The offspring of the female diabetic "nonobese diabetic" (NOD) mouse are large for gestational age and have elevated pancreatic insulin content: a new animal model of human diabetic pregnancy

Pregnancy in diabetic mothers is associated with intrauterine death, perinatal mortality, and birth weight greater than that of infants born of normal mothers. The use of rodents made diabetic by alloxan or streptozotocin as an animal model for human diabetic pregnancy has been controversial because of the severity of the diabetes as well as the direct effect of diabetogenic drugs on the developing organism. Among our female NOD (nonobese diabetic) mice, insulin-dependent diabetes occurs spontaneously in 9% by 12 weeks and in 80% by 29 weeks of age. Offspring born within 21 days of conception to mildly hyperglycemic NOD pregnant mice between 26 and 52 weeks of age, and prior to the onset of maternal ketonuria are macrosomic with an average of 31% increase in body weight and 44% increase in kidney weight, in comparison to controls. Besides organomegaly, the macrosomic offspring have significantly higher pancreatic insulin content which was elevated 80% when compared with that of controls, and litter sizes are significantly 50% smaller. These results suggest that the mildly hyperglycemic pregnant NOD mouse represents a promising model for the study of pregnancy complicated by diabetes.     

Effects of maternal diabetes on the development of carbohydrate metabolizing enzymes in fetal rat liver

Effects of streptozotocin-induced maternal diabetes on fetal hepatic carbohydrate-metabolizing enzyme development and hormonal status has been explored in the rat. Hepatic glycogen synthase a activity of the normal fetus rose to a maximum at 20 days of gestation, then fell prior to parturition. In fetuses of diabetic mothers, this prepartum decline was curtailed, resulting in enhanced synthase a activity and increased glycogen content in fetal livers at term. Elevation in hepatic synthase a in fetuses of diabetic mothers was due, not to altered interconversion between existing synthase a and b, but to equivalent increases in both forms of the enzyme. Both hepatic and free plasma corticosterone levels were elevated in fetuses of diabetic mothers and may be responsible for the enhanced development of total glycogen synthase observed in these fetuses. In normal fetuses hepatic phosphofructokinase and pyruvate kinase activities also rose to maxima at 20 days, then declined prior to term. In fetuses of diabetic mothers pyruvate kinase activity attained higher than normal maximal levels and phosphofructokinase activity fell more gradually, thus resulting in elevations in both enzyme activities at term. Augmentations in these glycolytic enzymes are compatible with hyperinsulinemia observed in fetuses of diabetic mothers. The following conclusions may be drawn from these findings. During late fetal life developmental patterns of rate-limiting hepatic glycogen-synthesizing and glycolytic enzymes are adapted to glucose utilization. In the normal fetus these patterns reverse at term, thereby promoting glucose mobilization, which prepares the fetus for abrupt deprivation of maternal glucose at birth. Maternal diabetes results in retardation of these reversal processes, presumably due to elevations in fetal glucocorticoid and insulin levels. Glycogenolytic and glucogenic capacities are thereby impaired in these fetuses.     

The effect of maternal and fetal corticosteroids on the development of function of the pituitary-adrenocortical system.

The pituitary-adrenocortical system of rat fetuses was stimulated (larger adrenals at birth) by maternal adrenalectomy, or suppressed (smaller adrenals at birth) by implantation of an ACTH secreting pituitary tumor (MtTF4). Offspring were delivered by caesarean section and fostered to untreated females. Offspring of intact females delivered by caesarean section and normally delivered offspring of intact mothers both fostered to untreated lactating females served as controls. Body growth in the first three weeks of life was delayed in offspring of tumor bearing mothers in Control-fostered subjects as compared to the 2 other groups. At 70 days of age female offspring of the tumor implanted and adrenalectomized mothers, as well as the Control-caesarean females, had smaller adrenals than Control-fostered animals of the same sex. The adrenal size of males was not significantly affected. No significant differences were found in resting concentrations of corticosterone in plasma, although offspring of adrenalectomized mothers had high values. Suppressed adrenal response to ether stress was found in offspring of tumor bearing mothers. The supposition is that interference with maternal pituitary-adrenocortical activity during pregnancy has a long lasting effect on fetal hypothalamo-pituitary-adrenocortical system.     

Smoking in pregnancy: associations with skinfold thickness,maternal weight gain,and fetal size at birth.

Skinfold thickness is an index of subcutaneous fat, and certain maternal conditions during pregnancy affect the skinfold thicknesses of the baby. A study was performed to investigate the effect of smoking on skinfold thickness, maternal weight gain, and fetal size at birth. A total of 452 mothers with normal singleton pregnancies were groups as: non-smokers, light-to-moderate smokers, or heavy smokers. Maternal age, height, parity, and duration of pregnancy were similar in the three groups. Heavy smokers gained significantly less weight than non-smokers, but there was no significant difference in skinfold thickness. Babies born to smokers had lower birth weights and smaller head circumferences and were shorter than those born to non-smokers, but skinfold thicknesses were similar. The presence of a normal layer of subcutaneous fat in babies whose mothers smoked suggests that fetal growth retardation is not caused by nutritional deficiencies.     

Birth weight, sexual orientation and the sex of preceding siblings.

This study's first objective was to compare the mean birth weights of homosexual and heterosexual men and women. Its second objective was to investigate whether prior male and female fetuses have different effects on the birth weight of subsequent fetuses. The subjects were 3229 adult men and women (the probands), who weighed at least 2500 g at birth, and whose mothers knew the sex of the child (or fetus) for each pregnancy prior to the proband. Information on birth weight, maternal gravidity and other demographic variables was reported on questionnaires completed by the probands' mothers. The results confirmed earlier reports that boys with older brothers weigh less at birth than boys with older sisters, but they did not confirm reports that girls with older brothers weigh less than girls with older sisters. The results did not show across-the-board differences in the mean birth weights of homosexual versus heterosexual women or homosexual versus heterosexual men. However, the homosexual males with older brothers weighed about 170 g less at birth than the heterosexual males with older brothers. It is suggested that this pattern of results may reflect a maternal immune response to Y-linked minor histocompatibility antigens (H-Y antigens). According to this hypothesis, when the maternal immune response is mild, it produces only a slightly reduced birth weight, but when it is stronger, it produces a markedly reduced birth weight as well as an increased probability of homosexuality.     

The influence of moderate exercise in diabetic and normal pregnancy on maternal and fetal outcome in the rat

The effect of treadmill exercise prior to and during pregnancy on maternal and fetal outcome was studied in nondiabetic and streptozotocin-induced diabetic rats. Animals were exercised daily on a motorized treadmill (16.1 m/min, 45 min/d) for three weeks prior to mating and throughout gestation. The catabolic state of diabetes was evidenced by changes in maternal body composition. Overall, fetuses of diabetic dams were smaller, lighter, had less calcified skeletons and had more malformations compared to control fetuses. Exercise in the nondiabetic dams resulted in a retardation of skeletal ossification compared to fetuses from sedentary controls. However, exercise improved fetal outcome in diabetic rats, resulting in increased fetal weight and a lower frequency of malformations compared to fetuses from sedentary diabetic dams.     

Risk factors in congenital abdominal wall defects (omphalocele and gastroschisi): a study in a series of 265,858 consecutive births.

The aim of this study was to describe the prevalence at birth of two abdominal wall defects (AWD), omphalocela and gastroschisis and to identify possible etiologic factors. The AWD came from 265,858 consecutive births of known ouome registered in the registry of congenital malformations of Strasbourg for the period 1979 to 1998. Request information on the child, the pregnancy, the parents and the family was obtained for cases and for controls. Hundred five cases with AWD were analysed, 55.2 % were omphalocele and 44.8 % were gastroschisis. The mean prevalence rate for omphalocele was 2.18 per 10,000 and for gastroschisis 1.76 per 10,000. Associated malformations were found in 74.1 % of omphalocele compared with 53.2 % of gastroschisis; 29.3 % of fetuses with omphalocele had an abnormal karyotype, 44,8 % had a recognizable syndrome, association or an unspecified malformation pattern; 51.0 % of fetuses with gastroschisis had additional malformations that were not of chromosomal origin, but 1 case. Antenatal ultrasound examination was able to detect 39 (67.2 %) cases of omphaloceles and 27 (57.4 %) cases of gastroschisis. In 30 (51.7 %) cases of omphalocele and in 7 (14.9 %) cases of gastroschisis parents opted for termination of pregnancy. The overall survival rate was 14 (24.1 %) for omphalocele and 30 (63.8 %) for gastroschisis. Weight, length and head circumference at birth of infants with AWD were less than those of controls. The weight of placenta of infants with AWD was not different from the weight of placenta of controls. Gastroschisis was associated with significantly younger maternal age than omphalocele. Pregnancies with AWD were more often complicated by threatened abortion, oligohydramnios and polyhydramnios. Mothers of children with AWD took more often medication during pregnancy than mothers of controls.     

Different Diabetogenic Response to Moderate Doses of Streptozotocin in Pregnant Rats,and Its Long-Term Consequences in the Offspring

Diabetes during pregnancy results in congenital malformations and long-term postnatal diseases. Experimental models are still needed to investigate the mechanism responsible for these alterations. Thus, by the administration of different doses of streptozotocin (STZ) (0, 25, 30, or 35 mg/kg body weight, intravenous) at the onset of pregnancy in rats, the present study sought an appropriate animal model for this pathology. At day 6 of pregnancy, plasma glucose was progressively higher with an increasing STZ dose, and in rats receiving the 35-mg dose, 2 subgroups were detected: some animals had plasma glucose levels above controls but below 200 mg/dL (mildly diabetic, MD), whereas others had levels above 400 mg/dL (severely diabetic, SD). At day 20 of pregnancy, the MD rats had normal glycemia, but after an oral glucose load (2 g/kg body weight), plasma glucose increased more and insulin increased less than in controls. The SD rats maintained their hyperglycemia and had a greatly impaired oral glucose tolerance. At day 20, fetuses of SD dams were fewer, weighed less, and had enhanced plasma glucose and triglycerides and decreased insulin, whereas those from MD dams did not differ from controls. At birth, newborns from MD dams had higher body weight, plasma insulin, and liver triglycerides as well as total body lipid concentrations than controls, and on day 21, remained macrosomic and showed higher plasma glucose and liver triglyceride concentrations. At 70 days of age, offspring of MD dams had impaired oral glucose tolerance but normal plasma insulin change in the case of females, whereas plasma insulin increased less in males. These alterations were manifest more in those offspring from dams that had > 50% macrosomic newborns than in those from dams that had < 50% macrosomic newborns. In conclusion, whereas our MD rats mimic the changes taking place in gestational diabetic women and show the long-term risk of macrosomia, the SD rats are more similar to uncontrolled diabetics. Thus these two rat models, obtained with moderate amounts of STZ, could be used to study the pathophysiological consequences of these different diabetic conditions.     

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy.

Ninety-nine insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the seventh to 14th weeks of pregnancy. As judged by the crown-rump length 38 fetuses were smaller than normal. The term early growth delay is suggested for this phenomenon. Nine fetuses had major congenital malformations, and seven of them were smaller than normal in early pregnancy (p less than 0.02). The risk of fetal malformation in diabetic pregnancy increases with the severity of the diabetes. Early fetal growth delay is apparently another risk marker, in this series indicating a risk of 18% (7/38). The combination of severe maternal diabetes (White''s classes D and F) and early growth delay yielded a risk of major congenital malformation of 27% (6/22). These observations suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis (and maybe even fetal death). The mechanism is unknown but probably influenced by the quality of regulation of diabetes.     

Different fatty acid pattern in breast milk of obese compared to normal-weight mothers

IntroductionThe aim of this study was to investigate the fatty acid (FA) pattern in breast milk of obese mothers and their neonates' plasma compared to those of normal weight mothers.Patients and methodsThis was an observational study of 41 obese and 41 normal weight pregnant women. Twenty-nine obese women participating in a weight reduction program were investigated for comparison. FAs were analyzed in breast milk collected at 3 and 10 days and one and two months postnatally and in infant's plasma 3 days after birth.Results and conclusionsThe concentration of long-chain n-3 FA were lower and the ratio n-6/n-3 FA higher in neonates and in consecutive samples of breast milk of obese mothers compared to normal weight mothers. The obese mothers that participated in an intervention program with general dietary advice had FA concentrations approaching that of the normal-weight mothers. The study indicates importance of dietary advice in pregnancy.     

Relationships between fetal biometry, maternal factors and birth weight of purebred domestic cat kittens

The goal of this study was to evaluate the relation between kittens' birth weights and biometrical factors from the kittens and the mother during pregnancy. Knowing fetal birth weight could help in detecting abnormalities before parturition. A Caesarean-section or a postnatal management plan could be scheduled. Consequently, the neonatal mortality rate should be decreased. We used ultrasonographic measurements of femur length (FL) or fetal biparietal diameter (BPD), pregnancies, and maternal factors to obtain a model of prediction. For this purpose, linear mixed-effects models were used because of random effects (several fetuses for one queen and a few paired measurements) and fixed effects (litter size, pregnancy rank, weight, wither height, and age of the queen). This study was performed in 24 purebred queens with normal pregnancies and normal body conditions. Queens were scanned in the second half of pregnancy, using a micro-convex probe. They gave birth to 140 healthy kittens whose mean birth weight was 104 g (ranged 65 to 165 g). No correlation between the birth weight and the age of the queen, as a maternal factor alone, was observed. But the birth weight was found to be inversely proportional to the pregnancy rank and the litter size. Moreover, birth weight increased when the weight and wither height of queen increased. BPD and FL increased linearly during pregnancy so a model was used to estimate mean birth weight. Using this model, we found a correlation between mean birth weights and an association of parameters: maternal factors (wither height and age), and litter size.     

Relationships between fetal biometry,maternal factors and birth weight of purebred domestic cat kittens

The goal of this study was to evaluate the relation between kittens' birth weights and biometrical factors from the kittens and the mother during pregnancy. Knowing fetal birth weight could help in detecting abnormalities before parturition. A Caesarean-section or a postnatal management plan could be scheduled. Consequently, the neonatal mortality rate should be decreased. We used ultrasonographic measurements of femur length (FL) or fetal biparietal diameter (BPD), pregnancies, and maternal factors to obtain a model of prediction. For this purpose, linear mixed-effects models were used because of random effects (several fetuses for one queen and a few paired measurements) and fixed effects (litter size, pregnancy rank, weight, wither height, and age of the queen). This study was performed in 24 purebred queens with normal pregnancies and normal body conditions. Queens were scanned in the second half of pregnancy, using a micro-convex probe. They gave birth to 140 healthy kittens whose mean birth weight was 104 g (ranged 65 to 165 g). No correlation between the birth weight and the age of the queen, as a maternal factor alone, was observed. But the birth weight was found to be inversely proportional to the pregnancy rank and the litter size. Moreover, birth weight increased when the weight and wither height of queen increased. BPD and FL increased linearly during pregnancy so a model was used to estimate mean birth weight. Using this model, we found a correlation between mean birth weights and an association of parameters: maternal factors (wither height and age), and litter size.     

Effect of maternal diabetes on fetal bile acid metabolism in the rat

Effect of diabetes induced by streptozotocin during pregnancy on fetal bile acid metabolism was investigated in the rat. Serum bile acid levels of diabetic pregnant rats were higher than those of control pregnant rats. Total pool of primary bile acids (cholic and chenodeoxycholic acids) in fetuses of diabetic mothers was significantly lower than that of control fetuses. However, the concentration of secondary bile acids, i.e., lithocholic, deoxycholic, and 3β, 12α-dihydroxycholanoic acids, was significantly higher in fetuses of diabetic mothers. These results suggest that the alteration in bile acid metabolism noted previously (4) in neonates of diabetic mothers is probably a manifestation of the effect of maternal diabetes at the fetal level.     

Gastroschisis, low maternal age, and fetal morbidity outcomes

OBJECTIVE: To determine if the risk for fetal growth inhibition among gastroschisis-afflicted fetuses is heightened among younger gravidas (teen mothers). METHOD: This was a retrospective cohort study on live-born infants with isolated gastroschisis delivered in New York State from 1983 through 1999. We compared infants of mature (>20 years) mothers with those of younger (<20 years) mothers with respect to the following indices of fetal morbidity outcomes: low birth weight and very low birth weight, preterm and very pre-term, and small for gestational age. We used adjusted odds ratios to approximate relative risks. RESULTS: A total of 368 infants with isolated gastroschisis were analyzed. The two groups differed in terms of mean gestational age at delivery [Mean + standard deviation(SD) for infants with gastroschisis born to mature mothers = 37.2 weeks +/- 2.8 versus 36.3 weeks + 3.6 for those of teenage mothers(p = 0.01)], as well as mean birth weight [mean birth weight +/- SD for infants with gastroschisis born to mature mothers = 2562.4 grams +548.8 versus 2367.9 grams +/- 645.2 for those of younger mothers (p = 0.004)]. Infants of teen mothers were about twice as likely to be of low birth weight (OR = 1.70; 95% CI = 1.05-2.77) and about three times as likely to be born very preterm when compared to those of mature mothers (OR = 2.80; 95% Cl = 1.02-8.00). No significant differences were observed with respect to very low birth weight, pre-term and small for gestational age. CONCLUSION: Low maternal age appears to be a risk factor for low birth weight and very preterm birth among gastroschisis-affected fetuses. This information is potentially useful for planning by care providers and in counseling affected parents.     

Etiology of individual differences in birth weight of twins as a function of maternal smoking during pregnancy.

Birth weight is in large extent influenced by gestational age. In addition genetic and environmental factors determine intrauterine growth and birth weight. The contributions of these factors may be influenced by maternal smoking during pregnancy. We examined birth weight and maternal smoking in a sample of 2930 twin pairs from the Netherlands Twin Register using structural equation modelling. Gestational age accounted for 27-44% of the variance in birth weight. A lower variability of birth weight and a lower association of birth weight with gestational age was found in twins whose mothers smoked during pregnancy. The variance not associated with gestational age was independent of maternal smoking during pregnancy. A systematic smaller part of the variability in birth weight was associated with variability in gestational age in second born twins compared to first born twins. The heritability of interindividual differences in birth weight was modest (10% for twins with non-smoking mothers and 11% for twins with smoking mothers). Common environmental influences other than gestational age accounted for a slightly larger part of the variance not associated with gestational age (17-20%).     

Birth Weight,Intrauterine Growth Retardation and Fetal Susceptibility to Porcine Reproductive and Respiratory Syndrome Virus

The severity of porcine reproductive and respiratory syndrome was compared in pregnant gilts originating from high and low birth weight litters. One-hundred and eleven pregnant gilts experimentally infected with porcine reproductive and respiratory syndrome virus on gestation day 85 (±1) were necropsied along with their fetuses 21 days later. Ovulation rates and litter size did not differ between groups, but fetuses from low birth weight gilts were shorter, lighter and demonstrated evidence of asymmetric growth with large brain:organ weight ratios (i.e. brain sparing). The number of intrauterine growth retarded fetuses, defined by brain:organ weight ratios greater than 1 standard deviation from the mean, was significantly greater in low, compared to high, birth weight gilts. Although γδ T cells significantly decreased over time in high compared to low birth weight gilts, viral load in serum and tissues, gilt serum cytokine levels, and litter outcome, including the percent dead fetuses per litter, did not differ by birth weight group. Thus, this study provided no substantive evidence that the severity of porcine reproductive and respiratory syndrome is affected by dam birth weight. However, intrauterine growth retarded fetuses had lower viral loads in both fetal thymus and in endometrium adjacent to the umbilical stump. Crown rump length did not significantly differ between fetuses that survived and those that died at least one week prior to termination. Taken together, this study clearly demonstrates that birth weight is a transgenerational trait in pigs, and provides evidence that larger fetuses are more susceptible to transplacental PRRSv infection.     

The influence of mother's active smoking during pregnancy on body mass index of newborns

Many investigations have noted bad influence of smoking during pregnancy. In the present article, the influence of mothers smoking during pregnancy on the body mass index (BMI), birth weight and birth length are examined. This retrospective research included 219 children: Group I: 109 children from rural area of east Slavonia (born in General Hospital-Vinkovci) and group II: 110 children from industrial area (born in Zagreb). The questioned subjects were divided into two groups depending on mothers smoking during pregnancy: newborns of mothers who didn't smoke during pregnancy (subgroup A) and newborns of mother who did smoke 10 or more cigarettes per day during pregnancy (subgroup B). Anthropometric parameters (BMI, birth length and birth weight) in newborns of non-smoking mothers were statistically higher (p < 0.05) than in newborns of smoking mothers. Moderate correlation between birth length and birth weight in newborns of non-smoking and smoking mothers from rural area and from non-smoking mothers in urban area was statistically significant, but correlation in the group in newborns of smoking mothers from Zagreb was not statistically significant. Results of this research show that smoking during pregnancy significantly influences the birth weight and birth length. Further investigation is needed, to investigate the lack of correlation between the birth length and birth weight in newborns of smoking mothers from industrial city.     

Clinical,hormonal, and hematologic characteristics of bovine calves derived from nuclei from somatic cells

Although healthy animals are born after nuclear transfer with somatic cells nuclei, the success of this procedure is generally poor (2%-10%) with high perinatal losses. Apparently normal surviving animals may have undiagnosed pathologies that could develop later in life. The gross pathology of 16 abnormal bovine fetuses produced by nuclear transfer (NT) and the clinical, endocrinologic (insulin-like growth factors I and II [IGF-I and IGF-II], IGF binding proteins, post-ACTH stimulation cortisol, leptin, glucose, and insulin levels), and biochemical characteristics of a group of 21 apparently normal cloned calves were compared with those of in vitro-produced (IVP) controls and controls resulting from artificial insemination. Oocytes used for NT or IVP were matured in vitro. NT to enucleated oocytes was performed using cultured adult or fetal skin cells. After culture, Day 7, grade 1-2 embryos were transferred (one per recipient). All placentas and fetuses from clones undergoing an abnormal pregnancy showed some degree of edema due to hydrops. Mean placentome number was lower and mean placentome weight was higher in clones than in controls (69.9 +/- 9.2 placentomes with a mean weight of 144.3 +/- 21.4 g in clones vs. 99 and 137 placentomes with a mean individual weight of 34.8 and 32.4 g in two IVP controls). Erythrocyte mean cell volume was higher at birth (P < 0.01), and body temperature and plasma leptin concentrations were higher and T4 levels were lower during the first 50 days and the first week (P < 0.05), respectively, in clones. Plasma IGF-II concentrations were higher at birth and lower at Day 15 in clones (P < 0.05). Therefore, apparently healthy cloned calves cannot be considered as physiologically normal animals until at least 50 days of age.     

Streptozotocin-induced diabetes in the pregnant rat reduces 11 beta-hydroxysteroid dehydrogenase type 2 expression in placenta and fetal kidney

Several epidemiological and animal studies have shown that the offsprings of diabetic mothers have higher incidences of glucose intolerance, obesity, insulin resistance, and hypertension in later life. It is well known that glucocorticoid metabolism plays a crucial role on several adult disease originated from fetal environment. The aim of this study was to investigate the relation between diabetic pregnancy and glucocorticoid metabolism of both mother and fetus, focusing on the 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. A model of diabetic pregnancy was made by intravenous injection of streptozotocin (35 mg/kg body weight) to Sprague-Dawley rats, and blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, expression of 11 beta-hydroxysteroid dehydrogenase type 2 in placentas and fetal kidneys was decreased remarkably. Corticosterone levels of diabetic mothers were lower than those of control rats. Despite the differences in maternal corticosterone levels, fetal levels of corticosterone did not differ between the groups. Our results lend support to the concept that diabetic pregnancy imprints glucocorticoid regulation in these fetuses, which may contribute to their increased incidence of higher blood pressure as adults.     

Ontogeny of hematological cell and biochemical profiles in maternal and fetal baboons (Papio species)

The normal ranges of hematological cell profiles and biochemistry are documented in adult non-pregnant, pregnant, juvenile, and neonatal baboons. Despite the extensive use of the baboon as a model for the study of various aspects of pregnancy, there is no data from paired mothers and their fetuses at different stages of gestation. Hematologic and biochemical profile data were obtained from eight non-pregnant female baboons, 37 mothers and 38 fetal baboons at 30 +/- 2, 90 +/- 2, 125 +/- 2, and 175 +/- 2 days of gestation (mean +/- range; dGA; term, 180 dGA). Changes observed in fetal and maternal blood during normal baboon pregnancy were similar to those reported in human pregnancy. The level of alkaline phosphatase was two times higher in fetal blood circulation than that reported in human pregnancy.