Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [(11)C]-harmine positron emission tomography study.

Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.

Use and safety of antipsychotic drugs during pregnancy.

The incidence of schizophrenia in the general population ranges from about 1% to 2%. Schizophrenia affects men and women equally, occurring in all cultures and socioeconomic classes. The peak age of onset in women is 25 to 35 years, which are also the peak childbearing years, and women with psychotic illnesses are likely to have more unplanned pregnancies than women without a psychotic illness. Not only are antipsychotic medications prescribed for schizophrenia, but, especially since the introduction of the second-generation (atypical) antipsychotics, these drugs are also used to treat other psychiatric illnesses such as bipolar disorder. As a result, there is an increase in the number of women requiring antipsychotic drug therapy who are likely to become pregnant. It is important to evaluate the safety of these drugs in pregnancy, as most women with a serious psychiatric illness cannot stop taking their medication, as this would interfere with their activities of daily living, especially taking care of an infant. In this review, we describe available up-to-date, evidence-based information regarding the safety of antipsychotic drugs that are currently used in pregnancy. These include first-generation (conventional) antipsychotics (eg, promethazine, chlorpromazine, prochlorperazine, haloperidol, perphenazine, trifluoperazine, loxapine, thioridazine, flupenthixol, fluphenazine) and second-generation antipsychotics (eg, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone). To date, no definitive association has been found between use of antipsychotics during pregnancy and an increased risk of birth defects or other adverse outcomes. However, there is a paucity of information, with a lack of large, well designed, prospective comparative studies. The information presented here should therefore not be interpreted as conclusive with regard to the safety of these drugs, as more research is needed. Women who require treatment should always discuss the risks and benefits of pharmacotherapy with their physician and, if it is felt that treatment should be continued during pregnancy, the evidenced-based information presented here will be of help in this important decision.

Comparing folic acid pharmacokinetics among women of childbearing age: single dose ingestion of 1.1 versus 5 MG folic acid.

BACKGROUND: A 2001 study suggested that supplementation with 5 mg folic acid, among women of childbearing age, is needed to render maximum protection against neural tube defects (NTD). No human study is presently available which examined the pharmacokinetics of 5 mg folic acid. OBJECTIVE: To compare the pharmacokinetics of ingesting a single dose of 5 mg versus 1.1 mg folic acid contained in 2 prenatal multivitamins (PregVit and PregVit-Folic 5), and to estimate its contribution to steady-state folate levels. METHOD: The pharmacokinetics of 1.1 mg folic acid was determined in a previously published study. The method was replicated among 6 healthy, non-pregnant women who were given 5 mg folic acid to ingest. Blood samples were drawn and serum folate concentrations were measured at various time points during 10 hours post-ingestion. Standard pharmacokinetic parameters were determined and compared with Student's t-test, when appropriate. RESULTS: The mean area under the curve (AUC) of 1.1 mg and 5 mg folic acid were 147.6 +/- 52.8 (ng/mL) x hr and 997.5 +/- 271.9 (ng/mL) x hr, respectively (p<0.0002). An approximate 5-fold difference was detected in the peak concentrations (Cmax) between the 2 groups (p<0.0005), alongside a slight difference in the times to peak (Tmax) (p=0.02). The estimated steady-state serum folate concentrations produced by 1.1 mg and 5 mg folic acid were 6.2 +/- 2.2 ng/mL and 41.6 +/- 11.3 ng/mL, respectively (p<0.0002), prior to its summation with initial (baseline) steady-state levels. CONCLUSION: Single dose administration between 1.1 mg and 5 mg folic acid demonstrated linear pharmacokinetics, with approximately a 5-fold difference between the 2 doses in serum folate contribution to steady-state levels, under ideal adherence.

Treatment of nausea and vomiting in pregnancy: an updated algorithm.

QUESTIONMy patient has severe nausea and vomiting of pregnancy (NVP). I am having difficulty treating her, as nothing she has tried so far has been really effective. I heard that there is some new information regarding the treatment of this condition.ANSWEREven a less severe case of NVP can have serious adverse effects on the quality of a woman's life, affecting her occupational, social, and domestic functioning, and her general well-being; therefore, it is very important to treat this condition appropriately and effectively. There are safe and effective treatments available. We have updated Motherisk's NVP algorithm to include recent relevant published data, and we describe some other strategies that deal with secondary symptoms related to NVP.

Pregnancy outcome following high doses of Vitamin E supplementation.

The recommended dose of Vitamin E in human pregnancy is 22-30 mg/day. High doses of Vitamin E (>or=400 IU/day) have been shown to attenuate or even prevent the damaging effect of ethanol and diabetes on the fetus in experimental animal models. The Motherisk program prospectively enrolled, and followed-up on, 82 pregnant women exposed to high doses (>or=400 IU/day) of Vitamin E during the first trimester of pregnancy. Pregnancy outcome was compared to a matched control group. The study group (n=82) was exposed to Vitamin E at doses ranging from 400-1200 IU/day. There was one pregnancy with major malformation (omphalocele) in study group. There was an apparent decrease in mean birth weight (3173+/-467 g) in Vitamin E group as compare to control (3417+/-565 g; P=0.0015); however, there were no significant differences in rates of live births, preterm deliveries, miscarriages and stillbirths. Therefore, it is concluded that consumption of high doses of Vitamin E during the first trimester of pregnancy does not appear to be associated with an increased risk for major malformations, but may be associated with decrease in birth weight.

Is lack of morning sickness teratogenic? A prospective controlled study.

BACKGROUND: Case-control studies have suggested that the nausea and vomiting of pregnancy (NVP) may have a protective effect against specific malformations. These suggestions have been interpreted as if the lack of NVP may put mothers at an increased teratogenic risk. METHODS: A prospective, cohort-controlled study was done comparing pregnancy outcome in women not experiencing NVP with those experiencing NVP at two levels of clinical severity. Women who called the Motherisk program about first-trimester exposure to drugs and who had not experienced NVP were included as the study group. The NVP Healthline enrolled two control groups of women with NVP treated with a doxylamine-pyridoxine combination for morning sickness. These women were exposed during the first trimester of gestation to either higher than the standard dose (5-12 tablets/day) or a standard dose (1-4 tablets/day) of doxylamine-pyridoxine. The women in all three groups were followed up four to six months after the expected date of birth to ascertain pregnancy outcomes and child health. RESULTS: There were no major malformations among offspring of 130 women not experiencing NVP. There were two major malformations among 246 women experiencing NVP. The two control groups of women with NVP had similar distributions of gestational ages, birth rates, as well as rates of miscarriages and stillbirths, as in the no-NVP group. CONCLUSIONS: This study did not show an association between lack of NVP and an increase in the overall rates of major malformations.

Placental handling of fatty acid ethyl esters: perfusion and subcellular studies.

The measurement of fatty acid ethyl esters (FAEE) in neonatal meconium is a novel test to confirm prenatal ethanol exposure. The origin of FAEE in the maternal-placental-fetal unit is not known. The objectives of this study were to investigate whether FAEE are transferred and metabolized by the human placenta. Isolated placental cotyledons were perfused with a mixture of four FAEE (palmitic, stearic, oleic, and linoleic acid ethyl esters) commonly detected in the meconium of neonates exposed to ethanol in utero, and the transfer of FAEE to the fetal unit was investigated in the absence and presence of albumin. The metabolic degradation of FAEE by human placental microsomes was subsequently determined. FAEE disappeared from the maternal circulation but remained undetectable in the fetal unit following perfusions. The addition of albumin had no effect on FAEE transfer. The unrecoverable fraction of individual FAEE in the perfusion system accounted for >50% of the initial amount used, suggesting significant metabolic degradation. Subcellular studies documented the enzymatic degradation of FAEE by placental microsomes (mean Km, 35-95 microM; Vmax, 0.6-1.8 nmol/min/mg for individual FAEE). FAEE at levels found in alcoholics that are originated from the mother are not transferred to the fetus because they are taken up and degraded extensively by the human placenta. Hence, FAEE detected in neonatal matrices are likely produced by the fetus from ethanol that has been transferred to and metabolized by the fetus, rendering FAEE a powerful direct biomarker reflective of true fetal exposure to ethanol in utero.

In vitro analysis of human transplacental transport of desmopressin.

OBJECTIVE: Desmopressin (DDAVP) therapy may be required during pregnancy, but there are limited data about its safety. We wished to verify whether DDAVP is transported across the human placenta. METHODS: Using the in vitro human placental cotyledon perfusion model, we performed serial measurements of maternal and fetal DDAVP concentrations. After introducing the drug into the maternal circulation at estimated baseline therapeutic (30 pg/ml) and supratherapeutic (16,000 and 60,000 pg/ml) concentrations, we measured the rate of transplacental drug transfer up to 2 h. RESULTS: There was no detectable transport of DDAVP at a 30 pg/ml concentration, and the maternal drug concentration remained stable over time. At a much higher maternal concentration of 60,000 pg/ml, the mean peak fetal DDAVP concentration was 2990 pg/ml, equivalent to 4.8% of the baseline maternal concentration. CONCLUSION: At a therapeutic maternal drug concentration, DDAVP does not appear to cross the placenta within detectable limits. At much higher drug concentrations, DDAVP may cross the placenta in a small amount. Future in vitro clinical studies should attempt to reproduce these findings.

Diclectin therapy for nausea and vomiting of pregnancy: effects of optimal dosing.

OBJECTIVES: (1) To quantify rates of suboptimal use of pyridoxine hydrochloride-doxylamine (Diclectin); and (2) to study responses to optimal doses of Diclectin in women previously taking a suboptimal dose. METHODS: Women who called the Motherisk NVP helpline, and were taking only Diclectin (vitamin B6 10 mg and doxylamine 10 mg), were enrolled in the study and assessed for the severity of nausea and vomiting of pregnancy (NVP) with the Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system. Their Diclectin doses were subsequently increased according to body weight and individual symptoms. A follow-up phone call occurred within 1 to 3 weeks after the intervention, at which time the overall PUQE score was repeated, along with individual scoring of symptoms of nausea, vomiting, and retching. RESULTS: Sixty-eight women were enrolled and completed the study. Despite moderate to severe NVP, defined by the validated PUQE scoring system, most women (50/68) were receiving 2 tablets a day of Diclectin instead of the recommended dose of 4 tablets a day. Following a mean doubling of the dose to 4 tablets a day, there was a significant decrease in length of nausea (from 4 to 3 hours, P < 0.001), frequency of vomiting (from mean 1.6 to 1.3 a day, P = 0.02), and overall PUQE score (from mean 7.5 to 6.1, P < 0.001). CONCLUSION: Women suffering from NVP are often given subtherapeutic doses of Diclectin. Women should receive a dosage according to their body weight and severity of their symptoms.

Effects of aspirin consumption during pregnancy on pregnancy outcomes: meta-analysis.

BACKGROUND: We assessed the effects and safety of aspirin treatment during pregnancy on fetal and neonatal outcomes. METHODS: We searched MEDLINE (1966-2001), EMBASE (1980-2000), TOXLINE (1994-2000), EB M Cochrane Database of Systematic Reviews (1991-2000), Reproductive Toxicology (2001), teratology texts, and bibliographies of all the included studies. We looked for published randomized controlled studies reporting aspirin treatment to improve outcomes of moderate- and high-risk pregnancies. The key words used to search for articles about exposure to aspirin were salicylic acid, pregnancy, and pregnancy complications; key words used to search for outcome were neonatal diseases and abnormalities. Based on our search strategy, 1904 citations were identified; their titles and abstracts were reviewed by one reviewer. Of these citations, 182 papers were selected for detailed review. Two reviewers independently determined whether a study should be included in the final analysis. In cases of disagreement, the decision was based on the assessment of a third reviewer. RESULTS: Data were extracted independently by each reviewer. We calculated the pooled relative risk (RR) or weighted mean difference and 95% confidence intervals (CI), assuming a random-effect model. Thirty-eight studies met the inclusion criteria. The risk for miscarriage did not differ between women treated with aspirin andplacebo (seven studies; RR, 0.92; 95% CI, 0.71-119). Women who took aspirin had a significantly lower risk of preterm delivery than did those treated with placebo (22 studies; RR, 0.92; 95% CI, 0.86-0.98). There was no significant difference in perinatal mortality (20 studies; RR, 0.92; 95% CI, 0.81-1.05) and in the rate of small-for-gestational-age infants (12 studies; RR, 0.96; 95% CI, 0.87-1.07) among offspring of mothers treated with aspirin and those of mothers treated with a placebo. CONCLUSION: For women with moderate- and high-risk pregnancies, aspirin treatment seemed to have a small but significant effect on reducing the rate of preterm deliveries, but did not reduce the rate of perinatal death.

Seroprevalence of Toxoplasma gondii infection among veterinary staff in Ontario, Canada (2002): implications for teratogenic risk.

BACKGROUND: Toxoplasma gondii infection is embryotoxic in humans. It is mainly transmitted through raw/undercooked meat and ingestion of oocysts in cat feces. There remains controversy about the actual risk of cats transmitting the disease to humans. Our primary objective was to determine the seroprevalence of T. gondii antibody among veterinary staff, to ascertain whether they have an increased risk through occupational exposure. Our secondary objective was to examine their practices regarding cats, toxoplasma infection, and pregnancy. METHODS: Veterinary staff attending the 2002 Annual Ontario Veterinary Medical Association Conference were invited to discuss their toxoplasma seroprevalence. Interested attendees completed a questionnaire and a physician drew blood samples to determine T. gondii titres using the ELISA IgG test. RESULTS: We collected 161 completed questionnaires, and 141 blood samples. There were 20 (14.2%, CI 95%:8.4-19.9%) reactive titres among the veterinarian staff (80% females aged 30-45). All were regularly exposed to cats, washed their hands when in contact and few wore gloves routinely. CONCLUSIONS: These findings of low positive rates may be used to reassure veterinary staff that their exposure to cats does not appear to increase their risk of contracting toxoplasma infection and that pregnant women are not at an increased risk by owning a cat.

Transfer of insulin lispro across the human placenta: in vitro perfusion studies.

OBJECTIVE: Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro. RESEARCH DESIGN AND METHODS: Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 micro U/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay. RESULTS: No placental transfer of lispro could be detected during perfusion with 100 and 200 micro U/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 micro U/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 micro U x min(-1) x g tissue(-1) at maternal levels of 580 micro U/ml and 0.045 micro U x min(-1) x g(-1) tissue at maternal levels of 1000 micro U/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 micro U/ml with apparent linear correlation between dose and levels. CONCLUSIONS: Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.

Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis.

OBJECTIVE: The purpose of this study was to determine, on the basis of published reports, whether aspirin use during the first trimester of pregnancy is associated with an increased risk of congenital malformations. STUDY DESIGN: We reviewed the literature for published studies that reported exposure to aspirin during the first trimester of pregnancy and congenital malformations. Two reviewers independently determined whether a study should be included in the final analysis and extracted the data. We calculated the pooled odds ratio and 95% CI. RESULTS: Twenty-two studies met the inclusion criteria. In the eight studies that reported an overall risk, the risk of congenital malformations in offspring of women who were exposed to aspirin was not significantly higher than that in control subjects (odds ratio, 1.33; 95% CI, 0.94-1.89). However, a significantly increased risk of gastroschisis (odds ratio, 2.37; 95% CI, 1.44-3.88) was found. CONCLUSION: We found no evidence of an overall increase in the risk of congenital malformations that could be associated with aspirin. Aspirin exposure during the first trimester may be associated with an increased risk of gastroschisis.