Second Trimester Of Human Pregnancy Research Articles

Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis.

Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (p < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression.

Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors.

Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to invitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized invitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2.

Alterations in cognitive function and behavioral response to amphetamine induced by prenatal inflammation are dependent on the stage of pregnancy

Maternal infection during human pregnancy has been associated with the development of schizophrenia in the adult offspring. The stage of development and the maternal inflammatory response to infection, which undergoes quantitative and qualitative changes throughout gestation, are thought to determine critical windows of vulnerability for the developing brain. In order to investigate how these two factors may contribute to the outcome in the offspring, we studied the inflammatory response to turpentine (TURP) injection (100 μl/dam) and its consequences in the adult offspring, in pregnant rats at gestational day (GD) 15 or 18, which correspond to late first and early second trimester of human pregnancy, respectively. Maternal inflammatory response to TURP was different between the two GDs, with fever and circulating levels of the pro-inflammatory interleukin (IL)-6 significantly attenuated at GD 18, compared to GD 15. In the adult offspring, TURP challenge at GD 15 induced a significant decrease in pre-pulse inhibition (PPI) of acoustic startle, increased latency in the cued task of the Morris-water maze, prolonged conditioned fear response and enhanced locomotor effect of amphetamine. In contrast, the same immune challenge at GD 18 induced only a prolonged conditioned fear response. These results suggest a window of vulnerability at GD 15, at which TURP seems to affect several behaviors that are strongly modulated by dopamine. This was supported by increased tyrosine hydroxylase expression in the nucleus accumbens of the adult offspring of mothers treated at GD 15.

Systemic Reduction of Functionally Suppressive CD4dimCD25highFoxp3+ Tregs in Human Second Trimester Pregnancy Is Induced by Progesterone and 17β-Estradiol

CD4(+)CD25(high) regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17beta-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4(dim)CD25(high) Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4(+) population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17beta-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4(dim)CD25(high)Foxp3(+) cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4(+)CD25(-) responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-alpha, and IFN-gamma secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

THE STEROID HORMONAL MILIEU OF THE HUMAN FETUS AND MOTHER AT 16-20 WEEKS OF GESTATION

The inter-relations of steroid hormone levels in plasma from mothers and their undisturbed fetuses during the second trimester of human pregnancy have not been defined previously. Maternal vein (MV), fetal artery (FA), fetal vein (FV) and amniotic fluid (AF) levels of progesterone (P), 17-OHP, 11 deoxycortisol (S), DOC, cortisone (E), cortiaol (F), corticosterone (B) and aldosterone (Aldo) were measured in microassays in 12 conscious but sedated mothers and their fetuses undergoing therapeutic termination of pregnancy at 16-20 weeks gestation. The study received the approval of the Hospital Ethical Committee and maternal consent for the studies was obtained in each case. FA and FV samples were obtained by direct vessel puncture through a fetoscope without fetal disturbance. FA levels of F and B were significantly higher (p<0.01) than in FV; FV levels of P and E were higher (p<0.01) than FA values. No significant differences between FV or FA were found for levels of DOC, 17-OHP or S. MV levels of Aldo, F and B were significantly higher, with values of P, 17-OHP, DOC and S significantly lower than those in either fetal vessel. AF values of F, B, S, Aldo and DOC tended to be lower than those reported previously from mothers undergoing routine amniocentesis. We conclude: there is evidence that the fetal adrenal cortex is functioning independently of the mother in mid-gestation; maternal premedicatlon may lower fetal stress hormone secretion.

Response of the fetal rat brain to trauma during the 17th to 21st days of gestation.

Ultrasonography has made it possible to diagnose abnormalities of the human central nervous system early in pregnancy. However, more needs to be known about the response of the fetal brain before the mother and fetus are subjected to the risks of complex neurosurgical procedures. This study investigated the effects of trauma on fetal rat brains during a period equivalent to the early part of the second trimester of human pregnancy. Trauma inflicted on the fetal rat brains caused haemorrhage and necrosis of the cerebral hemisphere, which was not followed by significant regeneration of neural tissue. This preliminary study suggests that it cannot be assumed that the fetal brain will regenerate itself after injury, and that this should be considered when making plans for operative procedures on the central nervous system in utero.

Sodium excretion in human pregnancy: A role for arginine vasopressin

Plasma arginine vasopressin concentration was measured before and after 1 week's dietary sodium loading (>250 mmol/day) or deprivation (<50 mmol/day) in 50 second-trimester and 34 third-trimester primigravidas. A significant rise in plasma arginine vasopressin was observed only in second-trimester subjects following sodium loading (5.6 ± 0.5 to 6.6 ± 0.5 pg/ml; p < 0.05). Plasma sodium concentration and blood pressure did not alter, and plasma volume increased slightly in this group (24.4 ± 0.5 to 25.9 ± 0.7 ml/cm height; p < 0.01). Hence the observed increment in plasma arginine vasopressin concentration in this group could not be explained by alterations to the major factors regulating arginine vasopressin release. It is suggested that arginine vasopressin secretion increases to assist natriuresis following dietary sodium loading in the second trimester of human pregnancy.

Cell proliferation in the embryonic mouse neocortex following acute maternal alcohol intoxication

Experiments were conducted to examine the effects of ‘binge’ or acute maternal alcohol intoxication during the early proliferative phase of embryonic brain development. Primiparous mice received ethanol as 0, 10, 15 or 20% (v/v) aqueous solutions by gavage on days 13, 14 and 15 of gestation. Mean daily doses were 0.0, 2.58, 4.03 and 5.40 ml/kg, respectively. There was no alcohol-related reduction in fetal body weight, length or fixed brain weight. Coronal sections (1 μm) of the dorsal roof of the lateral ventricles over the optic chiasma were examined from nine embryonic day 15 brains for each treatment group. The ventricular surface index of mitotic figures, the number and distribution of non-surface mitotic figures, and the depth of the cortical roof and its constituent layers were determined. There was no alcohol-related difference in any of these parameters. These results are in contrast to those of a previous experiment using the same mouse strain, in which prolonged or chronic maternal alcohol consumption in the drinking water from days 11 to 19 of pregnancy was associated with a reduction in the surface index, a reduction in the depth of the cortical roof and an increase in the non-surface mitotic figures. These latter changes, however, occurred in the presence of reduced body weight. Our observations suggest that during this particular developmental period (corresponding to the second trimester of human pregnancy) alcohol-related reductions in brain growth parallel restrictions in general body growth.

Development of angiotensin converting enzyme in fetal lung and placenta of the rat and human.

Angiotensin converting enzyme (ACE) activity in fetal lung and placenta was determined by the method of Cushman and Cheung (1971) during the second trimester of human pregnancy and throughout the rat gestation. The enzyme activity in the neonatal rat lung was also determined during the first 19 days of life. The enzyme activity in both tissues of both species increased with gestation. The activity in human fetal lung at the end of the second trimester was already 70% of that present in the adult human lung while rat fetal lung enzyme activity at term was only 15% of the adult value. The activity in the term placenta of the human and rat was respectively 13% and 5% that of the adult lung value. Developmental increases in enzyme activity continued in the neonatal rat lung till adult value at about 19 days postpartum. The pattern of fetal lung enzyme development in the rat resembled that of the rabbit fetal lung as determined by other investigators using different techniques but was different from that of the human. The findings support the suggestion that ACE in the lung and placenta play important roles in the maintenance of circulatory homeostasis during the latter part of gestation, at birth and early postpartum, albeit at a different extent in different species.

Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy

Morphometric and statistical techniques were used to assess the relation of myometrial interstitial trophoblast to the uteroplacental vasculature in 27 intact hysterectomy specimens ranging from 8 to 18 weeks' gestation. It was found that the volume density of cytotrophoblast in the myometrium and in particular the proximity of such trophoblast to the placental bed spiral arteries correlated significantly with morphological alterations in these vessels. The changes included swelling of endothelium, hypertrophy of individual medial smooth muscle cells, and oedema and disruption of the architecture of the vessel wall as a time-related continuum. Some of the changes, such as swollen endothelium and basophilia of medial smooth muscle cells were noted also in spiral arteries in the non-placental bed endometrium but to a considerably less extent than in the placental bed. Intimal vacuolation was common to placental bed and non-placental bed arteries, increased with gestational age and can be considered as a non-specific feature. The migration of endovascular trophoblast into the myometrial spiral arteries in the second trimester occurred only when these arteries had been considerably altered in their morphology. These findings indicate that migratory interstitial cytotrophoblast probably has a role to play in the preparation of the myometrial segments of the uteroplacental arteries for the second wave of endovascular trophoblast migration that occurs in the second trimester of human pregnancy.

Serum relaxin levels in prostaglandin E 2 induced abortions

Relaxin, a peptide hormone produced only by the corpus luteum of pregnancy, can be used as a marker of luteal function in human pregnancy. Serum immunoreactive relaxin levels were measured serially in six women having second trimester abortions induced with intravaginal prostaglandin E2 (PGE 2) suppositories. All patients aborted within 17 hours of the first suppository. No significant changes were detectable in serum relaxin levels in any of the patients. It is concluded that PGE 2 does not interfere with the corpus luteum's ability to secrete relaxin in the second trimester of human pregnancy.

Serum steroid levels following a large intravenous dose of a steroid sulfate precursor during the second trimester of human pregnancy. I. Dehydroepiandrosterone sulfate.

ABSTRACT Serum levels of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), 16α-hydroxydehydroepiandrosterone (16α-OH DHEA), estrone (E1), estradiol-17β (E2), and estriol (E3) were measured by radioimmunoassay after intravenous infusion of a large dose of unlabeled DHEA-S to 11 healthy women during midtrimester pregnancy. Subjects were divided into three groups. The first group consisted of 5 subjects with a live fetus and intact placenta in whom the DHEA-S infusion was carried out before the pregnancy was disturbed. The second group consisted of 3 subjects with a dead fetus and an intact placenta in whom the DHEA-S infusion was performed after hypertonic saline amnioinfusion. The third group consisted of 3 subjects in whom the DHEA-S infusion was performed following passage of the fetus and placenta. DHEA-S levels fell exponentially following infusion. The mean DHEA-S half-life for all subjects with an intact placenta regardless of fetal viability was 3.86 ± 0.52 hr. With removal of ...

Serum steroid levels following a large intravenous dose of a steroid sulfate precursor during the second trimester of human pregnancy. II. Pregnenolone sulfate.

ABSTRACT Serum levels of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), 16α-hydroxydehydroepiandrosterone (16α-OH DHEA), estrone (E1), estradiol-17β (E2), and estriol (E3) were measured by radioimmunoassay after intravenous infusion of a large dose of unlabeled DHEA-S to 11 healthy women during midtrimester pregnancy. Subjects were divided into three groups. The first group consisted of 5 subjects with a live fetus and intact placenta in whom the DHEA-S infusion was carried out before the pregnancy was disturbed. The second group consisted of 3 subjects with a dead fetus and an intact placenta in whom the DHEA-S infusion was performed after hypertonic saline amnioinfusion. The third group consisted of 3 subjects in whom the DHEA-S infusion was performed following passage of the fetus and placenta. DHEA-S levels fell exponentially following infusion. The mean DHEA-S half-life for all subjects with an intact placenta regardless of fetal viability was 3.86 ± 0.52 hr. With removal of ...

EFFECTS OF CYTOTOXIC AGENTS ON THE FETUS

To the Editor:— The paper by Sokal and Lessmann inThe Journal, April 16, page 1765, on the effects of cancer chemotherapeutic agents on the human fetus is a valuable contribution, but I believe that the statement in their summary that other drugs (than aminopterin) have proved far less toxic for the fetus than would have been anticipated from theoretical considerations or animal experiments is misleading and potentially dangerous. The animal data indicate that antimetabolites are likely to cause abortion and resorption of embryos if administered early in gestation and fetal malformation if administered later during the major period of organogenesis (i. e., 10th to 12th day in the rat). These periods correspond roughly to the first trimester of human pregnancy, particularly to the first eight weeks. The second third of the 22-day rat pregnancy is not comparable to the second trimester of human pregnancy. Only three patients given 6-mercaptopurine