Growth Retardation In Rats Research Articles

Increased secretion of insulin-like growth factor-binding proteins and decreased secretion of insulin-like growth factor-II by muscle from growth-retarded neonatal rats

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) may be important factors in the control of neonatal growth. We have examined the production, in vitro, of IGFBPs and IGFs by hind-limb skeletal muscle from normal and small-for-gestational age (SGA) neonatal rats. Conditioned medium was collected from muscle strips after incubation at 37 degrees C for 2 h in Ham's F-12 medium. The conditioned medium was subjected to acid-gel permeation chromatography to separate IGFBPs from IGFs. The binding of 125I-labelled IGF-I to IGFBPs from both control and SGA muscle was displaced equipotently by IGF-I and IGF-II and not at all by insulin. IGFBPs from control and SGA muscles bound IGF-I with comparable affinities (Kd = 0.071 and 0.069 nmol/l respectively). When IGF-II was used as tracer, neither IGF-I nor insulin competed for binding. Western ligand blots of IGFBPs in conditioned media from both control and SGA muscles showed three bands of radioactivity at molecular masses equivalent to 24, 30 and 40 kDa. When the release of IGFBPs by muscle tissue in vitro was quantified by measuring the number of IGF-I binding sites in acid-fractionated medium it was apparent that the muscles from SGA pups secreted significantly more IGFBPs (39.3 +/- 7.5 fmol/mg muscle protein per 2 h) than the muscles from control pups (17.8 +/- 2.7 fmol/mg protein per 2 h; P less than 0.05). In contrast to the IGFBPs, more IGF activity was secreted by the muscles from the control pups (61.1 +/- 15.6 fmol/mg muscle protein per 2 h) than the muscles from the SGA pups (12.6 +/- 5.8 fmol/mg muscle protein per 2 h; P less than 0.05). Analysis of the IGF activity with assays specific for IGF-I and IGF-II showed that both SGA and control muscles secreted predominantly IGF-II with approximately 10% of the total IGF activity measurable as IGF-I. This differential secretion of IGFBPs and IGFs may be associated with the reduced growth potential of the SGA neonate.

Twin pregnancy: the impact of the Higgins Nutrition Intervention Program on maternal and neonatal outcomes

Perinatal outcomes were compared between 354 twins treated with the Higgins Nutrition Intervention Program and 686 untreated twins. After differing distributions of key confounding variables were adjusted for, the twins in the intervention group weighed an average of 80 g more (P less than 0.06) than the nonintervention twins; their low-birth-weight rate was 25% lower (P less than 0.05) and their very-low-birth-weight rate was almost 50% lower (P less than 0.05). Although the rate of preterm delivery was 30% lower in the intervention group (P less than 0.05), the rates of intrauterine growth retardation were similar in the two groups. Fetal mortality was slightly higher (14 vs 12 per 1000, NS), but early neonatal mortality was fivefold lower (3 vs 19 per 1000, P less than 0.06) in the intervention group. Maternal morbidity was significantly lower (P less than 0.05) in the intervention group. There was a trend towards lower infant morbidity in the intervention group. These results suggest that nutritional intervention can significantly improve twin-pregnancy outcome.

THE AUSTRALIAN & NEW ZEALAND JOURNAL OF OBSTETRICS & GYNAECOLOGY

Summary: During the years 1971–1984 urinary oestriol excretion was tested in 51,427 patients (group 1). One or more low oestriol value was found in 10.7% of patients; in this group the stillbirth rate was 6.8 times higher, the neonatal death rate 3.8 times higher, and fetal growth retardation rate 3.5 times higher than in patients with normal oestriol values (all p 0.00001).During the years 1985–1989 a further 20,635 patients were tested (group 2) and 7.6% had one or more low oestriol value. The perinatal mortality rate in patients with normal oestriol excretion fell from 0.8% in group 1 to 0.5% in group 2 (p< 0.005), and in patients with low oestriol excretion from 4.2% in group 1 to 2.4% in group 2 (p 0.002). However, patients in group 2 with low oestriol values still had significantly unfavourable results, compared to those with normal oestriol values ‐ stillbirth rate 3.3 times higher, neonatal death rate 4.6 times higher, and fetal growth retardation rate 3.2 times higher (all p < 0.00001).Intravenous dextrose and aminoacid infusions were given to 967 patients who had persistently low oestriol values in spite of rest in hospital, in an attempt to correct fetoplacental function; the perinatal mortality rate was 0.9% in the 660 (68.3%) who responded favourably, and 9.8% in the 307 (31.7%) who did not respond (p<0.0001).Although perinatal results have improved, fetal growth retardation and the risk of perinatal death are still identified by urinary oestriol estimation.

Potentiation of the growth-promoting activity of porcine growth hormone (pGH) with an antibody generated in rabbits to the peptide sequence pGH110–118

An effort was made to identify the antigenic epitope(s) of porcine GH (pGH) capable of inducing antibodies which would enhance the growth-promoting activity of the hormone. Several peptide sequences of the pGH molecule were synthesized and the antibodies to these peptides were generated in rabbits. The majority of these antibodies were found to be immunoreactive with both intact pGH and their respective peptide antigens. The biological activity of the antibodies was tested in growth-retarded hypophysectomized rats. Daily injections with pGH alone significantly increased their growth rate and treatment with a combination of pGH and antibody specific to the peptide sequence 110-118 further heightened the somatogenic effect. Administration of this antibody alone did not enhance the growth rate of hypophysectomized rats, neither did antibodies raised to intact pGH or the other peptide sequences. The present findings suggest that antibody with a particular pGH epitope specificity is able to increase the somatogenic activity of pGH and that the peptide corresponding to pGH amino acids 110-118 may prove useful in the development of growth promoting vaccines.

Relation of maternal CMV viremia and antibody response to the rate of congenital infection and intrauterine growth retardation

Pregnancy outcome after maternal primary CMV infection initiated at different times during gestation was investigated by using the inbred Strain-2 guinea pig model of congenital CMV infection. The highest vertical transmission rates occurred in pups from dams that were initially viremic in late gestation presumably because delivery occurred prior to detectable maternal CMV-specific immune response. In contrast, conceptus loss was highest with maternal CMV infection initiated at conception. Intrauterine resorptions, intrauterine growth retardation, and disseminated neonatal CMV infection with CNS involvement were more frequent in pups born to mothers that were initially viremic prior to rather than after midgestation. Maternal viremia was prolonged and antibody responses were delayed after CMV inoculation in early gestation compared to late gestation. Prolonged maternal viremia plus early gestational virus exposure/infection of the fetus appeared to be associated with the most severe outcome. These findings suggest that the timing of initial maternal viremia and immune responses, the stage of fetal development, and the length of in utero exposure to CMV are important factors in subsequent disease expression and rates of congenital infection.

Differences in Sialic Acid Expression of Lung Alveolar Cells between Normal and Intrauterine Growth-Retarded Rat Fetuses

The expression of sialic acid on the luminal surface of lung alveolar epithelial cells was compared in normal developing and intrauterine growth-retarded (IUGR) rat fetuses during the late gestational and early neonatal periods using neuraminidase treatment of the tissues and staining with a galactose-binding lectin from peanut. In IUGR fetal lung tissues, there were more staining for free galactosyl residues (before neuraminidase treatment) and less staining for sialic acid-bound galactosyl residues (after neuraminidase treatment) than in normal fetal lung tissues during the developmental stages. The staining reaction after neuraminidase treatment was mostly confined to the type 2 alveolar cell surfaces especially on microvillous surfaces. These findings suggest that in IUGR rat fetuses galactosyl residues of the lung alveolar epithelial cell surfaces are not sufficiently masked with terminal sialic acids resulting in a disturbance in the normal maturation process of the alveolar epithelial cells.

Effects of Secondary Bile Acids on the in vitro Development of Early Somite Rat Embryos

Effects of secondary bile acids--lithocholic (LCA) and deoxycholic (DCA)--on the in vitro development of early somite (10.5 days old) rat embryos were studied. It was shown that an addition to the culture medium of 0.1 mM LCA (final concentration) resulted in 9% growth-retarded and 12% malformed embryos when the duration of exposure was 24 h. When treatment with LCA was prolonged to 48 h, the rate of growth retardation increased to 18% and that of malformations to 40% versus 0.5% for both parameters observed in controls. This could be interpreted as a reversible or time-dependent effect of LCA on the in vitro development of the mammalian embryo. Culture of embryos in medium with 0.5 mM DCA resulted in 22% of growth retardation and 50% of malformations. DCA in 0.1 mM final concentration had only slight and statistically nonsignificant effects. Retardation of growth development could be demonstrated by a decrease in crown-rump length and the number of somites. Among malformed embryos, abnormalities in the development of the neural tube and exencephaly were the most common types of malformations. Abnormalities as well as growth retardation were accompanied by significant pathological changes in structure and perhaps in function of the endodermal visceral yolk sac cells. It could be suggested that secondary bile acids when present in pathophysiological concentrations can affect the embryonic development by direct inhibitory effects and that these effects may be time and dose dependent.

Cocaine, Pregnancy, and the Neonate

With the increasing use of cocaine in the U.S. population, women of childbearing age have particularly shown an increasing prevalence of use. In an ongoing study at the Perinatal Center for Chemical Dependence (PCCD) at Northwestern University Medical School, 70 infants delivered to cocaine-using women were evaluated. Pregnancy and neonatal outcome were compared to a group of drug-free controls who had no history or evidence of licit or illicit drug use. These controls were selected on the basis of social, demographic, and environmental backgrounds and were comparable for cigarette use during pregnancy. The cocaine-addicted women had a high incidence of pregnancy complications, and infants born to cocaine-using women demonstrated an increased rate of intrauterine growth retardation, prematurity, microcephaly, and perinatal morbidity. Further research will begin to focus not only on the effects of cocaine per se, but also on the interactive effects of polydrug use, the dynamics of maternal/infant interaction in the substance abusing mother, and the environmental factors that place cocaine-exposed infants at high risk for future medical and developmental disabilities.

Cocaine Abuse in Pregnancy

To the Editor.— The article entitled Temporal Patterns of Cocaine Use in Pregnancy1 should be useful in improving pregnancy outcomes, in that it demonstrates correlations between maternal cocaine abuse and low birth weight and between maternal cocaine abuse and poor neurological development. However, the lower rate of intrauterine growth retardation and prematurity in the group of infants whose mothers used cocaine only during their first trimesters, as opposed to the mothers who used cocaine throughout their pregnancies, should be interpreted with caution. One of the stated goals of the Perinatal Center for Chemical Dependence, where the study took place, was to facilitate the mothers' stopping their cocaine abuse. Therefore, an element of self-selection may be confounding the results. I suspect that mothers who were successful in abstaining from cocaine abuse after their first trimester may also have successfully stopped or reduced use of alcohol, tobacco, marijuana, caffeine, or other drugs

Growth hormone secretion and ultradian rhythms in growth-retarded rats with dorsomedial hypothalamic lesions

Rats with lesions of the dorsomedial nucleus of the hypothalamus (DMN-L) are hypophagic and have reduced linear growth and body weight, but normal body composition. Male Sprague-Dawley rats (170–190 g) housed individually under a 12:12 L:D schedule with lights out at 1430 hr received jugular cannulas, and on return to precannulation body weight (4.2±0.6 days), they received bilateral electrolytic DMN-L or sham-operations (SHAM). Rats with DMN-L (n=8) were hypophagic postsurgery and weighed less ( p<0.05) than SHAM at six days postlesion surgery. The difference in body weight between the two groups continued to expand over the next four weeks. Six days postsurgery, the rats were bled (RBC's returned in 10% BSA-saline) every 15 minutes between 0600–1215 hr and growth hormone (GH) subsequently assayed. The total GH secretion, as computed from the area under each rat's ultradian pattern, was similar in both groups (DMN-L versus SHAM, 2952.2±346.5 versus 2950.4±337.5). Using the PULSAR computer program, the baseline secretion (12.2±4.0 versus 11.8±2.7 ng/ml), total number of peaks (2.4±0.4 versus 2.4±0.2), and interpeak interval (2.8±0.5 versus 2.7±0.4, hr) were not significantly different between the DMN-L and SHAM rats, respectively. These data show that the growth-retarded DMN-L rat does not have a deficiency in total growth hormone secretion or an altered ultradian pattern, at a time when their body weight is diverging from the sham-operated controls. These data give further support to the previously suggested concept of a DMN-L reduced change in body weight ‘set-point’ or the alteration of an, as yet, undefined growth factor.

Impact of the Higgins Nutrition Intervention Program on birth weight: A within-mother analysis

A study was conducted to evaluate the impact of the Higgins Nutrition Intervention Program of individual nutritional assessment and rehabilitation on pregnancy outcome in a group of urban low-income women. Developed as an adjunct to routine prenatal care, the Higgins program utilizes an individualized approach to dietary treatment that combines an assessment of the risk profile for the presenting pregnancy with the application of specific nutritional rehabilitation allowances to compensate for the negative impact of diagnosed risks. This report presents results of analyses evaluating differences in birth outcomes between 552 sibling pairs; each mother had participated in the Higgins program during the pregnancy of the second-born, but not of the first-born, member of her pair. After adjustment for parity and sex, the intervention infants weighed an average of 107 gm more than their matched siblings at birth (p less than .01). The rate of low birth weight was 50% lower among the intervention infants than among their siblings (p less than .01); rates of intra-uterine growth retardation and perinatal mortality were also lower in the intervention group. The high risk of poor pregnancy outcome in this group of urban low-income women was reduced by the Higgins program.

Clearance of Calcium across in Situ Perfused Placentas of Intrauterine Growth-Retarded Rat Fetuses'

Maternofetal clearance of 45Ca and 51Cr-EDTA (diffusional marker) were simultaneously measured across in situ perfused placentas of intrauterine growth-retarded (IUGR) and control rat fetuses on d 20 of gestation. IUGR was induced by uterine artery and vein ligation on d 17 of gestation. Control fetuses and their placentas were taken from sham-operated dams. We hypothesized that calcium transfer would be impaired across placentas of IUGR fetuses. The mean body wt of IUGR fetuses was 42% lower, and the mean nose-anus length was 16% lower than those of control fetuses. The mean total calcium content of IUGR fetuses was significantly lower than that of control fetuses, but not when it was normalized to body wt. The mean maternal whole blood ionized calcium concentration was not significantly different in the two groups. The materno-fetal clearance of 45Ca across IUGR placentas was significantly lower than that across control placentas (IUGR = 35.2 +/- 1.9 micro L/min/g placenta, mean +/- SEM; control = 93.1 +/- 12 microliters/min/g placenta, p less than 0.002). In contrast, the maternofetal clearance of 51Cr-EDTA, the reference diffusional marker, was not significantly different across IUGR and control placentas. We conclude that maternofetal transfer of calcium is reduced across placentas of IUGR rat fetuses.

Temporal Patterns of Cocaine Use in Pregnancy

Seventy-five cocaine-using women enrolled in a comprehensive perinatal care program were divided into two groups: those who used cocaine in only the first trimester of pregnancy (group 1 [N = 23]) and those who used cocaine throughout pregnancy (group 2 [N = 52]). Perinatal outcomes of these pregnancies were compared with perinatal outcomes of a matched group of obstetric patients with no history or evidence of substance abuse (group 3 [N = 40]). Group 2 women had an increased rate of preterm delivery and low-birth-weight infants as well as an increased rate of intrauterine growth retardation. Group 1 women had rates of these complications similar to the drug-free group. Mean birth weight, length, and head circumference for term infants were reduced in only the group 2 infants. However, both groups of cocaine-exposed infants demonstrated significant impairment of orientation, motor, and state regulation behaviors on the Neonatal Behavioral Assessment Scale.

Prematurity, postdates, and growth retardation: The influence of use of ultrasonography on reported gestational age

The preterm and postterm delivery rates and the percentage of infants with intrauterine growth retardation are dependent on the gestational age recorded at delivery. At our institution a sharp increase in the preterm delivery rate and a coincident decrease in the postterm delivery rate and the rate of intrauterine growth retardation were noted. Over a 3-year period, while the characteristics of the obstetric population changed only slightly, the gestational age distribution shifted, with a decrease in the mean gestational age of about 1 week and a risk in the reported preterm delivery rate from 12% to 17%. About 15% of this rise was explained by an increase in obstetric interventions, and another 15% can be explained by changes in the way physicians rounded off gestational age. The majority of the increase in the preterm delivery rate was related to changes involving ultrasonographic examinations. These changes included a greater percentage of the population examined, trends toward earlier examinations, a tendency for the physicians to use ultrasonography rather than the last menstrual period in choosing the final gestational age, the use of different standards, an increase in the number of structures measured, and the weight given to various structures for determination of gestational age. It is apparent that changes in use of ultrasonography had a profound effect on the reported gestational age distribution at our institution.

Perinatal Cocaine and Methamphetamine Exposure

Maternal and neonatal growth, behavior, and physiologic organization were evaluated in 104 mother-infant pairs with positive results of urine toxicology screens. ANOVA comparison of cocaine, methamphetamine, and cocaine plus methamphetamine groups revealed no significant differences in perinatal variables. The Finnegan withdrawal scoring scheme demonstrated that all three groups of infants had altered neonatal behavioral patterns, characterized by abnormal sleep patterns, poor feeding, tremors, and hypertonia. Infants exposed to cocaine or methamphetamine or both were combined and compared with both narcotic-exposed and drug-free mother-infant pairs matched for known maternal risk factors. All drug-exposed groups had significantly higher rates of prematurity and intrauterine growth retardation and smaller head circumferences than did the drug-free comparison group. A significantly higher rate of placental hemorrhage occurred in the cocaine plus methamphetamine group. Stepwise multiple regression analysis assessed the independent contribution of maternal factors; cocaine or methamphetamine was adversely, negatively assoclated with gestational age, birth weight, length, and occipitofrontal circumference. The increased rate of prematurity, intrauterine growth retardation, and perinatal complications associated with perinatal exposure to cocaine or methamphetamine was greater than that predicted by coexisting risk factors and was consistent with the pharmacologic properties of these drugs.

Does infection with HIV affect the outcome of pregnancy?

Details are presented on the outcome of pregnancy in a group of Edinburgh women identified as positive for antibodies to HIV and in women who had a history of drug abuse or a partner known to be seropositive but who were themselves negative for HIV antibody. Pregnant women who had been tested for HIV up to June 1987 were identified. HIV state was known for 205 pregnant women. Most cases were determined during pregnancy, but in 23 (9 seropositive patients) it was determined retrospectively. Seropositivity was only found in women who had been intravenous drug users or whose partner was known seropositive. Of 50 women who were seropositive, 46 were intravenous drug users and 4 had seropositive partners. In 64 cases who were seronegative, 45 had used intravenous drugs since 1983, and 19 had a seropositive partner. These women tended to be young, unmarried, and smoked heavily. They usually lived in areas of Edinburgh with multiple deprivation. Both they and their partners were usually unemployed. In the seropositive group, spontaneous abortion showed an apparent increase, but this may be due to differences in ascertainment as the incidence in the seronegative group was low. Premature delivery, intrauterine growth retardation, and low birth weight were common compared with the total population, but seropositive and seronegative women did not differ from each other in these variables. Compared with rates in the total population of Edinburgh, the rates of prematurity and intrauterine growth retardation were increased more than 2-fold and the rate of low birthweight babies was increased nearly 4-fold, though the 1 twin pregnancy contributed to this. Adverse outcome was equally distributed between the seropositive and seronegative women, and there was no suggestion that infection with HIV itself had any effect. Although no evidence from this study shows that infection with HIV per se affects the outcome of pregnancy, none of these women showed symptomatic illness.

Perinatal cocaine and methamphetamine exposure: Maternal and neonatal correlates

Maternal and neonatal growth, behavior, and physiologic organization were evaluated in 104 mother-infant pairs with positive results of urine toxicology screens. ANOVA comparison of cocaine, methamphetamine, and cocaine plus methamphetamine groups revealed no significant differences in perinatal variables. The Finnegan withdrawal scoring scheme demonstrated that all three groups of infants had altered neonatal behavioral patterns, characterized by abnormal sleep patterns, poor feeding, tremors, and hypertonia. Infants exposed to cocaine or methamphetamine or both were combined and compared with both narcotic-exposed and drug-free mother-infant pairs matched for known maternal risk factors. All drug-exposed groups had significantly higher rates of prematurity and intrauterine growth retardation and smaller head circumferences than did the drug-free comparison group. A significantly higher rate of placental hemorrhage occurred in the cocaine plus methamphetamine group. Stepwise multiple regression analysis assessed the independent contribution of maternal factors; cocaine or methamphetamine was adversely, negatively associated with gestational age, birth weight, length, and occipitofrontal circumference. The increased rate of prematurity, intrauterine growth retardation, and perinatal complications associated with perinatal exposure to cocaine or methamphetamine was greater than that predicted by coexisting risk factors and was consistent with the pharmacologic properties of these drugs.

Does fetal gut obstruction cause hydramnios and growth retardation?

In order to study the effects of impaired fetal intestinal absorption of amniotic fluid, two series of neonates (551 from Liverpool and 172 from Rome) with different types of congenital gut obstruction were divided into two groups and compared. Group A consisted of patients with complete obstruction at or above the proximal jejunum (within 15 cm of the ligament of Treitz). Patients of group B had either incomplete obstruction at group A level or either incomplete or complete obstruction at a lower level. Maternal hydramnios and fetal growth retardation rates were found to be significantly higher in group A than in group B. Maternal hydramnios was associated with an increased prematurity rate (P less than .001). Fetal growth retardation was not related to the presence of additional anomalies. In group A growth retardation was more frequent in babies born after 37 weeks of gestation (P less than .05). No differences were found between the Liverpool and Rome series of patients. These findings suggest that fetal gut function not only contributes to the control of amniotic fluid volume but also, in the final stages of pregnancy, to normal fetal growth. Maternal hydramnios may be the cause of premature delivery of fetuses with upper gut obstructions.

A reappraisal of urinary oestriol excretion as a screening test in pregnancy.

During the years 1971-1982 urinary oestriol excretion was tested in 38,536 patients (group 1). One or more low oestriol value was found in 11.0% of patients; in this group the stillbirth rate was 8 times higher, the neonatal death rate 4 times higher, and fetal growth retardation rate 4 times higher than in patients with normal oestriol values (all p less than 0.001). During the years 1982-1984 a further 12,887 patients were tested (group 2) and 9.5% had one or more low oestriol value. The perinatal mortality rate in patients with normal oestriol excretion fell from 0.8% in group 1 to 0.5% in group 2 (p less than 0.05), and in patients with low oestriol excretion from 4.7% in group 1 to 2.4% in group 2 (p less than 0.01). However, patients in group 2 with low oestriol values still had significantly unfavourable results, compared to those with normal oestriol values--stillbirth rate 4 times higher, neonatal death rate 5 times higher, and fetal growth retardation rate 4 times higher (all p less than 0.001). Although perinatal results have improved, fetal growth retardation and the risk of perinatal death are still identified by urinary oestriol assay.

Effect of lead on Na+,K+ATPase activity in the developing brain of intra-uterine growth-retarded rats.

Lead (Pb) intoxication in developing mammals, including humans, produces serious brain damage. In addition, it is known that nutritional status influences the susceptibility to Pb toxicity. We developed an in utero undernutrition model based on restriction of blood supply to fetuses on d 17 of pregnancy (IUGR rats). The aim of this study was to investigate in vitro the possible effect of Pb on Na+, K+ATPase activity in the brain of developing IUGR and control rats from 6 to 60 d after birth. In addition, we measured the stimulation of Na+, K+ATPase by the monoamines noradrenaline and serotonin. Our results show that: The neurotoxic effect of Pb is an age-related phenomenon. Both IUGR and control rats were more sensitive to Pb in the first week of life. In adults, Pb had a weak inhibitory potency; the delayed matured brain in IUGR animals seemed less sensitive to Pb when compared to age-paired control rats; in the IUGR group, at 15 and 22 d, low doses of Pb had a stimulatory effect on Na+, K+ATPase instead of an inhibitory effect; noradrenaline and serotonin stimulated Na+, K+ATPase activity to an equivalent extent, but this was greater in IUGR than control rats; and at low Pb concentrations, the studied monoamines reversed Pb-induced inhibition.