Use of Acitretin Among Girls and Women of Childbearing Age and Occurrence of Acitretin-Exposed Pregnancies in Germany.

BACKGROUND AND OBJECTIVE: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero. METHODS: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations. RESULTS: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation). CONCLUSIONS: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug.

Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study.

OBJECTIVE: To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used four Nordic countries' nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations. RESULTS: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46-1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44-1.58) or both metformin and insulin (0.98, 0.56-1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55-1.84) for any metformin, 0.92 (0.47-1.81) for metformin alone, and 1.72 (0.76-3.91) for both metformin and insulin. CONCLUSIONS: No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.

Risk of Major Malformations Following First-Trimester Exposure to Olanzapine: Preliminary Data From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

PURPOSE/BACKGROUND: Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanzapine during pregnancy compared with a group of nonexposed infants. METHODS/PROCEDURES: The National Pregnancy Registry for Psychiatric Medications is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Labor and delivery and pediatric medical records were screened for evidence of major malformations followed by adjudication by a dysmorphologist blinded to medication exposure. Infants with first-trimester exposure to olanzapine were compared with controls without second-generation antipsychotic exposure. FINDINGS/RESULTS: As of April 18, 2022, 2619 women have enrolled in the study. At the time of data extraction, 49 olanzapine-exposed infants and 1156 infants in the comparison group were eligible for these analyses. There were no major malformations associated with olanzapine exposure in the first trimester. The absolute risk for major malformations in the exposure group was 0.00% (95% confidence interval, 0.00-7.25) for olanzapine compared with 1.64% (95% confidence interval, 0.99-2.55) in the control group. IMPLICATIONS/CONCLUSIONS: In this prospective cohort, no major malformations were associated with olanzapine exposure during the first trimester. Although these data are preliminary and cannot rule out more modest effects, they are nonetheless important, adding to the growing reproductive safety data for olanzapine.

The North American Antiepileptic Drug Pregnancy Registry: A Canadian Subgroup Analysis.

BACKGROUND: The North American AED Pregnancy Registry (NAAPR) provides crucial data for understanding the risks of antiepileptic drug (AED) exposure in pregnancy. This study aims to quantify the Canadian contribution to NAAPR and compare AED usage in pregnancy in Canada and the USA. METHODS: Enrollment rate ratios (ERR) to NAAPR, adjusted for the populations of women of childbearing age, were calculated for the USA, Canada, and for the different Canadian provinces. Methods of enrollment to NAAPR and AED usage were compared between the two countries using chi-squared tests. RESULTS: Between 1997 and 2019, 10,215 pregnant women enrolled into NAAPR: 4.1% were Canadian (n = 432, ERR = 0.39, CI95% = 0.35-0.43). Within Canada, no patients were enrolled from the three northern territories or from Prince Edward Island. While fewer patients than expected enrolled from Quebec (ERR = 0.35, CI95% = 0.19-0.58), Nova Scotia had the highest enrollment rate (ERR = 1.55; CI95% = 0.66-3.11). Compared with their American peers, Canadians were less likely to have been enrolled by their healthcare provider and more likely to have been enrolled via social media (p < 0.01). Canadian women were more likely to be taking carbamazepine (24% vs. 15%; p < 0.01) or valproic acid (8% vs. 4%; p < 0.01). CONCLUSION: The proportion of Canadian enrollees into NAAPR was less than expected based on the relative population size of Canadian women of reproductive age. Greater Canadian enrollment to NAAPR would contribute to ongoing worldwide efforts in assessing the risks of AEDs use in pregnant women and help quantify rates of AED usage, major congenital malformations, and access to subspecialized epilepsy care within Canada.

The Use of Antiepileptic Drugs During Pregnancy and Fetal Outcomes.

Epilepsy affects approximately 1 percent of the population and roughly 1 million women of childbearing age. Estimates suggest that 0.3-0.7 percent of pregnancies occur in women with epilepsy. Epilepsy itself increases the risk of congenital malformation and medications add to this risk. Also, approximately one-half of the use of medications for epilepsy are used for other indications, possibly increasing exposure in some women. As controlled trials with these medications are not performed during pregnancy, data has been accumulated primarily through databases and case studies. This review is intended to update the practitioner about the use and concerns of antiepileptic medications in the presnant woman and the potential effects on the fetus and neonate.

Epilepsy in Pregnancy-Management Principles and Focus on Valproate.

An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20-40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Contemporary trends in antiepileptic drug treatment among women of childbearing age with epilepsy in the United States: 2004-2015.

OBJECTIVE: Certain antiepileptic drugs are associated with an increased risk for major congenital malformations (MCM). However, little is known regarding recent patterns of antiepileptic drug (ASM) prescriptions to women of childbearing age with epilepsy (WCE) in the United States. METHODS: Data from the Medical Expenditure Panel Survey was analyzed between the years 2004-2015 to determine trends in national antiepileptic drug prescriptions for WCE. Analysis of associations between demographic covariates and prescription of ASMs with MCM rate > 5% (topiramate, valproate, or phenobarbital) was performed with logistic regression. RESULTS: There was a weighted total of 395,292 WCE. 29.1% (23.2%-35.8%) of WCE were prescribed an AED with MCM rate > 5%. The odds of a LEV prescription significantly increased in the 2010-2012 (OR 2.91, 95% CI 1.09-7.79) and 2013-2015 (OR 5.06, 95% CI 2.02-12.67) intervals compared to 2004-2006. Conversely, the odds of PB prescriptions significantly decreased in 2010-2012 (OR 0.13, 95% CI 0.02-0.83) and 2013-2015 (OR 0.13, 95% CI 0.02-0.93) compared to 2004-2006. WCE between the ages of 25-34 (OR = 2.67, 95% CI = 1.32-5.41) and 35-44 years (OR = 2.59, 95% CI = 1.23-5.45), had lower odds of being prescribed ASMs with MCM rate > 5% compared to those between the ages of 15-24 years. SIGNIFICANCE: Between 2004 and 2015, the prescriptions of ASMs given to WCE has changed. Regardless, nearly one third were prescribed potentially teratogenic medications despite available and affordable safer alternatives. Identifying factors associated with the prescription of teratogenic drugs to WCE is critical so that it may be further limited in the future.

Levetiracetam Use During Pregnancy in Women With Active Epilepsy: A Hospital-Based, Retrospective Study from a Tertiary Care Hospital in North Eastern INDIA.

BACKGROUND AND PURPOSE: Epilepsy during pregnancy is a therapeutic challenge. Since the 1990s, the number of licensed antiepileptic drugs has substantially increased, but safety data on managing epilepsy during conception, pregnancy, and postpartum period use of newer generation antiepileptic drugs and birth defects are limited. We analyzed efficacy and safety of levetiracetam during pregnancy in northeast Indian women with active epilepsy (WWAE) which is being presented here. DESIGN: Hospital based retrospective study. PATIENTS AND METHODS: A retrospective analysis was conducted based on clinical records at a tertiary care teaching hospital and referral center in Northeast India between June 2008 through June 2018 without any personal identifying information. The Obstetric data from pregnancy register was supplemented with detailed neurologic data retrieved from medical records. RESULTS: Of 103 women with active epilepsy, 47 (45.6%) received levetiracetam as monotherapy and 56 (54.4%) as polytherapy. During pregnancy, the seizure frequency was unchanged, or the change was better in the majority (61.1%) of the patients. With one twin pregnancy, there were 96 live births, 5 spontaneous abortions, 2 induced abortions, 1 stillbirth. However, the rate of small for gestational age was higher in WWAE, Apgar score at 5 min was lower in infants of WWAE, and the need for care in the neonatal ward and neonatal intensive care was higher. Seven of 103 exposed pregnancies had a major congenital malformation (6.79%), all 7 were exposed to other antiepileptic drugs. Generalized epilepsy accounted for 57.2%. CONCLUSION: Pregnancy course is uncomplicated and neonatal outcome is good in the majority of women with active epilepsy with proper antenatal and neurologic care. Levetiracetam taken in monotherapy can be considered as safer alternative for women with epilepsy of childbearing age. Long-term follow-up of neuropsychological and cognitive development of the children of WWAE is still needed.

Establishing or Excluding a Diagnosis of Fetal Valproate Spectrum Disorder is a Multi-layered Process.

Background In 2017/2018, the Health Products Regulatory Authority issued new guidance on the prescription of Sodium Valproate (VPA) to female patients of reproductive age. A review was initiated of VPA exposed individuals to identify whether previously unascertained cases of VPA related Embryopathy could be identified. Methods Forty patients under twenty-three years of age were reviewed. Results Eleven (27.5%) new cases of Fetal Valproate Spectrum Disorder (FVSD) were identified. Twenty-four (60%) cases were felt not to satisfy diagnostic threshold for this teratogenic disorder. Five (12.5%) cases were indeterminate. Six of the forty patients (15%) had an alternative genetic cause of developmental delay established. Conclusion There is increased awareness regarding avoidance of VPA use in women of childbearing age. An equal awareness is warranted that developmental delay in the context of VPA exposure in pregnancy does not necessarily constitute a diagnosis of FVSD but that other competing diagnostic hypotheses have to be considered.

Alpha-lipoic acid ameliorates cytarabine-induced developmental anomalies in rat fetus.

Cytarabine (Ara-C) is a nucleoside analogue used in the treatment of cancers and viral infections. It has teratogenic potential and causes a variety of birth defects in fetuses. Alpha-lipoic acid (ALA) is a natural antioxidant offers protection against the developmental toxicity induced by drug- or toxicant-exposure or pathological conditions. This study was aimed at evaluating the protective effect of ALA against Ara-C induced developmental toxicity in rat fetus. Pregnant rats divided into five groups and received normal saline, ALA200 mg/kg, Ara-C12.5 mg/kg, Ara-C25 mg/kg and, Ara-C25 mg/kg plus ALA200 mg/kg respectively from gestational day (GD) 8 to GD14 and sacrificed on GD21. Ara-C treatment led to a significant and dose-dependent decrease in food intake, weight gain, placental weight, and an increase in oxidative stress in pregnant rats. Further, the in-utero exposure to Ara-C led to an increase in fetal mortality, resorptions, oxidative stress, external morphological anomalies and limb abnormalities, and impaired ossification. Co-administration of ALA resulted in amelioration of the footprints of Ara-C induced toxicity in pregnant rats as well as the fetus. These findings indicate that the ALA supplementation offers protection against developmental toxicity caused by Ara-C prenatal exposure in rats.

Folic acid reduces the ethanol-induced morphological and behavioral defects in embryonic and larval zebrafish (Danio rerio) as a model for fetal alcohol spectrum disorder (FASD).

The objective of this work was to determine whether folic acid (FA) reduces the embryonic ethanol (EtOH) exposure induced behavioral and morphological defects in our zebrafish fetal alcohol spectrum disorder (FASD) model. Teratogenic effects, mortality, the excitatory light-dark locomotion (ELD), sleep (SL), thigmotaxis (TH), touch sensitivity (TS), and optomotor response (OMR) tests were evaluated in larvae (6-7 days post-fertilization) using four treatment conditions: Untreated, FA, EtOH and EtOH + FA. FA reduced morphological defects on heart, eyes and swim bladder inflation seen in EtOH exposed fish. The larvae were more active in the dark than in light conditions, and EtOH reduced the swimming activity in the ELD test. EtOH affected the sleep pattern, inducing several arousal periods and increasing inactivity in zebrafish. FA reduces these toxic effects and produced more consistent inactivity during the night, reducing the arousal periods. FA also prevented the EtOH-induced defects in thigmotaxis and optomotor response of the larvae. We conclude that in this FASD model, EtOH exposure produced several teratogenic and behavioral defects, FA reduced, but did not totally prevent, these defects. Understanding of EtOH-induced behavioral defects could help to identify new therapeutic or prevention strategies for FASD.

Pregnancy and Neonatal Outcomes Following Prenatal Exposure to Dolutegravir.

BACKGROUND: Birth outcome data with dolutegravir exposure during pregnancy, particularly in the first trimester, are needed. SETTING: Data were prospectively collected from the Antiretroviral Pregnancy Registry and European Pregnancy and Paediatric HIV Cohort Collaboration. METHODS: We reviewed 2 large, independent antiretroviral pregnancy registries to assess birth outcomes associated with maternal dolutegravir treatment during pregnancy. RESULTS: Of 265 pregnancies reported to the Antiretroviral Pregnancy Registry, initial exposure to dolutegravir occurred at conception or first trimester in 173 pregnancies and during the second or third trimester in 92 pregnancies. There were 246 (92.8%) live births resulting in 255 neonates (9 twins), 6 (2.3%) induced abortions, 11 (4.2%) spontaneous abortions, and 2 (0.8%) stillbirths. Birth defects occurred in 7 (2.7%) of 255 live-born neonates, 5 (3.1%) of 162 (includes 6 twins) with conception/first-trimester exposure. Of 101 pregnancies reported to the European Pregnancy and Paediatric HIV Cohort Collaboration, outcomes were available for 84 pregnancies (16 continuing to term and 1 lost to follow-up). There were 81 live births (80 with known initial dolutegravir exposure at conception or first, second, and third trimesters in 42, 21, and 17 live births, respectively), 1 stillbirth (second-trimester exposure), 1 induced abortion (first-trimester exposure), and 1 spontaneous abortion (first-trimester exposure), respectively. Birth defects occurred in 4 live births (4.9%; 95% confidence interval: 1.4 to 12.2), 3 of 42 (7.1%) with exposure at conception or first trimester. CONCLUSIONS: Our findings are reassuring regarding dolutegravir treatment of HIV infection during pregnancy but remain inconclusive because of small sample sizes.

Resveratrol and vitamin E rescue valproic acid-induced teratogenicity: the mechanism of action.

1. Valproic acid (VPA) induces haemorrhagic liposis of the cervical muscles in the chicken embryo model (CEM). Vitamin E and resveratrol (RV) exhibit prominent anti-oxidative and glutathione (GSH)-protecting effects. 2. In the present study we hypothesized that vitamin E and RV would ameliorate VPA induced haemorrhagic liposis in chick embryos. To this end, 120 Day 0 fertilized eggs were divided into 10 groups (n = 12 in each). The effects of different combinations of VPA (60 mmol/L), RV (0.2 and 2.0 mmol/L) and vitamin E (0.2 and 2.0 mmol/L) applied to Hamburger and Hamilton (HH) Stage 10 (Day 1.5) embryos were tested in the CEM using established methods. 3. Both RV and vitamin E (both at 2.0 mmol/L) effectively rescued neural tube defects in the early stage CEM and inhibited the malformation rate compared with that in the control group (8.4% and 5.0% vs 36.5 ± 3.0%, respectively; P < 0.05) and suppressed serum homocysteine and S-adenosylhomocysteine concentrations, downregulated cervical muscular carnitine, triglycerides, H2 O2 , malondialdehyde, interleukin-6 and ACC expression (P < 0.05 for all) and upregulated CPT1 expression and GSH (P < 0.05 for both). 4. The haemorrhagic liposis of cervical muscles can be alleviated by RV and vitamin E. It appears that the main mechanism of action of RV and vitamin E in rescuing VPA-induced teratogenicity is through the suppression of reactive oxygen species and upregulation of GSH.

Fetal warfarin syndrome.

A case of a baby born preterm with an antenatal diagnosis of aortic coarctation for which prostin was electively started at birth. The baby was found to be profoundly anaemic with no clear obstetric cause. Features consistent with antenatal intracerebral haemorrhage were noted on cranial ultrasonography in the context of severe coagulopathy, prompting investigations which confirmed fetal-maternal haemorrhage. It transpired that, following aortic and mitral valve replacements, the mother was anticoagulated with warfarin at conception, having misunderstood her cardiologist's advice that: 'you cannot get pregnant whilst on warfarin'. Following conversion to low molecular weight heparin, she suffered a stroke, thus warfarin was restarted, with an international normalised ratio of 3-4.7 during pregnancy. Following transfer to the paediatric intensive care unit, fetal warfarin syndrome was diagnosed. The coagulopathy and anaemia were corrected and aortic coarctation was excluded. The baby returned to the neonatal intensive care unit for ongoing care and was discharged home in good condition around his due date. At the present time, there is no clinically overt neurological deficit.

Spirulina (arthrospira) protects against valproic acid-induced neural tube defects in mice.

Valproic acid (VPA) is a potent inducer of neural tube defects in human and mouse, its teratogenicity is associated with its potential to generation of free radicals and increase oxidative stress. Furthermore, spirulina (SP) has shown pharmacological properties against teratogenicity, which are attributed to its antioxidant potential. Accordingly, the present study was performed to investigate the influence of SP on the teratogenicity of VPA in imprinting control region mice and the possible mechanisms of action. VPA (sodium valproate) was administered intraperitoneally to mice on gestation day (GD) 8 at a dose of 600 mg/kg. SP was given orally at 125, 250, and 500 mg/kg daily from GD0 through GD18. The most common finding in fetuses with VPA exposure was exencephaly. SP decreased the incidence of this and other malformations and increased levels of superoxide dismutase, catalase, and glutathione peroxidase. In conclusion, these results illustrate the protective action of SP through its antioxidant activity against VPA-induced teratogenicity.

Impact of estrogen replacement on letrozole-induced embryopathic effects.

BACKGROUND: The aromatase inhibitor, letrozole, exerts embryo toxic effects in rats, causing increased embryo lethality and anomalies of the axial skeleton at pharmacologically relevant doses. Letrozole acts by inhibiting estrogen biosynthesis. It may thus be feasible that estrogen deprivation is a crucial determinant of the elicited developmental toxic effects. In order to gain insight on this hypothesis, the present study tested the capacity of estrogen replacement in preventing letrozole-mediated embryopathy. METHODS: Pregnant Sprague Dawley rats were exposed to letrozole alone (0.04 mg/kg), or in combination with estradiol cyclopentylpropionate (ECP) at 0.5, 1 or 2 microg/rat. A control group receiving only the vehicles was also included. Animals were exposed during gestation Days 6-16 (corresponding approximately to 3-10 weeks of gestation in the human). Developmental end-points, including intrauterine mortality, fetal growth, placental weight and incidence of structural abnormalities, were evaluated near term gestation. RESULTS: Exposure to letrozole alone was lethal for 41% of conceptuses, and caused minor axial skeletal anomalies in 51% of live fetuses. ECP co-administration effectively prevented letrozole-induced embryolethality, but failed to reduce the incidence of axial skeletal alterations. CONCLUSION: The obtained results support the concept that inhibition of estrogen biosynthesis represents a critical determinant of letrozole-induced embryonic mortality. A mechanism other than estrogen deprivation appears to underlie the initiation of skeletal anomalies.

Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects.

BACKGROUND: Alcohol exposure during development can produce severe and long-lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor-mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK-801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK-801's ability to mitigate ethanol's teratogenic effects. METHODS: Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge-like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty-one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK-801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18-19, activity level was monitored, and on PD 40-42, serial spatial discrimination reversal learning was assessed. RESULTS: Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol-induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05-0.5 mg/kg) of MK-801 during withdrawal. The performance of ethanol-exposed subjects treated with the high dose of MK-801 (1.0 mg/kg) did not differ from that of the Ethanol Only group. CONCLUSIONS: These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.

IGF-I treatment attenuates renal abnormalities induced by neonatal ACE inhibition.

An intact renin-angiotensin system (RAS) during nephrogenesis is essential for normal renal development. We have shown previously that neonatal inhibition of the RAS, either with ANG II type 1-receptor blockade or angiotensin-converting enzyme (ACE) inhibition, induces irreversible renal abnormalities. The aim of the present study was to investigate whether an interrupted RAS can be compensated for by exogenous administration of another important renal growth-promoting factor, the insulin-like growth factor-I (IGF-I). Rats were treated daily with either the ACE inhibitor enalapril (10 mg/kg), recombinant human IGF-I (3 mg/kg), or the combination enalapril + IGF-I from perinatal day 3 to 13. Urinary concentrating ability, renal function, and renal morphology were assessed at adult age. The gene expression and localization of IGF-I, its receptor, and the growth hormone receptor (GHR) were investigated during ongoing ACE inhibition. The present study demonstrates normalized renal function and histology in enalapril + IGF-I-treated animals. Ongoing ACE inhibition suppressed the medullary IGF-I mRNA expression and altered the local distribution of both IGF-I and GHR. Thus the present study provides evidence for an interaction between the RAS and GH/IGF-I axis in renal development.

Serine-enhanced restoration of 2-methoxyethanol-induced dysmorphogenesis in the rat embryo and near-term fetus.

Effects of serine on restorative growth were characterized by comparing embryo/fetal responses after maternal exposure to 2-methoxyethanol (ME) and ME + serine by gavage on gestation day (gd) 13, a day of heightened limb sensitivity. Paws (gd 20) and limb buds (gd 15) were examined after ME alone at 50, 100, and 250 mg/kg, and after ME (either 100 or 250 mg ME/kg) + serine (1734 mg serine/kg) administered within minutes (0 hr) to 24 hr after ME. Paw development was not altered after ME at 100 mg/kg, but was highly sensitive to 250 mg ME/kg with all fetuses and litters exhibiting defects (ectrodactyly, syndactyly, and short digit) in the preaxial region. In contrast, the limb bud displayed dose-related incidences of abnormalities after maternal treatment with the low and high levels of ME. The condensing (precartilaginous, pentadactyl pattern) and noncondensing (undifferentiated mesenchymal cells) regions exhibited changes in their size, number, and location. Serine administration after 250 mg ME/kg was effective in reducing the occurrence of paw dysmorphogenesis with its protection potency inversely related to its delay of administration (i.e., 0% paw defect incidence after 0-hr delay, 25% after 4-hr delay, 41-45% after 8- and 12-hr delays, and 76% after 24-hr delay). The occurrences of limb bud pattern disturbances produced by ME were also markedly decreased by serine cotreatment. Higher incidences of embryonic defects versus those of fetal defects demonstrate that restorative growth followed ME exposure. Serine attenuation of ME teratogenicity appears to emanate from enhanced restorative growth so that tissue damage, which otherwise would be expressed as a defect at parturition, is repaired and replaced to resume development of the limb toward its normal structure.