Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice.

IGF binding protein-1 (IGFBP-1) is a secretory product of decidualized endometrium and a major constituent of amniotic fluid. It is thought to modulate the actions of the IGFs on trophoblast cells and is therefore potentially important in regulating placental development and fetal growth. To investigate this hypothesis, we have studied the effects of decidual IGFBP-1 excess on fetoplacental growth in transgenic mice overexpressing human IGFBP-1. Endogenous fetal IGFBP-1 overexpression is associated with a transient impairment of fetal growth in midgestation. Maternal decidual IGFBP-1 excess is also associated with impaired fetal growth in midgestation independent of fetal genotype, indicating placental insufficiency. Our data also demonstrate that amniotic fluid IGFBP-1 is derived almost exclusively from maternal sources. Decidual IGFBP-1 overexpression has a marked effect on placental development. Placental morphology is abnormal in transgenic females due to altered trophoblast invasion and differentiation. These changes result in an increase in placental mass throughout pregnancy. This study provides the first compelling in vivo evidence that IGFBP-1 plays a role in placentation and suggests that IGFBP-1 has a pathological role in preeclampsia, a disorder characterized by shallow uterine invasion and altered placental development.

Endocrine pancreas development in growth-retarded human fetuses.

Glucose intolerance in adults born with intrauterine growth retardation (IUGR) may involve peripheral insulin resistance and/or abnormal endocrine pancreas development during fetal life. We quantified insulin-containing cells in deceased human fetuses with IUGR (<10th percentile, n = 21) or normal growth (control fetuses, n = 15). Paraffin-embedded pancreatic tissues from fetuses older than 32 weeks were obtained from two fetopathology departments. Mean gestational age was 36 weeks in both groups. Tissues with lysis and those fetuses with defects, aneuploidy, or genetic abnormalities were excluded. For each subject, six pancreatic sections spaced evenly throughout the organ were immunostained with anti-insulin antibody. Total tissue and insulin-positive areas were measured by computer-assisted quantitative morphometry. Results were expressed in percentages. To evaluate islet morphogenesis, the percentages of beta-cells inside and outside islets were determined. Islet density was similar in the two groups (P = 0.86). The percentage of pancreatic area occupied by beta-cells (beta-cell fraction) was not correlated with gestational age (r = 0.06 and P = 0.97 in IUGR fetuses; r = 0.12 and P = 0.67 in control fetuses) or body weight (r = 0.16 and P = 0.47 in IUGR fetuses; r = 0.24 and P = 0.39 in control fetuses). Mean beta-cell fraction was 2.53% in the IUGR fetuses and 2.86% in the control fetuses (P = 0.47). The percentage of beta-cells located within islets was identical in the two groups (mean 35%). Our data militate against a primary developmental pancreatic abnormality in human IUGR, leaving peripheral insulin resistance as the most likely mechanism of glucose intolerance in adults born with IUGR.

Early sonographic evaluation for fetal growth delay and congenital malformations in pregnancies complicated by insulin-requiring diabetes. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study.

OBJECTIVE: It has been reported that early fetal growth retardation may be a useful marker for congenital malformations in diabetic pregnancies. To test this hypothesis, diabetic and nondiabetic women were sonographically evaluated during the first trimester. RESEARCH DESIGN AND METHODS: Fetal crown-rump lengths were measured sonographically at least once during the first 15 wk of pregnancy in 329 nondiabetic and 312 diabetic women. Of these, 289 nondiabetic and 269 diabetic women had sonograms before 10 wk of gestation and 283 nondiabetic and 269 diabetic women had sonograms between 10 and 15 wk of gestation. Early fetal growth delay was defined as a sonographic gestational age of greater than or equal to 6 days less than menstrual gestational age. RESULTS: The mean crown-rump lengths at 8 wk were 17.9 +/- 4.6 mm in the diabetic and 18.7 +/- 4.9 mm in the nondiabetic groups (P = 0.13). At 12 wk, the mean fetal crown-rump length was 58.5 +/- 8.8 mm for diabetic subjects and 60.6 +/- 8.7 mm for nondiabetic subjects (P = 0.04). Between 5 and 9 wk, 28 of 289 (9.7%) fetuses of nondiabetic subjects, 34 of 259 (13.1%) normal fetuses of diabetic subjects, and 2 of 10 (20%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.31, normal vs. malformed diabetic). Between 10 and 15 wk of gestation, 28 of 283 (9.9%) fetuses of nondiabetic subjects, 32 of 256 (12.5%) normal fetuses of diabetic subjects, and 4 of 13 (30.8%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.06, normal vs. malformed diabetic). Early fetal growth delay did not predict a reduced birth weight at term. CONCLUSIONS: Among insulin-dependent diabetic subjects who were moderately well controlled at conception, statistically significant but mild early fetal growth delay was present but did not appear to be useful clinically in predicting congenital malformations. Recommendations that growth delay demonstrated on early ultrasound be used as a predictor of congenital malformation require careful reexamination.

Metabolic effects of IGF-I in the growth retarded fetal sheep.

It has been shown that IGF-I has an anabolic effect in the normal fetus. However, there is evidence to suggest that there may be IGF-I resistance in the growth retarded fetus. Therefore, we investigated the effects of acute IGF-I infusion to chronically catheterised fetal sheep. At 128 days gestation, fetuses underwent a 4 h infusion of IGF-I (50 microg/kg/h). Three groups of animals were studied. Nine normally grown fetuses were studied as controls. Embolised animals (n=8) received microspheres into the uterine vasculature, and animals with spontaneous intra-uterine growth retardation (IUGR animals) (n=6) were fetuses found at post mortem to be spontaneously growth restricted. The effects of IGF-I infusion on feto-placental carbohydrate and protein metabolism were similar in our control group to previous similar experiments. IGF-I infusion decreased fetal blood glucose, oxygen, urea and amino-nitrogen concentrations, and inhibited placental lactate production. The same fetal blood metabolite concentrations also fell during IGF-I infusion in the embolised fetuses, but the effect on placental lactate production was not seen. The only effect of IGF-I infusion in the spontaneous IUGR animals was a fall in fetal blood amino-nitrogen concentrations. We conclude that fetal IGF-I infusion does not have the same anabolic effects in the growth retarded fetus as the normal fetus. In addition, the effects of IGF-I were different in the two growth retarded groups. Our data support previous evidence that the growth retarded fetus has altered IGF-I sensitivity, and this may vary depending on the cause, severity and duration of growth retardation.

Renal anomalies in Marden-Walker syndrome: a clue for prenatal diagnosis.

Marden-Walker syndrome is an autosomal-recessive disorder characterized by psychomotor retardation, blepharophimosis, joint contractures, arachnodactyly, failure to thrive, and, infrequently, renal anomalies. We report on the prenatal diagnosis of Marden-Walker syndrome in a fetus which had had a previously affected sib with this syndrome. The ultrasonic findings indicative of the diagnosis in this fetus were intrauterine growth retardation and renal cystic disease. We emphasize the importance of renal anomalies which, when present in combination with other ultrasound evidence of this syndrome, should be used as a clue for the diagnosis of Marden-Walker syndrome.

Second trimester oligohydramnios, a predictor of poor fetal outcome.

Twelve cases of severe second trimester oligohydramnios are reported. The outcome of these pregnancies was uniformly poor, with no survivors in the present series. Four patients had therapeutic abortions, one woman had spontaneous labor at 22 weeks' gestation, and seven patients continued to viability. Of these, five patients had severe renal abnormalities incompatible with life. Two infants died at, or shortly after, birth from severe intrauterine growth retardation (IUGR), one of which had a triploid karyotype. Review of the literature shows a similar poor outcome for pregnancies with severe oligohydramnios in the second trimester.

The effects of intrauterine growth retardation on the development of the Purkinje cell dendritic tree in the cerebellar cortex of fetal sheep: a note on the ontogeny of the Purkinje cell.

The development of the fetal sheep cerebellum at 80, 100, 120 and 140 days gestation (term = 146 days) and 3 months postnatally was studied using Nissl stained sections and rapid Golgi preparations. The most rapid expansion of the Purkinje cell dendritic tree occurred between 100 and 120 days of gestation (5-6 fold increase in area). By 140 days it had acquired its adult form after which time growth continued mainly in the vertical direction. The effects of intrauterine growth retardation on the growth of granule and Purkinje cell dendrites in the cerebellar cortex of fetal sheep (140 days) were investigated in Golgi preparations. Compared with control cerebella the length (but not the number) of granule cell dendrites was reduced by 14% (P less than 0.01); the area of the Purkinje cell dendritic field was reduced by 20% (P less than 0.01); the branching density was reduced by 8% (P less than 0.01); the total branch length was reduced by 27% (P less than 0.002); the density of dendritic spines per row was not affected. These factors resulted in a decrease of 26% (P less than 0.002) in the total number of dendritic spines per row per Purkinje cell. These findings show that the growth of granule cell dendrites and the Purkinje cell dendritic tree have been significantly affected by chronic intrauterine deprivation. Such structural abnormalities could affect the pattern of neuronal connectivity and could be associated with functional deficits.

The effects of intrauterine growth retardation on synaptogenesis and mitochondrial formation in the cerebral and cerebellar cortices of fetal sheep.

In an experimental model of growth retardation which involves the reduction of placental mass in sheep, we have investigated the effects of intrauterine deprivation on synaptogenesis, synaptic ultrastructure and mitochondrial formation in the cerebral and cerebellar cortices of fetal sheep (140 days gestation). In the growth-retarded fetus, the numerical density of synapses in layer I of the visual cortex was reduced by 17% (P less than 0.05) compared with controls but there was no detectable difference between the two groups in the density of parallel fibre-Purkinje cell synapses in the molecular layer of the cerebellum. The length and curvature of the postsynaptic density at synapses in both regions were not affected in growth retardation but the synaptic cleft was 13% wider in the cerebellum (P less than 0.05) in growth retardation compared with controls. The number of mitochondrial profiles per unit area of neuropil in the visual cortex was increased by 20% (P less than 0.01) in growth retardation and the electron density of the inner matrix increased but the average profile area was not affected. These findings show that intrauterine growth retardation affects some aspects of synaptic development in the cerebellum and the visual cortex. The increase in the number of mitochondrial profiles in the visual cortex of growth-retarded fetuses might be an attempt by the cortical neurons to compensate for the reduced efficiency of aerobic metabolism in individual mitochondria.

Zinc deficiency in the 11 day rat embryo: a scanning and transmission electron microscope study.

Zinc deficient rat embryos were obtained on the 11th day of pregnancy and examined by scanning and transmission electron microscopy. Scanning electron microscopy revealed an increase in the number of deformed embryos, as well as embryonic growth retardation. In addition, the epithelium of zinc deficient embryos displayed a marked increase in surface microvilli, as well as the presence of blebbing. Transmission electron microscopy indicated extensive cell death in the neural epithelium which was apparently more severely damaged by zinc deficiency than were mesenchymal cells. Mitochondrial cristae were affected to a greater degree than any other membrane of the cell and cristael disintigration appeared to represent the principal cellular lesion preceding necrosis of neural cells and neural tube teratology.

Fetal and fetal brain volume estimation in the third trimester of human pregnancy using gradient echo MR imaging.

The Cavalieri method has been applied in combination with gradient echo magnetic resonance imaging (MRI) to investigate the increase in the volume of the fetus and fetal brain in the third trimester of pregnancy. Eighteen women with singleton pregnancies were recruited. Birthweights for the fetuses all lay within the 10-90th centile based on Liverpool data. A regression analysis, weighted using values derived from the coefficient of error predicted for each volume estimate, revealed a linear relationship between total fetal volume and gestational age (R2 = 0.88) and between fetal brain volume and gestational age (R2 = 0.71) during the third trimester. Fetal volume increased by an average of 25.2 ml per day and fetal brain volume increased by an average of 2.3 mL per day. Fetal brain volume is on average a constant proportion (10%, SD = 2%) of total fetal volume throughout the third trimester. Volume data were also obtained for eight fetuses diagnosed as abnormal. The volume of seven of the eight abnormal fetuses fell outside the 95% confidence interval established from the data obtained for the normal fetuses. However, for only three of the eight abnormal fetuses did brain volume fall outside the 95% confidence interval established for normals, possibly due to brain sparing occurring in asymmetrical growth retardation. The volume of the fetus and fetal brain may be readily estimated directly using the Cavalieri method and magnetic resonance imaging. These parameters represent potentially useful information for assessing fetal growth.

Adaptive changes in the developing brain during intrauterine stress.

Maturation of neurological performance in moderately to severely growth-retarded newborn infants (SGA) can be accelerated by 3 to 4 weeks or more when compared to the development of appropriately grown infants (AGA) of the same gestation. This is particularly the case in multiple pregnancies or pregnancies characterized by maternal hypertension. This clinical finding has been confirmed by neurophysiological studies on the maturation of brainstem auditory evoked responses (BAERs). The possible mechanisms which underly this phenomenon are not yet elucidated. Glucocorticoids, other steroid hormones and catecholamines are elevated in pregnancies with placental dysfunction, and it is known that these substances have multiple actions on neuronal maturation, particularly on mechanisms of release of neurotransmitters. These observations suggest that the acceleration of brain maturation, and lung maturation, in SGA infants reflects an adaptation of the fetus to early extrauterine life. However, if the placental dysfunction progresses, these mechanisms of adaptation will be overwhelmed by severe malnutrition and anoxia which result in cerebral lesions and risk of death. The clinical goal at the present time for obstetric management of these risk pregnancies is to distinguish between these two periods.

Role of asphyxia and slow intrauterine growth in morbidity among breech delivered infants.

The outcome of breech delivery was evaluated by a neonatal neurological score and a follow-up examination at 18 months of age. The subjects were 132 children identified by ultrasound to be in breech presentation in the 33rd gestational week. 62 were born in breech presentation, while 70 turned to vertex presentation. During the early neonatal period, a neurological score was obtained based on the results of 29 items concerning posture, muscle tone, reflexes and reactions. Although there was no difference, in neurological score or in general development when the entire breech and vertex groups were compared, the SGA (small-for-gestational age) infants and the infants with low Apgar scores of the breech group had the poorest neurological scores. The contribution of certain maternal and fetal factors to postnatal condition was evaluated by a multiple linear regression analysis. Within the breech group, relationships were found between the neurological score and the variables intrauterine growth, fetal sex, and low Apgar score. A major part (66%) of the variation in neurological score was explained by the combination of these variables. These factors should therefore be taken into consideration when deciding on the mode of delivery in breech presentation.

Fetal urine production at different gestational ages: correlation to various compromised fetuses in utero.

To reveal which fetal life-threatening diseases significantly contribute to impairment of in-utero urine production and also to determine the gestational age at which time aberrant urine production becomes manifest, we observed 376 compromised fetuses (subject group) at 21-42 weeks' gestation using ultrasonography. A total of 358 uncomplicated fetuses, aged 21-40 weeks, were separately chosen as a control group. Statistical differences in the urine production rate between subject- and control-group fetuses were analysed using the Grubbs-Smirnoff test at corresponding gestational ages. Significant decreases were evident in: bilateral renal agenesis (100%) at 21-23 weeks; bilateral infantile polycystic kidney (100%) at 21-28 weeks; bilateral multicystic kidney disease (100%) at 21-31 weeks; donor fetuses with twin transfusion syndrome (TTS) (100%) at 21-28 weeks; post-term fetuses (100%) at 42 weeks; bilateral hydronephrosis (60%) at 21-38 weeks; non-immunologic hydrops fetalis (42%) at 21-35 weeks; intrauterine growth retardation (41%) at 29-40 weeks; and upper gastrointestinal tract obstruction (36%) at 30-38 weeks. Significant increases were noted in: recipient fetuses with TTS (100%) at 21-28 weeks, and unilateral hydronephrosis (36%) at 27-32 weeks. All indicate that urine production clearly delineates various fetal conditions in utero, in a closely disease-dependent relation to gestational age.

Utilizing sonography to follow fetal growth.

In utero diagnosis of fetal growth abnormalities continues to pose a clinical dilemma. Although significant advances have been made in the understanding of growth disturbances and their clinical importance, false-positive and false-negative diagnoses of IUGR and excessive fetal growth continue to affect the accuracy of antenatal diagnosis. Until more accurate methods are developed to aid in diagnosis, multiple biometric parameters should be assessed in patients either at risk for or with a suspected growth disturbance. Serial measurements obtained every 2 to 3 weeks may enhance diagnostic capabilities. Although antenatal diagnosis of IUGR has been shown to be of benefit in improving outcome, more study is needed to determine whether there is a benefit in antenatal diagnosis of macrosomia or LGA.

The nutrition of the fetus with intestinal atresia: studies in the chick embryo model.

This article examines the effects of experimental prenatal intestinal obstruction on the growth and blood composition of chick embryos. Intestinal atresia (IA) was produced by bipolar bowel electrocoagulation in fertile eggs on the 14th day of incubation. The chicks killed on the 19th day were measured, weighed, and blood-sampled. Twenty-three control, 10 sham-operated, and 11 IA chicks were studied. Animals with IA were severely undernourished by weight (43.4 +/- 4.7 v 70.3 +/- 7.6% of egg weight, P < .001) and length (15.3 +/- 1.1 v 18.1 +/- 0.9 mm tibial length, P < .001) in comparison with sham-operated ones. Their hematocrit was slightly lower, and total protein increased. Prealbumin was absent in their sera and albumin, alpha and beta globulins were significantly decreased, whereas gamma-globulin was greatly increased. Sodium, potassium chloride, urea, and glucose remained within normal limits. The lack of placenta in the avian embryo precludes any supply of nutrients by this route and the ingestion of amniotic fluid, which is protein-rich after the 13th day of incubation, when the opening of the seroamniotic connection allows albumen to be mixed with it, becomes the main source of nutrients until hatching. Obstruction of the main incoming avenue by IA induces severe malnutrition in this model which relies on this route to a greater extent than the human fetus. In spite of the obvious biological differences between the avian embryo and the human fetus, the present evidence supports the hypothesis that prenatal interruption of the amniotic fluid transit contributes to fetal undergrowth in IA.

Lung fractional moving blood volume in normally grown and growth restricted foetuses.

OBJECTIVE: To examine foetal lung blood perfusion using power Doppler ultrasound (PDU) and to compare fractional moving blood volume (FMBV) and mean pixel intensity (MPI) estimations in the lungs of normally grown (NG) foetuses and foetuses with intrauterine growth restriction (IUGR) and also to correlate foetal lung FMBV and MPI with respiratory complications after birth. METHODS: Lungs of 47 NG and 25 IUGR foetuses after 32 weeks of gestation were examined with PDU. FMBV and MPI were estimated in a defined region in the posterior part of the foetal lung closest to maternal abdominal wall. FMBV and MPI were correlated to foetal weight deviation and gestational age. Perinatal outcome and respiratory complications after birth were recorded in both groups. RESULTS: There were significantly lower FMBV and MPI values in IUGR than in NG foetuses. The overall variation was lower for FMBV than for MPI. There was a slightly higher correlation between FMBV and foetal weight deviation [r = 0.33, 95% confidence intervals (CI) 0.11-0.52] than between MPI and foetal weight deviation (r = 0.26, 95% CI 0.03-0.46). There was no significant correlation between FMBV or MPI and gestational age. No differences between the groups were found in the rate of respiratory complications, and they were not correlated either to the FMBV or MPI. CONCLUSION: FMBV and MPI, estimated from the PDU signals of foetal lung circulation, showed lower values in third-trimester pregnancies complicated by IUGR. The frequency of neonatal respiratory complications was not increased in cases with low pulmonary FMBV and MPI values.

Coronary arteries in fetal life: physiology, malformations and the "heart-sparing effect".

The present knowledge of coronary arteries in prenatal diagnosis is reviewed with a focus on three aspects: the physiology and visualization of coronary flow, malformations involving the coronary arteries, and the "heart-sparing effect". Visualization of coronary arteries in a healthy human fetus is possible in real-time and colour Doppler during the last 10 wk of gestation when ultrasound conditions are excellent. Visualization at an earlier gestational age (up to 13 wk) is feasible mainly in association with malformations and impending hypoxia. The main coronary malformations that can be visualized in utero are the ventriculo-coronary communications in fetuses with pulmonary atresia. In the last few years, interest has been focused on the "heart-sparing effect", defined as the increased perfusion of the coronary arteries in fetuses with severe growth restriction and abnormal Doppler velocimetry in the peripheral vessels. Increased perfusion detectable with colour and pulsed Doppler is a late sign of fetal compromise in hypoxaemia. It confirms animal experiments that have demonstrated dilatory reserves of the fetal coronary arteries under chronic hypoxaemia. The outcome of 21 fetuses showing the "heart-sparing effect" before 32 wk gestation was poor: nine fetuses died in utero and two after birth, the median weight at birth was 630 g. In summary, our knowledge of the coronary arteries in the fetus is based on the diagnostic means used in prenatal diagnosis. New information in this field may also contribute to a better understanding of coronary heart disease later in life.

Assessment of developmental retardation and abnormality of in vivo produced preimplantation embryos in rat.

In most mammals studied, a substantial numbers of preimplantation embryos are believed to be lost in vivo. In vitro, embryos develop slowly and lose viability. Hence, there is a need to assess the extent and cause of embryonic loss both in vivo and in vitro. In this study, we assessed the quality of in vivo produced ovulation products/embryos, recovered on days 1-5 pregnancy, from naturally bred wistar rats. From day 1 pregnant rats (n = 24), 226 ovulation products were recovered which included 52% (117) unfertilized oocytes and empty zonae with/without cell debris (UFO-EZ:CD) and 48% (109) 1-cells. Flushings of day 2 rats (n = 27) contained 229 ovulation products, consisting of 70% (160) 2-cells and 30% (69) UFO-EZ:CD. Flushings of day 3 rats (n = 27) had 23% (56) 2-cells, 6% (15) 3-cells, 23% (57) 4-cells, 1% (2) 5-7 cells, 2% (5) 8-cells and 45% (112) UFO-EZ:CD, total being 247. Flushings of day 4 rats (n = 28) had 193 ovulation products comprising of one morula, 45% (86) 8-cells, 5% (9) 5-7-cells and the rest were 4-cells (2), 3-cells (2), 2-cells (1) and 48% (92) UFO-EZ:CD. Day 5 flushings (n = 27) had 202 ovulation products which included 13% (27) morulae, 17% (34) early, 36% (73) mid and 2% (5) late blastocysts; additionally, 4-cells (1), 8-cells (2) and 30% (60) UFO-EZ:CD were also recovered. On day 4, embryos (8-cells) migrated from the oviduct to the uterus. When pregnant rats (n = 25) were allowed to term, only 15 females (60%) delivered pups (128) with variable litter size (2-12). These results indicate that 56% (619/1097) of recovered rat preimplantation embryos are of expected developmental age with a mixture of asynchronously cleaving embryos. The remaining 44% (478) is comprised of 38% (417) UFO-EZ:CD and 6% (61) abnormal and developmentally retarded embryos, which are unlikely to produce viable pups at term.

The effect of prenatal protein-energy malnutrition on collagen metabolism in fetal bones.

We analyzed various biochemical variables of the bones in fetal rats whose dams were protein-energy malnourished. Dams were randomly divided into two groups and fed either a 6% protein diet as a malnourished group or a 20% protein diet as a control, from day 13 of gestation to day 22, when fetuses were removed. Hexosamine and hydroxyproline contents of the calvaria and hexosamine contents of long bones were greater in the malnourished group than in the controls. Sequential extractability of collagen differed among various bones in the malnourished group and controls. The ratio of alpha:beta obtained from SDS-polyacrylamide gel of neutral salt-soluble collagen tended to increase in the long bones and mandible, and decrease in the calvaria and ribs in the malnourished group. Also, the ratio of alpha 1:alpha 2 tended to be lower in the malnourished group than in the control group in all bones. Protein-energy malnutrition during pregnancy has shown to affect biochemical composition of various fetal bones.

[Epiphyseal points of the fetal knee. The impact of growth disorders on bone maturation]. / Points épiphysaires du genou du foetus. Retentissement des troubles de la croissance sur la maturation osseuse.

The radiological appearance of bone maturity can be used as a criterion for fetal maturity. This examination with limited irradiation to the fetus is an alternative to amniocentesis. The practice of the latter is not without risk. The authors carried out 194 examinations of the contents of the uterus to look at the epiphyses of the knee between the 34th and 40th week of amenorrhoea. The found three groups: 1) those with normal development; 2) those with delayed development and 3) those with more advanced development. They did not find significant correlation between small-for-dates growth and bony maturity. On the other hand, where there was increased growth of the fetus in cases where maternal diabetes was excluded there was demonstrated that bony maturity accelerated with the presence of Béclard's point from the 34th week onwards. With such great variation in the dates of the appearance of points of ossification the presence of epiphyseal points in the knee cannot be taken as a criterion to establish fetal maturity nor the minimum duration of the pregnancy.