Angiogenesis and placental growth in normal and compromised pregnancies

Research on the subject of pre-eclampsia has revolved around placental growth and angiogenesis, as both are central to the aetiology of the disease. Vascular angiogenic growth factor (VEGF) is elevated in pre-eclampsia and correlates with the severity of disease. Its actions in vitro mimic the actions of plasma from women with pre-eclampsia. This chapter examines the available evidence that implicates VEGF in the maternal systemic effects seen in pre-eclampsia, and discusses how an understanding of this growth factor could lead to diagnostic and therapeutic options. Oxygenation status is the unifying concept that surrounds the discussion of placental growth and angiogenesis. The concept that 'hypoxia' is too simplistic a notion to describe pre-eclampsia is discussed. Maldevelopment of the angiogenic process can be assessed by Doppler ultrasound. The future may see a role for magnetic resonance imaging in the identification of poorly perfused placenta.     

Changes in N-acetyl-beta-glucosaminidase activity in the maternal plasma and utero-placental tissues during normal pregnancy and parturition

In the ripening of the uterine cervix during parturition, glycosaminoglycan (GAG) in the cervical extracellular matrix has been reported to undergo drastic changes i.e. the increase in hyaluronic acid, and the decrease in dermatan sulfate and chondroitin sulfate. N-acetyl-beta-glucosaminidase (NAG; EC3.2.1.30), one of marker enzymes of lysosome, may also degrade extracellular GAG in the uterine cervix. This study is undertaken to determine if NAG plays a role in the ripening of the cervix during parturition. The maternal plasma were collected from 252 women with normal pregnancy (5-41 weeks gestation). Amnion, chorion and parietal decidua were obtained from 20 patients at more than 36 gestational weeks who had undergone cesarean section (CS) prior to labor, and from 24 who had undergone CS after the onset of labor. NAG activity in the maternal plasma gradually increased with the advance of gestation, and increased drastically after the onset of labor. The activity in the amnion and decidua, but not in the chorion, decreased significantly in the women who had undergone CS after the onset of labor compared with those who had undergone CS prior to labor. It is concluded that NAG is released into the maternal circulation from lysosomes in amnion and decidua, and it is also estimated that NAG plays a role in the ripening of the uterine cervix during parturition by degrading GAG in the cervical extracellular matrix.     

Role of placental growth hormone in the alteration of maternal arterial resistance in pregnancy

OBJECTIVE: To investigate the relation between arterial resistance and placental growth hormone (hGH-V) levels in the maternal circulation. STUDY DESIGN: Sixty-seven women with normal pregnancy, 13 with preeclampsia (PE) and 11 with intrauterine fetal growth restriction (IUGR) underwent Doppler sonography of the placental and nonplacental uterine and cubital artery and blood sampling. hGH-V was measured with a highly sensitive sandwich-type immunofluorometric assay and pituitary growth hormone (hGH-N) and insulinlike growth factor I (IGF-I) with a chemiluminescence assay. A p value of < 0.05 was considered significant. RESULTS: During normal pregnancy the arterial pulsatility index (PI) decreased (p < 0.001), serum levels of hGH-V and IGF-I increased (p < 0.0001), and hGH-N decreased (p < 0.0001). Pathologic pregnancies (PE, IUGR) showed a significant higher PI in all arteries, but hGH-V and the IGF-I were decreased. CONCLUSION: Our data demonstrate a strong correlation between decreasing uterine and peripheral arterial resistance and increasing hGH-V during normal pregnancies with impaired uterine blood flow there were lowered serum levels of hGH-V, hGH-N and IGF-I. Lower levels of hGH-V and hGH-N might contribute to impaired uteroplacental circulation.     

Prolactin and placental hormone levels during pregnancy in prolactinomas

Prolactin (PRL) and the placental hormones, estradiol (E2), estriol (E3), progesterone (PG), chorionic gonadotropin (HCG), and placental lactogen (HPL) were serially measured throughout pregnancy and early postpartum in three patients with prolactinomas in whom pregnancy was achieved by one of the three modalities of treatment: bromocriptine administration (patient I), irradiation of the pituitary (patient II), and human gonadotropin administration after excision of the adenoma (patient III). It was found that PRL in patient I reached the high pretreatment levels in the 2nd month of pregnancy and increased to further abnormal concentrations in the last 2 months, but fell at the onset of labor 1 week after an episode of severe headache. The PRL changes in this patient were attributed successively to tumor expansion and apoplexy. In patient II PRL decreased after irradiation, but was not normalized. During pregnancy it remained moderately increased presenting minor fluctuations. The third patient with postoperative GH and TSH pituitary insufficiency had low pretreatment PRL levels which remained practically unchanged throughout pregnancy. The two last patients gave birth to identical twins. The placental hormones were found normal in all three patients but E2 and PG were relatively increased during the last weeks of pregnancy in the twin pregnancies. Amniotic fluid and umbilical cord PRL and E2 concentrations were normal. The patients presented agalactia and suckling did not induce a PRL increase. We conclude that a) serial PRL measurements during pregnancy reflect the changes occurring in the prolactinomas and are essential in monitoring the patients bearing these tumors; b) maternal hyperprolactinemia or failure of PRL to increase during pregnancy do not influence either the secretion of placental hormones or PRL concentration in amniotic fluid and the newborn; and c) hyperprolactinemia during pregnancy is of maternal pituitary origin.     

Zinc in Danish women during late normal pregnancy and pregnancies with intra-uterine growth retardation

Zinc and alkaline phosphatase were examined in 41 pregnant women (gestational weeks 35-41) and in 12 women within 24 h of delivery. The serum-zinc level was reduced in all the women, though to a lesser degree in women giving birth to small for gestational age (SGA) babies than in the control mothers. The difference between the two groups was significant (p = 0.019). Erythrocyte-zinc increased during pregnancy, more in control mothers than in SGA mothers (p = 0.020). Granulocyte-zinc was not significantly reduced in pregnancy and no difference was found between SGA mothers and control mothers. Alkaline phosphatase levels in serum and granulocytes were elevated equally in the two groups. These findings show that zinc level changes occur in pregnancy, but that the changes do not appear to be a dominant cause of SGA pregnancy, in Danish women.     

Studies on maternal hemodynamics during normal pregnancy: correlation between maternal hemodynamics and fetal growth

The cardiac output (CO) and cardiac index (CI) were examined by echocardiography throughout pregnancy and 1 month of puerperium and the results were compared with fetal growth as determined by birth weight. The results are as follows. The changes in CO and CI during the pregnancy and puerperium of normal pregnant women (n = 48) were similar in all subjects, and reached the maximum at the 24th-31st week's of gestation. On the 5th day of puerperium, the CO and CI values were almost the same as those obtained at the 32nd-40th weeks of gestation, and after 1 month of puerperium the values were same as those obtained in the non-pregnant period. The CO and CI of HFD child-bearing group (n = 8), AFD child-bearing group (n = 30) and LFD child-bearing group (n = 10) were compared. The CO and CI values for the LFD group were lower than those for AFD group; particularly, significant differences (p less than 0.05) were observed in 24th-31st weeks and 32nd-40th weeks of gestation. The CO and CI values of HFD group tend to be higher than those for AFD group, but there is no statistical significance between the two groups. The birth weight correlated to the rate of increase in CO and CI during pregnancy with coefficients of correlation of 0.56 (p less than 0.05) and 0.54 (p less than 0.05), respectively. The rate indicates the ratio of maximum values of CO and CI obtained during pregnancy to the values after 1 month of puerperium, which have been shown to be consistent with those during the non-pregnant period. A significant correlation (r = 0.54, p less than 0.05) was found between placenta weight and birth weight. The correlations between placental weight and the rate of increase in CO and CI were also significant with coefficients of correlation of 0.40 (p less than 0.05), and 0.38 (p less than 0.05), respectively.     

Increase in normal placental weights related to increase in maternal body mass index

Objective. Reference values of normal placental weights are many decades old. Recently, a trend of increasing weights of normal placentas has been noted. We aimed to confirm this observation and to find any associated fetal and maternal factors.

Methods. Information on all live singleton deliveries that met our inclusion criteria was collected for the years 1995 and 2004 at Creighton University Medical Center in Omaha, Nebraska. This information was compared to the standards set forth in the older references. The Student's t-test and correlation-regression statistics were applied.

Results. The mean weight of the mature, term (37–42 weeks of gestation) placenta has increased significantly from 1995 to 2004 (499 g to 537 g, p = 0.02), as well as from the older standards (27% increase at 40 weeks of gestation). There has also been a significant increase in the maternal body mass index (BMI) from 1995 to 2004 (25.2 to 26.5, p = 0.02), which correlates with maternal weight gain during pregnancy, and fetal and placental weights.

Conclusions. Normal placental weights have increased over the last decades and this may correlate with increasing maternal obesity. Further studies with larger populations are needed to confirm these findings.     

First-trimester maternal serum human thyroid-stimulating hormone in chromosomally normal and Down syndrome pregnancies

Maternal serum human thyroid-stimulating hormone (TSH) levels were investigated in chromosomally normal and Down syndrome pregnancies to determine whether TSH can be used as a marker for Down syndrome in the first trimester. Measurements were conducted on stored serum samples collected from 23 Down syndrome pregnancies and 115 unaffected pregnancies before chorionic villus sampling (CVS), between 9 and 11 completed weeks of pregnancy. The samples were matched for gestational age, maternal age, maternal weight and duration of storage of the serum sample. Maternal TSH concentration was slightly decreased in Down syndrome pregnancies, with a median of 0.84 multiples of the median (MoM). Maternal serum human chorionic gonadotropin (hCG) concentration was slightly elevated in Down syndrome pregnancies, with a median of 1.03 MoM. Both differences were not significant applying matched rank analysis (p=0.50 for TSH and p=0.43 for hCG). The association between TSH and hCG in unaffected pregnancies was also measured. The Spearman correlation coefficient between TSH and hCG was -0.21 which was statistically significant (p=0.02, 95% confidence interval -0.38 to -0.03). However, it was concluded that TSH is not a useful marker for distinguishing Down syndrome-affected pregnancies from normal pregnancies in the first trimester.     

Growth hormone levels in maternal serum during pregnancy

Maternal growth hormone (GH) levels during pregnancy have been variously reported to be suppressed or, more lately, to be increased. In an attempt to clarify this point, maternal GH levels were estimated with two modern GH polyclonal radio-immunoassays (RIAs) and a new monoclonal enzyme-linked immunoassay (ELISA). The Cambridge Medical Diagnostics RIA and the more specific bioMérieux RIA gave similar results in control non-pregnant patients with raised GH levels, while the monoclonal ELISA gave slightly lower values. The bioMérieux assay gave results about 10 times higher than the Cambridge assay during pregnancy, at 12-61 ng/ml at 16-20 weeks and 47-153 ng/ml at 28-39 weeks (total n = 27). These high 'GH' levels did not correlate with maternal levels of prolactin or human placental lactogen. It is presumed that some unknown GH-like molecule(s) are being estimated in this assay, possibly the recently discovered human chorionic GH. That this is not pituitary GH was confirmed by the monoclonal ELISA, by which GH levels were almost undetectable during pregnancy.     

Increase in normal placental weights related to increase in maternal body mass index.

OBJECTIVE: Reference values of normal placental weights are many decades old. Recently, a trend of increasing weights of normal placentas has been noted. We aimed to confirm this observation and to find any associated fetal and maternal factors. METHODS: Information on all live singleton deliveries that met our inclusion criteria was collected for the years 1995 and 2004 at Creighton University Medical Center in Omaha, Nebraska. This information was compared to the standards set forth in the older references. The Student's t-test and correlation-regression statistics were applied. RESULTS: The mean weight of the mature, term (37-42 weeks of gestation) placenta has increased significantly from 1995 to 2004 (499 g to 537 g, p = 0.02), as well as from the older standards (27% increase at 40 weeks of gestation). There has also been a significant increase in the maternal body mass index (BMI) from 1995 to 2004 (25.2 to 26.5, p = 0.02), which correlates with maternal weight gain during pregnancy, and fetal and placental weights. CONCLUSIONS: Normal placental weights have increased over the last decades and this may correlate with increasing maternal obesity. Further studies with larger populations are needed to confirm these findings.     

Scintigraphic studies of uterine and placental growth and placental migration during pregnancy

Placental scintigraphy with 113mIn (Indium) combined with cervical marking with a shielded 57Co (Cobalt) radioactive source was used to study uterine and placental growth in human pregnancy and placental location and migration in a total of 176 patients. Uterine length measurements can be used for selecting growth retarded fetuses. There was an approximately constant ratio between placenta diameter and uterine length (0.68 +/- 0.03). When the placenta was located on the ventral uterine wall, low implantation occurred in 61%. The corresponding figure for low implantation when the placenta was located on the dorsal uterine wall was 30%. The difference was highly significant. Placental migration was studied in 20 patients. Significant migration occurred in 11 cases. The placental margin closest to the internal cervical os migrated outwards about 3 cm on average.     

Elevated maternal glucose concentrations and placental infection in twin pregnancies

OBJECTIVE: To evaluate the association between maternal screening glucose concentration and placental infection in nondiabetic twin pregnancies. STUDY DESIGN: One thousand sixty-one nondiabetic twin pregnancies at > or =28 weeks' gestation were divided into 3 groups based on the screening 50-g fasting glucose concentration at 24-28 weeks: lowest quartile (< 96 mg/dL), middle 2 quartiles (96-128 mg/dL) and upper quartile (> 128 mg/dL). Outcomes were modeled using general linear and multinomial logistic regression, controlling for confounding factors. RESULTS: The middle and highest glucose groups were associated with increased risks for clinical chorioamnionitis (adjusted OR [AOR] 3.18, 95% CI 1.34, 7.54; AOR 6.80, CI 1.89, 24.53, respectively). Birth at <32 weeks and histologic diagnosis of placental infection (chorioamnionitis, funisitis, necrosis, vasculitis or villitis) were significantly associated only with the highest glucose group (AOR 1.79, CI 1.02, 3.13; AOR 6.95, CI 1.10, 8.68, respectively). CONCLUSION: Elevated screening glucose in nondiabetic twin pregnancies may be a marker of placental inflammation and infection.     

Loss of growth hormone responsiveness to normal physiological stimuli during pregnancy.

The response of pituitary GH to acute hyperglycaemia induced by 75 g oral glucose load in 73 pregnant women at various stages of gestation was examined. According to the age of gestation, patients were grouped into three groups: less than 20 weeks, between 20-30 and more than 30 weeks. Plasma glucose, GH and C-peptide were measured at fasting and then at 30, 60, 120 and 180 min following the glucose load. There was a significant increase in plasma GH concentration with weeks of gestation. The results also showed a loss of the normal physiological suppressive effects of hyperglycaemia on GH secretion in tests performed after 20 weeks of gestation. Only in tests performed before 20 weeks, there was a significant negative correlation between plasma glucose and GH values. These findings are consistent with recent reports suggesting an almost complete suppression of pituitary GH secretion by a placental variant of GH. These changes in the dynamics of GH secretion suggest that, in pregnancy, GH plays a more significant role than was previously thought.     

The disappearance rate of Schwangerschaftsprotein 1 in normal and pathological pregnancies

In six women with a normal vaginal delivery at term, in 12 women who had a suction curettage between 6 and 12 weeks gestation and in eight women with an ectopic pregnancy, the post-partum or the post-surgery decline in radioimmunoassayable SP1 was faster during the first 24 h after surgery or delivery than later, so that two half-lives were calculated. The first 'half-life' of about 20 h (0-24 h after delivery or surgery) was of the same order of magnitude in all groups studied and corresponded well to previously published values. The mean second 'half-life' (greater than 24 h after delivery or surgery) was significantly longer in term (72.2 h) and in ectopic pregnancies (64.1 h) than in first trimester pregnancies (45.5 h). These results might indicate that the metabolism of SP1 either changes during pregnancy or that the changing SP1 beta/SP1 alpha ratio during pregnancy markedly influences the levels of SP1 as measured by radioimmunoassay.