Leptin secretion to both the maternal and fetal circulation in the ex vivo perfused human term placenta

The contribution of placental leptin, if any, to both the fetal and maternal circulation and its role in pregnancy remains to be determined. In an experiment to investigate this, 27 placentae from term pregnancies were perfused ex vivo (gestational age=39.5 s.d. 1.2; range=38-42 weeks: fetal weight=3285 s.d. 482; range=2480-4420; birthweight centile range=4th to the 98th) at both the maternal and fetal interface. Placental leptin was exported into both the maternal and fetal circulations. The log leptin production by the maternal side of the placenta was significantly greater (P=0.001) than that for the fetal side (5.193 s.d.1.049 versus 4.387 s.d. 0.768 ng/placenta/min). There was no significant relationship between maternal and fetal log leptin production and maternal body mass index, birthweight, birthweight centile, ponderal index or gestational age or with cord blood pO(2), pCO(2) and pH. There was however, a significant increase in the maternal log leptin production with increasing fetal to placental weight ratio (P=0.017; r(2)=20.7 per cent) but no corresponding relationship for fetal leptin production. It is proposed that such a mechanism would allow the placenta to modulate fat supply to the fetus in response to the fetal demand relative to placental supply.     

The breadth of the placental surface but not the length is associated with body size at birth

Studies of pregnancies complicated by preeclampsia led to the suggestion that the surface of the placenta is aligned along two axes, measured by its breadth and length. It was hypothesised that tissue along the breadth serves as a nutrient sensor, responding to the mother's nutritional state and fetal nutritional demands, while tissue along the length has different functions. To develop this hypothesis we measured the breadth and length of the placental surface in 401 neonates born in the King Khalid Hospital, Riyadh, Saudi Arabia, and related these measurements to the baby's body size. The breadth and length of the placental surface were highly correlated (coefficient = 0.7). Nevertheless, in a simultaneous regression with both measurements, only the breadth was associated with neonatal body size. There were strong trends of increasing birth weight, ponderal index, and the circumferences of the head, chest, abdomen and thigh with increasing placental breadth. In contrast no measurement of baby's body size was related to placental length. Birth weight increased by 125 g per cm increase in placental breadth (95% confidence interval 88 to 162, p < 0.001) but only by 20 g per cm increase in placental length (-13 to 53, p = 0.2). The corresponding figures for head circumference were 0.28 cm (0.17-0.39, p < 0.001) and 0.03 (-0.07 to 0.14, p = 0.5). The associations between placental breadth and neonatal body size were strongest if the mother's height was below the median (157 cm). The associations between a larger breadth of the placental surface and a larger baby are consistent with the hypothesis that tissue along the breadth plays a key role in nutrient transfer from mother to baby. Mothers who are short in stature are known to have lower rates of protein turnover in pregnancy. In these circumstances the ability of the placenta to transfer amino acids to the fetus may be critical.     

Human versus animal insulin in the management of insulin-dependent diabetes: lack of effect on fetal growth

It is generally accepted that the human placenta is impermeable to free insulin and that insulin present in the fetus is entirely of fetal origin. A recent study suggested that antibody-bound animal insulin crosses the placental barrier and may exert direct effects on fetal growth. We hypothesized that mothers with insulin-dependent diabetes treated with animal insulin would have infants with higher birth weights and ponderal indices compared with mothers treated with human insulin. We studied 209 mothers with insulin-dependent diabetes who were enrolled in our program and who delivered after 28 weeks' gestation: 170 were treated with animal insulin and 39 with human insulin. There were no differences between the groups in the mean birth weight (adjusted by gestational age at delivery) or ponderal index of the infants. The rate of macrosomia (birth weight greater than the 90th percentile for gestational age or ponderal index above 2.85) was similar in both groups. The sample size was adequate to yield a power of 80% to detect a difference between groups of 179 g or more in birth weight and 0.1 g/cm3 in ponderal index. We suggest that the type of insulin (animal versus human) used by the pregnant insulin-dependent diabetic mother has no bearing on fetal weight gain.     

Effectiveness of ultrasound determination of fetal abdominal circumference and fetal ponderal index in the diagnosis of asymmetrical growth retardation

A total of 310 unselected women attending an antenatal clinic was screened for growth retardation by ultrasound between 34 and 36 weeks gestation, by measuring the fetal abdominal circumference (AC) and femoral length (FL), from which the 'fetal ponderal index' (AC/FL) was calculated. Asymmetrical growth retardation in the newborn was assessed by Rohrer's ponderal index and the mid-arm/occipito-frontal circumference (MAC/OFC) ratio within 72 h of birth, a neonatal ponderal index or MAC/OFC ratio below the 10th centile being considered abnormal. The sensitivities of an AC below the 25th centile in identifying a birthweight, neonatal ponderal index or MAC/OFC ratio below the 10th centile were 86, 62 and 67% respectively, the specificities being 80, 78 and 76%. The sensitivities of a fetal ponderal index below the 25th centile in identifying a neonatal ponderal index or MAC/OFC ratio below the 10th centile were 52 and 47% respectively, the specificities being 77 and 77%. A possible reason for the poor performance of the fetal ponderal index is discussed.     

Effectiveness of ultrasound determination of fetal abdominal circumference and fetal ponderal index in the diagnosis of asymmetrical growth retardation

Summary. A total of 310 unselected women attending an antenatal clinic was screened for growth retardation by ultrasound between 34 and 36 weeks gestation, by measuring the fetal abdominal circumference (AC) and femoral length (FL), from which the 'fetal ponderal index' (AC/FL) was calculated. Asymmetrical growth retardation in the newborn was assessed by Rohrer's ponderal index and the mid-arm/ occipito-frontal circumference (MAC/OFC) ratio within 72 h of birth, a neonatal ponderal index or MAC/OFC ratio below the 10th centile being considered abnormal. The sensitivities of an AC below the 25th centile in identifying a birthweight, neonatal ponderal index or MAC/ OFC ratio below the 10th centile were 86, 62 and 67% respectively, the specificities being 80, 78 and 76%. The sensitivities of a fetal ponderal index below the 25th centile in identifying a neonatal ponderal index or MAC/OFC ratio below the 10th centile were 52 and 47% respectively, the specificities being 77 and 77%. A possible reason for the poor performance of the fetal ponderal index is discussed.     

Placenta and fetal growth restriction

The placenta, as the vector for all maternal-fetal oxygen and nutrient exchange, is a principal influence on birthweight. Placental weight summarizes laterally expanding growth of the chorionic disc, and villous arborization yielding the nutrient exchange surface. These different growth dimensions alter fetoplacental weight ratio and ponderal index, and thus may modify placental functional efficiency. The placenta may show a range of histopathologies, some of which are also associated with fetal growth restriction. Different fetal intrinsic abilities to compensate for gross and histo-pathology may clarify the imperfect relationships between fetal growth and both intrauterine pathology, and the long-term health risks associated with poor fetal growth.     

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

Placental transfer of alpha-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 alpha-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.     

Are placental lakes of any clinical significance?

The aim of this study was to determine prospectively whether an association exists between the finding of placental lakes at the 20 week scan and an increased risk of uteroplacental complications or a poor pregnancy outcome. We studied the placental appearances in 1,198 consecutive second trimester ultrasound scans performed for routine foetal abnormality screening at our institution. The placental thickness was measured at its widest diameter in the sagittal plane and the presence or absence of placental lakes was recorded. The birth weight in each case was plotted against the centile charts in use at the hospital and recorded. Specific outcome measures included foetal growth restriction (IUGR) with a birth weight below the 5th centile, pre-eclampsia, placental abruption, and perinatal deaths. Placental lakes were seen in 17.8 per cent of the scans. There was no significant association with either maternal socio-demographic factors or perinatal mortality (OR 0.94, 95 per cent CI 0.35-2.51). No association was seen with maternal cigarette smoking (OR 1.07, 95 per cent CI 0.75-1.52), a birth weight below the 5th centile (OR 0.68, 95 per cent CI 0.39-1.18), the development of pregnancy induced hypertension (OR 0.68, 95 per cent CI 0.35-1.32), severe pre-eclampsia (OR 0.72, 95 per cent CI 0.21-2.50), or placental abruption (OR 1.79, 95 per cent CI 0.46-6.99). A finding of placental lakes was six times more likely with a thick placenta >3 cm at 20 weeks gestation (OR 6.30, 95 per cent CI 4.39 to 9.05). A finding of placental lakes during the second trimester ultrasound scan does not appear to be associated with uteroplacental complications or an adverse pregnancy outcome. The lesions are more prevalent with increasing placental thickness.     

Fetal growth and body proportion in preeclampsia

OBJECTIVE: To evaluate the effects of early- and late-onset preeclampsia on fetal growth and body proportion. METHODS: This was a population-based study based on records of 672,130 pregnancies from the Medical Birth Registry of Norway during 1967-1998. Women with a prior birth, multiple births, those without valid data on the last menstrual period or newborn's crown-heel length, and chronic maternal disease were excluded. RESULTS: In newborns of women with preeclampsia, mean birth weight, crown-heel length, and ponderal index were 4.4%, 0.8%, and 2.6% lower than in births without preeclampsia, respectively. In preterm births, mean differences in birth weight ranged from -11% to -23% against near-equal birth weights in term births. Mean differences in crown-heel length and ponderal index ranged from -1% to -5% and from -5% to -10% before term, respectively. In late preeclampsia, rates of birth weight and crown-heel length above the 90th and 97.5th percentiles and ponderal index above the 97.5th percentile were slightly but significantly higher than in term births without preeclampsia (odds ratios = 1.1-1.5). However, infants born to mothers with preterm preeclampsia were less likely to be heavy, long, or with high ponderal index for gestational age (odds ratios = 0.4-0.6). CONCLUSION: Our results support the hypothesis that preeclampsia is an etiologically heterogeneous disorder that occurs in at least two subsets, one with normal or enhanced placental function, and another involving placental dysfunction and fetal growth restriction, often with asymmetric fetal body proportion, reduced fetal length, and preterm delivery. In future studies, distinguishing between the two subtypes may be important.     

Stereological study of the placentae in intrauterine growth retardation with different ponderal index]

10 placentae each from the cases of IUGR with normal ponderal index (NPI) and low ponderal index (LPI) and 10 from normal pregnancy as control were analysed quantitatively with stereological principles. This study showed the placental weight, volume, surface area of villi and villous fetal capillary in IUGR were significantly reduced than that in control group. The percentage ratio of the fetal capillary volume was increased significantly in IUGR group but the ratio of vasculo-syncytial membrane/villous fetal capillary decreased. It suggested that compensation to anoxemia in placenta of IUGR was incomplete. The data also found that all the parameters in NPI group were decreased significantly than that in LPI group, which implied NPI group had a more severe growth deficiency of the placental functional structure. When placental growth deficiency occurs in the first or second trimester, both the fetal length and weight will be severely affected.     

Histologic chorioamnionitis is associated with fetal growth restriction in term and preterm infants

OBJECTIVE: Our aim was to evaluate associations between chorioamnionitis and fetal growth restriction in infants enrolled in the Collaborative Perinatal Project. STUDY DESIGN: A total of 2579 nonanomalous, singleton infants delivered at 28 to 44 weeks' gestation with chorioamnionitis were matched 1:3 for ethnicity, gestational age, parity, and maternal cigarette use (all of which were correlated with both chorioamnionitis and markers of fetal growth restriction) with 7732 control infants. Moderate or marked leukocytic infiltrates of the placenta defined chorioamnionitis. Birth weight, length, head circumference, weight/length ratio, ponderal index, and birth weight/head circumference ratio in the lowest 5th percentile were markers of fetal growth restriction. Placental weight and the birth weight/placental weight ratio were also evaluated. RESULTS: Compared with data on matched control infants, histologic chorioamnionitis was associated with all markers of fetal growth restriction and with low birth weight/placental weight ratios (odds ratios, 1.3-1.7). The strongest associations were found at 28 to 32 weeks' gestation (odds ratios, 2.2-11). Attributable risks for several markers of fetal growth restriction exceeded 50% in infants born at <33 weeks' gestation. CONCLUSION: Histologic chorioamnionitis is associated with multiple markers of fetal growth restriction, with stronger associations noted in prematurity.     

Placental transfer of long-chain polyunsaturated fatty acids (LC-PUFA)

Considerable evidence exists for marked beneficial effects of omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) during pregnancy. The omega-3 LC-PUFA docosahexaenoic acid (DHA) is incorporated in large amounts in fetal brain and other tissues during the second half of pregnancy, and several studies have provided evidence for a link between early DHA status of the mother and visual and cognitive development of her child after birth. Moreover, the supplementation of omega-3 LC-PUFA during pregnancy increases slightly infant size at birth, and significantly reduces early preterm birth before 34 weeks of gestation by 31%. In our studies using stable isotope methodology in vivo, we demonstrated active and preferential materno-fetal transfer of DHA across the human placenta and found the expression of human placental fatty acid binding and transport proteins. From the correlation of DHA values with placental fatty acid transport protein 4 (FATP 4), we conclude that this protein is of key importance in mediating DHA transport across the human placenta. Given the great importance of placental DHA transport for infant outcome, further studies are needed to fully appreciate the effects and optimal strategies of omega-3 fatty acid interventions in pregnancy, dose response relationships, and the potential differences between subgroups of subjects such as women with gestational diabetes or other gestational pathology. Such studies should contribute to optimize substrate intake during pregnancy and lactation that may improve pregnancy outcome as well as fetal growth and development.     

Subcutaneous fat in the fetal abdomen as a predictor of growth restriction.

OBJECTIVE: To determine if measuring fetal abdominal fat antenatally using ultrasound can predict fetal growth restriction (FGR). METHODS: One hundred thirty-seven unselected women with singleton pregnancies had serial ultrasound scans at 20, 26, 31, and 38 weeks' gestation. Subcutaneous fat in the fetal abdomen was measured using the same section as the abdominal circumference (AC). Outcome measures were birth weight, neonatal morbidity, and ponderal index. RESULTS: Infants with subcutaneous fat less than 5 mm at 38 weeks (n = 51) were almost five times more likely to have a birth weight below the 10th centile than those with subcutaneous fat of 5 mm or more (n = 75). The incidence of neonatal morbidity was significantly higher in infants with subcutaneous fat less than 5 mm, compared with those with subcutaneous fat of 5 mm or more (20% versus 8%, P < .05). Decreased subcutaneous fat was also associated with a high prevalence of low ponderal index, regardless of birth weight category. CONCLUSION: Measurement of fat in the abdominal wall is a simple technique with a sensitivity for predicting low birth weight similar to that of conventional sonography and might potentially predict FGR irrespective of fetal weight.     

Evaluation of fetal growth by estimation of neonatal body composition.

To characterize the variation in normal fetal growth by body composition analysis, 188 neonates from uncomplicated singleton term pregnancies were evaluated within 24 hours of birth. Anthropometric measures used to estimate lean body mass and body fat included the following: birth weight 3553 +/- 462 g, lean body mass 3060 +/- 377 g (86.3%), fat mass 495 +/- 196 g (13.7%), and ponderal index 2.65 +/- 0.25. There was a significant linear correlation between birth weight and lean body mass (r2 = 0.83, P = .0001), fat mass (r2 = 0.46, P = .0001), and ponderal index (r2 = 0.22, P = .001). Although the ponderal index has been used as an index of corpulence, the correlation between ponderal index and percent body fat was poor (r2 = 0.15). These results suggest that although neonatal fat mass constitutes only 14% of total birth weight, it explains 46% of its variance. In contrast, the ponderal index explains only 22% of the variance in birth weight and correlates poorly with percent body fat. Body composition analysis explains a significant amount of the variance in normal birth weight.     

Intrauterine Growth Restriction: Implications for Placental Metabolism and Transport. A Review

Intrauterine growth restriction (IUGR) correlates with a specific placental phenotype, associated with defects in placental transport functions, that lead to fetal undernutrition. Both placental metabolism and transport may be affected, thus modifying the normal supply of nutrients. Models to investigate placental function may either couple or separate metabolism and transport. In human pregnancies, nutrient concentrations can be measured at the time of delivery or at cordocentesis in the umbilical vessels connecting the fetus to the placenta. The kinetics of placental transport can be evaluated in vivo using stable isotopes, i.e. infusing ¹³C labelled nutrient in the mother by bolus or steady state techniques prior to cordocentesis or cesarean section. In vitro studies, using the model of the dually perfused human placenta or investigating the activity of transporters in the placental membranes have also significantly contributed to our understanding of placental function.In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal–fetal gradients of glucose are increased in severe IUGR fetuses, i.e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated.This review summarizes the current knowledge about placental metabolism and transport in IUGR pregnancies and the relationship with severity of the disease.     

Ponderal index (PI) vs birth weight centiles in the low-risk primigravid population: which is the better predictor of fetal wellbeing?

Our objective was to compare Ponderal index (PI) with birth weight centiles as predictors of perinatal morbidity and to determine which best reflects the presence of placental disease. We prospectively recruited 1,011 low-risk primigravidas and calculated PI and birth weight centiles following delivery. Perinatal morbidity was defined as: pre-term birth (PTB); fetal acidosis; an Apgar score <7 at 5 min or neonatal resuscitation. Placental disease was defined as chronic uteroplacental insufficiency (CUPI); villous dysmaturity; infection or vascular pathology. Ponderal index was statistically reduced (25.33 vs 27.79 p =0.001) and the incidence of infant birth weight <9th centile was statistically higher (11.1% vs 5.1%; p =0.004) in cases with PTB and in CUPI (26.23 vs 27.84; p =0.001 and 28.2.1% vs 10.4%; p =0.002). Both PI and infant birth weight centile <9th centile for gestational age correlate with PTB, however overall, both are poor predictors of neonatal and placental disease.     

The intrauterine ponderal index in relation to birth weight discordance in twin gestations

Objective: To establish the relationship between the fetal ponderal index and birth weight discordance in twins. Method: The fetal ponderal index (estimated fetal weight ÷ femur length³) was calculated in 86 pairs of twins delivered within 2 weeks of the last sonography and analyzed in relation to birth weight discordance. Results: A weak but significant correlation between fetal ponderal index and birth weight (r = 0.26, P < 0.0007) but no correlation with gestational age (r = 0.035, P = 0.65) were found. Members of concordant pairs (<15% birth weight difference) had a significantly higher fetal ponderal index compared with members of mildly (15–25%) discordant pairs (P < 0.02), but not as compared with members of severely discordant (>25%) pairs. Conclusion: The characteristics of the fetal ponderal index in twins are similar to those in singletons. Fetal size seems to be diminished in severe but not in mild discordants. However, in its present form, the fetal ponderal index is a poor predictor of discordant growth and therefore should be employed cautiously in twin gestations.     

Control of placental glucose transfer

There is little evidence to suggest that the membrane transfer mechanism of the placenta for glucose becomes saturated until maternal blood glucose concentrations are quite high. Also, recent evidence suggests that the membrane transport system for glucose in the placenta is not stimulated by maternal or fetal insulin. Furthermore, there is no solid evidence that hormonal or non-hormonal factors function in vivo to limit membrane transport of glucose in the placenta. Therefore, the limited data which are available suggest that there are no specific mechanisms which acutely regulate placental membrane transport of glucose, and that this membrane transport mechanism operates to maximize maternal-to-fetal glucose transfer. The rate of maternal-to-fetal glucose transfer is a function of the transplacental concentration gradient. This gradient appears to be under the control of fetal insulin and placental lactogen. The available data suggest that both hormones act to increase this concentration gradient: insulin by decreasing fetal blood glucose, and placental lactogen by both decreasing fetal and increasing maternal blood glucose concentrations. Furthermore, high rates of glucose uptake by fetal erythrocytes tend to promote maintenance of this concentration gradient. Therefore, these influences of the maternal-fetal concentration gradient promote transplacental glucose flux to the fetus. As illustrated by the fetal complications associated with maternal hyperglycaemia, the cellular and organismic physiology of the fetus and placenta appears to maximize, rather than optimize, glucose availability to the fetus. It may be, however, that during normal pregnancy, maximal availability is optimal for fetal development.     

Regulation of placental nutrient transport--a review

Fetal growth is primarily determined by nutrient availability, which is intimately related to placental nutrient transport. Detailed information on the regulation of placental nutrient transporters is therefore critical in order to understand the mechanisms underlying altered fetal growth and fetal programming. After briefly summarizing the cellular mechanisms for placental transport of glucose, amino acids and free fatty acids, we will discuss factors shown to regulate placental nutrient transporters and review the data describing how these factors are altered in pregnancy complications associated with abnormal fetal growth. We propose an integrated model of regulation of placental nutrient transport by maternal and placental factors in IUGR.