Hormonal biomarkers for evaluating the impact of fetal growth restriction on the development of chronic adult disease / Biomarcadores hormonais para avaliar o impacto da restrição do crescimento fetal no desenvolvimento de doenças crônicas em adultos

Abstract The hypothesis of fetal origins to adult diseases proposes that metabolic chronic disorders, including cardiovascular diseases, diabetes, and hypertension originate in the developmental plasticity due to intrauterine insults. These processes involve an adaptative response by the fetus to changes in the environmental signals, which can promote the reset of hormones and of the metabolism to establish a "thrifty phenotype". Metabolic alterations during intrauterine growth restriction can modify the fetal programming. The present nonsystematic review intended to summarize historical and current references that indicated that developmental origins of health and disease (DOHaD) occur as a consequence of altered maternal and fetal metabolic pathways. The purpose is to highlight the potential implications of growth factors and adipokines in "developmental programming", which could interfere in the development by controlling fetal growth patterns. These changes affect the structure and the functional capacity of various organs, including the brain, the kidneys, and the pancreas. These investigations may improve the approach to optimizing antenatal as well as perinatal care aimed to protect newborns against long-termchronic diseases.

Resumo A hipótese das origens fetais de doenças em adultos propõe que distúrbios crônicos metabólicos, incluindo doenças cardiovasculares, diabetes e hipertensão, se originam na plasticidade do desenvolvimento devido a insultos intrauterinos. Estes processos envolvem uma resposta adaptativa do feto amudanças nos sinais ambientais que podem promover a redefinição dos hormônios e do metabolismo para estabelecer um "fenótipo poupador". Alteraçõesmetabólicas durante a restrição de crescimento intrauterino podem modificar a programação fetal. A presente revisão não-sistemática pretendeu resumir referências históricas e atuais que indicassem que as origens desenvolvimentistas da saúde e doença (DOHaD, na sigla em inglês) ocorrem como consequência de alterações nas vias metabólicas materna e fetal. O propósito é destacar as potenciais implicações de fatores de crescimento e adipocinas na "programação do desenvolvimento", que poderia interferir no desenvolvimento, controlando os padrões de crescimento fetal. Estas alterações afetam a estrutura e a capacidade funcional de inúmeros órgãos, incluindo o cérebro, os rins e o pâncreas. Estas investigações podemmelhorar a abordagempara otimizar os cuidados prénatais e perinatais, como objetivo de proteger os recém-nascidos contra doenças crônicas em longo prazo.

Asociación de nivel bajo de PAPP-A en primer trimestre con resultados obstétricos adversos / Association of low PAPP-A level in the first trimester with adverse obstetric outcomes

ANTECEDENTES: La PAPP-A es una proteína utilizada en obstetricia de forma rutinaria para el cribado de aneuploidías de primer trimestre. En los últimos años se está conociendo más acerca de su papel en la función placentaria. Diversos estudios están mostrando una asociación entre un nivel bajo de PAPP-A y distintos eventos obstétricos. OBJETIVO: Establecer una asociación entre PAPP-A baja y eventos obstétricos adversos. MÉTODO: Estudio retrospectivo de casos y controles anidado en una cohorte. Se han recogido las gestaciones únicas con PAPP-A inferior a percentil 5 en primer trimestre durante 2 años. Se ha recogido de la misma cohorte un grupo control, en proporción 2:1. Se compara mediante análisis estadístico la incidencia de eventos obstétricos adversos de cada grupo. RESULTADOS: Se incluyó un total de 285 pacientes en el grupo de casos y 570 pacientes en el grupo control. Se observó un aumento significativo en el grupo de casos de la incidencia de prematuridad, restricción del crecimiento, hipertensión gestacional y diabetes gestacional. Se ha correlacionado la PAPP-A baja con varios eventos obstétricos adversos, incluyendo prematuridad (OR 4,27), diabetes gestacional (OR 2,40), restricción del crecimiento (OR 2,36) e hipertensión gestacional (OR 2,22). No se observó relación con el resto de eventos obstétricos adversos. CONCLUSIÓN: Un nivel de PAPP-A bajo se asocia con aumentos significativos de prematuridad, diabetes gestacional, restricción del crecimiento e hipertensión gestacional.

BACKGROUND: PAPP-A is a placental protein used in obstetrics as a first trimester marker in aneuploidy screening. In the last few years we are knowing more about its placental function. Some studies are showing a association between low PAPP-A and obstetrical adverse events. AIM: Establish an association between low PAPP-A an obstetrical adverse events. METHOD: This is a retrospective nested case-control study. We identified each singleton pregnancy with a normal phenotype and a low PAPP-A (under percentile 5) in the last 2 years, and match it with a control group of the same population in a 2:1 proportion. It was compared the incidence of each obstetrical adverse outcomes with statistical analysis. RESULTS: We found 285 patients in the case group and match it with 570 patients from control group. It was observed a significative increase in the incidence of prematurity, intrauterine growth restriction, gestational hypertension and gestational diabetes. A low PAPP-A level was correlated with some obstetrical adverse events, like prematurity (OR 4.27), gestational diabetes (OR 2.40), intrauterine growth restriction (OR 2.36) and gestational hypertension (OR 2.22). We observe no correlation with the rest of outcomes. CONCLUSIONS: A low PAPP-A level is related with significative increases of prematurity, gestational diabetes, intrauterine growth restriction and gestational hypertension.

Evaluación de la globulina transportadora de hormonas esteroidales (SHBG) durante el embarazo como factor predictor de pre-eclampsia y restricción del crecimiento intrauterino / Sex-hormone binding globulin (SHBG) levels during pregnancy as predictors for pre-eclampsia and fetal growth restriction

Background: Sex-Hormone Binding Globulin (SHBG) may be associated to Pre-eclampsia (PE) and Fetal Growth Restriction (RCIU). Aim: To determine if maternal serum SHBG concentrations during the first and second trimesters are predictive biomarkers of Pre-eclampsia and RCIU. Patients and Methods: Prospective cohort study carried out in the Fetal Medicine Unit, Universidad de Chile Clinical Hospital between January, 2005 and December, 2006. Blood samples were obtained from unselectedpregnant women during routine 11-14 week and 22-25 week ultrasound examinations, conforming two different study groups. Posteriorly, serum SHBG concentrations were determined in women who developed Pre-eclampsia, RCIU and their respective controls. Results: Fifty five patients were included in the 11-14 weeks group. Nine women that developed PE, 10 that developed RCIU and 36 controls were selected from this group. There were no significant differences in SHBG levels between patients with PE, RCIU or controls (324.7 (26.6), 336.8 (33.9) and 377.5 (24.3) nmol/L, respectively). Fifty four women were included in the 22-25 weeks group. Eight women who developed Pre-eclampsia, 15 who developed RCIU and 31 controls were selected. Again, there were no significant differences in SHBG levels between patients with PE, RCIU or controls (345.5 (151.1), 383.8 (143.4) and 345.5 nmol/l (151.1), respectively). Conclusions: Maternal SHBG serum levels did not predict subsequent development of Pre-eclampsia and RCIU.

Endothelin-1 and leptin as markers of intrauterine growth restriction.

Objective. To explore the role of endothelin-1 (ET-1) and leptin in intrauterine growth restriction (IUGR) among preeclamptic and non-pre-eclamptic women. Methods. Forty three patients with a pregnancy complicated by IUGR, 23 cases with severe pre-eclampsia and 20 cases of non-pre-eclamptic were enrolled. Control group comprised 15 cases with uncomplicated pregnancy. Blood samples from umbilical artery and maternal venous blood were collected at the time of delivery for analysis of ET-1 and leptin levels. Mode of delivery, birth weight and Apgar score were also recorded. Results. The mean maternal and fetal ET-1 level was significantly higher in pregnancies complicated by IUGR than in control group. The mean maternal leptin level was significantly higher in pre-eclamptic patients when compared to nonpreeclamptic and control groups. Mean fetal leptin level was significantly lower in patients compared to control; however, when fetal leptin corrected to fetal weight, it was insignificantly different in the both groups. Conclusion. Maternal plasma ET-1 and leptin correlate with the degree of fetal growth restriction originating from deterioration of placental function. Maternal plasma leptin and ET-1 levels may reflect deterioration in fetal growth.

Growth hormone in intra-uterine growth retarded newborns.

OBJECTIVE: To study growth hormone levels in IUGR and healthy controls and its association with birth weight and ponderal index. METHODS: We studied 50 Intra uterine growth retarded (IUGR) and 50 healthy newborns born at term by vaginal delivery in JIPMER, Pondicherry, India. Cord blood was collected at the time of delivery for measurement of growth hormone. RESULTS: When compared with healthy newborns, IUGR newborns had higher growth hormone levels (mean +/- SD, 23.5 +/- 15.6 vs 16.2 +/- 7.61 ngm/ml, P = 0.019). A negative correlation was identified between growth hormone levels and birth weight (r2 = - 0.22, P = 0.03) and ponderal index (r2 = - 0.36, P = 0.008). Correlation of growth hormone levels was much more confident with ponderal index than with birth weight. CONCLUSION: At birth IUGR infants display increased growth hormone levels which correlate with ponderal index much more confidently than with birth weight.

Serum triglyceride level in IUGR babies and its comparison with preterm AGA and term normal babies.

Intrauterine growth and birth weight are probably the most important factors that affect in survival and future quality of life. Intrauterine growth retardation causes program changes in body systems specially lipid metabolism that creates various problems of which coronary heart disease is important. Higher serum triglyceride (TG) level in IUGR babies relates to increase incidence of coronary heart disease. This cross sectional study was conducted in Bhangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh during July 2004 to June 2005. Serum TG levels were estimated among three groups: IUGR (n=30), preterm appropriate for gestational age (AGA) (n=30) and term normal (n=30) new born babies. Blood samples were collected from the study population in the neonatal unit and serum TG level were measured with all accuracy in a computerized automated biochemical analyzer in Biochemistry department of BSMMU. Statistical analysis were done by using student's 't' test. It was observed that serum TG level (54.4 +/- 11.2 mg/dl) in IUGR babies were significantly higher than that of term normal babies (38.7 +/- 5.8 mg/dl), p value < 0.05. This implicate future coronary heart disease in these babies as shown by others in long term prospective studies.

Plasma zinc level and intrauterine growth retardation: a study in pregnant women in Ramathibodi Hospital.

The study was designed to establish the relationship between plasma zinc level and intrauterine growth retardation in 405 normal pregnant women with an age range from 20 to 35 years, who attended and delivered at Ramathibodi Hospital The data were gathered from October 1994 to April 1995. The zinc levels were obtained from blood plasma collection and the assessment of fetal status was made after birth. Using criteria of babies with a birthweight of less than the 10th centile at delivery. Plasma zinc level in mother was collected during antenatal care and labour. Plasma zinc level was determined by Atomic Absorption Spectrophotometry. The plasma zinc levels in mothers during antenatal care, labour and infant birthweight were 66.73 micrograms/dl, 69.91 micrograms/dl and 3152.25 g respectively. Maternal plasma zinc levels during antenatal care, labour and infant birthweight in the intrauterine growth retardation infant group were significantly lower than that in normal growth infants (P < 0.05). In conclusion, our study shows that measurement of maternal plasma zinc concentration in the third trimester would highly suggest mothers at risk of delivering intrauterine growth retardation babies. Mothers selected in this way might benefit from dietary advice and zinc supplementation during the remaining pregnancy.

Maternal zinc indices and small babies.

BACKGROUND: Maternal zinc deficiency has been reported to be associated with foetal growth retardation. This study aimed to determine if zinc deficiency is associated with foetal growth retardation in south Indian women. METHODS: A prospective study was undertaken to evaluate the maternal zinc indices in those bearing small-for-gestational age babies and in those with appropriate-for-gestational age babies. Zinc levels in plasma, red blood cells and white blood cells in both groups were assayed in 65 patients with small-for-gestational age babies (regardless of cause) and 51 women with appropriate-for-gestational age babies. RESULTS: There was no significant difference in the mean (SD) plasma [67.5 (9) v. 70.67 (13.9)], red blood cell [47.26 (5.8) v. 45.69 (8.2)] and white blood cell [55.61 (10.5) v. 54.77 (12.4)] zinc levels in mothers who gave birth to small-for-gestational age babies and those who delivered appropriate-for-gestational age babies. The presence of predisposing factors for intrauterine growth retardation also did not influence the maternal zinc levels. CONCLUSION: Maternal zinc levels were not associated with intrauterine growth retardation in our population.

Maternal hemoglobin and serum albumin and fetal growth.

Four hundred and eighty four pregnant women and their offsprings were studied to determine the relationship of maternal hemoglobin and serum protein levels on the birthweight of offspring. The correlation coefficient of maternal hemoglobin as well as serum albumin level (gamma = 0.1097 and 0.0936, respectively) with birthweight were not statistically significant. However, mean birthweight of neonates born to nonanemic mothers was significantly higher than of those born to anemic mothers. The prevalence of low birthweight babies was significantly higher among anemic mothers (p < 0.01); however, no such trend was observed in relation to maternal serum albumin (p > 0.05).

In vitro effect of intravenous immunoglobulin on serum opsonic activity in normal & intrauterine growth retarded neonates.

In vitro effect of intravenous immunoglobulin (IVIG), Intraglobin F, on serum opsonic activity against Staphylococcus aureus was studied in 26 full term normal healthy neonates and 18 intrauterine growth retarded (IUGR) neonates by the polymorphonuclear leucocyte overlay method (requiring only a few drops of blood). Cord IgG and IgM levels were determined by single radial immunodiffusion. Serum opsonic activity against Staph. aureus was significantly lower in the IUGR neonates (49.1 +/- 0.89), as compared to that in normal neonates (61.96 +/- 0.73; P less than 0.001). Immunoglobulin supplementation in vitro at a concentration of 5 g/dl significantly enhanced the opsonic activity of IUGR neonate sera. Cord IgG levels of IUGR neonates were significantly lower (P less than 0.01) than IgG levels of normal neonates. No significant difference was observed in cord IgM levels between the normal and IUGR neonates.

Study on blood level of human placental lactogen in abnormal pregnancy.

The hormone human placental lactogen (HPL) was measured in 15 expectant mothers with pre-eclamptic toxaemia, 5 with postdated pregnancy and 2 mothers with intrauterine growth retardation (IUGR). These levels were compared with that of 43 expectant mothers without any complications. In preeclamptic toxaemia (PET), HPL showed higher or normal values but in severe cases of PET and in those with proteinuria, hormone level was depressed as compared to normal pregnancy. Also in younger mothers (22 years or less) with the complication, the hormone level was low, though no relation with parity was observed. In case of IUGR, the hormone level was within the normal range although one pregnancy ended in intra-uterine foetal death. Low level of the hormone was found in pregnancies ending in low birth weight babies and in postdated pregnancies with foetal postmaturity syndrome.

Cord blood lipid levels in low birth weight newborns.

Cord blood cholesterol, triglyceride and FFA levels were estimated in 73 newborns, subdivided into various gestation weight categories (FTAGA, PTAGA, FTSGA and PTSGA). Cholesterol levels were not influenced by birth weight and gestation. Prematurity and growth retardation caused a significant elevation in triglyceride values. FFA levels were not influenced by prematurity, but growth retardation produced a significant increase. Birth weight and gestational age should be taken into consideration before labelling the newborn as hyperlipidemic.