Perinatal development and adult blood pressure

A growing body of evidence supports the concept of fetal programming in cardiovascular disease in man, which asserts that an insult experienced in utero exerts a long-term influence on cardiovascular function, leading to disease in adulthood. However, this hypothesis is not universally accepted, hence animal models may be of value in determining potential physiological mechanisms which could explain how fetal undernutrition results in cardiovascular disease in later life. This review describes two major animal models of cardiovascular programming, the in utero protein-restricted rat and the cross-fostered spontaneously hypertensive rat. In the former model, moderate maternal protein restriction during pregnancy induces an increase in offspring blood pressure of 20-30 mmHg. This hypertensive effect is mediated, in part, by fetal exposure to excess maternal glucocorticoids as a result of a deficiency in placental 11-ß hydroxysteroid dehydrogenase type 2. Furthermore, nephrogenesis is impaired in this model which, coupled with increased activity of the renin-angiotensin system, could also contribute to the greater blood pressure displayed by these animals. The second model discussed is the cross-fostered spontaneously hypertensive rat. Spontaneously hypertensive rats develop severe hypertension without external intervention; however, their adult blood pressure may be lowered by 20-30 mmHg by cross-fostering pups to a normotensive dam within the first two weeks of lactation. The mechanisms responsible for this antihypertensive effect are less clear, but may also involve altered renal function and down-regulation of the renin-angiotensin system. These two models clearly show that adult blood pressure is influenced by exposure to one of a number of stimuli during critical stages of perinatal development.

Assessment of fetal risk associated with exposure to cancer chemotherapy during pregnancy: a multicenter study

The objective of the present study was to evaluate and quantify fetal risks involved in the administration of cancer chemotherapy during gestation, as well as to assess the long-term effects on the exposed children. In this retrospective, cohort study, we reviewed the records of women aged 15 to 45 years with a diagnosis of malignancy or benign tumors with malignant behavior at three reference services in the State of Rio Grande do Sul, Brazil, from 1990 to 1997. All patients with a diagnosis of pregnancy at any time during the course of the disease were selected, regardless of whether or not they received specific medication. Fetal outcomes of 14 pregnancies with chemotherapy exposure were compared to that of 15 control pregnancies in which these drugs were not used. Long-term follow-up of the exposed children was carried out. Fisher's exact test was used to compare the groups. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. We found an increased rate of prematurity (6/8 vs 2/10; RR: 3.75; CI: 1.02-13.8; P = 0.03) in the exposed group. There was a trend to an increased fetal death rate (4/12 vs 0/10; P = 0.07) in the group exposed to chemotherapy. No malformations were detected in any child, which can be related to our small sample size as well as to the fact that most exposures occurred after the first trimester of pregnancy. Other larger, controlled studies are needed to establish the actual risk related to cancer chemotherapy during pregnancy.

Acute Effects of Maternal Smoking on Fetal-Placental-Maternal System Hemodynamics

OBJECTIVE: To study acute hemodynamic alterations in the fetal-placental maternal system immediately after maternal exposure to nicotine. METHODS: This is a noncontrolled experimental study involving 21 pregnant smoking women, randomly selected, with uncomplicated pregnancies and without risk factors for fetal heart disease. Patients underwent ultrasound and fetal echocardiography before and after smoking a cigarette. They were asked to abstain from smoking for 12 hours before the study. The mean nicotine content of the cigarettes used in the study was 0.5mg of nicotine and 6mg of carbon monoxide. RESULTS: The average number of cigarettes smoked per a day prior to the study was 9.67. Gestational age ranged between 18 and 36 weeks. The mean maternal heart rate was elevated (P<0.001) as was the mean fetal heart rate (P=0.044). Maternal systolic blood pressure (P=0.004) and diastolic blood pressure (P=0.033) were also elevated after smoking. A decrease occurred in the systolic/diastolic ratio in the right uterine artery (P=0.014) and in the left uterine artery (P=0.039). The other hemodynamic variables remained unchanged. CONCLUSION: Cigarette smoking can cause changes in physiologic variables of fetal-placental circulation, but it does not change fetal cardiac function, in the dose of nicotine and its components used in this study. The decrease in systolic/diastolic ratio in the uterine arteries is probably related to a dose-dependent nicotine pattern.

Adverse pregnancy outcome in rats following exposure to a Salacia reticulata (Celastraceae) root extract

The root extract of Salacia reticulata Wight (family: Celastraceae) is used in Sri Lanka by traditional practitioners as a herbal therapy for glycemic control even during pregnancy. It is recognized that some clinically used antidiabetic drugs have harmful effects on pregnancy but the effects of the S. reticulata root extract on reproductive outcome is unknown and deserves examination. We determined the effects of the S. reticulata root extract on the reproductive outcome of Wistar rats (250-260 g) when administered orally (10 g/kg) during early (days 1-7) and mid- (days 7-14) pregnancy. The root extract significantly (P<0.05) enhanced post-implantation losses (control vs treatment: early pregnancy, 4.7 ± 2.4 vs 49.3 ± 13%; mid-pregnancy, 4.7 ± 2.4 vs 41.7 ± 16.1%). Gestational length was unaltered but the pups born had a low birth weight (P<0.05) (early pregnancy, 6.8 ± 0.1 vs 5.3 ± 0.1 g; mid-pregnancy, 6.8 ± 0.1 vs 5.0 ± 0.1 g) and low birth index (P<0.05) (early pregnancy, 95.2 ± 2.4 vs 50.7 ± 12.9%; mid-pregnancy, 95.2 ± 2.4 vs 58.3 ± 16.1%), fetal survival ratio (P<0.05) (early pregnancy, 95.2 ± 2.4 vs 50.7 ± 12.9; mid-pregnancy, 95.2 ± 2.4 vs 58.3 ± 16.1), and viability index (P<0.05) (early pregnancy, 94.9 ± 2.6 vs 49.5 ± 12.5%; mid-pregnancy, 94.9 ± 2.6 vs 57.1 ± 16.1%). However, the root extract was non-teratogenic. We conclude that the S. reticulata root extract can be hazardous to successful pregnancy in women and should not be used in pregnancy complicated by diabetes.

Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

Ventricular septal defects (VSDs) are common congenital abnormalities which have been reported to be associated with maternal fever and various environmental factors. The aim of the present study was to evaluate the effect of prenatal exposure to cyclooxygenase (COX) inhibitors on heart defects. A retrospective statistical analysis was performed using data collected in our laboratory during various teratological studies carried out on albino CRL:(WI)WUBR Wistar strain rats from 1997 to 2004. The observations were compared with concurrent and historic control data, as well as findings from other developmental toxicological studies with selective and nonselective COX-2 inhibitors. Despite the lack of significant differences in the frequency of VSDs between drug-exposed and control groups, statistical analysis by the two-sided Mantel-Haenszel test and historical control data showed a higher incidence of heart defects in offspring exposed to nonselective COX inhibitors (30.06/10,000). Unlike other specific inhibitors, aspirin (46.26/10,000) and ibuprofen (106.95/10,000) significantly increased the incidence of the VSD when compared with various control groups (5.38-19.72/10,000). No significant differences in length or weight were detected between fetuses exposed to COX inhibitors and born with VSD and non-malformed offsprings. However, a statistically significant increase of fetal body length and decrease of body mass index were found in fetuses exposed to COX inhibitors when compared with untreated control. We conclude that prenatal exposure to COX inhibitors, especially aspirin and ibuprofen, increased the incidence of VSDs in rat offspring but was not related to fetal growth retardation.

Maternal undernutrition and the offspring kidney: from fetal to adult life

Maternal dietary protein restriction during pregnancy is associated with low fetal birth weight and leads to renal morphological and physiological changes. Different mechanisms can contribute to this phenotype: exposure to fetal glucocorticoid, alterations in the components of the renin-angiotensin system, apoptosis, and DNA methylation. A low-protein diet during gestation decreases the activity of placental 11ß-hydroxysteroid dehydrogenase, exposing the fetus to glucocorticoids and resetting the hypothalamic-pituitary-adrenal axis in the offspring. The abnormal function/expression of type 1 (AT1R) or type 2 (AT2R) AngII receptors during any period of life may be the consequence or cause of renal adaptation. AT1R is up-regulated, compared with control, on the first day after birth of offspring born to low-protein diet mothers, but this protein appears to be down-regulated by 12 days of age and thereafter. In these offspring, AT2R expression differs from control at 1 day of age, but is also down-regulated thereafter, with low nephron numbers at all ages: from the fetal period, at the end of nephron formation, and during adulthood. However, during adulthood, the glomerular filtration rate is not altered, due to glomerulus and podocyte hypertrophy. Kidney tubule transporters are regulated by physiological mechanisms; Na+/K+-ATPase is inhibited by AngII and, in this model, the down-regulated AngII receptors fail to inhibit Na+/K+-ATPase, leading to increased Na+ reabsorption, contributing to the hypertensive status. We also considered the modulation of pro-apoptotic and anti-apoptotic factors during nephrogenesis, since organogenesis depends upon a tight balance between proliferation, differentiation and cell death.

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

Estudo crítico da avaliação da maturidade fetal pela citologia do líquido âmnico: comparação com outros métodos

Através da amniocentese em 90 gestações de alto risco, foi feito estudo crítico da citologia do líquido amniótico pelo Sulfato de Azul do Nilo em comparação com a creatinina e o Rx simples de abdomen e sua relação com a idade do RN (calculados pelas tabelas de Lubchenco e Capurro). Concluiu-se que a técnica do Sulfato de Azul do Nilo apresenta real valor, nas nossas condições econômicas, com menor percentagem de falhas com os demais métodos, sendo melhor para a avaliação de maturidade fetal o emprego simultâneo de todos os métodos, aliados à clínica.

Relação entre estado nutricional da gestante, fumo durante a gravidez, crescimento fetal e no primeiro ano de vida

Estudou-se a relação entre estado nutricional e hábito de fumar maternos, peso do recém-nascido ao nascer e crescimento no primeiro ano de vida num grupo de 1.066 gestantes de baixo nível sócio-econômico. Os filhos de mulheres fumantes apresentaram pesos significativamente menores que os filhos de não-fumantes, quer fossem suas mães, normais ou obesas. Também foi possível verificar que filhos de mulheres desnutridas pesaram significativamente menos que filhos de mulheres normais e estes que os de obesas. O prejuízo no peso dos filhos de mulheres fumantes manteve-se apenas até os 3 meses de idade, ao passo que até os 9 meses os filhos de mulheres desnutridas pesaram significativamente menos que as demais crianças, mostrando que, mesmo em gestantes de baixa renda, o efeito do fumo sobre o crescimento se restringe ao ambiente intra-uterino. Já o efeito da desnutrição materna é mais duradouro nessa população. Verificou-se que houve uma associação negativa entre estado nutricional e hábito de fumar maternos, sugerindo que, ao menos em parte, o efeito do tabagismo materno sobre o concepto pode ser intermediado pelo estado nutricional.

Exposure to larva migrans syndromes in squares and public parks of cities in Chile

Between November 2001 and December 2002, 600 dog fecal samples were collected in main squares and public parks of 13 cities in Chile, from the extreme north to the extreme south of the country. The samples were processed in the laboratory by centrifugal sedimentation and the Harada-Mori methods. T. canis eggs were found in 12 cities. Detection rates ranged from 1.9 to 12.5% with an average of 5.2%. Seven percent of the samples had eggs and 9.5% had rhabditoid and/or filariform larvae of Ancylostomatidae. Strongyloides stercoralis were not found. Squares and public parks in Chile pose a potential risk of exposure to visceral, ocular, and/or cutaneous larva migrans syndromes.

Risk-factors for antepartum fetal deaths in the city of São Paulo, Brazil

OBJECTIVE: To assess risk factors for antepartum fetal deaths. METHODS: A population-based case-control study was carried out in the city of São Paulo from August 2000 to January 2001. Subjects were selected from a birth cohort from a linked birth and death certificate database. Cases were 164 antepartum fetal deaths and controls were drawn from a random sample of 313 births surviving at least 28 days. Information was collected from birth and death certificates, hospital records and home interviews. A hierarchical conceptual framework guided the logistic regression analysis. RESULTS: Statistically significant factors associated with antepartum fetal death were: mother without or recent marital union; mother's education under four years; mothers with previous low birth weight infant; mothers with hypertension, diabetes, bleeding during pregnancy; no or inadequate prenatal care; congenital malformation and intrauterine growth restriction. The highest population attributable fractions were for inadequacy of prenatal care (40%), hypertension (27%), intrauterine growth restriction (30%) and absence of a long-standing union (26%). CONCLUSIONS: Proximal biological risk factors are most important in antepartum fetal deaths. However, distal factors - mother's low education and marital status - are also significant. Improving access to and quality of prenatal care could have a large impact on fetal mortality.

Physical activity during pregnancy and fetal outcomes: a case-control study

OBJECTIVE: To investigate the relationship between physical activity during the second trimester pregnancy and low birth weight, preterm birth, and intrauterine growth restriction. METHODS: Case-control study including 273 low birth weight newborns and 546 controls carried out in the city of São Paulo, Southeastern Brazil, in 2005. Low birth weight cases were grouped into two subsamples: preterm birth (n=117) and intrauterine growth restriction (n=134), with their related controls. Information was collected by means of interviews with mothers shortly after birth and transcription of medical records. Data were analyzed using conditional multiple and hierarchical logistic regression. RESULTS: Light physical activity for over 7 hours per day was shown to be protective against low birth weight (adjusted OR=0.61; 95% CI 0.39-0.94) with a dose-response relationship (p-value for trend=0.026). A similar trend was found for intrauterine growth restriction (adjusted OR=0.51; 95% CI 0.26-0.97). Homemaking activities were associated as a protective factor for both low birth weight and preterm birth (p-value for trend=0.013 and 0.035, respectively). Leisure-time walking was found to be protective against preterm birth. CONCLUSIONS: Mild physical activity during the second trimester of pregnancy such as walking has an independent protective effect on low birth weight, preterm birth, and intrauterine growth restriction.

Association of dental enamel lead levels with risk factors for environmental exposure

OBJECTIVE: To analyze household risk factors associated with high lead levels in surface dental enamel. METHODS: A cross-sectional study was conducted with 160 Brazilian adolescents aged 14-18 years living in poor neighborhoods in the city of Bauru, southeastern Brazil, from August to December 2008. Body lead concentrations were assessed in surface dental enamel acid-etch microbiopsies. Dental enamel lead levels were measured by graphite furnace atomic absorption spectrometry and phosphorus levels were measured by inductively coupled plasma optical emission spectrometry. The parents answered a questionnaire about their children's potential early (05 years old) exposure to well-known lead sources. Logistic regression was used to identify associations between dental enamel lead levels and each environmental risk factor studied. Social and familial covariables were included in the models. RESULTS: The results suggest that the adolescents studied were exposed to lead sources during their first years of life. Risk factors associated with high dental enamel lead levels were living in or close to a contaminated area (OR = 4.49; 95% CI: 1.69;11.97); and member of the household worked in the manufacturing of paints, paint pigments, ceramics or batteries (OR = 3.43; 95% CI: 1.31;9.00). Home-based use of lead-glazed ceramics, low-quality pirated toys, anticorrosive paint on gates and/or sale of used car batteries (OR = 1.31; 95% CI: 0.56;3.03) and smoking (OR = 1.66; 95% CI: 0.52;5.28) were not found to be associated with high dental enamel lead levels. CONCLUSIONS: Surface dental enamel can be used as a marker of past environmental exposure to lead and lead concentrations detected are associated to well-known sources of lead contamination.

Symphysis-fundal height curve in the diagnosis of fetal growth deviations

OBJECTIVE: To validate a new symphysis-fundal curve for screening fetal growth deviations and to compare its performance with the standard curve adopted by the Brazilian Ministry of Health. METHODS: Observational study including a total of 753 low-risk pregnant women with gestational age above 27 weeks between March to October 2006 in the city of João Pessoa, Northeastern Brazil. Symphisys-fundal was measured using a standard technique recommended by the Brazilian Ministry of Health. Estimated fetal weight assessed through ultrasound using the Brazilian fetal weight chart for gestational age was the gold standard. A subsample of 122 women with neonatal weight measurements was taken up to seven days after estimated fetal weight measurements and symphisys-fundal classification was compared with Lubchenco growth reference curve as gold standard. Sensitivity, specificity, positive and negative predictive values were calculated. The McNemar χ2 test was used for comparing sensitivity of both symphisys-fundal curves studied. RESULTS: The sensitivity of the new curve for detecting small for gestational age fetuses was 51.6% while that of the Brazilian Ministry of Health reference curve was significantly lower (12.5%). In the subsample using neonatal weight as gold standard, the sensitivity of the new reference curve was 85.7% while that of the Brazilian Ministry of Health was 42.9% for detecting small for gestational age. CONCLUSIONS: The diagnostic performance of the new curve for detecting small for gestational age fetuses was significantly higher than that of the Brazilian Ministry of Health reference curve.

Impact of academic exposure on health status of university students

OBJECTIVE: To assess the impact of academic life on health status of university students. METHODS: Longitudinal study including 154 undergraduate students from the Universidade de Aveiro, Portugal, with at least two years of follow-up observations. Sociodemographic and behavioral characteristics were collected using questionnaires. Students' weight, height, blood pressure, serum glucose, serum lipids and serum homocysteine levels were measured. Regression analysis was performed using linear mixed-effect models, allowing for random effects at the participant level. RESULTS: A higher rate of dyslipidemia (44.0% vs. 28.6%), overweight (16.3% vs. 12.5%) and smoking (19.3% vs. 0.0%) was found among students exposed to the academic life when compared to freshmen. Physical inactivity was about 80%. Total cholesterol, high density lipoprotein-cholesterol (HDL-C), triglycerides, systolic blood pressure, and physical activity levels were significantly associated with gender (p<0.001). Academic exposure was associated with increased low density lipoprotein-cholesterol (LDL-C) levels (about 1.12 times), and marginally with total cholesterol levels (p=0.041). CONCLUSIONS: High education level does not seem to have a protective effect favoring a healthier lifestyle and being enrolled in health-related areas does not seem either to positively affect students' behaviors. Increased risk factors for non-transmissible diseases in university students raise concerns about their well-being. These results should support the implementation of health promotion and prevention programs at universities.