpregnancy, to predict birth outcome. Finally, duration of gestation, the major determinant of birthweight, and sex of the baby also must be taken into account. We hypothesized that maternal nutrition regulates fetal growth and that both are modified by conditioning factors (1,2). The prime objective has been to determine whether a significant relationship between them can be defined in order to predict expected fetal growth using maternal nutrition-related variables measured once at midpregnancy, which is at approximately about 21 wk.

Development in the first half of gestation of genetically abnormal human fetuses.

Linear measurements, total weight and organ weights were determined for 24 second trimester human fetuses with a cytogenetic or metabolic defect. The three fetuses with trisomy 13 or 18 tended to be smallest in all parameters. This data should be of value to other laboratories interested in human fetal growth. It demonstrates that the intrauterine growth retardation reported at term in cytogenetically abnormal newborns is already manifested at the eighteenth to twentieth week of gestation.

Somatomedin in newborns and the relationship to human chorionic somatotropin and fetal growth.

The significance of somatomedin A (SM) and human chorionic somatomammotropin (HCS) in fetal growth was examined. SM, determined by chick embryo assay, was studied during the last trimester of pregnancy, in maternal serum and cord blood at term and in a group of normal newborns in the first week of life. Furthermore a group newborns of diabetic mothers was studied in the first or second day of life. HCS was measured in maternal serum and in cord blood at term. In amniotic fluid inhibitory factors caused a low SM activity as measured by the bioassay. The following results were obtained: 1) Normal values of SM in the last trimester with a decline at term were found in 3 normal primigravidae. 2) The mean levels of SM in 22 mothers and their offspring were decreased. The difference between the two values was significant, but a positive correlation was found between the maternally related pairs of SM values. Moreover, a positive correlation was found between maternal SM, birth weight and length. HCS was not correlated to above-mentioned parameters, but there was positive correlation between placental weight and birth weight. 3) In 6 newborns during the first 5 days SM rose from very low values to normal values found in infants in their first year. 4) The mean value of SM in ten newborns of diabetic mothers was not significantly different from the mean value of control group. The results do not exclude the possibility of a transplacental transport of SM and the positive correlation between SM levels and birth weight found in this investigation supports the concept that SM plays an important role in fetal growth.

BOOK REVIEWS

Book reviews in this article: Maternity Care in the World. 2nd Edition. Present and Future of Diagnostic Ultrasound. Edited by Ian Donald and Salvator Levi. Paper Doctors. A Critical Assessment of Medical Research. Edited by V. Coleman. The Presentation of Original Work in Medicine and Biology. By H. Dudley. Immunobiology for the Clinician. Edited by Hugh R. K. Barber. Analysis of Intrauterine Contraception. Pediatric and Adolescent Gynecology. Edited by S. J. H. Emans and D. P. Goldstein. Perinatal Medicine. 5th European Congress of Perinatal Medicine. Edited by G. Rooth and Lars‐Eric Bratteby. Blizzard and the Holy Ghost. By Joseph Blizzard. Clinics in Endocrinology and Metabolism. Vol 6. No. 1. Edited by G. M. Besser. The Biology of Human Fetal Growth. Edited by D. F. Roberts and A. M. Thomson.