Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion

Angiogenic factors like placental growth factor and its antiangiogenic antagonist soluble fms-like tyrosine kinase 1 (sFlt1) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction. Because it is known that altered maternal sFlt1 and placental growth factor levels are detectable weeks before the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. This prospective study includes 63 second trimester pregnant women with abnormal uterine perfusion. Twenty five of them developed a later complication (12 with preeclampsia, 11 with intrauterine growth restriction, and 2 with intrauterine death), whereas 38 had a normal course of pregnancy. Pregnancies with adverse pregnancy outcome showed in the second trimester significantly higher sFlt1 (1403.6+/-555 versus 451.8+/-42 pg/mL; P<0.05) and lower placental growth factor (139.6+/-24 versus 184.1+/-21 pg/mL) levels compared with those with normal outcome. These alterations were more pronounced in pregnancies with subsequent preeclampsia compared with intrauterine growth restriction and early onset diseases (delivery <34 weeks) compared with late-onset diseases. The combination of Doppler and sFlt1 increases the sensitivity of Doppler alone for iatrogenic preterm delivery from 64% up to 79% and the specificity from 63% up to 80%. Using both factors, sFlt1 and placental growth factor, early onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. We conclude that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early onset pregnancy complications, particularly preeclampsia.     

Birthweight of Babies Born to Mothers with Type 1 Diabetes: is it Related to Blood Glucose Control in the First Trimester?

A retrospective study of 133 pregnancies in women with Type 1 diabetes was performed, and the 116 which progressed beyond 28 weeks were further analysed. Despite good maternal blood glucose control (mean (+/- SE) HbA1 levels 8.6 +/- 0.2% at the end of the first trimester; 6.9 +/- 0.2% at delivery; normal range 4.0-8.5%), 38% of babies had birthweights above the 90th centile and operative intervention occurred in 77 deliveries (66%). There was no significant correlation between birthweight and HbA1 level at any stage of pregnancy, but mothers with babies above the 90th centile for weight had a higher HbA1 at the end of the first trimester than mothers with babies below the 90th centile (9.3 +/- 0.5 vs 7.9 +/- 0.2%, p less than 0.05). In contrast there was no difference in the HbA1 levels at delivery (7.0 +/- 0.3 vs 6.8 +/- 0.2%). The perinatal mortality rate was 17.7 per 1000 births. The results confirm that in Type 1 diabetes large babies are common despite good blood glucose control, and suggest that maternal blood glucose control in the first trimester may be an important determinant of birthweight.     

Longitudinal study of serum placental GH in 455 normal pregnancies: correlation to gestational age,fetal gender,and weight

Placental GH is thought to be responsible for the rise in maternal IGF-I during pregnancy and is considered to be important for fetal growth. In this prospective longitudinal study of healthy pregnant women, we investigated determinants of placental GH in maternal serum. Serum was obtained from 455 women with normal singleton pregnancies at approximately 19 and 28 wk gestation. Serum placental GH concentrations were measured by a highly specific immunoradiometric assay, and fetal size was measured by ultrasound. Data on birth weight, gender, prepregnancy body mass index (BMI), parity, and smoking habits were obtained from medical records. Serum placental GH concentrations were detectable in serum from all women as early as 14 wk gestation and increased during pregnancy in all individuals (P < 0.001). Placental GH levels at second examination were found to be higher in women carrying female fetuses [median, 9.0 ng/ml; 95% confidence interval (CI), 4.7-23.0] compared with women carrying male fetuses (median, 8.2 ng/ml; 95% CI, 3.96-19.4; P = 0.004). Similarly, the increase in placental GH between 19 and 28 wk gestation was significantly larger in female fetus bearers than in male fetus bearers (P = 0.002). Placental GH at second examination was positively correlated with gestational age (P = 0.002) and negatively correlated with prepregnancy BMI (P = 0.039). Placental GH correlated with fetal weight at approximately 28 wk gestation (P = 0.002) but did not predict birth weight at term. Our study supports the role of maternal placental GH in the regulation of fetal growth. In conclusion, we found that 1) placental GH levels correlated significantly with fetal size at 28 wk gestation; 2) GH levels were measurable in serum from all women as early as 14 wk gestation; 3) maternal prepregnancy BMI and smoking were determinants of placental GH levels, although their specific effects on the serum maternal levels of placental GH remain to be seen; and 4) women carrying female fetuses have significantly higher placental GH levels compared with women carrying male fetuses at 28 wk gestation.     

Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition

Plasma CRH was measured in maternal plasma throughout the third trimester of pregnancy, during labor, and postpartum. CRH levels were also measured in arterial and venous umbilical cord plasma samples. In normal pregnant women, plasma CRH increased from 50 +/- 15 (+/- SEM) pg/mL at 28 weeks gestation (n = 41) to 1462 +/- 182 pg/mL at 40 weeks (n = 55) and 1680 +/- 101 pg/mL (n = 65) in labor. Women with pregnancy-induced hypertension (n = 49) had plasma CRH levels significantly elevated above this normal range. Similarly, women who subsequently went into premature labor had raised levels several weeks before the onset of labor. After delivery, plasma CRH returned to normal within 15 h. Total plasma cortisol levels varied little throughout the third trimester, but increased during labor and remained elevated 2-3 days postpartum. There was, therefore, no correlation between plasma cortisol and CRH, implying that this placental CRH is not primarily involved in the control of the maternal hypothalamo-pituitary adrenal axis during pregnancy. The concentrations of CRH in umbilical cord plasma samples were considerably lower than those in the maternal circulation and were close to those in normal nonpregnant adults.     

Serum cortisol binding capacity and cortisol concentration in the pregnant baboon and its fetus during gestation.

The cortisol binding capacity of serum from 11 pregnant baboons (38 samples) and from 7 baboon fetuses delivered prematurely or at term was measured after removal of endogenous steroids. Values for maternal serum collected between 60 and 120 days after mating (59.0 +/- 6.4 mug/100 ml, mean +/- SD) were greater than those for serum collected at term (42.3 +/- 4.9 mug/100 ml). The cortisol-binding capacity of fetal serum collected between 100 and 132 days' gestation was similar to that of the corresponding maternal sample, but at term was only 50% of the maternal value. The rate of clearance of cortisol from both fetal and maternal serum may therefore increase progressively during the last trimester of pregnancy. This effect is likely to be more marked in the fetus. The cortisol binding capacity of 15 serum samples from 9 non-pregnant baboons was 33.4 +/- 5.5 mug/100 ml. Mestranol2 (administered 200 mug/day im for 15 days) significantly increased the serum cortisol binding capacity. The concentration of cortisol in maternal serum from 7 pregnant baboons (10 samples) was 44.0 +/- 8.4 mug/100 ml and was independent of the state of gestation. In fetal serum the cortisol concentration was 4 mug/100 ml before 168 days' gestation and reached 49 mug/100 ml after normal delivery at term. These findings suggest that the mechanisms for production of cortisol by the fetus mature as gestation progresses. The physiological significance of the marked difference between the cortisol concentration and the cortisol binding capacity of fetal serum awaits elucidation.     

Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia

To evaluate whether angiogenic factor levels correlate with preeclampsia-related adverse maternal and perinatal outcomes in women with twin pregnancy, we studied 79 women with suspected preeclampsia in the 3rd trimester. Antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and proangiogenic placental growth factor (PlGF) were measured at presentation on an automated platform. An adverse outcome was defined as hemolysis, elevated liver enzymes, and low platelets syndrome; disseminated intravascular coagulation; abruption; pulmonary edema; cerebral hemorrhage; maternal, fetal, and neonatal death; eclampsia; acute renal failure; small for gestational age; and indicated delivery. All outcomes were ascertained 2 weeks after initial evaluation. Comparing the 52 women (65.8%) who experienced an adverse outcome with the 27 women (34.2%) without an adverse outcome, the median sFlt-1 was elevated (11461.5 pg/mL [8794.0-14847.5] versus 7495.0 pg/mL [3498.0-10482.0; P=0.0004]), PlGF was reduced (162.5 pg/mL [98.0-226.5] versus 224.0 pg/mL [156.0-449.0]; P=0.005), and sFlt-1/PlGF ratio was elevated (74.2 [43.5-110.5] versus 36.2 [7.1-71.3]; P=0.0005). Among those presenting <34 weeks (n=40), the difference in sFlt-1/PlGF ratio was more striking (97.7 [76.6-178.1] versus 31.7 [6.5-48.7]; P=0.001). Addition of sFlt-1/PlGF to the highest systolic blood pressure and proteinuria improved prediction of adverse outcomes. We conclude that in women with twin pregnancy and suspected preeclampsia, the sFlt-1/PlGF ratio at the time of initial evaluation is associated with subsequent adverse maternal and perinatal outcomes. These findings are similar to those in singleton pregnancies and may implicate common pathogenic pathways.     

妊娠期糖尿病对双胎妊娠母婴围产结局的影响

目的:探讨妊娠期糖尿病（GDM）对双胎妊娠母婴围产结局的影响。方法:对2013年1月至2019年10月在北京市海淀区妇幼保健院住院分娩的772例双绒毛膜性双胎妊娠孕妇进行回顾性研究,收集孕妇基本信息和母婴围产结局数据（包括年龄、孕产次、孕周、受孕方式、分娩方式）及孕产妇及新生儿并发症等。所有研究对象于孕24~28周行口...     

Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia

Concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) increase in maternal blood with the approach of clinical preeclampsia. Although alterations in these circulating antiangiogenic factors herald the signs and symptoms of preeclampsia, in vitro studies suggest they may also play a role in regulating early placental cytotrophoblast functions. Early pregnancy changes in sFlt1 and sEng may thus identify women destined to develop preeclampsia. We performed a nested case-control study of 39 women who developed preeclampsia and 147 contemporaneous normotensive controls each with serum collected in the first (11 to 13 weeks of gestation) and second (17 to 20 weeks) trimesters. Whereas levels of sFlt1 and sEng at 11 to 13 weeks were similar between cases and controls (sFlt1: 3.5+/-0.3 ng/mL versus 3.0+/-0.1, P=0.14; sEng 6.9+/-0.3 ng/mL versus 6.6+/-0.2, P=0.37, respectively), at 17 to 20 weeks both were elevated in the women destined to develop preeclampsia (sFlt1: 4.1+/-0.5 ng/mL versus 3.1+/-0.1, P<0.05; sEng, 6.4+/-0.4 ng/mL versus 5.2+/-0.1, P<0.01). Women who developed preterm (<37 weeks) preeclampsia demonstrated even greater sequential changes: difference [delta{d}] between second and first trimester levels: dsFlt1, 0.63+/-0.91 ng/mL in preterm PE versus 0.05+/-0.15 in controls; dsEng, 0.73+/-0.77 ng/mL versus -1.32+/-0.18, P<0.01. Similar findings were noted in a cross-sectional analysis of specimens collected from the Calcium for Preeclampsia Prevention Study. In conclusion, sequential changes in antiangiogenic factors during early pregnancy may be useful for predicting preterm preeclampsia.     

Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery

We previously reported that immunoreactive corticotropin-releasing hormone (CRH) is present in human placenta and third trimester maternal plasma, and that such material is very similar to rat CRH and the predicted structure of human CRH. We suggested that maternal plasma immunoreactive CRH may be of placental origin. To further investigate this possibility, we measured plasma immunoreactive CRH in women during pregnancy, labor, and delivery and 1 and 2 h postpartum, and in nonpregnant women. Umbilical cord plasma and placental CRH concentrations were also measured. In the first trimester of pregnancy, the mean maternal plasma level was 5.9 +/- 1.0 pg (+/- SEM)/ml (n = 24), not significantly different from that in 10 nonpregnant women (5.8 +/- 0.8 pg/ml). Plasma CRH concentrations progressively increased during pregnancy (second trimester, 35.4 +/- 5.9 pg/ml (n = 39); early third trimester (28-34 weeks), 263 +/- 41 pg/ml (n = 14); late third trimester (35-40 weeks), 800 +/- 163 pg/ml (n = 20)]. There was a significant correlation between maternal plasma CRH levels and weeks of pregnancy. Plasma CRH concentrations were further elevated (2215 +/- 329 pg/ml; n = 9). During early labor, peaked at delivery (4409 +/- 591 pg/ml; n = 28), and declined rapidly after delivery [1 h postpartum, 1042 +/- (353 pg/ml (n = 13); 2 h postpartum, 346 +/- 91 pg/ml (n = 13)]. There was a significant correlation (r = 0.562; P less than 0.01) between matched maternal plasma and placental CRH concentrations. The mean umbilical cord plasma CRH level (50.6 +/- 6.1 pg/ml; n = 28) was much lower than that in the mother at the time of delivery. Umbilical venous plasma CRH levels were significantly greater than those in simultaneously obtained umbilical arterial plasma (70.8 +/- 11.3 and 41.8 +/- 4.9 pg/ml, respectively; n = 11). There was a significant correlation (r = 0.384; P less than 0.05) between maternal and fetal CRH concentrations. Gel filtration of plasma obtained from women during the third trimester, at delivery, and early postpartum and placental extracts revealed two major peaks of immunoreactive CRH: a high mol wt peak and one at the elution position of rat CRH. In contrast, only rat CRH-sized material was detected in plasma from nonpregnant women and umbilical cord plasma. Maternal plasma immunoreactive CRH-sized material stimulated ACTH release from anterior pituitary tissue in a dose-dependent manner and was equipotent with rat CRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy

Serum melatonin concentrations were studied in normal pregnant women and in women with several types of pathologic pregnancies, e.g., twins, preeclampsia or intrauterine growth retardation (IUGR). Blood samples were collected from the maternal antecubital vein at 14:00 hr (daytime) and 02:00 hr (nighttime) during pregnancy, and also from the umbilical vein and artery immediately after delivery. Serum melatonin concentrations were measured by radioimmunoassay. Daytime serum melatonin levels in normal (single fetus; singleton) pregnancies were low. While the levels showed an increasing tendency toward the end of pregnancy, no statistically significant changes occurred. On the other hand, the nighttime serum melatonin levels increased after 24 weeks of gestation, with significantly (P < 0.01) high levels after 32 weeks; these values decreased to non-pregnant levels on the 2nd day of puerperium. Nighttime serum melatonin levels were significantly (P < 0.05) higher in twin pregnancies after 28 weeks of gestation than in singleton pregnancies, whereas the patients with severe preeclampsia showed significantly (P < 0.05) lower serum melatonin levels than the mild preeclampsia or the normal pregnant women after 32 weeks of gestation. Melatonin concentrations in umbilical vessels showed a higher tendency in neonates who were born during at night compared with the other neonates; moreover, those in the umbilical artery were generally higher than those in the umbilical vein. The present results indicate that in humans, the maternal serum melatonin levels show a diurnal rhythm, which increases until the end of pregnancy, reflecting some pathologic states of the feto-placental unit. Fetuses may produce melatonin with a circadian rhythm.     

Growth hormone (GH) replacement therapy in GH-deficient women during pregnancy

OBJECTIVE: The present recommendation is to discontinue GH replacement therapy in hypopituitary women, as they become pregnant. We report our experience of managing GH deficiency with GH replacement therapy in pregnant hypopituitary women. PATIENTS AND MEASUREMENTS: Eight hypopituitary women, median age 30.5 years (range 20-39 years), were followed prospectively during 12 distinct pregnancies. Six women were receiving replacement therapy for other pituitary hormone deficiencies and five pregnancies were achieved with ovulation induction therapy. GH replacement therapy was maintained at the same pregestational dose during the first trimester, with a gradual decrease of the dose during the second trimester and discontinuing the treatment at the beginning of the third trimester. Serum IGF-1 levels were measured in four selected pregnancies at three different points, one in each trimester of gestation. RESULTS: Seven pregnancies resulted in normal vaginal deliveries and five had programmed Caesarian sections. The median gestation age at time of delivery was 40 weeks (range 33-42 weeks). Newborns had a median birthweight SD score of -0.37 (range -1.93 to 1.21) and a median birthlength SD score of 0.07 (range -2.73 to 1.53). No congenital malformations were observed. Three women were able to breastfeed their babies. Before gestation, the median daily dose of GH was 0.5 mg (range 0.3-0.8 mg) and the median serum IGF-1 was 37.5 nmol/l (range 7.6-54.5 nmol/l). IGF-1 levels were fairly constant in the first and second trimesters of gestation, showing an increment during the last trimester, when GH treatment was discontinued. CONCLUSION: The GH replacement regimen presented for pregnant women with GH deficiency was safe. No major side-effects and no negative influences on maternal and fetal outcome were observed.     

Maternal wave reflections and arterial stiffness in normal pregnancy as assessed by applanation tonometry

Normal pregnancy is associated with profound alterations in the maternal cardiovascular system. The aim of the present study was to assess noninvasively, using applanation tonometry, the maternal central aortic blood pressures (BP), effects of wave reflection and arterial stiffness (aortic and brachial pulse wave velocity) in normal pregnancy. This was a cross sectional study including 193 women with normal singleton pregnancies at 11 to 41 weeks of gestation and 23 nonpregnant controls, matched for age and height. Compared to nonpregnant controls, pregnant women had lower mean arterial pressure (85+/-8.9 mm Hg versus 81.1+/-7.2 mm Hg; P=0.01), central systolic BP (103+/-11 mm Hg versus 96+/-8 mm Hg, P=0.001), central diastolic BP (71+/-9 mm Hg versus 67+/-7 mm Hg, P=0.008), and augmentation index (AIx) (19+/-11% versus 4+/-12%, P<0.001). The AIx changed significantly with gestation reaching its nadir at midpregnancy (R(2)=0.05, P=0.007). This change was present even after adjusting for maternal age (P<0.001), heart rate (P<0.001), and mean arterial BP (P<0.001); known determinants of AIx. The pulse wave velocity (carotid-radial and carotid-femoral) did not change significantly with gestation and was marginally different between pregnant and nonpregnant women (P=0.03 and P=0.05 for carotid-radial and carotid-femoral respectively). However, adjustments for maternal age and mean arterial pressure rendered these differences nonsignificant (P=0.2 for carotid-radial, P=0.5 for carotid-femoral). In summary, we found that normal pregnancy is associated with a reduction in central BP and wave reflection.     

DIURNAL SALIVARY CORTISOL PATTERNS DURING PREGNANCY AND AFTER DELIVERY: RELATIONSHIP TO PLASMA CORTICOTROPHIN-RELEASING-HORMONE

The circadian rhythm of salivary cortisol was studied in 10 healthy women every 4 weeks throughout pregnancy. In addition, in 12 women the diurnal patterns of salivary cortisol, serum cortisol, plasma ACTH, plasma CRH and serum progesterone were analysed in late third trimester pregnancy and again 3-5 days after delivery. Salivary cortisol profiles exhibited a clear circadian rhythm during pregnancy with an increase in mean salivary cortisol from the 25th to 28th week onwards reaching concentrations in late pregnancy more than twice as high as in non-pregnant controls, rapidly returning to normal concentrations after delivery. The coefficient of variation of salivary cortisol profiles decreased in third trimester pregnancy due to a parallel upward shift of cortisol concentrations (40.2 +/- 3.4% vs 77.6 +/- 6.6% after delivery, P less than 0.01). A diurnal pattern was also found for plasma ACTH and serum cortisol before and after delivery with lower concentrations post-partum (P less than 0.01). In late pregnancy, progesterone concentrations were significantly higher in the evening (930 +/- 85 nmol/l vs 813 +/- 74 nmol/l at 0900 h, P less than 0.01) but showed no diurnal variation post-partum. Plasma CRH was significantly elevated in late third trimester pregnancy (1.22 +/- 0.23 micrograms/l at 0900 h) but showed no diurnal change (1.30 +/- 0.28 micrograms/l at 1900 h). Moreover, no correlation between the free cortisol increase in late pregnancy and plasma CRH was noted despite a wide range of CRH levels (0.13-3.60 micrograms/l). In contrast, a significant correlation was observed between the serum progesterone increase and the salivary cortisol increase in late pregnancy (r = 0.70, P less than 0.05). These findings demonstrate that placental CRH is not the only regulator of maternal ACTH and cortisol release. Instead, our study suggests that placental CRH has little influence on baseline maternal adrenocortical function in pregnancy. The elevated salivary cortisol levels in pregnancy may be explained by glucocorticoid resistance owing to the antiglucocorticoid action of high progesterone concentrations.     

Alterations in circulating human chorionic gonadotropin free alpha-subunit in insulin-dependent diabetic pregnancy: correlation with maternal characteristics.

Circulating concentrations of hCG free alpha-subunit (alpha hCG) increase throughout pregnancy. To address the hypothesis that maternal plasma alpha hCG may reflect placental dysfunction and/or adverse perinatal outcome during insulin-dependent diabetic pregnancy, alpha hCG was measured serially throughout gestation, beginning before week 12, with a specific RIA using a monoclonal antibody in 54 insulin-dependent diabetic (randomly assigned to strict and customary glycemic control) and 25 nondiabetic pregnancies. alpha hCG was significantly lower in pregnant insulin-dependent diabetic subjects than in nondiabetics subjects until 24 weeks gestation, after which it was higher until delivery. Plasma alpha hCG stabilized in nondiabetics at 32 weeks, whereas it continued to increase in diabetics until delivery, at which time it was 37% greater than that in nondiabetics (mean +/- SE, 1441 +/- 90 vs. 1052 +/- 78 micrograms/L; P less than 0.002). Values in diabetic subjects assigned to strict control were intermediate between those in diabetic subjects assigned to customary control and nondiabetic subjects. alpha hCG was greater in diabetic subjects with pregestational hypertension or microvascular disease, but not in those with pregnancy-induced hypertension. These findings were independent of the assigned goals of glycemic control. alpha hCG was not correlated with the duration of diabetes or related to premature delivery, fetal distress, birth asphyxia, or macrosomia. Thus, alpha hCG is increased during the third trimester of the type I diabetic pregnancy and is associated with preexisting hypertension and maternal microangiopathy, but is not a predictor of adverse perinatal outcome. Excessive alpha hCG secretion in diabetes may share pathophysiological mechanisms in common with those underlying diabetic microangiopathy.     

High concentrations of plasma immunoreactive inhibin during normal pregnancy in women

The plasma inhibin concentrations in 190 normal pregnant women at 5-40 weeks gestation and in 4 puerperal women were measured by a specific RIA for human inhibin. The average plasma inhibin concentrations in pregnant women throughout pregnancy (minimum, 2.25 +/- 0.48 IU/mL at 17 weeks gestation; maximum, 24.15 +/- 6.99 IU/mL at 39 weeks gestation) were much higher than those in nonpregnant women with a normal menstrual cycle (0.46 +/- 0.04 IU/mL in the midfollicular phase and 2.02 +/- 0.47 IU/mL in the midluteal phase). The inhibin concentrations were already high at 5 weeks gestation (7.54 +/- 1.10 IU/mL) and rose to peak at 8-10 weeks gestation. The concentrations then decreased and remained relatively low during 14-30 weeks gestation, but rose again during the third trimester. The inhibin concentrations decreased to undetectable levels after delivery. Immunoreactive inhibin was demonstrated in the corpus luteum and term placental extracts, and the dose-response curves were parallel to an inhibin preparation from human follicular fluid. Immunoreactive inhibin concentrations were also high in both the umbilical vein and artery (7.77 +/- 0.80 and 7.84 +/- 0.78 IU/mL, respectively). These observations suggest that both the corpus luteum and placenta are likely sources of inhibin.     

A longitudinal study of intrauterine growth and the placental growth hormone (GH)-insulin-like growth factor I axis in maternal circulation: association between placental GH and fetal growth

The aim of the study was 1) to evaluate the association of maternal serum levels of placental GH and IGF-I with fetal growth, and 2) to establish reference data for placental GH, IGF-I, and IGF-binding protein-3 (IGFBP-3) in normal pregnancies based on longitudinal measurements. A prospective longitudinal study of 89 normal pregnant women was conducted. The women had, on the average, seven blood samples taken and three ultrasound examinations performed. All had normal umbilical artery pulsatility indexes during pregnancy and gave birth to singletons between 37 and 42 wk gestation with birth weights above -2 SD. Placental GH levels were detectable in all samples from as early as 5 wk gestation and increased significantly throughout pregnancy to approximately 37 wk when peak levels of 22 ng/ml (range, 4.64-69.22 ng/ml) were reached. Subsequently, placental GH levels decreased until birth. The change in placental GH during 24.5-37.5 wk gestation was positively associated with fetal growth rate (P = 0.027) and birth weight (P = 0.027). Gestational age at peak placental GH values (P = 0.007) was associated with pregnancy length. A positive association between the change in placental GH and the change in IGF-I levels throughout gestation was found in a multivariate analysis (r(2) = 0.42; P < 0.001). There was no association between placental GH and IGFBP-3 levels. The change in IGF-I throughout gestation (P = 0.039), but not placental GH, was significantly positively associated with placental weight at birth. We found a significant association between placental GH and fetal growth. In addition, we found a highly significant association between the increase in placental GH and the increase in IGF-I. The gestational age at peak placental GH levels was associated with pregnancy length.     

Expression of pro-EPIL peptides encoded by the insulin-like 4 (INSL4) gene in chromosomally abnormal pregnancies

The recent development of a specific immunoassay based on monoclonal antibodies directed to chain C and chain A of early placenta insulin-like peptide (EPIL) encoded by the INSL4 gene, has made it possible to demonstrate pro-EPIL peptide expression during normal pregnancy. In the present study, we report on the expression of pro-EPIL peptides in chromosomally abnormal pregnancies, namely trisomy 21 and 18. EPIL peptide levels were measured in amniotic fluid (AF) and maternal serum (MS) from pregnancies with trisomy 21 (n=16) or 18 (n=14) and compared to levels detected in AF and MS from 33 chromosomally normal pregnancies between 12 and 32 weeks of gestation. Pro-EPIL peptide levels were significantly higher in amniotic fluids from T21 than in AF from chromosomally normal pregnancies (mean pro-EPIL levels +/- SEM, 449+/-129.2 ng/mL vs 137+/-29.6 ng/mL, P = 0.0195), whereas there was only a trend towards an increase in pro-EPIL peptide levels in maternal serum. In a limited matched gestational age range (15 to 17 weeks), it was confirmed that pro-EPIL peptide levels were significantly higher in AF from T21 pregnancies (644.0+/-155.9 ng/mL, n = 11) than in AF from normal pregnancies (177.8+/-39.0 ng/mL, n = 12; P < 0.0001). Interestingly, the expression patterns of pro-EPIL peptides, human chorionic gonadotropin (hCG) and its free subunits were parallel in T21 pregnancies as recently observed in normal pregnancies. These results are in line with previous observations suggesting that the biosynthesis of both hCG and EPIL follows common regulation pathways.     

Ghrelin and its relationship to growth hormones during normal pregnancy

OBJECTIVE: Ghrelin and GH secretagogue receptors have been found in reproductive organs, including the placenta. The physiology of ghrelin in pregnancy has not been explored. In human pregnancy, pituitary GH is gradually replaced by placental GH (PGH). The present study was undertaken to examine serum ghrelin levels during normal pregnancy and to determine to what extent changes in ghrelin levels coincide with changes in serum levels of free and total GH and PGH. Design Prospective study with blood sampling from pregnant women in gestational weeks 8, 18, 26 and 36 and postpartum. PATIENTS: Eleven nondiabetic pregnant women with singleton pregnancies. MEASUREMENTS: Serum ghrelin was determined using an in-house radioimmunoassay. Serum PGH was determined in a solid-phase immunoradiometric assay, serum GH and insulin in a time-resolved immunofluorometric assay, and serum GHBP in an in-house immunofunctional assay. RESULTS: Serum ghrelin levels peaked in week 18 (1.20 +/- 0.09 microg/l) and the lowest levels were observed in late third trimester (0.87 +/- 0.06 microg/l), corresponding to a mean decrease of 27.7% (P < 0.001) from peak levels. An increase was observed again postpartum. Serum GH diminished throughout pregnancy to low third-trimester values (0.12 +/- 0.03 microg/l; P < 0.001), and PGH increased to 25.7 +/- 2.86 microg/l (P < 0.001) in week 36. Neither total nor calculated free levels of growth hormones correlated to ghrelin levels, and no significant correlations were observed between ghrelin and maternal body mass index (BMI) or fasting insulin levels. CONCLUSIONS: Serum ghrelin levels peak around mid-gestation in human pregnancy. Ghrelin levels during pregnancy are at their lowest in the third trimester at a time of increased body weight, development of insulin resistance and high serum levels of PGH. However, no associations were observed between ghrelin and the two growth hormones.     

11 Beta-hydroxylase deficiency congenital adrenal hyperplasia: update of prenatal diagnosis

Hormonal measurements in maternal urine and amniotic fluid (AF) during pregnancy and/or at delivery correctly predicted the postnatal diagnosis of 11 beta-hydroxylase deficiency congenital adrenal hyperplasia (11 beta-OH deficiency CAH) in 7 fetuses at risk. In the 4 affected ones, maternal urinary tetrahydro-11-deoxycortisol (THS) excretion was high during the first trimester [0.3-2.2 mg/day (1.1-7.7 mumol/day)] and rose further during the third trimester [0.5-3.5 mg/day (1.8-12.3 mumol/day)] compared to urinary THS excretion in 20 normal pregnancies of the same gestational age (P less than 0.01). In 1 mother, dexamethasone administration (2 mg/day for 72 h) greatly reduced urinary THS excretion (and plasma steroid levels). Urinary THS excretion was low after delivery in these mothers, in normal pregnancies, and in parents of affected individuals [less than 0.05 mg/day (less than 0.08 mumol/day); P = NS]. However, 2 of the 3 heterozygous mothers who carried nonaffected fetuses excreted moderately increased amounts of THS during pregnancy, ranging from 0.15-0.26 mg/day (0.53-0.91 mumol/day), significantly higher than normal (P less than 0.01). Although urinary THS excretion in these mothers was similar to that in 2 mothers with affected fetuses early in pregnancy, urinary THS excretion was higher in mothers with affected compared to those with nonaffected fetuses after the first trimester (P less than 0.01). AF THS and 11-deoxycortisol concentrations were markedly elevated in pregnancies with affected fetuses (P less than 0.01), but normal in nonaffected ones. AF delta 4-androstenedione levels were high in 2 pregnancies and borderline elevated in a third. Although the AF tetrahydrocortisol and tetrahydrocortisone levels were always within the normal range, the AF THS to tetrahydrocortisol plus tetrahydrocortisone ratio was significantly elevated in all pregnancies with affected fetuses (2.8-5.5; P less than 0.01) and normal in nonaffected ones (0.48-1.2; P = NS) compared to that in 160 normal pregnancies [0.64 +/- 0.34 (+/- SD)]. AF 17-hydroxyprogesterone, testosterone, and 11-deoxycorticosterone levels were normal in all pregnancies. Maternal plasma 11-deoxycortisol and delta 4-androstenedione concentrations, determined sequentially throughout gestation, were variable and did not contribute to prenatal diagnosis. All affected infants were born hyperpigmented, 2 were large for gestational age, and the female was severely virilized. In the first week of life 2 males developed severe hypertension with seizures and adrenal insufficiency, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

125I-human epidermal growth factor specific binding to placentas and fetal membranes from various pregnancy states

Specific binding of 125I-human epidermal growth factor (hEGF) to homogenates of term human placentas and fetal membranes from normal and appropriate for gestational age (N = 20), intrauterine growth retarded (N = 9), twin (N = 11), White class A/B diabetic (N = 12), and large for gestational age (N = 13) pregnancies was measured. In all pregnancy states, placentas bound approximately four times more 125I-hEGF than did fetal membranes (P less than 0.001). There was no significant difference in 125I-hEGF binding to fetal membranes from the various pregnancy states (P greater than 0.05). 125I-hEGF specific binding to placentas from intrauterine growth retarded or twin pregnancies was significantly greater compared with placentas from normal and appropriate for gestational age pregnancies (P less than 0.05). The binding to placentas from pregnancies complicated by White class A/B diabetes or large for gestational age infants, on the other hand, was not significantly different from that to placentas from normal and appropriate for gestational age pregnancies. 125I-hEGF specific binding did not differ between placentas from intrauterine growth retarded or twin pregnancies (P greater than 0.05). Placental and fetal membrane 125I-hEGF binding did not vary with fetal sex, maternal race, placental weight, or gestational age between 37 to 42 weeks (P greater than 0.05). Placental but not fetal membrane 125I-hEGF binding increased with increasing infant weight when appropriate for gestational age and large for gestational age infants were included (P less than 0.05, r = 0.38, N = 32) but not for intrauterine growth retarded, appropriate for gestational age, or large for gestational age infants alone.