Reduction In Fetal Weight Research Articles

Evaluation of the Teratogenicity of Morphine Sulfate Administered Via a Miniature Implantable Pump

A technique has been developed for the implantation of miniature infusion pumps in pregnant mice with minimal teratogenic and toxic side effects. In 7- to 10-day pregnant CF-1 mice receiving constant low doses of morphine sulfate via the infusion pump, the results, including fetal weight reduction and various skeletal and soft tissue abnormalities, were similar to those reported in previous investigations using single injections.

Intrauterine growth retardation and diabetic pregnancy: Two types of fetal malnutrition

Placental transfer of α-aminoisobutyric acid and methylglucose was studied near term in normal guinea pigs carrying growth-retarded fetuses and in streptozotocin-treated diabetic guinea pigs. Compared with their normal littermates, growth-retarded fetuses had lower placental weights and a diminished transfer of both nutrient analogues in proportion to the reduction in fetal weight. Fetuses from diabetic animals had normal fetal weight and placental methylglucose transfer but reduced litter size and a 40% reduction in placental α-aminoisobutyric acid transfer. These data suggest that intrauterine growth retardation in an otherwise normal pregnancy is associated with a small placenta and a reduced transfer of nutrients. Diabetic pregnancy may represent a different type of fetal malnutrition due to amino acid deprivation. It is speculated that birth weight does not necessarily reflect the degree of fetal malnutrition in diabetic pregnancy since fetal growth may be maintained by glucose and fat deposition.

Dimethoxyethyl Phthalate: Embryopathy, Teratogenicity, Fetal Metabolism and the Role of Zinc in the Rat

A single intraperitoneal injection (0.6 ml/kg) of dimethoxyethyl phthalate (DMEP) was given to groups of Wistar strain rats on day 10, 11, 12, 13 or 14 of gestation. Control rats received 0.6 ml/kg of physiological saline intraperitoneally. In phthalate-treated rats, embryopathy was manifested by a high incidence (12-79%) of fetal deaths and fetal resorptions. Fetotoxic effects were expressed by a significant reduction in fetal weights. Hydrocephalus interna, a congenital malformation of the brain, was caused by DMEP. Congenital skeletal deformities (66-96%), with multiple skeletal (14-64%) and appendicular malformations (25-57%), were also induced by DMEP. Control rats exhibited no congenital malformations of the brain and no appendicular or multiple skeletal deformities. DMEP caused a significant decrease in the zinc content of the fetus. Fetoplacental metabolism 1 and 4 hr after intravenous administration of 14C-DMEP suggested rapid transfer of the parent compound to the fetus across the placenta and that DMEP is a teratogenic moiety. The possible role of zinc in phthalate-induced teratogenesis in rats is also discussed.

Dimethoxyethyl phthalate: embryopathy, teratogenicity, fetal metabolism and the role of zinc in the rat.

A single intraperitoneal injection (0.6 ml/kg) of dimethoxyethyl phthalate (DMEP) was given to groups of Wistar strain rats on day 10, 11, 12, 13 or 14 of gestation. Control rats received 0.6 ml/kg of physiological saline intraperitoneally. In phthalate-treated rats, embryopathy was manifested by a high incidence (12-79%) of fetal deaths and fetal resorptions. Fetotoxic effects were expressed by a significant reduction in fetal weights. Hydrocephalus interna, a congenital malformation of the brain, was caused by DMEP. Congenital skeletal deformities (66-96%), with multiple skeletal (14-64%) and appendicular malformations (25-57%), were also induced by DMEP. Control rats exhibited no congenital malformations of the brain and no appendicular or multiple skeletal deformities. DMEP caused a significant decrease in the zinc content of the fetus. Fetoplacental metabolism 1 and 4 hr after intravenous administration of 14C-DMEP suggested rapid transfer of the parent compound to the fetus across the placenta and that DMEP is a teratogenic moiety. The possible role of zinc in phthalate-induced teratogenesis in rats is also discussed.

Blood flow of the reproductive system in renal hypertensive rats during pregnancy

An experimental study on pregnant rats was undertaken to explore whether renal hypertension interferes with uteroplacental blood supply and fetal weight. Renal hypertension was induced by standardized clamping of the left renal artery. Two days before expected delivery, blood flow to the reproductive organs was determined by the microsphere technique in normal control rats, rats with short-standing renal hypertension induced early in pregnancy, and rats with established renal hypertension induced 4 weeks before pregnancy. Myometrial and placental blood supply was considerably reduced in renal hypertensive rats compared to that in normotensive pregnant rats, with the reduction in placental blood flow being as much as 68% in rats with established renal hypertension. Nevertheless, there was no reduction in fetal weights, placental weights, or number of fetuses in the litters. These findings suggest that the nutritional blood supply of the placenta normally has a considerable overcapacity, perhaps a necessary safety margin so that the fetus can manage the circulatory demands associated with delivery. If hypertension causes intrauterine growth retardation only by means of reduced placental blood flow, this reduction in flow obviously must be considerable.

Pregnancy and fetal development in hamsters treated with prostaglandin F 2α

The influence of PGF 2α on pregnancy and fetal outcome was investigated in the hamster. Following subcutaneous treatment with 50, 100, 200, 400, and 800 μg PGF 2α prenatal loss was significantly increased only at the highest dose level. The offspring of the treated animals were all alive and normal. Fetal weight was not affected. However, following intravenous injection of 100 and 200 μg PGF 2α there was a significant reduction in fetal weight, and at the 400 μg dose level an increase in fetal resorptions. All fetuses recovered were alive and normal. These results indicate that PGF 2α is not teratogenic in hamsters despite the apparent greater sensitivity of the hamster embryo to prostaglandin.

Studies on the teratogenic effects of different oral preparations of caffeine in mice

Caffeine in doses up to 250 mg/kg per day in drinking water or up to 150 mg/kg per day in sustained release pellets was administered to pregnant mice. Apart from a low incidence of cleft palate, in the 50 mg/kg and 150 mg/kg caffeine pellet groups no gross abnormalities were observed which were attributable to caffeine treatment. The most important effect observed was a reduction in fetal weight. Retarded ossification particularly of the supraoccipital bones was observed in fetuses when caffeine (150 mg/kg) was administered in the drinking water but not when the same dose was given as a sustained release pellet. Analysis of caffeine blood level data showed that the total exposure from the pellets was greater than from the drinking water. It would thus appear that the effect on the supraoccipital bones is an indirect one mediated through reduced food and water intake of the dams when caffeine is administered in drinking water.

Effects of 2.45 GHz CW microwave radiation on embryofetal development in mice.

The embryofetal toxicity and teratogenicity of plane-wave 2.45 GHz continuous wave (CW) microwave radiation at different intensities were investigated in the CD-1 mouse. Mice were exposed on days 1-15 of gestation to an incident power density of 5 mW/cm2 (specific absorption rate of 6.7 mW/gm) and either on days 1-6 or 6-15 of gestation to 21 mW/cm2 (specific absorption rate of 28.14 mW/gm) or to 30 mW/cm2 (specific absorption rate of 40.2 mW/gm) for 8 hours daily. Exposure either on days 1-6 or 6-15 of gestation to a power density of 21 or 30 mW/cm2 caused an increase in colonic temperature of exposed dams of 1 degree C and 2.3 degrees C, respectively. To distinguish between "thermal" and "nonthermal" effects of 21 or 30 mW/cm2, groups of mice were also exposed to elevated ambient temperature to raise their body temperature to the level of those animals exposed to microwave. Ambient temperatures of 30 degrees C and 31 degrees C increased the deep colonic temperature to that obtained with the 21 and 30 mW/cm2 microwave exposure, respectively. The temperature-exposed mice were handled in exactly the same manner as the microwave-exposed mice. A significant reduction in maternal weight gain, either during treatment on days 1-6 or 6-15 of gestation was observed in females of all handled groups. Handling plus exposure to elevated ambient temperature (30 degrees C or 31 degrees C) during days 6-15 of gestation increased this reduction in maternal weight gain. A significant decrease in implantation sites per litter and reduction in fetal weight was noted in the group exposed to 30 mW/cm2 during days 1-6 of gestation. Exposure of mice to a power density of 30 mW/cm2 (days 6-15 of gestation) resulted in a slight, but significant increase in the percentage of malformed fetuses, predominantly with cleft palate, when compared to all other groups.

Deleterious effects of prenatal prednisolone exposure upon morphological and behavioral development of mice.

The influence of prenatal exposure to the synthetic glucocorticoid prednisolone (PRED) was examined in female offspring of mice administered the drug on Days 13-18 of pregnancy. The offspring weighed significantly less than control animals at birth and weaning. Animals born of mothers given the highest dosage of the drug (400 microgram) weighed less than controls in adulthood. Fetal exposure to PRED also resulted in morphological masculinization as evidenced by an increase in anogenital distance. In addition to its marked influence, prenatal PRED exposure retarded the attainment of the developmental milestones of eye opening, lifting, walking, and gripping. The effect of PRED upon the fetus is relatively rapid in that a reduction of fetal weight was observed in 13-day-old conceptae 7.5 hr following a maternal injection of PRED. The administration of an antiestrogenic compound (MER-25) concurrently with PRED prevented the reduction in birth weight, thereby suggesting that PRED acts, in part, by its known attenuation of fetoneonatal estrogen-binding protein. And finally, fetal exposure to PRED had virtually no effect upon reproductive competence as assessed by proportion of successful pregnancies, lactation performance, and postpartum fighting behavior. It is concluded that prenatal exposure to PRED markedly affects somatic and muscular/motor development and it may be worthwhile to examine the influence of the drug upon levels of gonadal hormones in an attempt to elucidate the mechanism through which its effects are produced.

Comparative Effects of Fission Neutron and X Irradiation on 7.5-Day Mouse Embryos

Dl MAJO, V., BALLARDIN, E., AND METALLI, P. Comparative Effects of Fission Neutron and X Irradiation on 7.5-Day Mouse Embryos. Radiat. Res. 87, 145-158 (1981). Fission spectrum neutrons (0-46.5 rad) were compared with 250-kV X rays (0-200 rad) for reduction of fetal weight and for embryolethal and teratogenic effects in mice. Animals were irradiated 7.5 days postcoitum (p.c.) and fetuses were examined 18.5 days p.c. Mortality showed a definite shoulder for both types of radiation. The shoulder was smaller for neutrons than for X rays, and at 20% mortality, the dose ratio was approximately 3. The relative biological effectiveness (RBE) for weight loss was 3.2 ? 0.8. The dose-effect relationships for major malformations after X irradiation showed a large shoulder (approximately 100 rad), while no apparent threshold could be seen in the neutron series, so that the relative efficiency of neutrons was dependent on the neutron dose. The equal effectiveness dose ratio estimated at 7% incidence of severe external malformations was 2.4, increasing to about 3.4 if more common head abnormalities were also included. In conclusion, fission neutrons induce the same types of effects as X rays in 7.5-day mouse embryos, being two to four times more effective than sparsely ionizing radiation at relatively high doses, except for major malformations where the RBE is higher with decreasing neutron doses.

Comparative Teratogenicity of Cortisone and Phenytoin in Mice

Single administrations of cortisone or phenytoin to pregnant mice on Days 11‐14 of gestation caused similar skeletal and dissimilar soft tissue fetal anomalies. Cortisone reduced both maternal and fetal weight, whereas phenytoin only reduced fetal weight without adversely affecting maternal weight. A correlation between fetal weight reduction and cleft palate incidence was evident for each drug. Because probit analysis of dose‐response regression lines did not deviate from parallelism after drug challenge, it was concluded that cortisone and phenytoin may produce palatal anomalies in the mouse fetus by a similar mechanism.

Limb development in mouse embryos. III. Cellular events underlying the determination of altered skeletal patterns following treatment with 5'fluoro-2-deoxyuridine.

A potent inhibitor of thymidylate synthetase, 5-Fluorodeoxyuridine (FUdR), produced dose- and stage-dependent skeletal defects in embryos of mice injected during early development (10th--13th day). The dose of 25 mg/kg was teratogenic producing few resorptions and little reduction in fetal weight. Hindlimbs were much more sensitive to the drug than were the forelimbs and showed dose-dependent long bone reductions. Specific long bone reductions occurred after treatment on the 11th or 11.5 day and were accompanied by preaxial polydactyly; treatment on the 12th or 12.5 day produced high incidence of ectrodactyly but no long bone reductions. Limbs were insensitive on the 13th day of development and beyond. Limb buds in organ culture demonstrated a direct action of FUdR on undifferentiated mesenchymal cells, incurring what has been previously termed "thymineless" cell death. Dose-dependent reduction of viable cell number led to a reduction in chondrogenic expression in vitro--more so in the hindlimb than the forelimb. Similar occurrence of cell death was also noted after in utero exposure, and here, it was followed by a process of recovery. The recovery phase was characterized by the formation of a distal synchronized cell population derived from undamaged subridge cells leaving damaged cells at the proximal extent of the subridge zone. Limb segments maintained their temporal sequence of differentiation, and their regulatory capability was related to the time allotted for repopulation of the subridge zone. We propose that a faster growth during early development of the elements of the hindlimb versus analogous ones of the forelimb allows the former less time for regulation--and hence, higher sensitivity to antiproliferative agents such as FUdR.

Studies on reproduction in prolific ewes:7. Variability in the growth of individual foetuses in relation to intra-uterine factors

SUMMARYThe weights of 44 twin foetuses, 99 triplets and 44 quadruplets, varying in gestational age from 55 to 145 days, were studied in relation to age, sex, litter size, uterine position, placental structure and weight, and ovulation rate. Triplet and quadruplet foetuses were more variable in weight, within litters, than were twins. The difference increased with foetal age and was attributed to increased competition between foetuses which were located within the same horn of the uterus. The effect was largely associated with differences in placental development, i.e. numbers of cotyledons and weight, but those differences did not entirely account for the reduction in foetal weight with increasing litter size. Differences in placental development, arising from embryo mortality, also accounted for the reduction in foetal weight when ovulation rate exceeded litter size. In contrast, differences in foetal weight associated with the sex of the foetuses were only partly mediated by differences in cotyledon weight. Foetuses in the larger litters are thus not only lighter in weight but are more variable in weight, the increased variability being controlled by events in early pregnancy.

High oxygen affinity of maternal blood reduces fetal weight in rats

In order to obtain information on the physiological significance of the difference in oxygen affinity between maternal and fetal blood, we have examined the effect of an acute increase of the oxygen affinity of maternal blood in pregnant rats, on fetal body weight, fetal brain and liver weights, placental weight, and the hematocrit of fetal blood. The increase in oxygen affinity was produced by exchange-transfusing pregnant rats on day 19 of gestation with blood that had been treated previously with sodium cyanate. As a result of the exchange transfusion, the difference in oxygen affinity between maternal and fetal blood essentially disappeared. Pregnant rats exchanged with normal blood served as controls. On day 21 of gestation, the fetal body weight and the fetal liver weight were significantly smaller by 18% and 25% respectively, in the group where the oxygen affinity of the maternal blood was acutely raised when compared to the controls. Also, the hematocrit of the fetal blood was significantly higher in the group where mothers had the high blood oxygen affinity. Placental weight and fetal brain weight were not significantly altered. We infer, that the reduction of fetal weight is due to fetal hypoxia which is caused by the abolishment of the difference in oxygen affinity between maternal and fetal blood. Human infants, whose birth weight is too small for their gestational age have a significantly increased postnatal mortality compared to babies with normal weight. We suppose that the increased mortality of newborns who are too small for their gestational age, represents a selective pressure that has favoured the evolution of a high oxygen affinity of fetal in comparison with maternal blood.

Teratogenic Activity in the Mouse after Oral Administration of Acetazolamide

Acetazolamide was administered orally by gavage to pregnant mice twice a day on days six through 15 of gestation at a dose level of 300.0 mg/kg. This treatment produced maternal toxicity as evidenced by significantly reduced food consumption and body weight gain. Embryotoxicity demonstrated by significant reductions in fetal weight and crown-rump length was also observed. Resorption rates were considerably higher (77.9%) for the acetazolamide treated litters when compared to those from the control group (8.23%). A variety of malformations was observed in the acetazolamice-treated rats (rib and vertebral fusion, gastroschisis, tail defects, cleft palate and ectrodactyly). These results further establish acetazolamide as an acceptable positive teratogenic control by demonstration of species and strain susceptibility in the CD-1 mouse.

The extent of fetal ossification as an index of delayed development in teratogenic studies on the rat.

In teratogenic studies toxic effects may manifest themselves in retarded fetal development, such as a reduction in fetal weight. In searching for an additional index, the number of centers of ossification in seven skeletal districts (sternum, metacarpus, metatarsus, cervical and caudal vertebrae, anterior and posterior proximal phalanges) of rat fetuses delivered on days 19, 20 and 21 of gestation were counted and compared. Results showed uneven ossification in day-19 and -20 fetuses, but sufficiently advanced, homogeneous and uniform ossification in day-21 fetuses to provide a reliable quantitative index for evaluating retarded fetal development. It is therefore proposed that the stage of skeletal ossification in day-21 fetuses be used in teratogenic studies in the rat to evaluate retarded fetal development.

Effect of acute maternal ethanol exposure upon fetal development in the rat

Two studies on the effect of acute ethanol administration during Days 9-12 of gestation showed significant fetal weight reduction (6%-8%) in rats from ethanol-treated dams compared to water controls. Maternal weight gains could not account for the differences. These effects of acute doses (3-4 g ethanol/kg body weight), given only during organogenesis, suggest that chronic ethanol exposure during gestation is not required for some developmental retardation to occur. What effect this retardation may have upon subsequent behavioral development remains to be determined.

Carbon disulphide tetratogenicity and postnatal effects in rat

Pregnant albino rats were exposed to carbon disulphide vapour in concentrations of 50, 100 or 200 mg m 3 throughout gestation. Two successive generations (F 1 and F 2) were studied. Concentration levels of 100 and 200 mg m 3 produced marked dose-related impairment in the prenatal development of the F 1 progeny, with increase of early embryonal lethality, reduction in foetal weight and a high incidence of malformations affecting mostly the brain and limbs. Postnatal viability, body weight, lipid and energy metabolism and behaviour were also impaired. Behavioral deviations were observed even at 50 mg m 3 . After reaching sexual maturity the F 1 rats were mated within their experimental groups, but no further carbon disulphide exposure was applied. The adverse effects on progeny were still detectable in the F 2 generation. Structural abnormalities of the same type as those found in the F 1 at 100 and 200 mg m 3 exposure were observed in their progeny and, postnatally, statistically significant behavioral changes were observed in the progeny of all test groups.

Placental transfer of lead, mercury, cadmium, and carbon monoxide in women: II. Influence of some epidemiological factors on the frequency distributions of the biological indices in maternal and umbilical cord blood

We have investigated the influence of various epidemiological factors (smoking habits, residence, age, occupation, drinking habits, duration of pregnancy, number of previous pregnancies) in the exposure of 474 European pregnant women and their newborns to lead, mercury, cadmium, and carbon monoxide. Smoking has a statistically significant influence on carboxyhemoglobin level in mothers and newborns and on cadmium concentration in maternal blood. The association of smoking with a reduction of fetal weight was confirmed. A slight but statistically significant effect of environmental pollution by lead (urban and industrial semirural rural area) on lead uptake by the pregnant mothers and its transfer to their fetuses was demonstrated. Some results suggest that during pregnancy lead could be mobilized from maternal tissue depots, but further investigations are required to confirm this tentative conclusion. No significant relationships were found between the other epidemiological parameters and the various biological measurements performed on mother and cord blood.

Fetal growth retardation following maternal morphine administration: nutritional or drug effect?

The effects of maternal morphine administration on maternal nutrition and on fetal growth have been systematically examined in a rabbit model. Significant alterations in maternal food intake occurred morphine exposure. These nutrition changes did not result in fetal growth retardation. Fetal morphine exposure was associated with significant reductions in fetal weight, length, placental weight and in the weights of most organs including the brain. When organ weight was considered as a fraction of total fetal weight morphine exposure was associated with a significant increase in the relative weight of the brain and a significant decrease in the relative weight of liver and kidneys. These narcotic effects were dose dependent.