The urinary excretion of pregnanediol during pregnancy determined by gas-liquid chromatography. II. Its relation with other parameters controling pregnancy (author's transl)]

The relation between the urinary pregnanediol determined by gas-liquid chromatography during pregnancy, with ultrasonic findings (biparietal diameter, thickness and echorrefringency of the placenta and the appreciated quantity of amniotic fluid), with biochemical parameters of control of pregnancy (beta-glucoronidase, total and thermostable alkaline phosphatase), with amnioscopic findings, and with several studied parameters of the amniotic fluid by amniocentesis, were studied. A good relation exists with the parameters which denote placentary insufficiency and fetal risk (irregularity in the homogeneity of the placenta, elevation of the total and thermostable alkaline phosphatase, positive amnioscopy) and also with those that are related with fetal maturity (biparietal diameter, shake test, organge cells, creatinine in amniotic fluid, etc.). These results indicate that the determination of urinary pregnanediol can be one of the tests controlling the normal and pathological pregnancies, being useful in the detection of fetal risk and the diagnosis of the intrauterine fetal maturity.     

The urinary excretion of pregnanediol during pregnancy determined by gas-liquid chromatography. I. Its evolution throughout the normal and pathological pregnancy (author's transl)]

Employing the technique described by Van Kampen and Anker, modified by Macarulla et al., 180 pregnant women have been studied (66 normals and 114 with different pathology: infertility, toxemia, diabetes, Rh isoinmunization, gemelar pregnancy and abortions), taking 319 determinations of pregnanediol in 24 hours urine samples. The analysis of the results show in normal pregnancy a progressive increase of the urinary pregnanediol from the beginning of gestation, this increase being more intense from the 20th week, reaching the maximum value in the 37th week and from this point descending slowly. In patients with toxemia, the values of pregnanediol (in the majority of the cases) are decreased, while in pregnant women with antecedents of infertility are increased from the 36th week of pregnancy, although they had protective treatment from first months of pregnancy. No manifest deviations of urinary pregnanediol from the normal values exist in diabetic pregnant women, Rb isoinmunization or gemelar pregnancies. In aborted pregnancies the pregnanediol values are markedly decreased without a tendency to increase, contrary to the threats of abortion in full-term pregnancies.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: II: effects of placental malaria on perinatal outcome; malaria and HIV

Placental malaria is recognized as a common complication of malaria in pregnancy in areas of stable transmission, and, as a consequence, serious health problems arise for the mother and especially her baby [1]. Although malaria in pregnancy is a major factor associated with adverse perinatal outcome, the link between malaria and perinatal morbidity/mortality is less clear in areas with stable endemic malaria where pregnant women have acquired immunity [2]. Histological examination of the placenta is a predictor of fetal morbidity, as well as being the most sensitive detector of maternal infection [3]. Adverse perinatal outcome has been described as an important indicator of poor quality of obstetric care and social development [4]. A variety of adverse perinatal outcomes associated with placental malaria have been described, including low birth weight, preterm delivery, intrauterine growth retardation, fetal anemia, congenital malaria, and fetal mortality. The most common clinical features in 80 percent of perinatal cases are fever, anemia, and splenomegaly [5]. Other signs and symptoms include hepatomegaly, jaundice, regurgitation, loose stools, poor feeding, and, occasionally, drowsiness, restlessness, and cyanosis also can be seen [5,6].A review of studies that investigated these poor fetal outcomes associated with placental malaria in sub-Saharan Africa is presented here.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: I: introduction to placental malaria

Placental malaria is one of the major features of malaria during pregnancy and has been widely used as a standard indicator to characterize malaria infection in epidemiologic investigations. Although pathogenesis of placental malaria is only partially understood, placental sequestration of Plasmodium falciparum results in the accumulation of parasitized erythrocytes in the intervillous space, infiltration by inflammatory cells, and release of pro-inflammatory mediators, which cause pathologic alterations that could impair materno-fetal exchanges, often resulting in adverse pregnancy outcome. In this report, the impact of placental malaria on pregnancy and perinatal outcome is reviewed using data from studies conducted in sub-Saharan Africa. Generally, placental malaria was associated with increased risk of maternal anemia, HIV infection, and maternal mortality, with younger women and primigravidae more likely to be affected. A variety of adverse perinatal outcomes, including low birth weight, preterm delivery, intrauterine growth retardation, reduced fetal anthropometric parameters, fetal anemia, congenital malaria, increased mother-to-child HIV transmission, and perinatal mortality, were associated with placental malaria. There were, however, conflicting reports on whether the risk of these adverse perinatal outcomes associated with placental malaria were statistically significant. There is a clear need to strengthen the malaria prevention and intervention measures for pregnant women in sub-Saharan Africa.     

Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP

During pregnancy, parathyroid hormone-related protein (PTHrP) is one of many growth factors that play important roles to promote fetal growth and development, including stimulation of placental calcium transport. Angiotensin II, acting through the AT(1a) receptor, is also known to promote placental growth. We examined the effects of bilateral uterine artery and vein ligation (restriction), which mimics placental insufficiency in humans, on growth, intrauterine PTHrP, placental AT(1a), and pup calcium. Growth restriction was surgically induced on day 18 of pregnancy in Wistar-Kyoto female rats by uterine vessel ligation. Uteroplacental insufficiency reduced fetal body weight by 15% and litter size (P < 0.001) compared with the control rats with no effect on placental weight or amniotic fluid volume. Uteroplacental insufficiency reduced placental PTHrP content by 46%, with increases in PTHrP (by 2.6-fold), parathyroid hormone (PTH)/PTHrP receptor (by 11.6-fold), and AT(1a) (by 1.7-fold) relative mRNA in placenta following restriction compared with results in control (P < 0.05). There were no alterations in uterine PTHrP and PTH/PTHrP receptor mRNA expression. Maternal and fetal plasma PTHrP and calcium concentrations were unchanged. Although fetal total body calcium was not altered, placental restriction altered perinatal calcium homeostasis, as evidenced by lower pup total body calcium after birth (P < 0.05). The increased uterine and amniotic fluid PTHrP (P < 0.05) may be an attempt to compensate for the induced impaired placental function. The present study demonstrates that uteroplacental insufficiency alters intrauterine PTHrP, placental AT(1a) expression, and perinatal calcium in association with a reduction in fetal growth. Uteroplacental insufficiency may provide an important model for exploring the early origins of adult diseases.     

Incidence of anencephaly and other major malformations when oestriol excretion is very low.

A study of 533 women with very low urinary oestriol excretion during the third trimester of pregnancy showed an incidence of major fetal malformations among their infants of 7-1% and a perinatal mortality rate of 14-6%. Thirteen of the malformations were cases of anencephaly, and 26 of the 78 perinatal deaths were due to or associated with major fetal malformations. The incidence of these complications was higher when maternal oestriol excretion was lower. Routine screening by urinary oestriol assay, with fetal radiography when values below 20-8 mumol/24 hours (6 mg/24 h) are detected is the most reliable method of detecting anencephaly before birth.     

Predictors of poor perinatal outcome following maternal perception of reduced fetal movements--a prospective cohort study

Background

Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.

Objective

To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).

Design

Prospective cohort study.

Methods

305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.

Results

22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.

Conclusion

Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.     

Altered maternal metabolism during mild gestational hyperglycemia as a predictor of adverse perinatal outcomes: A comprehensive analysis

Mild gestational hyperglycemia (MGH), as assessed using the normal oral glucose tolerance test (OGTT) and detection of an altered glycemic profile, is associated with adverse perinatal outcome. This study described the results of 40 years of research conducted at the Perinatal Diabetes Research Centre at São Paulo State University (UNESP), Brazil, on the maternal MGH environment and placental markers. This study also described the unidirectional relationship between MGH and excessive fetal growth, also supplying moderator analysis. In addition to hyperglycemia, MGH is associated with an increased incidence of hypertension, metabolic syndrome, persistent insulin resistance after pregnancy, and high risk of developing type 2 diabetes mellitus (T2DM) after pregnancy. Structural changes and functional abnormalities resulting from MGH were observed in placenta. The fully adjusted model concluded that the predictor variable (MGH), which creates a complex environment for the fetus, has a direct effect on excessive birth weight and produces a z-score for ratios of birth weight to gestational age of ≥2. Maternal age, pre-pregnancy BMI, number of previous pregnancies, numbers of prenatal visits, and 1 h OGTT are moderator variables that impact MGH and excessive fetal growth. These results show that maternal MGH has some characteristics associated with similar long-term T2DM development and similar adverse perinatal results to those of gestational diabetes mellitus (GDM) mothers, making it an intermediate maternal and placental marker between normoglycemic and GDM mothers.     

Lipid peroxidation, antioxidant defence and acid-base status in cord blood at birth: the influence of diabetes.

Pregnancy complicated by poor control of diabetes is associated with a higher risk of embryopathies, spontaneous abortions and perinatal mortality. A number of authors suggest an involvement of reactive oxygen species (ROS) in diabetic pregnancy. Determining lipid peroxidation products (LP), scavenging enzyme activities and the umbilical cord blood's acid-base balance may contribute to an adequate diagnosis of the neonate at birth. Nevertheless, such measurements seem to have limited value in practical clinical routine. The present study evaluates LP, antioxidant defence and acid-base status related to diabetic pregnancy. Twenty-eight women with type 1 diabetes (PGDM), 19 with gestational diabetes (GDM) and 13 control cases were investigated. An additional control group consisted of 15 healthy patients with negative diabetic history; all women underwent vaginal delivery. Immediately after delivery cord blood samples and placental tissue were collected for malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) determination. Additionally, pH, pCO2, pO2 and base excess were measured in both vessels and compared to identify and exclude double venous samples. MDA levels in both cord blood and placental homogenates were significantly higher in both pregestational and gestational diabetic groups, but SOD activity was significantly diminished. Cord blood GSH was markedly elevated in PGDM and GDM. We have also shown significant differences in acid-base parameters in infants of PGDM group. Statistical analysis was performed using the Mann-Whitney U-test.These findings indicate an excessive oxidative stress in pregnancy complicated by diabetes mellitus. Evaluating LP products and scavenging enzyme activities may be valuable, sensitive indexes of fetal/neonatal threat in diabetic pregnancy in humans. Since oxidative stress is an important pathway for fetal injury, we believe that obtaining adequate measurements at the time of birth would contribute to clarifying the fetal/neonatal status in a medical and legal context and might be of value in altering therapy in newborn infants.     

Disproportionate Fetal Growth and the Risk for Congenital Cerebral Palsy in Singleton Births

ObjectiveTo investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP).ResultsWe identified 503,784 singleton births, of which 983 were confirmed cases of CP. Head/ abdominal circumference ratio (aHR:1.12; 95%CI:1.07-1.16) and cephalization index (aHR:1.14; 95%CI:1.11-1.16) were associated with the risk of CP irrespective of gestational age. Birth weight-placental weight ratio was also associated with CP in the entire cohort (aHR:0.90; 95%CI:0.83-0.97). Ponderal index had a u-shaped association with CP, where both children with low and high ponderal index were at higher risk of CP.ConclusionsCP is associated with disproportions between birth weight, birth length, placental weight and head circumference suggesting pre and perinatal conditions contribute to fetal growth restriction in children with CP.     

Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion

Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3-4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.     

Moderate Exercise Attenuates Lipopolysaccharide-Induced Inflammation and Associated Maternal and Fetal Morbidities in Pregnant Rats

Fetal growth restriction (FGR) and coagulopathies are often associated with aberrant maternal inflammation. Moderate-intensity exercise during pregnancy has been shown to increase utero-placental blood flow and to enhance fetal nutrition as well as fetal and placental growth. Furthermore, exercise is known to reduce inflammation. To evaluate the effect of moderate-intensity exercise on inflammation associated with the development of maternal coagulopathies and FGR, Wistar rats were subjected to an exercise regime before and during pregnancy. To model inflammation-induced FGR, pregnant rats were administered daily intraperitoneal injections of E. coli lipopolysaccharide (LPS) on gestational days (GD) 13.5–16.5 and sacrificed at GD 17.5. Control rats were injected with saline. Maternal hemostasis was assessed by thromboelastography. Moderate-intensity exercise prevented LPS-mediated increases in white blood cell counts measured on GD 17.5 and improved maternal hemostasis profiles. Importantly, our data reveal that exercise prevented LPS-induced FGR. Moderate-intensity exercise initiated before and maintained during pregnancy may decrease the severity of maternal and perinatal complications associated with abnormal maternal inflammation.     

Urinary endocrine monitoring of the ovarian cycle and pregnancy in Goeldi's monkey (Callimico goeldii)

A non-invasive study of urinary hormones in 6 captive female Goeldi's monkeys provided accurate information on reproductive function. Conjugated oestrone accounted for 80-85% of the urinary oestrone and oestradiol measured. Radioimmunoassay measurements of conjugated oestrone provided a reliable indicator of cyclic ovarian function (mean cycle length: 24.1 +/- 0.9 days; n = 9) and pregnancy (gestation: 145, 155 days; n = 2). Measurements of urinary progesterone and pregnanediol glucuronide were only reliable as indicators of ovarian cyclicity. Elevations in urinary conjugated oestrone coincided with luteal-phase elevations of urinary progesterone and pregnanediol glucuronide. Urinary LH concentrations provided no indication of pituitary activity. However, the frequencies of female sexual solicitations of males were maximal when oestrone conjugate concentrations rose, suggesting a peri-ovulatory period. Ovulation was suppressed in 1 of 3 subordinate females housed in male-female-female trios.     

Regulation of maternal and fetal hemodynamics by heme oxygenase in mice

Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5-15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.     

儿童癫痫的围产期高危因素分析

目的：研究儿童癫痫相关的国产期高危因素。方法：随访16986例新生儿后期癫痫的患病情况,分为儿童癫痫组与非癞痫组,比较两组各项围产期高危因素,进行单因素与多因素统计分析。结果：随访期内儿童癫痫的发病例数为118例（6．95‰）,癫痫的发病率在1岁以下的儿童最高（27．12％）。儿童癫痫的发生与孕周、高龄产妇、低出生体重、流产史、宫内窘迫、喂养方式、孕期感染、子痫、胎盘早剥、新生儿惊厥都有相关性,并且孕周、子痫和新生儿惊厥是儿童癫痫发生的独立危险因素。结论：儿童癫痫的发生与围产期高危因素密切相关,这对临床儿童癫痫的诊疗可能有提示作用。     

Trisomy 16 confined to chorionic villi and unfavourable outcome of pregnancy.

Two cases of trisomy 16 confined to placental tissue associated with an unfavourable outcome of the pregnancy are reported. In the first case, after a diagnosis of an apparent non-mosaic trisomy 16 at chorionic villi sample (CVS), an intrauterine fetal death occurred at the 22nd week. In the second case a mosaic with trisomy 16 was found in chorionic villi and the fetus was still-born at 38 weeks. From a comparison of their cases with those of the literature, the authors conclude that a trisomy 16 confined to placental tissue has a negative effect on fetal growth and pregnancy outcome.     

Prospective population based survey of outcome of pregnancy in diabetic women: results of the Northern Diabetic Pregnancy Audit, 1994.

OBJECTIVE: To determine whether the St Vincent declaration (1989) target of diabetic pregnancy outcome approximating non-diabetic pregnancy outcome in near to being achieved. DESIGN: Prospective collection of population based information on pregnancies in women with diabetes from all participating hospitals. SETTING: District general and teaching hospitals of the former Northern region. SUBJECTS: 111 diabetic women booking with pregnancy during 1 January to 31 December 1994. MAIN OUTCOME MEASURES: Diabetic control, perinatal mortality rate, fetal abnormality rate. RESULTS: The perinatal mortality rate was 48/1000 for diabetic pregnancies compared with 8.9/1000 for the background population (odds ratio 5.38; 95% confidence interval 2.27 to 12.70) and the neonatal mortality rate was 59/1000 compared with 3.9/1000 (15.0; 6.77 to 33.10). Two late neonatal deaths were due to congenital heart defects. Six per cent of all fetal losses (6/109 cases) were due to major malformations. The congenital malformation rate was 83/1000 compared with 21.3/1000 (3.76; 2.00 to 7.06) in the background population. CONCLUSIONS: Diabetic pregnancy remains a high risk state with perinatal mortality and fetal malformation rates much higher than in the background population.     

Gene expression pattern of IGF2, PHLDA2, PEG10 and CDKN1C imprinted genes in spontaneous miscarriages or fetal deaths

Genomic imprinting is defined as an epigenetic modification that leads to parent-of-origin specific monoallelic expression. Some current research on the fetal control growth has been focused on the study of genes that display imprinted expression in utero. Four imprinted genes, two paternally expressed (IGF2 and PEG10) and two maternally expressed (PHLDA2 and CDKN1C), are well known to play a role in fetal growth and placental development. Pregnancy loss in the general reproductive population is a very common occurrence and other genetic causes beyond chromosomal abnormalities could be involved in spontaneous miscarriages or fetal deaths, such as alteration of expression in imprinted genes particularly those related to fetal or placental growth. Quantitative Real Time PCR was performed to evaluate gene expressions patterns of the four mentioned genes in spontaneous miscarriages or fetal deaths from 38 women. Expression levels of PHLDA2 gene were upregulated in the first trimester pregnancy cases and all four imprinted genes studied were upregulated in the second trimester of pregnancy cases comparing with controls. In third trimester PEG10 was downregulated in fetal samples group. This is the first study presenting data from human imprinted genes expression in spontaneous miscarriages or fetal deaths cases from the three trimesters of pregnancy.     

不同类型妊娠高血压疾病对产妇妊娠结局的影响

目的:探讨不同类型妊娠高血压疾病(PIH)对产妇妊娠结局的影响。方法:选取2011年1月~2013年12月我妇产科院收治的妊娠期出现高血压症状的产妇106例为观察组,并选取同期正常孕产妇100例为对照组,根据诊断标准将观察组患者再分为PIH组(75例)、子痫前期组(21例)以及子痫组(10例),对比4组产妇的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率。结果:观察组产妇的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率明显高于对照组,差异有统计学意义(P0.05);妊娠期高血压组、子痫前期组、子痫组的胎儿窘迫、胎盘早剥、早产、剖宫产、产后出血以及新生儿窒息的发生率,依次升高,差别有统计学意义(P0.05)。结论:应正确认识到不同类型PIH对妊娠结局的影响以及其并发症的规律,做好预防措施,以减少不良妊娠结局的发生。     

Adrenomedullin in perinatal medicine

This review will consider whether adrenomedullin (AM) plays a role in the different aspects of perinatal medicine: contributing to maternal systemic vasodilatation during pregnancy, regulating uterine and placental blood flow, being involved in the process of implantation and participating in uterine quiescence prior to parturition. In addition, this will also consider whether a modification of AM secretion contributes to some pathological conditions in pregnancy such as preeclampsia and impairment of fetal growth. The biosynthesis of AM increases in gravid rats and in pregnant women, and the placenta represents an important site of AM production during pregnancy. Both the peptide and its receptors have been found in the uterus, placenta, fetal membranes and cord vessels, and fetal membranes and placental tissues in culture secrete AM. AM contributes to maternal systemic vasodilatation, the placental vessels are relaxed by AM in a dose-dependent manner and AM is expressed in the fetoplacental and umbilical vascular endothelium where basal production of AM contributes to low fetoplacental vascular resistances. Controversy exists over the status of circulating and placental AM in preeclampsia and of the relative contribution of AM to impaired fetoplacental circulation and fetal growth. Moreover, the uterus expresses AM mRNA and exogenous AM relaxes the myometrium in a dose-dependent manner; however, clinical studies have shown that AM does not decrease before the onset of parturition. Rather, AM secretion increases during spontaneous labor and in preterm delivery.