Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation

Patterns of fetoplacental angiogenesis vary during gestation and in association with certain pregnancy pathologies. In a set of three linked reviews, we provide a survey of current knowledge about the molecular regulation, cellular players, qualitative and quantitative morphological features of the vascularization of human placental villi. Here, an account is given of the role played by hypoxia-inducible factor in mediating the effects of oxygen on production of growth factor ligands and receptors which regulate angiogenesis and vessel maturation. However, it should be noted that, for the human placenta early in gestation, the normal (i.e. physiological) partial pressure of O(2)is low but this does not mean that the tissue is hypoxic. Thus, the mechanisms of regulating angiogenic growth factor production may differ at this time in comparison to those found later in gestation or in other tissues or organs. The vasculature in the placenta is plastic and changes markedly as gestation progresses. This is controlled by the complex interplay between physical factors and chemical factors including oxygen, growth factors and growth inhibitors. The companion reviews describe morphological features of normal and pathological development of the human placenta in the context of the factors discussed here.     

Optimal gestational age for twin delivery.

OBJECTIVE: We evaluated the timing of twin delivery associated with perinatal outcome in gestations of at least 36 completed weeks. STUDY DESIGN: This was a retrospective analysis of infant and maternal hospital records for a consecutive series of twin deliveries at New York Hospital-Cornell Medical Center. The inclusion criteria were delivery after 36 weeks' gestation during a 7-year period (1987 to 1993), without congenital anomalies or early fetal demise. Adverse perinatal outcomes were compared between deliveries before 38 weeks' gestational age and those at or after 38 weeks' gestation. RESULTS: Of 776 twin deliveries during the study period, 329 met the inclusion criteria. Adverse perinatal outcome was significantly higher among the twin pregnancies that delivered before 38 weeks' gestation compared with those that delivered at or after 38 weeks' gestation. Twin pregnancies that delivered between 36 and 37 weeks' gestation were 13 times more likely to require neonatal intensive care compared with those who delivered at or after 38 weeks' gestation (95% confidence interval 1.8 to 95.9; p < 0.001). CONCLUSION: In uncomplicated twin gestations, delivery at between 36 and 37 weeks' gestation was not associated with a reduction in neonatal complications compared with deliveries at or after 38 weeks' gestation.     

Bilateral ectopic gestations.

Bilateral ectopic gestations are a rare form of double ovum pregnancy. The following case report of a patient with a ruptured ectopic gestation of the left fallopian tube and an unruptured ectopic gestation of the right fallopian tube is presented to demonstrate the importance of thoroughly examining the entire pelvis at the time of exploratory laparotomy undertaken for suspicion of ectopic pregnancy.     

Hydranencephaly in a twin gestation.

Hydranencephaly in a twin gestation was demonstrated prenatally by ultrasonography and confirmed following delivery by cranial computerized axial tomography (CAT). Prenatal diagnosis of intracranial anomalies is possible with the use of ultrasonography. This is the third report of the occurrence of hydranencephaly in a twin gestation.     

Ectopic gestation following emergency contraception with levonorgestrel.

Reports of ectopic gestation after failure of emergency contraceptive pills have thus far been rare, although the use of various types of emergency contraceptive pills is becoming more and more popular world-wide. We report two cases of ectopic gestation following failure of levonorgestrel as over-the-counter emergency contraceptive pills. The women personally purchased the pills over-the-counter at a drugstore and took them routinely. Clinicians should be aware of the possibility of an ectopic gestation when an emergency contraceptive pill fails. We recommend to women the full use of established service networks to enhance education and dissemination of information on emergency contraception. Additionally, health providers should advise women very clearly that, if treatment fails, pregnancy could occur, including ectopic gestation.     

First-trimester ultrasonic diagnosis of twin reversed arterial perfusion sequence.

Twin reversed arterial perfusion (TRAP) syndrome sequence is a rare specific anomaly of twin gestation with fused placentae and umbilical anastomosis. This syndrome occurs once in very 35,000-48,000 births and has been described in the second trimester (23-29 weeks of gestation). We report on early sonographic diagnosis (10 and 12 weeks' gestation) of two cases of TRAP sequence, together with their umbilical cord Doppler studies.     

Simultaneous ovarian and intrauterine pregnancy: case report.

The simultaneous presence of an ovarian and a normal intrauterine pregnancy is a very rare condition. We report such a case seen as an ovarian cyst during gestation. It was immediately and successfully treated, thus allowing for the normal physiologic continuation of the gestation.     

The value of sonography in suspected ectopic pregnancy.

Of 356 women undergoing sonography to diagnose or rule out an ectopic gestation, data sufficient to assign a final diagnosis were available on 260 of them. Ectopic gestation was diagnosed in 25 cases in this group and intrauterine pregnancy in 99, while the remaining 136 patients were found not to be pregnant. During sonography, ectopic gestations were suspected or diagnosed in 27 instances: In 17 cases this was in agreement with the final diagnosis, but neither an intrauterine nor an extrauterine gestation existed in 10 cases, although neoplastic or inflammatory masses were present. Of the 25 patients with the final diagnosis "ectopic pregnancy," this was not detected with sonography in 8 instances. Intrauterine pregnancies were diagnosed by sonar in 94 of the 99 cases. Although reliable sonar identification of ectopic gestation is not always possible, sonography is helpful in diagnosing intrauterine pregnancy so that surgical intervention can be avoided.     

Emergency cerclages: a review of 40 consecutive procedures.

This report describes 40 consecutive emergency cerclages on dilated and effaced cervices prior to 26 weeks' gestation. These "emergency" cerclages were associated with a mean extension of gestational age of 12 weeks (range, 3 days to 20.5 weeks). Thirty-one of 40 pregnancies were carried to 28 weeks' gestation and 23 were carried to 34 weeks' gestation or greater. Twelve of 19 women with amniotic membranes bulging into the vagina carried pregnancies to 28 weeks' gestation, with seven of these 19 women carrying the gestation to 34 weeks' or beyond. There was no maternal morbidity. Thirty-four of 41 infants survived (83%). Two pregnancies delivered within 8 days of the procedure. Emergency cerclages should be considered as a management option in women with painless dilation of the cervix and previable gestation.     

Fibrinogen turnover in pregnant rabbits during the first and last thirds of gestation.

Although thrombin-mediated fibrinogen derivatives have been observed in normal pregnancy, an increased turnover of fibrinogen has been suspected but has not yet been demonstrated. Fibrinogen turnover was studied in 14 pregnant and 10 nonpregnant female rabbits by use of purified rabbit 125I-labeled fibrinogen. In the last third of gestation the half life of fibrinogen was shortened by 45% and the fractional catabolic rate increased by 44% in comparison to the values for the first third of gestation obtained in the same rabbits. The distribution volume of the injected fibrinogen representing the plasma volume increased by a mean of 18% during gestation. Fibrinogen concentration did not change during gestation. From a comparison of the measured data from the first and last thirds of gestation, it can be calculated that the synthesis rate of fibrinogen increased by about 80%. Furthermore, a positive correlation was found between the number of young per litter and the acceleration of fibrinogen elimination, indicating that a local process of intravascular coagulation in the placenta is responsible for the accelerated turnover of fibrinogen during gestation.     

Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age

Birth weight, gestational age at delivery, and other factors were collected for 171 white children with spastic cerebral palsy. Their birth weights were compared with the birth weight distribution expected for a population of the same race, gestation, sex, maternal height, and parity, born in the same geographic area, and during the same time period. Birth weights of children with spastic cerebral palsy tended to be significantly lower than the median birth weight of their comparison population. Analysis stratified by gestation at delivery suggested that if the reduced birth weight were causally associated with the spastic cerebral palsy, 22% of cases were attributable to being below the 10th percentile of the comparison population birth weight distribution. The risk of spastic cerebral palsy associated with poor intrauterine growth was dependent on gestation at delivery; poorly grown infants delivered between 34 and 37 weeks' gestation were at highest risk. Some probable pathways by which growth retardation could result in brain damage (intrapartum hypoxia, hypoglycemia, and hypothermia) were investigated. Only intrapartum hypoxia may have played a causal role but probably accounted for less than 2% of all cases. These data suggest that spastic cerebral palsy is associated with poor intrauterine growth in infants of more than 33 weeks' gestation, but no important causal mechanism has yet been identified.     

Changes of lipid peroxidation and superoxide dismutase activity in the human placenta.

The oxygen radical may induce peroxidation of unsaturated fatty acids in vivo. We studied changes in superoxide dismutase (SOD) activity and lipid peroxidation using human placental tissue. Lipid peroxidation was marked in early stages (2 to 4 months) of gestation but decreased with growth and was very small by the end of pregnancy. The SOD activity of placental tissue in early gestation was approximately 250 to 500 U per gram of wet weight. The activity increased with growth of the placenta and reached a level of 400 to 1,500 U per gram of wet weight by the end of gestation. These results for SOD activity suggest that the oxygen requirement in the placenta at early stages of gestation is low compared with that at the end of gestation.     

Biomechanical characteristics of human fetal membranes. Preterm fetal membranes are stronger than term fetal membranes

The purpose of this study was to determine the biomechanical characteristics of human fetal membranes (FM) throughout gestation. Biomechanical properties were determined for 115 FM of 23-41 weeks gestation using our previously described methodology. The areas of membrane immediately adjacent to the strongest and weakest tested spots were sampled for histomorphometric analysis. Clinical data on the patients whose FM were examined were also collected. FM less than 28 weeks gestation were associated with higher incidence of abruption and chorioamnionitis. Topographically FM at all gestations had heterogeneous biomechanical characteristics over their surfaces with distinct weak areas. The most premature membranes were the strongest. FM strength represented by rupture force and work to rupture decreased with increasing gestation in both weak and strong regions of FM. This decrease in FM strength was most dramatic at more than 38 weeks gestation. The FM component amnion-chorion sublayers were thinner in the weak areas compared to strong areas. Compared to term FM, preterm FM are stronger but have similar heterogeneous weak and strong areas. Following a gradual increase in FM weakness with increasing gestation, there is a major drop-off at term 38 weeks gestation. The FM weak areas are thinner than the stronger areas. Whether the difference in thickness is enough to account for the strength differences is unknown.     

Ultrasound measurement of fetal size in rural Guatemala.

OBJECTIVES: To describe the fetal growth pattern of a population from rural Guatemala and determine when during gestation growth faltering becomes evident. METHODS: Ultrasound examinations were conducted for 319 women. Femur length (FL), biparietal diameter (BPD), abdominal (AC) and head circumference (HC) were compared with reference values. RESULTS: FL and AC were similar to reference values throughout gestation. BPD and HC were below the 50th percentile by 30 weeks' gestation and below the 10th percentile later in gestation. We expected all four dimensions to show marked growth restriction during gestation. Measurement differences may explain the results but would call into question the value of cross-study comparisons. Infants born small for gestational age were small in all measures as early as 15 weeks. CONCLUSIONS: Fetal growth faltering begins in early gestation among infants who were born small. The lack of deviation from reference data for FL and AC requires further clarification.     

A comparison of D & C and vacuum aspiration for performing first trimester abortion.

In a study of techniques for first trimester abortion conducted at Kandang Kerbau Hospital in Singapore from September 1973 to April 1975, 420 physically healthy gravidas were randomly assigned to one of two treatment groups either by D & C or vacuum aspiration. Half of the patients in each group were 6 to 10 menstrual weeks' gestation and half were 11 to 12 week's gestation. The numbers of women with one or more complications were the same for the two treatment groups, but were significantly less when termination was carried out at 11 to 12 weeks' gestation. Estimated blood loss was significantly lower for patients treated by VA (32.3 ml) than for patients treated by D & C (39.0 ml) at 6 to 10 week's gestation, but the difference in blood loss was not statistically significant at 11 to 12 weeks' gestation. Time from insertion to removal of the speculum was significantly less with VA than D & C at 6 to 10 weeks' gestation but not at 11 to 12 weeks' gestation. Since vacuum aspiration is at least as safe as D & C, and appears to be more convenient and costeffective, it should on the basis of this experience be accepted over D & C as the standard method for treatment of first trimester abortion.     

Placenta percreta.

A patient with an unsuspected placenta percreta presented with intraperitoneal bleeding at 33 weeks' gestation. Because of the clinical picture and a lecithin/sphingomyelin ratio of 1:1, this patient was treated conservatively until 38 weeks' gestation when an L/S ratio test indicated fetal maturity. The pregnancy was successfully terminated by cesarean hysterectomy.     

Glycogen metabolism in the rat visceral yolk sac. 2. Activity of glycogen-degrading enzymes

In an attempt to explain the previous observation of the rise and subsequent fall in glycogen content of the rat visceral yolk sac during the latter half of gestation, the activities of glycogen phosphorylase, glucose-6 phosphatase and lysosomal α-glucosidase were measured. Glycogen phosphorylase was found to be present in the yolk sac and, as in adult rat liver, was predominantly in the ‘a’ (active) form. The specific activity of the enzyme was lower than in adult rat liver, when expressed per mg tissue protein or per mg tissue wet weight, but similar when expressed per mg tissue glycogen. Phosphorylase activity in yolk sac was similar at 16.5 and 18.5 days of gestation. Glucose-6-phosphatase activity was not detectable in the yolk sac at either 15.5 or 18.5 days of gestation. Two lysosomal enzymes, acid α-glucosidase and N-acetyl-β-hexosaminidase, were shown to be present in the yolk sac at higher specific activity than in adult liver. α-Glucosidase activity in yolk sac was similar at 15.5 and 18.5 days of gestation. It is concluded that the net degradation of yolk sac glycogen initiated around 18.5 days of gestation does not serve to provide glucose for the fetus, and may indicate an increased demand for metabolic energy within the yolk sac itself.     

Early diagnosis of proximal femoral deficiency.

A case of proximal femoral deficiency in a fetus, associated with ventriculomegaly and oligohydramnios is described. Vaginal ultrasonographic diagnosis was made in the 14th week of gestation in a 37-year-old asthmatic woman. Ultrasonic follow-up until termination of pregnancy in the 20th week of gestation was performed. The importance of early diagnosis and the possible roles of oligohydramnios and antiasthmatic medications are discussed.     

Fetus papyraceus. Case report

The term fetus papyraceus is used to describe a mummified fetus associated to a multi-fetal gestation. We present the case of a of 20 years old patient who entered under the diagnosis of pregnancy of 41.1 weeks of gestation by last menstrual period, and effective labor work. It was conducted labor and delivery obtaining a live, male product. The uterine cavity was revised due to suspicion of retention of placenta and/or fetal membranes and it was obtained a product of approximated 15 weeks of gestation; the patient presented uterine atony and postpartum hemorrhage (PPH) quantified in approx 1,500 cc. Therefore it was decided to perform an obstetrical abdominal hysterectomy, which took place without incidents. The patient cursed pathological puerperium and received blood transfusion for 4 U. She was discharged at the 7th day after surgery. The histopathologic result was fetus papyraceus.     

Characterization of human placental activity for transport of L-alanine, using brush border (microvillous) membrane vesicles.

To characterize the placental activity for the transport of amino acids, the uptake of L-alanine was investigated by rapid membrane filtration using brush border membrane vesicles separated from the human placenta of early pregnant (12-13 gestational weeks) and late pregnant (37-38 gestational weeks) women. The uptake of L-alanine into the brush border membrane vesicles at early and late stage of gestation showed a pattern of transport dependent on the intra- and extravesicular Na+ concentration gradient (extravesicular Na+ greater than intravesicular Na+). The Na+ concentration gradient-dependent uptake of L-alanine into the brush border membrane vesicles at early and late stage of gestation also showed a dependency on the potential difference of the internal and external membrane. The transport of L-alanine into the brush border membrane vesicles was markedly augmented at late stage of gestation. On the basis of the double reciprocal plotting of the L-alanine concentration and the Na(+)-dependent uptake of L-alanine into the vesicles, Km and Vmax were calculated as parameters of the Na(+)-dependent uptake of L-alanine into the vesicles. In the early stage of gestation Km was 0.78 mM, and in the late stage of gestation was 0.80 mM. In the early stage of gestation Vmax (nmol/mg protein/20 sec) was 0.62, and in the late stage of gestation was 3.53. From the results, it was considered that the placental active transport mechanism of L-alanine is the same in the early and late stages of gestation, and it was shown that its transport activity increases greatly in late stages compared to the early stages of gestation.