Maternal plasma corticotrophin-releasing factor and urocortin levels in post-term pregnancies

OBJECTIVE: Corticotrophin-releasing factor (CRF) and urocortin are two placental neuropeptides that are involved in the mechanisms of labour by modulating myometrial activity. Maternal plasma levels of both CRF and urocortin are increased at term and preterm labour, whilst those of CRF are reduced in women who are destined to experience post-term delivery. The present study evaluated maternal plasma levels in term and post-term pregnancies out of labour. DESIGN: A group of healthy pregnant women was enrolled and subdivided as follows: (i) at term out of labour (n = 19; 276 +/- 0.7 days of gestation; samples collected at the time of elective caesarean section due to previous uterine surgery); (ii) post-term (n = 19; 291 +/- 1.4 days of gestation), from whom samples were collected before induction of labour. METHODS: Urocortin and CRF measurements by radioimmunoassay; digital palpatory cervical examination and Bishop score computation; cervical length and funnelling presence assessment by transvaginal ultrasonography. RESULTS: Maternal plasma CRF concentrations were significantly (P < 0.05) lower whilst those of urocortin were unchanged in post-term compared with term pregnancy. However, CRF and urocortin levels were both significantly (P < 0.05 and P < 0.001 respectively) higher in pregnancies delivered within 12 h of labour induction than in those that remained undelivered, and were significantly correlated with the induction-delivery interval (CRF: r = -0.676, P = 0.0015; urocortin: r = -0.783, P < 0.0001). CONCLUSIONS: CRF and urocortin levels are decreased and unchanged, respectively, in post-term pregnancy when compared with term pregnancy. Both CRF and urocortin correlate with the time of labour onset after induction. Since CRF derives from the placenta, and urocortin from the fetus, the concerted expression of these neuropeptides appears to be relevant in determining the length of human gestation.     

Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor

BACKGROUND & AIMS: Hepatitis A virus (HAV) infection is the most common cause of acute hepatitis but is rarely reported during pregnancy. Our aim was to evaluate the impact of acute HAV infection on pregnancy outcome. METHODS: Consecutive admissions of 79,458 pregnant females during a 25-year period were retrospectively reviewed. RESULTS: Thirteen cases of second and third trimester HAV infection were found and evaluated. Nine of the 13 patients (69%) developed gestational complications, including premature contractions (n = 4), placental separation (n = 2), premature rupture of membranes (n = 2), and vaginal bleeding (n = 1). In 8 of these patients, complications led to preterm labor, at a median of 34 gestational weeks (range, 31-37 weeks). Delivery was vaginal in 12 of the 13 cases; fetal distress was noted in a single case, and meconium in amniotic fluid in 2 cases. Median birth weight was 1778 grams and 3040 grams in preterm and term deliveries, respectively (P < .05). Child outcome was favorable in all cases. In 4 cases, neonatal serum HAV RNA levels were measured and found negative. The presence of fever and hypoalbuminemia were associated with delivery at an earlier gestational week. There was a positive relation between gestational week at diagnosis of HAV infection and birth week (r = 0.68, P = .02), suggesting a causality relationship. All mothers featured full recovery from HAV infection. CONCLUSIONS: Acute HAV infection during pregnancy is associated with high risk of maternal complications and preterm labor. HAV serology and maternal vaccination during prepregnancy evaluation should be considered in areas of the world in which susceptible adult populations exist.     

Prediction of preterm delivery based on maternal plasma urocortin

CONTEXT: Preterm birth still remains a significant management problem, and a large number of markers of the disease have been investigated. OBJECTIVE: We measured plasma levels of urocortin, a neuropeptide expressed by gestational tissues, in women with threatened preterm labor (TPTL) to evaluate whether the measurement may predict preterm delivery (PTD). DESIGN: We studied patients as part of an open observational study. SETTING: The study was conducted at a tertiary referral center for obstetric care. PATIENTS: Eighty-five women with singleton pregnancies between 28 and 34 completed gestational weeks with TPTL participated in the study. INTERVENTIONS: Interventions included clinical examination and urocortin measurement. MAIN OUTCOME MEASURES: Pregnancy outcome and evaluation of sensitivity, specificity, and predictive values of urocortin as diagnostic test for PTD were measured. RESULTS: Thirty of 85 patients (35.3%) had PTD: 23 of 30 delivered within 7 d from admission (delivery time interval: 2.91 +/- 1.62 d; gestational weeks at delivery: 32.12 +/- 1.7); the remaining delivered later (delivery time interval: 11.71 +/- 4.27 d; gestational weeks at delivery: 33.5 +/- 2.18). Urocortin was significantly higher in women who delivered preterm (median 131.2 pg/ml, interquartile interval 115.1-139.4 pg/ml) than in those who progressed to term delivery [95.4 (69.9-101.3) pg/ml, P < 0.0001] and still higher in those delivering within 7 d from admission [137.7 (124.8-141.2) pg/ml]. Receiver operating characteristic curve analysis revealed that urocortin at the cutoff of 113.9 pg/ml had sensitivity of 80%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 90% as a marker for PTD. CONCLUSIONS: Maternal plasma urocortin concentration is increased in patients with TPTL who have PTD, and its measurement may be a promising new biochemical marker of PTD.     

Physiological induction of transient receptor potential canonical proteins, calcium entry channels, in human myometrium: influence of pregnancy, labor, and interleukin-1 beta

This study investigated gestational regulation of transient receptor potential canonical (TrpC) proteins, putative calcium entry channels in human myometrium, and the potential modulation of TrpC expression by IL-1 beta, a cytokine implicated in labor. Total RNA and proteins were isolated from myometrial biopsies obtained from NP women, pregnant women at term not in labor (TNL), or term active labor (TAL) and from primary cultured human myometrial smooth muscle cells incubated with IL-1 beta or IL-1 beta with or without nimesulide. Semiquantitative RT-PCR demonstrated significant up-regulation of TrpC1 in TAL and TNL (P < or = 0.01) and TrpC6 (P < or = 0.01) and TrpC7 (P < or = 0.05) in TAL samples. TrpC3 and TrpC4 mRNA expression was unaffected. Western blot demonstrated significant up-regulation of TrpC1 in TAL and TNL (P < or = 0.05) and TrpC3 (P < or = 0.01), TrpC4 (P < or = 0.05), and TrpC6 (P < or = 0.01) in TAL samples. IL-1 beta did not alter TrpC1, 3, 4, 6, or 7 mRNA expression; but IL-1 beta exclusively up-regulated TrpC3 protein expression (P < or = 0.05). TrpC3 up-regulation was unaffected by cyclooxygenase blockade. These data demonstrate physiological regulation of TrpC mRNA and protein and suggest an important role for TrpC proteins in human myometrium during labor.     

Circulating ghrelin levels in the newborn are positively associated with gestational age

OBJECTIVE: Ghrelin exerts potent GH-releasing activity and stimulates food intake. Circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity and restored by weight recovery. Newborns are characterized by GH hypersecretion associated with low IGF-I levels reflecting peripheral GH resistance. STUDY DESIGN: The aim of our study was to measure cord ghrelin levels in 117 newborns appropriate for gestational age, born either at term or preterm. RESULTS: Ghrelin levels in cord blood (median; 25th-75th centile: 327.6; 206.0-413.0 pg/ml) were higher (P < 0.0001) than those in maternal blood at delivery (133.0; 89.0-173.7 pg/ml), without gender differences. A positive correlation between ghrelin levels in mothers and newborns (r = 0.26, P < 0.01) was observed. Ghrelin levels in newborns born at term (399.0; 229.0-438.0 pg/ml) were remarkably higher (P < 0.0001) than those in born preterm (208.0; 144.5-278.9 pg/ml). A clear positive association was present between ghrelin levels and gestational age. No association between ghrelin and GH, IGF-I, insulin, glucose and leptin levels were found. CONCLUSIONS: Cord ghrelin levels show clear gestational age-related dependency. The lack of any direct relationship between ghrelin and anthropometric or biochemical parameters in adequate for gestational age newborns does not support the hypothesis that ghrelin has major role in foetal GH secretion and growth.     

Time-course of leptin levels in term and preterm human milk

OBJECTIVE: To compare the time-course of breast milk leptin levels between term and preterm pregnancy. DESIGN: Open longitudinal prospective randomised study. METHODS: RIA of leptin levels in milk from 33 mothers (term pregnancy: n=24; preterm: n=9) at three postpartum intervals: 2-3 days, 4-5 days and 6 weeks (intervals A, B and C), combined with serum in 23 mothers (term: n=17; preterm: n=6) in interval A. Milk samples were sonicated before incubation. RESULTS: Interval A leptin levels were approximately tenfold higher in serum than in milk (term: 13.24+/-2.48 vs 1.34+/-0.14 ng/ml, P<0.0001; preterm: 4.46+/-1.05 vs 0.63+/-0.18 ng/ml, P<0.0005), and higher in term than in preterm serum (P=0.03). Milk levels were higher in the term vs preterm group in intervals A (P<0.01) and B (P<0.05). In the term group they declined significantly from interval A to interval B (P<0.05) but did not vary significantly in the preterm group. Serum levels correlated with maternal body mass index; milk levels showed only moderate correlation with maternal and infant weight or body mass index. CONCLUSION: The reasons for the presence and differential longitudinal expression of leptin in human milk after term and preterm pregnancy remain unknown. A hypothesis, requiring further study, is that persistently lower leptin levels in preterm milk act as a compensatory release of a brake on neonatal growth.     

Preterm birth: associated neuroendocrine, medical, and behavioral risk factors

Increased CRH secretion by the placenta of pregnant women has been associated with preterm birth. Certain indices of risk, both medical and psychosocial in nature, have been linked to preterm delivery. Levels of total, bound, and free CRH, CRH-binding protein (CRH-BP), and cortisol were measured prospectively in a large sample of pregnant Danish women who delivered preterm and term infants. Measures of maternal serum hormones were taken at 7--23 and 27--37 weeks gestation and, for those who delivered at term, at 37--43 weeks gestation. At 7--23 weeks gestation, maternal levels of total CRH (P = 0.01), bound CRH (P = 0.03), and CRH-BP (P = 0.01) were higher in the preterm than in the term group. At 27--37 weeks gestation, levels of total CRH (P < 0.0001), bound CRH (P < 0.0001), free CRH (P < 0.0001), and cortisol (P < 0.0001) were all higher in the preterm than the term group, whereas levels of CRH-BP (P < 0.0001) were lower in the preterm than in the term group. The best medical and behavioral factors associated with preterm delivery were, respectively, previous preterm delivery (P < 0.0001) and engagement in certain risk-taking behaviors (P = 0.008). The positive relations between preterm delivery and various adverse medical and socioeconomic variables with increases in placental secretion of CRH suggest that the latter may participate in the pathophysiology of preterm delivery.     

Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term

Adiponectin is an adipocyte-derived hormone with profound insulin-sensitizing, antiinflammatory, and antiatherogenic effects. Apart from its obvious potential as a mediator of adult metabolic syndrome, adiponectin could have a significant role in regulating fetal growth.We measured plasma adiponectin concentrations by ELISA in cord vein of 197 infants. Of them, 122 were born preterm (gestational age, 22-32 wk), and 75 at term (49 from a healthy and 26 from a diabetic pregnancy, with similar findings, and thus all data from term infants pooled).Mean adiponectin concentrations increased from less than 1 microg/ml at 24 wk gestation to approximately 20 microg/ml at term. One week increase in gestational age corresponded in preterm infants to 43% increase (95% confidence interval 34-53%; P < 0.0001) in adiponectin and term infants to 21% increase (12-31%; P < 0.0001). In preterm infants, one unit increase in birth weight sd score corresponded to 42% increase (22-66%; P = 0.0001) in adiponectin, and females had 57% higher adiponectin concentrations (0-146%; P = 0.05) than males. These differences were not seen in term infants. Adiponectin levels were lower in preterm infants with recent (<12 h) exposure to maternal betamethasone but were unrelated to mode of delivery, preeclampsia, or impaired umbilical artery flow.In conclusion, adiponectin concentrations in fetal circulation show a 20-fold rise between 24 wk gestation and term and, in preterm infants are associated with birth weight sd score, sex, and glucocorticoid exposure. Adiponectin may play an important role in regulating fetal growth and explaining its links to the metabolic syndrome and its consequences during adult life.     

Quantitative ultrasound for the assessment of osteopenia in preterm infants

OBJECTIVE: To evaluate the potential role of quantitative ultrasound (QUS) investigation in assessing the osteopenia of prematurity. DESIGN: QUS parameters measured at the time of discharge were related to the anthropometric characteristics and age (postnatal and gestational) of 51 (34 female and 17 male) preterm infants fed fortified human milk. METHODS: QUS evaluation was performed at the humerus (h) by measuring two parameters: ultrasound velocity (hSOS, in m/s) and bone transmission time (hBTT, in micros). A group of 43 term infants (29 female and 14 male) was also evaluated. RESULTS: In preterm infants, significant correlations were found for hSOS and hBTT vs gestational age (r=0.504, 0.477, P<0.0001), length (r=0.641, 0.594, P<0.0001) and weight (r=0.580, 0.562, P<0.0001) at birth, and length (r=0.341, 0.332, P<0.05) and weight (r=0.331, r=0.362, P<0.05) at QUS measurement. In preterm infants, both QUS parameters were negatively correlated with age (r=-0.536, P<0.0001, r=-0.443, P<0.001) and were significantly lower than in the term infants (hSOS: 1664+/-42 m/s vs 1734+/-28 m/s, P<0.0001; hBTT: 0.58+/-0.24 micros vs 1.06+/-0.15 micros, P<0.0001) even when adjusted for body length (P<0.05). In preterm infants, hSOS was also negatively correlated with postconceptional age (r=-0.322, P<0.05). CONCLUSIONS: This study suggests that bone mineral accrual is mainly determined by the development in utero, and that prematurity induces a halt in the bone development process in the early postnatal period. QUS parameters are correlated with the severity of prematurity and might therefore have clinical applications when bone maturation in early life needs to be determined.     

Differential expression of myometrial oxytocin receptor and prostaglandin H synthase 2, but not estrogen receptor alpha and heat shock protein 90 messenger ribonucleic acid in the gravid horn and nongravid horn in sheep during betamethasone-induced labor

In the present study, we characterized four myometrial contraction-associated proteins (mCAPs): oxytocin receptor (OTR), prostaglandin H synthase 2 (PGHS2), estrogen receptor alpha (ERalpha), and heat shock protein 90 (Hsp90) messenger RNA (mRNA) expression in the nongravid horn of pregnant sheep and compared them with their expression in the gravid horn that is exposed to a greater degree of stretch. We also examined the regulatory effects of estrogen and progesterone on OTR mRNA expression in ovariectomized nonpregnant sheep. In addition, we determined the ontogeny of mCAP expression in the gravid horn throughout late pregnancy and during spontaneous term labor. Gravid horn and nongravid horn myometria were removed under general anesthesia from control ewes not in labor at 130-140 days gestational age (dGA; n = 3) and during betamethasone-induced labor (n = 6) at the same gestational age. Gravid horn myometrium was also collected from ewes not in labor at 95 dGA (n = 3), 101-110 dGA (n = 3), 111-120 dGA (n = 3), 121-130 dGA (n = 3), 131-140 dGA (n = 3), and 141-145 dGA (n = 4) and from ewes in spontaneous term labor (n = 4). All ewes were carrying single fetuses. Myometrium was also collected from ovariectomized nonpregnant ewes treated with saline (n = 5), estradiol (50 microg/day; n = 5), progesterone (0.3 g, intravaginally; n = 5), and estradiol plus progesterone (n = 5). Myometrial RNA was extracted and analyzed by Northern blot for OTR, PGHS2, ERalpha, and Hsp90 mRNA, normalized for 18S ribosomal RNA or beta-actin. ERalpha, Hsp90, OTR, and PGHS2 mRNA were all significantly up-regulated during betamethasone-induced labor (P < 0.01) in gravid and nongravid horn myometrium. The level of gravid horn OTR mRNA during labor was 3 times the level of nongravid horn OTR mRNA (P < 0.0001). Gravid horn PGHS2 mRNA was also higher than nongravid horn PGHS2 (P < 0.02). In contrast, in spontaneous term labor nongravid horn, ERalpha and Hsp90 mRNA were similar to gravid horn. Myometrial ERalpha and Hsp90 mRNA remained unchanged throughout late pregnancy and increased at spontaneous term labor (P < 0.05). In contrast, myometrial OTR increased around 130 dGA (P < 0.01) and further increased at spontaneous term labor (P < 0.02). Progesterone significantly inhibited myometrial OTR mRNA expression in nonpregnant sheep and estradiol antagonized progesterone's inhibitory effect. Mechanical stretch differentially regulated mCAP mRNA expression in the ovine gravid horn and nongravid horn. Mechanical stretch appears largely responsible for increased OTR mRNA and to a lesser degree PGHS2 mRNA. In addition, endocrine factors may be required for full activation of OTR and PGHS2 mRNA associated with labor. ERalpha and Hsp90 mRNA are not under the control of uterine stretch in keeping with our previous results, indicating that systemic hormones such as estradiol, are prime regulators for these two mCAP mRNA expression during labor.     

Maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) levels in post-term pregnancy: effect of prostaglandin administration

OBJECTIVE: Placental corticotropin-releasing factor (CRF) affects myometrial contractility and the secretion of several uterotonins such as prostaglandins (PGs); however, the activity of CRF is counteracted by CRF-binding protein (CRF-BP). At term and pre-term labor, CRF levels in maternal plasma are highest whereas those of CRF-BP are falling, and the cause of this fall is unknown. Thus, in this study, we investigated the effect of PG administration for labor induction on maternal plasma CRF and CRF-BP concentrations. DESIGN: Maternal plasma CRF and CRF-BP levels were assayed before and after (2 h later) induction of labor by intracervical administration of prostaglandin E(2) (PGE(2)), and at delivery in a group of healthy post-term pregnancies (n=18). Controls were women at term out of labor (n=22), who subsequently progressed to deliver a healthy singleton baby. METHODS: CRF was measured by two-site immunoradiometric assay, and CRF-BP was assayed by radioimmunoassay. RESULTS: Maternal plasma CRF levels were significantly (P<0.0001) lower and CRF-BP significantly (P<0.0005) higher in post-term than in term pregnancies. With respect to induction of labor, 2 mg PGE(2) were sufficient to increase maternal plasma CRF levels at delivery (P<0.005). While 0.5 mg PGE(2) significantly decreased maternal plasma CRF-BP levels at delivery (P<0.001), 2.0 mg PGE(2) significantly reduced CRF-BP concentrations both after 2 h (P<0.05) and at delivery (P<0.0001). CONCLUSIONS: In the light of the well-known stimulation of prostaglandin release by CRF, these data suggest a positive feedback effect of PGE(2) on maternal CRF release during induced labor.     

Plasma concentrations of prostaglandins during late human pregnancy: influence of normal and preterm labor.

Highly sensitive and specific RIA procedures have been used to measure prostaglandin concentrations in the peripheral circulation of late pregnant and parturient women. The concentrations of prostaglandin E (PGE) and prostaglandin F (PGF) in plasma samples assayed within 4 weeks of collection were not significantly different among the groups studied, the levels (mean +/- SEM, picograms per ml) were: late pregnancy (n = 13): PGE, 4.8 +/- 1.0; PGF, 6.2 +/- 0.5; early term labor (n = 5): PGE, 6.8 +/- 1.5; PGF, 7.9 +/- 0.7; late term labor (n = 5): PGE, 5.4 +/- 2.2; PGF, 12.4 +/- 3.5; and preterm labor (n = 7): PGE, 4.4 +/- 0.4; PGF, 6.9 +/- 1.4. The concentration of 13,14-dihydro-15-keto-prostaglandin F (PGFM) in late pregnancy was 59.0 +/- 7.8 pg/ml. During spontaneous term labor, the concentration of PGFM was significantly elevated (P less than 0.01) to 142.8 +/- 32.3 pg/ml in early labor and 282.7 +/- 55.3 pg/ml in late labor. The concentration of PGFM in plasma from patients in preterm labor (62.7 +/- 17.4 pg/ml) was not significantly different from that found during late pregnancy, but was significantly lower than levels found at term during early labor (P less than 0.05). The concentration of PGE increased significantly in frozen plasma samples stored for more than 4 weeks in all groups studied; the concentration of PGF was significantly elevated after storage only in the late pregnancy group (P less than 0.01). The plasma concentration of PGFM in all groups studied was unaffected by storage. It is concluded that measurement of PGFM concentrations is the most reliable method available of monitoring prostaglandins in the peripheral circulation and that great care must be exercised in the assay and interpretation of prostaglandin levels in human plasma.     

Glycogen phosphorylase isoenzyme BB plasma concentration is elevated in pregnancy and preterm preeclampsia

Glycogen phosphorylase is a key enzyme in glycogenolysis. Released with myocardial ischemia, blood concentration of glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pregnancy imposes metabolic stress, and preeclampsia is associated with cardiac complications. However, plasma GPBB concentration during pregnancy is unknown. This study was conducted to determine maternal plasma GPBB concentration in normal pregnancy and in preeclampsia. Plasma samples from 6 groups (n=396) were studied: nonpregnant and pregnant women with normal term delivery, term and preterm preeclampsia, and term and preterm small-for-gestational-age neonates. GPBB concentration was measured with a specific immunoassay. Placental tissues (n=45) obtained from pregnant women with preterm and term preeclampsia, spontaneous preterm delivery, and normal term delivery were analyzed for potential GPBB expression by immunoblotting. Median plasma GPBB concentration was higher in pregnant women than in nonpregnant women (38.7 versus 9.2 ng/mL; P<0.001), which remained significant after adjusting for age, race, and parity. Maternal plasma GPBB concentrations did not change throughout gestation. Cases of preterm (but not term) preeclampsia had higher median plasma GPBB concentrations than gestational age-matched normal pregnancy cases (72.6 versus 26.0 ng/mL; P=0.001). Small-for-gestational-age neonates did not affect plasma GPBB concentration. GPBB was detected in the placenta and was less abundant in preterm preeclampsia than in preterm delivery cases (P<0.01). There is physiological elevation of plasma GPBB concentration during pregnancy; an increase in maternal plasma GPBB is a novel phenotype of preterm preeclampsia. It is strongly suggested that these changes are attributed to GPBB of placental origin.     

Regulation of membrane-associated prostaglandin E2 synthase 1 in pregnant sheep intrauterine tissues by glucocorticoid and estradiol

This study was designed to determine the regulatory effect of glucocorticoid and estradiol on expression of ovine intrauterine membrane-associated prostaglandin E(2) synthase 1 (mPTGES1) in late gestation and at labor. For gestational and labor groups, 16 pregnant ewes from 95-147 d gestational age (dGA) and four pregnant ewes at spontaneous term labor were used. The fetal glucocorticoid group, 14 pregnant ewes at 123-125 dGA with fetuses, was divided into the following groups: after sham adrenalectomy (n = 5), adrenalectomy (n = 4), and adrenalectomy with fetal cortisol replacement to late gestation levels (n = 5). For the maternal glucocorticoid group, nine pregnant ewes were treated with saline (n = 4) and three courses of maternal dexamethasone (n = 5). For the estradiol group, 10 pregnant ewes at 119-121 dGA were treated with sesame oil (n = 5) or estradiol (n = 5) to produce labor levels of estradiol in maternal plasma. Endometrial, myometrial, and placental mRNA and proteins were analyzed by Northern and Western blot and immunocytochemistry for mPTGES1. Data were analyzed by Student's t test and ANOVA. There was a significant increase of placental mPTGES1 in late gestation. Glucocorticoids, given to the mother or fetus, significantly stimulated mPTGES1 in placenta. mPTGES1 was elevated only in the endometrium during spontaneous term labor and after estradiol treatment. The mPTGES1 was localized in the myometrial smooth muscle cells, endometrial stromal cells, and placental trophoblast cells. Our study suggested that increased expression of placental mPTGES1 throughout late gestation might result from the increased fetal and maternal circulating glucocorticoids, whereas elevated maternal plasma estradiol concentration might be responsible for the induced mPTGES1 expression in the endometrium during labor.     

Activin A and activin receptors in gestational tissue from preeclamptic pregnancies

Maternal serum activin A levels are elevated in women with preeclampsia. To explore whether this could be due, at least in part, to increased production by the gestational tissues, we have measured activin A in the serum of women with (n=23) or without preeclampsia (n=62) at 29-40 weeks of gestation and in placenta and fetal membranes from preterm preeclamptic (PT-PE, n=8), term preeclamptic (T-PE, n=10) and healthy term controls (T-C, n=10). We have also explored if there are associated changes in activin receptor Alk2, ActRII and ActRIIB in these tissues. The relative amounts of receptor proteins were measured by densitometry on Western blots and receptors and activin beta(A) subunit localised by immunohistochemistry in PT-PE, T-PE and T-C gestational tissues (n=8-10/group). Maternal serum activin A levels were significantly elevated in women with preeclampsia (multiples of the normal median (MoM)=3.5, P<0.0001, Mann-Whitney U test) compared with healthy women (median MoM=1.0). Compared with control tissues, the activin A content was significantly higher in preeclamptic placentae (P=0.001 and P=0.0005 for PT-PE and T-PE respectively, Mann-Whitney U test), but significantly lower in the amnion (P=0.005 and P=0.014 for PT-PE and T-PE respectively) and choriodecidua (P=0.009 for T-PE). The maternal serum activin A level in women with preeclampsia was significantly correlated with elevated placental production (P=0.01, Pearson's correlation). Receptor Alk2 protein levels were significantly elevated in T-PE placentae (P=0.0006, Mann-Whitney U test), ActRIIB levels were significantly lower in PT-PE placentae (P=0.01) and ActRII levels were significantly lower in PT-PE choriodecidua (P=0.0002) compared with controls. There were no apparent differences in the distribution of the beta(A) subunit and receptors Alk2, ActRII and ActRIIB between control and preeclamptic tissues. These findings suggest that elevated levels of activin A in the maternal circulation in association with preeclampsia are due, at least in part, to increased placental production, and that the regulation of activin synthesis in placenta and fetal membranes is differentially regulated. Further, the differences in activin receptor protein levels between preeclamptic and control placenta and choriodecidua suggest that activin A-induced regulation may be altered in preeclampsia.     

The impact of birth weight and gestational age on blood pressure in adult life: A population-based study of 49-year-old men

The impact of birth weight and gestational age on blood pressure in adult life was studied in a population of 49-year-old men born in 1926–27 who took part in a screening investigation of blood pressure performed in 1975–76 in Göteborg, Sweden. Birth records were traced in 430 subjects and compared with screening records. The adult systolic blood pressure (SBP) was not correlated with birth weight but was inversely correlated with gestational age in the whole study group (r = −0.10, P = .04; n = 430). The correlation between adult blood pressure and gestational age was stronger in preterm subjects, ie, those with a gestational age less than 38 weeks (for SBP, r = −0.46, P = .001 and for diastolic blood pressure [DBP], r = −0.44, P = .01; n = 44), and these correlations were independent of birth weight. There was, however, no correlation between adult blood pressure and gestational age in subjects born at term (between 38 and 41 complete weeks of gestation) or postterm (more than 42 weeks of gestation).The inverse correlation between adult SBP and gestational age was stronger in low-birth-weight subjects (≤ 2500 g; r = −0.86, P < .001; n = 14). After adjustment for birth weight, in this group an increase by 1 week of gestation was associated with a decrease in adult SBP of 7.2 mm Hg (95% CI, 10.1–4.2). In the whole study group, a positive correlation was found between adult blood pressure and adult body mass index (BMI) (r = 0.30, P < .001 for SBP and r = 0.33, P < .001 for DBP). In preterm subjects, however, no such correlation was found, but in subjects born at term or postterm, adult blood pressure was significantly correlated with BMI (for SBP at term, r = 0.34, P < .001 and postterm, r = 0.47, P < .001 and for DBP at term, r = 0.36, P < .001 and postterm, r = 0.30, P < .05).This study indicates that adult blood pressure appears to be related to different variables in different ranges of gestation. In preterm subjects, gestational age appears to have a great impact on adult blood pressure. In subjects born at term or later, however, adult blood pressure was not associated with factors related to birth, but only to the adult BMI.     

The influence of prematurity and low birthweight on transplacental antibody transfer in Sri Lanka.

The influence of gestational age, the neonate's birthweight, and maternal age, weight, height and parity on transplacental antibody transfer was assessed in 141 mothers from Sri Lanka and their neonates. Paired blood samples were collected from the mothers and the umbilical cords of the newborns. The sera separated from these samples were categorized as: preterm but adequate birthweight (< 37 weeks' gestation and birthweight > or = 2500 g); term but low birthweight (> or = 37 weeks' gestation and birthweight < 2500 g); or term and adequate birthweight (> or = 37 weeks' gestation and birthweight > or = 2500 g). Neonatal and maternal sera were assessed, in ELISA, for specific IgG antibodies against measles virus (MeV), herpes simplex virus type-1 (HSV1), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), tetanus toxoid (TT), diphtheria toxoid (DT), and Streptococcus pneumoniae (Pn) and Haemophilus influenzae type-b (Hib) capsular antigens. Placental antibody transfer to certain antibody specificities was significantly lower in preterm neonates than term neonates. Thus the ratios between geometric mean cord antibody levels and geometric mean maternal antibody levels (the antibody-transfer ratios) were lower in preterm sera than term sera, for MeV (1.51 v. 2.03; P = 0.03), HSV1 (1.29 v. 1.76; P = 0.04), VZV (0.96 v. 2.50; P = 0.01), TT (1.13 v. 1.33; P = 0.04), DT (1.03 v. 2.39; P = 0.02), Pn (0.68 v. 0.98; P = 0.01) and Hib (0.58 v. 0.98; P = 0.00). Geometric mean levels of antibody to MeV, VZV, TT, DT and Pn were also significantly lower in preterm neonates than term. Compared with the values for 'adequate-birthweight' sera, low birthweight was independently associated with significantly lower levels of antibody transfer, for MeV (with antibody-transfer ratios of 1.51 v. 2.03; P = 0.02), VZV (0.99 v. 2.50; P = 0.03), TT (1.01 v. 1.33; P = 0.04) and DT (1.16 v. 2.39; P = 0.04) and significantly lower levels of antibodies to MeV, HSV1, VZV, TT, DT and Pn in the neonates. Maternal age, weight, height and parity had no independent influence on placental IgG transfer for antibodies to any of the pathogens investigated. These results demonstrate that prematurity and low birthweight may influence the level of maternally acquired immunity in Sri Lankan neonates.     

CRH acts on CRH-R1 and -R2 to differentially modulate the expression of large-conductance calcium-activated potassium channels in human pregnant myometrium

CRH has been implicated to play a key role in the control of human pregnancy and parturition. Large-conductance potassium channels (BKCa) play a pivotal role in the modulation of uterine contractility during pregnancy. The objectives of the present study were to investigate the effect of CRH on BKCa expression in human pregnant myometrial cells. Myometrial tissues were collected at cesarean section from pregnant women not-in-labor (TNL) or in-labor (TL) at term, and myocytes were isolated and cultured. CRH was identified in human pregnant myometrium and mainly expressed in myometrial myocytes. Cultured myometrial cells were able to secrete CRH. In TNL myometrial cells, CRH treatment increased the expression of BKCa α- and β-subunits. CRH receptor type 1 (CRH-R1) antagonist, antalarmin, decreased whereas CRH receptor type 2 (CRH-R2) antagonist, astressin2b, increased the expression of BKCa. CRH-R2 small interfering RNA (siRNA) caused an increase, but CRH-R1 siRNA resulted in a decrease, in BKCa expression. In contrast to TNL cells, CRH exhibited an opposite effect on BKCa expression in TL myometrial cells, i.e. decreased BKCa expression. Antalarmin enhanced but astressin2b reduced BKCa expression. CRH-R2 siRNA decreased whereas CRH-R1 siRNA increased BKCa expression. 1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one significantly inhibited the frequency of spontaneous contractions of myometrial strips, and this effect was significantly decreased in TL strips compared with TNL ones. Our data suggest that CRH-R1 and CRH-R2 show differential regulation of BKCa expression. These effects mediated by CRH-R1 and CRH-R2 are changed after the onset of labor. This leads us to suggest that CRH may fine-tune myometrial contractility by modulating the expression of BKCa during pregnancy and labor.     

Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses

Paired fetal and maternal samples were obtained, at fetal blood sampling and intrauterine transfusion, to study hypothalamic-pituitary-adrenal stress responses. This confirmed that the fetus mounts an hypothalamic-pituitary-adrenal stress response to transfusion via the intrahepatic vein, which involves piercing the fetal trunk, but not to transfusion via the placental cord insertion [mean cortisol response via intrahepatic vein delta = 52.6 nmol/L, 95% CI (25.3-79.9), P = 0.001; mean beta-endorphin response delta =106 pg/mL, 95% CI (45.3-167), P = 0.002]. Baseline maternal fetal ratios were 13 [95% CI (10.7-15.2)] for cortisol and 0.8 [95% CI (0.5-1.0)] for beta-endorphin. The novel findings were: 1) that the fetal responses were independent of those of the mother, which did not change during transfusion at either site; 2) that there was a correlation between baseline fetal and maternal cortisol levels (r = 0.58, n = 51, P < 0.0001) but not between baseline fetal and maternal ss-endorphin levels, suggesting cortisol transfer across the placenta, rather than joint control by placental CRH; and 3) that fetal beta-endorphin responses were apparent from 18 weeks gestation and independent of gestational age, whereas fetal cortisol responses were apparent from 20 weeks gestation and were dependent on gestational age (y = -91.4 + 5.08x, r = 0.51; n = 16; P = 0.04; CI for slope, 0.16-10.0), consistent with the maturation of the fetal pituitary before the fetal adrenal.