Activities of Proline-Specific Proteinases in the Serum and Cerebrospinal Fluid of Rats with the Fetal Valproate Syndrome.

In 60-day-old Wistar rats with fetal valproate syndrome, the brain to body weight ratio was higher by 9.4% and activity of dipeptidyl peptidase IV in the serum and cerebrospinal fluid was higher by 18.4 and 40.6%, respectively, than in healthy controls. Activity of prolylendopeptidase in the serum and cerebrospinal fluid in rats with the fetal valproate syndrome did not differ from the control.

A neonatal prolonged QT syndrome due to maternal use of oral tricyclic antidepressants.

UNLABELLED: It is known that tricyclic antidepressants induce long QT intervals associated with forms of life-threatening arrhythmia such as torsades de pointes (TdP), and these adverse effects may also occur in neonates whose mothers take tricyclic antidepressants. We report a neonatal case of prolonged QT interval and TdP caused by clomipramine that was transferred transplacentally from the mother. Administration of magnesium sulfate was effective to abolish TdP. CONCLUSION: When mothers take tricyclic antidepressants during pregnancy, their newborns should be watched carefully for drug-induced long QT syndrome and TdP. WHAT IS KNOWN: •Tricyclic antidepressant can prolong the QT interval. It may be used for depression in pregnancy. What is New: •This is the first neonatal case report of prolonged QT interval and TdP caused by clomipramine transferred transplacentally from the mother.

Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms.

Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3ß-hydroxysteroid dehydrogenase (3ß-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3ß-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a "two-programming" mechanism for PEE-induced adrenal developmental toxicity: "the first programming" is a lower functional programming of adrenal steroidogenesis, and "the second programming" is GC-metabolic activation system-related GC-IGF1 axis programming.

The new biologics in pregnancy.

Growing numbers of women of reproductive age are prescribed new biological agents. This is resulting in more pregnancies exposed to these drugs. What are the new biologics (also referred to as biologicals) and what are their indications? How are they currently used in pregnant women? What are the concerns when treating pregnant women with biologics? What do we know about the reproductive safety of these agents? Current and future research is discussed.

Maternal rat serum concentrations of dimethadione do not explain intra-litter differences in the incidence of dimethadione-induced birth defects, including novel findings in foetal lung.

To investigate mechanisms of chemical-induced congenital heart defects (CHD) we have developed a rat model using dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with inter litter variability ranging from 40 to 100%. The goal of this study was to determine if the variability in maternal serum concentrations of DMO on GD 14, a surrogate marker for total exposure, was related to the inter-litter differences in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses were collected by caesarean section, assessed for a number endpoints and the outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure was associated with decreased foetal body weight, increased incidence of sternal defects and CHD, but these endpoints were not meaningfully correlated with maternal concentrations of DMO. Novel findings were decreased viability as measured one-hour following caesarean section, and delayed alveolar maturation. The major conclusions from these studies were first, that serum DMO concentrations on GD 14 did not predict teratogenicity, and second, delayed lung development may contribute to the decreased survival of foetuses at the time of caesarean section.

Risk of congenital anomalies in relation to the uptake of trihalomethane from drinking water during pregnancy.

OBJECTIVES: Congenital anomalies have been inconsistently associated with maternal crude estimated exposure to drinking water trihalomethane (THM). We investigated the relationship between individual THM uptake during the first trimester of pregnancy and congenital anomalies. METHODS: We estimated maternal THM uptake for 3074 live births using residential tap water concentrations, drinking water ingestion, showering and bathing, and uptake factors of THM in the blood. Multiple logistic regression was used to investigate the association of THM exposure with congenital anomalies. RESULTS: We observed no statistically significant relationships between congenital anomalies and the total THM internal dose. We found little indication of a dose-response relationship for brominated THM and congenital heart anomalies. The relationship was statistically significant for bromodichloromethane (BDCM) (OR=2.16, 95% CI 1.05 to 4.46, highest vs lowest tertile) during the first month of pregnancy. During the first trimester of pregnancy, the probability of developing heart anomalies increased for every 0.1 µg/d increase in the BDCM and for every 0.01 µg/d increase in the internal dibromochloromethane (DBCM) dose (OR 1.70, 95% CI 1.09 to 2.66, and OR 1.25, 95% CI 1.01 to 1.54, respectively). A dose-response relationship was evident for musculoskeletal anomalies and DBCM exposure during the first and second months of pregnancy, while BDCM exposure tended to increase the risk of urogenital anomalies. CONCLUSIONS: This study shows some evidence for an association between the internal dose of THM and the risk of congenital anomalies. In particular, increased prenatal exposure to brominated THM might increase the risk of congenital heart and musculoskeletal anomalies.

Cancer chemotherapeutic agents as human teratogens.

BACKGROUND: Cancer is the second leading cause of death among women of reproductive age. Although the coincidence of pregnancy and cancer is rare and treatment may sometimes be safely delayed, the use of chemotherapeutic agents in pregnancy is sometimes unavoidable or inadvertent. METHODS: We review the literature for the use of antineoplastic agents in single-agent and combination therapy from 1951 through June 2012. We also summarize the evidence relating to teratogenicity of disorder-specific combination chemotherapy treatments for those malignancies frequently encountered in women of childbearing age. Major endpoints were called "adverse pregnancy outcomes" (APOs), to include structural anomalies (congenital malformations), functional defects, blood or electrolyte abnormalities, stillbirths, spontaneous abortions (miscarriages), and fetal, neonatal, or maternal deaths. RESULTS: The registry totals 863 cases. Rates of APOs (and congenital malformations) after any exposure were 33% (16%), 27% (8%), and 25% (6%), for first, second, and third trimesters. Among the groups of cancer drugs, antimetabolites and alkylating agents have the highest rates of APOs. Mitotic inhibitors and antibiotics seem more benign. Mixed results were observed from single-agent exposure, often because of small numbers of exposures. As a whole, the alkylating agents and antimetabolites are more harmful when given as a single agent rather than as part of a regimen. First-trimester exposure poses a more permanent risk to the fetus. CONCLUSIONS: Systematic ascertainment of women early in pregnancy, preferably in a population base, is needed for assessment of true risks. Long-term follow-up is needed to rule out neurobehavioral effects.

Genotoxicity and fetal abnormality in streptozotocin-induced diabetic rats exposed to cigarette smoke prior to and during pregnancy.

BACKGROUND: Maternal hyperglycemia during early pregnancy is associated with increased risk of abnormalities in the offspring. Malformation rates among the offspring of diabetic mothers are 2-5-fold higher than that of the normal population, and congenital malformations are the major cause of mortality and morbidity in the offspring of diabetic mothers. Metabolic changes, such as hyperglycemia and the metabolites obtained from cigarettes both increase the production of reactive oxygen species (ROS) in the embryo or fetus, causing DNA damage. OBJECTIVE: To evaluate the maternal and fetal genotoxicity, and to assess the incidence of fetal anomaly in diabetic female rats exposed to cigarette smoke at different stages of pregnancy in rats. MATERIAL AND METHOD: Diabetes was induced by streptozotocin administration and cigarette smoke exposure was produced by a mechanical smoking device that generated mainstream smoke that was delivered into a chamber. Female Wistar rats were randomly assigned to: non-diabetic (ND) and diabetic (D) groups exposed to filtered air; a diabetic group exposed to cigarette smoke prior to and during pregnancy (DS) and a diabetic group only exposed to cigarette smoke prior to pregnancy (DSPP). On pregnancy day 21, blood samples were obtained for DNA damage analysis and fetuses were collected for congenital anomaly assessment. Statistical significance was set at p<0.05 for all analysis. RESULTS AND CONCLUSION: Exposure of diabetic rats to tobacco smoke prior to pregnancy increased fetal DNA damage, but failed to induce teratogenicity. Thus, these results reinforce the importance for women to avoid exposure to cigarette smoke long before they become pregnant.

Epilepsy and pregnancy.

Since 1963, the association between antiepileptic drugs (AEDs) and congenital malformations in the offspring of women with epilepsy has received attention. A number of articles reported affirmative as well as some negative findings regarding an increased risk of congenital malformations. Although a consensus has not been regarding the presence of the specific malformation syndromes in relation to individual AEDs, such as fetal hydantoin syndrome, it is evident that women taking AEDs carry a two- to sevenfold higher risk of congenital malformations than do the general population. In most recent studies, special attention has been placed on polytherapy, including the specific AED, or AED combinations, and high AED serum concentrations, responsible for the higher risk of congenital malformations. Based on these cumulative results, therapy guidelines for women of childbearing age with epilepsy have been established.

[Lamotrigine in women with epilepsy. Review of present data]. / Lamotrigin bei Frauen mit Epilepsie. Ein Uberblick über die Datenlage.

The manuscript deals with the tolerability of Lamotrigine in women. The recent literature is reviewed with respect to interactions with oral contraceptives, sexuality, infertility, interactions with sex hormones, polycystic ovarian syndrome, adipositas, cosmetic side effects, osteoporosis, pregnancy, breast feeding, and teratogenetic effects. The available data have practical implications for the safe use of Lamotrigine in women.

[Two consecutive pregnancies in a type 1 diabetic under treatment with insulin Lispro]. / Zwei konsekutive komplikationslose Schwangerschaften einer Typ-1-Diabetikerin unter Insulin Lispro.

BACKGROUND: Glucose control is mandatory in pregnant women with type 1 diabetes to keep the incidence of malformations and complications low. Insulin Lispro is a new and popular fast-acting insulin analog used for intensified insulin therapy. Although popular among young patients, this drug has not been licensed for use in pregnancy due to a possibly increased risk of fetal malformations. CASE REPORT: Retrospectively, the case of a 34-year-old woman with diabetes type 1, gravid III and para III, which carried her second and third child full time under Lispro treatment, was analyzed. We performed an interview of the patient and her doctors. Additionally, the pregnancy documents along with the examination documents of the children, our patient files, and the blood glucose documentation were investigated. Contrary to the first pregnancy which was carried out in the absence of Lispro (first degree hip dysplasia), both subsequent pregnancies were completely normal despite continuous Lispro therapy. HbA(1c) values in the range of 4.9-5.9% showed an adequate glucose control throughout these pregnancies. CONCLUSION: This case supports the hypothesis that insulin Lispro which is highly popular among young patients can safely and effectively be used in pregnancies. In order to be able to adequately assess possible risks associated with this application, additional cases need to be documented and analyzed.

Drinking patterns and alcohol-related birth defects.

The consequences of maternal alcohol use during pregnancy on the outcome of offspring depend, among other factors, on the amount and pattern of alcohol consumption. Animal studies found that bingelike drinking patterns, in which the fetus is exposed to high blood alcohol concentrations (BACs) over relatively short periods of time, are particularly harmful, even if the overall alcohol amount consumed is less than those of more continuous drinking patterns. Long-term studies in humans have confirmed that children of binge-drinking mothers exhibited especially severe cognitive and behavioral deficits. Binge drinking may be particularly harmful because it results in high BACs, may occur during critical periods of brain development, and may be associated with repeated withdrawal episodes.

Thyroid hormones in the pathogenesis of lung hypoplasia and immaturity induced in fetal rats by prenatal exposure to nitrofen.

BACKGROUND/PURPOSE: Nitrofen is believed to act on prenatally exposed fetuses by changing maternal or fetal thyroid hormone physiology. The aim of this study was to determine whether the amounts of circulating and lung tissue T3 and T4 are decreased in rat fetuses with nitrofen-induced pulmonary hypoplasia and diaphragmatic hernia. METHODS: Timed-pregnant rats were given 100 mg of nitrofen in oil on gestational day 9.5, and their fetuses were recovered on the 21st day. Lung weight to body weight ratio was determined. Hormonal studies consisted in measurement of plasma T3, T4, and TSH, and of T3, T4, and DNA in lung tissue. Suitable groups of control fetuses prenatally exposed to oil were used for comparison. RESULTS: The lungs of nitrofen-treated fetuses were hypoplastic and those who had congenital diaphagmatic hernia were even more so. Nitrofen treatment led to decreased plasma T3 and T4 levels without TSH changes. T3 and T4 in lung tissue were apparently decreased in treated fetuses when expressed by weight, but these differences disappeared when expressed by DNA (cell content). CONCLUSIONS: Lung hypoplasia and immaturity induced by nitrofen treatment are not related to decreased levels of thyroid hormones in tissue near term. This should be kept in mind when proposing hormonal treatment for prenatal induction of lung maturation.

[Pharmacologic principles of drug prescribing in pregnancy]. / Pharmakologische Grundlagen der Arzneimittelverordnung in der Schwangerschaft.

The administration of drugs to pregnant women comprises special problems. This review gives an overlook on changes in the pharmacocinetics due to pregnancy and on the possible side effects of drugs on embryo and fetus. Finally, general rules for the prescription of drugs to pregnant women are given.

Teratogenic risk with etretinate and acitretin treatment.

Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

Effects of in vivo exposure of pregnant hamsters to glucose. 1. Abnormalities in LVG strain fetuses following intermittent multiple treatments with two isomers.

The increased frequency of congenital malformations including caudal regression syndrome, in infants of women with insulin-dependent diabetes mellitus is well documented. Most of the related animal research has involved the in vitro embryo culturing methodology. This study involved the alternative in vivo approach in order to determine the effects of treatment of pregnant hamsters with the D- and L-isomers of glucose at five times just before and during the period of embryonic organogenesis on maternal blood glucose levels and the rates and types of fetal abnormalities. One group of animals was injected with 5 doses (4 g/kg each) of D-glucose, i.e., on gestation day (D) 6, 3 PM; D7, 8 AM and 3 PM; D8, 8 AM and 3 PM. Two other groups were treated the same way but with L-glucose (4 g/kg per dose) and water (10 ml/kg per dose), respectively. The D-glucose treatment produced alternating periods of hyperglycemia and normoglycemia in the pregnant hamsters, enlarged placentae and fetuses with small urinary bladders, microphthalmia and skeletal abnormalities of the sternum, caudal vertebrae, pelvic bones, and femora. The L-glucose treatment did not produce changes in maternal blood D-glucose levels but did produce fetuses with small urinary bladders, microphthalmia and abnormal ossification limited to the manubrium. Several interpretations of the D-glucose-induced fetal abnormalities involving the vertebrae, proximal hindlimb bones and urinary bladders are discussed, including the consideration that this cluster has interesting similarities to the spectrum of skeletal and soft tissue abnormalities of human diabetes-related caudal regression syndrome.