Alterations of human placental epidermal growth factor receptor in intrauterine growth retardation.

We studied human placental microvillous EGF receptor (EGFR) and its relationship with maternal and placental features in 14 cases of intrauterine growth retardation. Placental EGFR phosphorylation was significantly decreased or absent in 12 cases of small for gestational age neonates, as shown by SDS-PAGE, autoradiography, and scanning analysis. Specific [125I]EGF binding and Scatchard plots of the binding data showed a decreased number of EGFR in 6 of the 12 cases, with a mean maximal binding capacity of 1.09 +/- 0.32 pmol/mg for high affinity sites (mean control value = 2.30 +/- 0.23 pmol/mg). Most of the hypertensive women and smokers belonged to this subgroup. In three of the remaining six cases of small gestational age placentas with low EGFR phosphorylation, there was no maternal pathology or significant parenchymatous placental lesions. Five showed a 175-kD EGFR species when probed by [125I]EGF cross-linking and Western blotting with RK2 and C-Term, two polyclonal anti-EGFR antibodies, suggesting abnormal transduction of the EGF-induced signal. The sixth placenta yielded a single 145-kD EGFR band consistent with an abnormal EGFR structure; Western blot analysis showed no immunoreactive band. In conclusion, maternal and placental pathologies in intrauterine growth retardation are associated with various alterations of placental EGFR, pointing out the importance of EGFR ligands in the regulatory pathway of placental and fetal growth.

The human SRY protein is present in fetal and adult Sertoli cells and germ cells.

Sex determination in mammals is controlled by the Y chromosome located SRY gene. Despite recent advances towards understanding the mechanisms that regulate sex determination in mammals, the expression profile of the SRY protein in human tissues is unknown. To localize the SRY protein and determine its cellular distribution, we prepared monoclonal antibodies (mAb) against the recombinant SRY protein. One antibody, LSRY1.1, recognizes a SRY-specific epitope and was used to localize the protein in different cells and tissues. The mAb recognizes a protein of 27 kDa in total lysates of HeLa SRYB3 cells. Immunocytochemical staining showed a nuclear localization of the protein. Immunohistochemical studies performed on gonadal tissue of a fetus, a one month-old boy and an adult man, demonstrated the presence of SRY protein in the nucleus of Sertoli and germ cells. In addition two 46,XX SRY(+) males had the SRY protein in their gonadal tissues. All other samples were negative, including all female tissue studied and the testis of a 46,XX SRY(-) male. The presence of SRY protein in fetal and adult gonadal tissues including germ cells suggests that SRY may have other male-specific functions in addition to sex determinism.

Morphological aspects of the placenta in HIV pregnancies.

Forty-nine placentae from HIV-seropositive mothers were collected in various hospitals in France and Belgium. Twenty [corrected] placentae with seven fetuses from interrupted pregnancies and 29 [corrected] placentae from spontaneous deliveries, including two stillborns and a set of twins, were studied morphologically. No significant abnormalities were observed in the aborted material. The placentae corresponding to deliveries presented no significant gross abnormalities but the ratio of fetal to placental weight was significantly decreased in the study group compared with the control group (6.13 versus 7.41; P less than 0.001), associated with a congestive and mature aspect of the parenchyma. Histologically a high incidence of chorioamnionitis (43 per cent) was found, contrasting with the absence of villitis. A relative villous hypercellularity was observed in the study group compared with the control group. Ultrastructural studies of 13 placentae corresponding to gestations of 10 to 40 weeks are presented. In six cases, retrovirus-like particles were found at various sites, such as villous fibroblasts, syncytiotrophoblast and endothelial cells, and in the free membranes.

Fetus with Casamassima-Morton-Nance syndrome and an inherited (6;9) balanced translocation.

We report on a fetus with cranio-facial anomalies, a narrow thorax, imperforate anus with cloacal cyst, and a genitourinary malformation with absent uterus, vagina, and external genitalia. Major thoracic defects were seen on roentgenographic examination, including absent vertebrae and ribs, a supernumerary vertebra, a hemivertebra, and rib fusion. These findings are compatible with Casamassima-Morton-Nance syndrome. The patient was the carrier of a translocation t(6;9)(p12;q12), inherited from the mother. Although the occurrence of this rearrangement may be coincidental, it may also indicate a possible locus for this autosomal recessive thoracic dysplasia.

Computerized microscope morphometry of umbilical vessels from pregnancies with intrauterine growth retardation and abnormal umbilical artery Doppler.

Computerized microscope morphometry was used to study cross sections from the vessels of the umbilical cord in placentas of patients with intrauterine growth retardation (IUGR) that displayed either normal or abnormal umbilical arteries (UA) Doppler flow velocity waveforms (FVW). Cords from 63 eutrophic fetuses with normal Doppler (controls), 47 IUGR fetuses with normal Doppler and 32 IUGR fetuses with abnormal Doppler underwent morphometric analysis using a highly optimized microscope environment (HOME) and "CordHOME" software. IUGR with an accompanying normal Doppler versus control showed a reduction of Wharton jelly and both the total and lumen vein areas. IUGR with an accompanying pathological Doppler showed a comparable reduction in wall thickness and areas of every vessel. These findings indicate that the hypoplastic umbilical vessels are associated with an increase in placental vascular resistance that may be the consequence of underdevelopment in response to a chronic reduction in placental blood flow.

Assessing the early luteal phase in in vitro fertilization cycles: relationships between plasma steroids, endometrial receptors, and endometrial histology.

The corpus luteum-endometrial unit was investigated in in vitro fertilization (IVF) cycles using endocrine, morphologic, and biochemical measurements on the day normally scheduled for embryo transfer (day 16), in 12 stimulated and 4 natural cycles. Advanced endometrial histologic maturity was recorded in 9 of the 12 stimulated cycles. No in-phase endometria were seen when the preovulatory plasma estradiol (E2) was greater than 500 pg/ml or the day 16 plasma progesterone (P) greater than 10 ng/ml in natural or stimulated cycles. Significant negative correlations were noted between both preovulatory E2 and day 16 P and the concentration of cytosolic progesterone receptor (PRc). Advanced endometrial maturity tended to be associated with low concentrations of PRc. Regardless of endometrial maturity, the natural cycle was characterized by low cytosolic E2 receptors (ERc) and high PRc, whereas the concentration of both receptors was usually greatly reduced in stimulated cycles. It is concluded that the advanced endometrial maturation observed in stimulated IVF cycles is a consequence of the production of supraphysiologic levels of sex steroids by the corpus luteum that cause profound modifications of endometrial receptor dynamics.

The "dysharmonic luteal phase" syndrome: endometrial progesterone receptor and estradiol dehydrogenase.

The dysharmonic luteal phase (DLP) syndrome is defined by delayed endometrial maturation despite normal plasma progesterone (P) values. In ten patients with DLP the actual date of the endometrial biopsy, dated retrospectively, was 24.7 +/- 2.3 days, whereas the histologic date was 20.0 +/- 2.6 days. The concentration of cytosolic P receptor in DLP endometrium tended to be lower, whereas the concentration of nuclear receptor was significantly higher in DLP than in seven matched patients with normal luteal phases. Endometrial estradiol-dehydrogenase activities were identical in both groups. The DLP syndrome cannot be explained by a decreased sensitivity of the endometrium to P and is probably merely functional in nature.

Supratentorial parenchyma in the developing fetal brain: in vitro MR study with histologic comparison.

PURPOSE: To assess the in vitro MR signal of the developing brain through histologic comparisons. METHODS: Five healthy fetal specimens aged 16, 19, 22, 27, and 34 gestational weeks were studied in vitro using T1- and T2-weighted sequences in frontal and axial planes. Neuropathologic studies included sections in the same frontal plane. Comparison of histologic sections with measurements of the relative widths of the layers of different signal intensities enabled us to assign cellular correspondence to each MR layer. RESULTS: In the cerebral mantle, a layered pattern was observed on both T1- and T2-weighted images. In the basal ganglia, signal from the pallidum and thalamus was isointense with white matter from 16 to 22 weeks' gestation; then, from 27 and 34 weeks' gestation, the signal was relatively high on T1-weighted images and low on T2-weighted images. The neostriatum had a relatively low signal on T1-weighted images and a high signal on T2-weighted images from 16 to 27 weeks' gestation: then, at 34 weeks' gestation, the signal was relatively high on T1-weighted images and low on T2-weighted images. CONCLUSION: MR imaging can clearly show specific patterns of growing fetal brain in vitro.

Placental aryl hydrocarbon hydroxylase activity and placental calcifications.

Induction of aryl hydrocarbon hydroxylase (AHH) activity in the placenta as a result of maternal exposure to polycyclic aromatic hydrocarbons contained in cigarette smoke has been well documented. Furthermore, calcifications are more prevalent in the placentas of pregnant smokers than in those of non-smokers. The present study examines whether this latter relationship could be explained by the induction of AHH activity in the placenta. AHH levels were determined at birth in 141 unselected pregnant women admitted for delivery. Macroscopic placental examination was performed for vascular lesions, abnormalities of placental shape, of the cord and parameters of placental maturity such as basal and parenchymatous calcifications. Significant increases in the prevalence of calcifications of the placental basal plates and parenchyma with the induction of placental AHH were found. A similar significant association between smoking and AHH activation was also observed. These findings remained unchanged when controlling for smoking status assessed both by questionnaire and presence of cotinine in mother's urine. Moreover, the apparent association between smoking 'factor' and calcifications disappeared when controlling for AHH induction. Therefore, the association between smoking and placental calcifications previously related could be mediated by the AHH induction.

Environmental exposure to cadmium and human birthweight.

Fetal toxicity of cadmium (Cd) is well documented in rodents. However, little information is available regarding the human fetus. To investigate the effect of low levels of Cd on the human placenta and the consequences on birthweight, we conducted a study of 102 mothers and their newborns in an obstetrical care unit. Placental and hair samples were collected at delivery to determine Cd concentrations. The main finding of this study was the relationship between a decrease in birthweight and an increase of newborn hair Cd which varied in the presence of placental calcification. In cases of parenchymal calcifications, placental Cd levels were higher (Wilcoxon test, P < 0.05) and newborn hair Cd levels were lower (Wilcoxon test, P < 0.01) than in the absence of calcification. These relationships remained significant even after taking into account smoking habits and gestational age. In the presence of calcification, an increase in the level of Cd in newborn hair was related to a decrease in birthweight which was independent of placental Cd concentration (rpartial = -0.49, P < 0.01). In the absence of calcification, a decrease in birthweight was observed for the upper values of newborn hair Cd (r = -0.44, P < 0.05 when Cd > or = 0.3 ppm). The difference in birthweight between infants in the first and last quartiles of newborn hair Cd was 472 g in cases of calcifications and 122 g in the absence of calcification. Other placental parameters were not significantly related to placental Cd concentration.

Aryl hydrocarbon hydroxylase activity in human placenta and threatened preterm delivery.

Induction of aryl hydrocarbon hydroxylase (AHH) activity in the placenta has been well documented. This enzyme may be induced by a variety of Polycyclic Aromatic Hydrocarbons (PAHs) and the AHH inducibility is associated with harmful effects of environmental chemicals. Toxic effects of PAHs in tissues such as placenta have been demonstrated to be due to their metabolites, epoxides, which interact with DNA. Thus, environmental PAHs may be related to its alterations in fetal development. Founded on these findings the PAH metabolites could interfere with the normal course of the pregnancy and may be an aborticide, a teratogen or a carcinogen. We hypothesize that low increased activity of placental Aryl Hydrocarbon Hydroxylase (AHH) may be an important determinant of human fetotoxicity. The present investigation was designed to examine the possible implications of PAH exposure at environmental exposure levels on the normal course of the pregnancy using AHH induction as an indicator of PAH exposure. Threatened Preterm Delivery (TPD) was used as an index of problems in the normal course of pregnancy. A group of forty pregnancies at term with TPD was compared with eighty controls for placental AHH induction. Macroscopic placental examination was also performed. A significant increase in prevalence of placental AHH induction with TPD was shown (Odds-Ratio = 2.8; 95% confidence bounds [1.3-6.2]; chi 2 = 6.7 p < 0.01). No such increases were found associated with placental pathology. When taking into account the group of placenta without basal plate calcifications, the significant increase in prevalence of placental AHH induction with TPD above mentioned was greatly increased (Odds-Ratio = 8.9; 95% confidence bounds [2.4-32.9]; chi 2 = 11.1 p < 0.001) controlling for gestational age. The increase in prevalence of placental AHH induction with TPD disappeared when taking into account the subgroup with basal plate or parenchyma calcifications. It is hypothesized that the high estrogen and progesterone at term may explain these associations.

Focal cerebral anomalies and retinal dysplasia in a 23-24-week-old fetus.

A 23-24-week-old fetus was the product of a normal pregnancy terminated because of diaphragmatic hernia and hydrocephalus diagnosed by ultrasound. Karyotype on fetal blood was normal. At autopsy, hydrocephalus was associated with multiple large intrameningeal nodules and focal cerebral dysplasia resembling type II lissencephaly. In addition, many structures of the brainstem were dysmorphic and the retina showed multiple rosettes. Skeletal muscle was normal. The peculiar features described in this case pose problems for classification and genetic implications of the anomalies.

Fetal tachycardia and meconium staining: a sign of fetal infection.

A retrospective study was carried out on 72 liveborn babies in whom perinatal infection was suspected. Twenty-nine of the 72 neonates were effectively infected. Analysis of intrapartum FHR recordings showed that tachycardia (base line FHR above 160 beats/min) during labor, occurred more often among infected babies (P less than 0.001). When fetal tachycardia is associated with meconium stained amniotic fluid (MSAF), the relative risk of fetal infection is 51 times as great as in babies without MSAF. Fetal tachycardia is not related to maternal fever nor to prematurity. It is not a sign of limited placental or amniotic fluid infection, but implies infection of the fetus itself. Since most infected babies displayed infectious diarrhea immediately at birth, it is suggested that MSAF may eventually be due to antenatal intestinal infection and intrauterine emission of infected stools. Although great caution is advocated for the management of labor in the presence of fetal tachycardia, MSAF should not be always regarded as a sign of acute fetal distress when antenatal infection of the fetus is suspected.

[Normal placental development and ovular anomalies during the 1st trimester of gestation]. / Développement placentaire normal et anomalies ovulaires au 1er trimestre de la gestation.

Normal placental development and ovular anomalies during the first trimester of gestation. The normal sequences of placental development are first briefly summarized to allow a better understanding of ovular pathology. Fifteen percent of recognized pregnancies end with miscarriages, and probably one out of two conceptuses fail even before implantation. Most spontaneous abortions occur before 15 weeks of gestation, and are caused by zygotic defects: abnormal karyotypes represent more than 50% of the cases. Trisomies predominate (50 to 60%), followed by triploidy (20%), monosomy X (15%) and structural anomalies (4%). The phenotype of these lethal anomalies have been meticulously described so that the pathologist is allowed to diagnose aneuploidy on morphological features. It should be emphasized that similar abnormal phenotypes have been observed with normal karyotypes suggesting undetected genetic factors. Hydatidiform mole, twinning, whose incidence is much higher among aborted material than among live births, are other zygotic causes of abortion. Embryonic death or placental insufficiency leading to miscarriage can also result from abnormal implantation or be secondary to lesions of the membranes, as observed in amniotic band syndrome. Maternal causes of spontaneous abortions, local or general, are probably rare at this stage of gestation and difficult to diagnose by the pathologist. Retroplacental haematoma, infarcts or endometritis are often undistinguishable from leucocytic infiltrates or necrosis following the usual long period of retention.

[Assessment of fetal maturation]. / Critéres de maturation foetale.

Few organs or tissues are convenient to use for the pathologist to assess fetal maturity: the brain, particularly the external configuration of the cerebral hemispheres: the primary and secondary sulci appear in a definite chronologic order; the lungs; four developmental stages are defined: the last stage is characterized by attenuation of alveolar epithelial lining, and increase and superficial migration of capillaries. It must be reached necessarily to have postnatal respiration; the kidneys have a typical pattern of development, especially after 28 weeks, when it is possible to count the number of immature glomerular layers in the cortex; for the differentiation of the skin, specimens taken from special regions of the body are characteristic enough to determine the maturity, especially during the second trimester.

[Importance of examination of the placenta]. / Apport de l'examen du placenta.

It is necessary to examine the placenta in two conditions at least: when the fetus is still born or dies in the neonatal period, and when there is a gestational or a neonatal pathology. Placental examination is essentially macroscopic. It is recommended to practice it on fresh placenta, so that cytobacteriological investigation can be done at the same time. Histological samples are taken in one third of the cases. The principal abnormalities or lesions are described, with their clinical significance: shape abnormalities, pathology of the cord and membranes, vascular lesions (decidual haematoma, infarcts, perivillous fibrin deposition), chorioangioma, abscess. Some more "genetical" aspects of the placentology are also approached, for instance chromosomal aberrations, or multiple pregnancies.