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.

Zika virus damages the human placental barrier and presents marked fetal neurotropism

An unusually high incidence of microcephaly in newborns has recently been observed in Brazil. There is a temporal association between the increase in cases of microcephaly and the Zika virus (ZIKV) epidemic. Viral RNA has been detected in amniotic fluid samples, placental tissues and newborn and fetal brain tissues. However, much remains to be determined concerning the association between ZIKV infection and fetal malformations. In this study, we provide evidence of the transplacental transmission of ZIKV through the detection of viral proteins and viral RNA in placental tissue samples from expectant mothers infected at different stages of gestation. We observed chronic placentitis (TORCH type) with viral protein detection by immunohistochemistry in Hofbauer cells and some histiocytes in the intervillous spaces. We also demonstrated the neurotropism of the virus via the detection of viral proteins in glial cells and in some endothelial cells and the observation of scattered foci of microcalcifications in the brain tissues. Lesions were mainly located in the white matter. ZIKV RNA was also detected in these tissues by real-time-polymerase chain reaction. We believe that these findings will contribute to the body of knowledge of the mechanisms of ZIKV transmission, interactions between the virus and host cells and viral tropism.

Correlation between specific IgM levels and percentage IgG-class antibody avidity to Toxoplasma gondii

Toxoplasmosis is an usually asymptomatic worldwide disseminated infection. In its congenital presentation it may lead to abortion or fetal malformations. Antenatal evaluation is considered of paramount importance to identify seronegative women and allow for prophylaxis. Recent improvements in sensitivity of IgM tests has made IgM detection an extremely protracted acute phase marker, and IgG avidity evaluation test became necessary. Observation has shown that a correlation can be established between IgM levels and avidity percentages, suggesting that frequently the avidity test may not be necessary. In this study we analyzed Toxoplasma gondii IgM levels of 202 samples and their IgG avidity percentages, in order to define specific levels whose IgM quantification could by itself define serodiagnosis and therefore make the avidity evaluation unnecessary. We showed that for IgM levels bellow 2.0 and above 6.0 serodiagnosis of toxoplasmosis could be established without need of IgG avidity test. IgM levels between these two parameters are associated with varying avidity indexes highlighting the importance of its evaluation as a means to confirm toxoplasmosis. Following this demonstration it was possible to avoid the avidity test for 75% of the cases, to reduce the turnaround time and to reduce costs.

Do induced twin pregnancies influence the obstetric and neonatal results of multiple births born before 32 weeks? Comparison to spontaneous gestation

PURPOSE: To compare obstetric outcomes of induced preterm twin births (under 32 weeks gestation) with those spontaneously conceived. METHODS: Prospective study of twin pregnancies (25 induced and 157 spontaneously conceived) developed over a period of 16 years in a tertiary obstetric center. Demographic factors, obstetric complications, gestational age at delivery, mode of delivery, birth weight and immediate newborn outcome were compared. RESULTS: The analysis of obstetrical complications concerning urinary or other infections, hypertensive disorders of pregnancy, gestational diabetes, fetal malformations, intrauterine fetal death, intrauterine growth restriction and intrauterine discordant growth reveal no significant statistical differences between the two groups. First trimester bleeding was higher in the induced group (24 versus 8.3%, p=0.029). The cesarean delivery rate was 52.2% in spontaneous gestations and 64% in induced gestations. Gestational age at delivery, birth weight, Apgar scores at first and fifth minutes, admissions to Neonatal Intensive Care Unit and puerperal complications show no statistically significant differences between the two groups. These results were independent of chorionicity and induction method. CONCLUSION: The mode of conception did not influence obstetric and neonatal outcomes. Although induced pregnancies have higher risk of first trimester bleeding, significant differences were not observed regarding other obstetric and puerperal complications and neonatal results.

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.

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.

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.

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.

Qualidade das informações registradas nas declarações de óbito fetal em São Paulo, SP

OBJETIVO: Avaliar a qualidade da informação registrada nas declarações de óbito fetal. MÉTODOS: Estudo documental com 710 óbitos fetais em hospitais de São Paulo, SP, no primeiro semestre de 2008, registrados na base unificada de óbitos da Fundação Sistema Estadual de Análise de Dados e da Secretaria de Estado da Saúde de São Paulo. Foi analisada a completitude das variáveis das declarações de óbito fetal emitidas por hospitais e Serviço de Verificação de Óbitos. Os registros das declarações de óbito de uma amostra de 212 óbitos fetais de hospitais do Sistema Único de Saúde foram comparados com os dados dos prontuários e do registro do Serviço de Verificação de Óbitos. RESULTADOS: Dentre as declarações de óbito, 75% foram emitidas pelo Serviço de Verificação de Óbitos, mais freqüente nos hospitais do Sistema Único de Saúde (78%). A completitude das variáveis das declarações de óbito emitidas pelos hospitais foi mais elevada e foi maior nos hospitais não pertencentes ao Sistema Único de Saúde. Houve maior completitude, concordância e sensibilidade nas declarações de óbito emitidas pelos hospitais. Houve baixa concordância e elevada especificidade para as variáveis relativas às características maternas. Maior registro das variáveis sexo, peso ao nascer e duração da gestação foi observada nas declarações emitidas no Serviço de Verificação de Óbitos. A autópsia não resultou em aprimoramento da indicação das causas de morte: a morte fetal não especificada representou 65,7% e a hipóxia intrauterina, 24,3%, enquanto nas declarações emitidas pelos hospitais foi de 18,1% e 41,7%, respectivamente. CONCLUSÕES: É necessário aprimorar a completitude e a indicação das causas de morte dos óbitos fetais. A elevada proporção de autópsias não melhorou a qualidade da informação e a indicação das causas de morte. A qualidade das informações geradas de autópsias depende do acesso às informações hospitalares.

Fetal deaths in Brazil: a systematic review

OBJECTIVE To review the frequency of and factors associated with fetal death in the Brazilian scientific literature.METHODS A systematic review of Brazilian studies on fetal deaths published between 2003 and 2013 was conducted. In total, 27 studies were analyzed; of these, 4 studies addressed the quality of data, 12 were descriptive studies, and 11 studies evaluated the factors associated with fetal death. The databases searched were PubMed and Lilacs, and data extraction and synthesis were independently performed by two or more examiners.RESULTS The level of completeness of fetal death certificates was deficient, both in the completion of variables, particularly sociodemographic variables, and in defining the underlying causes of death. Fetal deaths have decreased in Brazil; however, inequalities persist. Analysis of the causes of death indicated maternal morbidities that could be prevented and treated. The main factors associated with fetal deaths were absent or inadequate prenatal care, low education level, maternal morbidity, and adverse reproductive history.CONCLUSIONS Prenatal care should prioritize women that are most vulnerable (considering their social environment or their reproductive history and morbidities) with the aim of decreasing the fetal mortality rate in Brazil. Adequate completion of death certificates and investment in the committees that investigate fetal and infant deaths are necessary.

Study on the growth promoting capacity of calf and fetal bovine serum for animal cells "in vitro" II: electrophoretic study and survey on the antiproteolytic activity of pools of calf and fetal bovine serum

Calf serum and fetal bovine serum present great variability as to its growth promoting efficiency (GPE). As supplement of culture media to cultivate cells of animal origin they stimulate the "in vitro" multiplication and maintain cell viability. When fourteen lots of calf sera of variable GPE had the total protein contents as well as the percentages of serum fractions determined, no significant differences that could possibly explain the variability of the GPE were observed. Evaluation of the antiproteolytic activity of nineteen lots of calf serum and eighteen serum lots of younger calves showed that the former exhibited lower antiproteolytic titers (1:40 to 1:80) than the latter (1:80 to 1:160). Twelve lots of fetal bovine serum studied in parallel, showed the highest concentration of antiproteolytic factors, with titers equal to 1:320. Sera of bovine origin, but not fetal sera, are usually heat-inactivated, what was demonstrated to be responsible for the decrease of the antiproteolytic activity of 75% of the lots tested. This could explain the inability of certain heat-inactivated sera in promoting multiplication of some cells "in vitro", as verified with primary monkey kidney cells. The results obtained in this study indicated the convenience of submiting each lot of serum to be introduced in cell culture to previous determination of its characteristics, such as growth promoting efficiency, antiproteolytic activity and also toxicity, absence of extraneous agents, etc., in order to minimize the possibility of using serum lots of questionable quality, thus preventing not only the loss of cell lines, but also undesirable and sometimes expensive delays.

A prospective study with children whose mothers had dengue during pregnancy

Dengue congenital disease was not confirmed in 10 children whose mothers had the infection during pregnancy. The fetal sera presented anti-dengue IgG antibodies which progressively declined, and disappeared after 8 months. IgM antibodies to dengue were not observed in the sera. Other normal data suggesting the healthy state of the children included: absence of malformations, pregnancy time, Apgar index, weight, and placenta aspect

Detection of parvovirus B19 infection in formalin-fixed and paraffin-embedded placenta and fetal tissues

Parvovirus B19 infection was first discovered in 1975 and it is implicated in fetal death from hydrops fetalis the world over. Diagnosis is usually made through histological identification of the intranuclear inclusion in placenta and fetal organs. However, these cells may be scarce or uncharacteristic, making definitive diagnosis difficult. We analyzed histologically placentas and fetal organs from 34 cases of non-immune hydrops fetalis, stained with Hematoxylin and Eosin (HE) and submitted to immunohistochemistry and polymerase chain reaction (PCR). Of 34 tissue samples, two (5.9%) presented typical intranuclear inclusion in circulating normoblasts seen in Hematoxylin and Eosin stained sections, confirmed by immunohistochemistry and PCR. However, PCR of fetal organs was negative in one case in which the placenta PCR was positive. We concluded that parvovirus B19 infection frequency is similar to the literature and that immunohistochemistry was the best detection method. It is highly specific and sensitive, preserves the morphology and reveals a larger number of positive cells than does HE with the advantage of showing cytoplasmic and nuclear positivity, making it more reliable. Although PCR is more specific and sensitive in fresh or ideally fixed material it is not so in formalin-fixed paraffin-embedded tissues, frequently the only one available in such cases.