Safety classification of herbal medicines used in pregnancy in a multinational study.

BACKGROUND: The use of herbal medicines for health prevention and ailments is an increasing trend worldwide. Women in pregnancy are no exception; the reported prevalence of herbal medicine use in pregnancy ranges from 1 to 60 %. Despite a common perception of safety, herbal medicines may have potent pharmacological actions, and historically, have been used for this reason. METHODS: A multinational, cross-sectional study on how women treat disease and pregnancy-related health ailments was conducted between October 2011 and February 2012 in Europe, North America, and Australia. This study's primary aim was to evaluate and classify the herbal medicines used according to their safety in pregnancy and, secondly, to investigate risk factors associated with the use of contraindicated herbal medicines during pregnancy. RESULTS: In total, 29.3 % of the women (n = 2673) reported the use of herbal medicines in pregnancy; of which we were able to identify 126 specific herbal medicines used by 2379 women (89.0 %). Twenty seven out of 126 herbal medicines were classified as contraindicated in pregnancy, and were used by 476 women (20.0 %). Twenty-eight were classified as safe for use in pregnancy and used by the largest number of women (n = 1128, 47.4 %). The greatest number was classified as requiring caution in pregnancy; these sixty herbal medicines were used by 751 women (31.6 %). Maternal factors associated with the use of contraindicated herbal medicines in pregnancy were found to be working in the home, having a university education, not using folic acid, and consuming alcohol. Interestingly, the recommendation to take a contraindicated herbal medicine was three times more likely to be from a healthcare practitioner (HCP) than an informal source. CONCLUSION: Based on the current literature the majority of women in this study used an herbal medicine that was classified as safe for use in pregnancy. Women who reported taking a contraindicated herb were more likely to have been recommended it use by an HCP rather than informal source(s), indicating an urgent need for more education among HCPs. The paucity of human studies on herbal medicines safety in pregnancy stands in stark contrast to the widespread use of these products among pregnant women.

Preconception counseling: rational, practice and challenges.

Preconception counseling (PCC) is aimed at identifying and modifying risks related to maternal health and pregnancy outcome, prior to pregnancy. The main components of PCC include: maternal risk assessment, maternal education, and initiation of interventions. It is an opportunity to provide essential information regarding pregnancy, possible risks and available management options. At times, PCC provides a unique "time window" for an intervention, prior to the pregnancy, which may reduce maternal and fetal risks. Specific maternal populations may benefit from PCC more than others with regard to optimizing pregnancy outcome. Although PCC has been recommended for years as standard of care, most providers do not offer it and most consumers do not ask for it. The present review discusses the essence of preconception counseling and the evidence for its effectiveness. In addition, specific topics are reviewed in depth including folic acid supplementation, obesity, depression, seizure disorders, and drug therapy during pregnancy.

Adherence and tolerability of iron-containing prenatal multivitamins in pregnant women with pre-existing gastrointestinal conditions.

Prenatal multivitamin supplements (PMS) are recommended during pregnancy. Suboptimal adherence in women experiencing gastrointestinal (GI) conditions is thought to be attributed to the high elemental iron content in PMS. This study sought to quantify adherence and tolerability of iron-containing PMS in women with pre-existing GI conditions by recruiting women who called the Motherisk Helpline. Women with (n = 36) and without (n = 166) pre-existing GI conditions were randomised to either PregVit (n = 106) or Orifer F (n = 96). Monthly follow-up interviews were conducted to assess pill intake and GI adverse effects associated with PMS. The results of our study suggest that with the use of small size and low dose iron PMS, women with pre-existing GI conditions do not experience (1) more GI adverse effects, (2) lower adherence than women with no such conditions, and (3) may experience less severe nausea and vomiting of pregnancy. Supplementing with small tablets of low dose iron PMS should be considered.

The effectiveness of discontinuing iron-containing prenatal multivitamins on reducing the severity of nausea and vomiting of pregnancy.

Nausea and vomiting of pregnancy (NVP) is experienced by the majority of pregnant women, and can negatively affect a women's quality of life. It has been suggested in observational studies that iron-containing prenatal multivitamins may increase the severity of NVP. The objective of this study was to determine whether decreasing iron exposure can mitigate NVP symptoms. Data were collected from a prospective cohort at the Motherisk Program in Toronto. Women (n = 97) seeking advice on managing severe NVP were advised to discontinue prenatal multivitamin administration and switch to folic acid, an adult multivitamin or a children's chewable multivitamin. Two-thirds (63 out of 97) (p < 0.001) of those women qualitatively reported an improvement in NVP symptoms after discontinuation of iron-containing prenatal multivitamins. These findings were verified quantitatively using both the pregnancy-unique quantification of emesis and nausea (PUQE) (p < 0.001) and well-being (p < 0.001) scoring systems. This is the first interventional study showing that discontinuation of iron results in improvement of NVP symptoms. Our data suggest that avoiding iron-containing prenatal multivitamins in the first trimester is effective in improving NVP symptoms in the majority of pregnant women suffering from morning sickness.

Folic acid in pregnancy and fetal outcomes.

Folic acid has become recognised as an important nutrient during pregnancy. The following review highlights the significant developments in recognising folic acid importance in fetal development.

Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis.

Prenatal supplementation of folic acid has been shown to decrease the risk of several congenital malformations. Several studies have recently suggested a potential protective effect of folic acid on certain pediatric cancers. The protective role of prenatal multivitamins has not been elucidated. We conducted a systematic review and meta-analysis to assess the potential protective effect of prenatal multivitamins on several pediatric cancers. Medline, PubMed, EMBASE, Toxline, Healthstar, and Cochrane databases were searched for studies published in all languages from 1960 to July 2005 on multivitamin supplementation and pediatric cancers. References from all articles collected were reviewed for additional articles. Two blinded independent reviewers assessed the articles for inclusion and exclusion. Rates of cancers in women supplemented with multivitamins were compared with unsupplemented women using a random effects model. Sixty-one articles were identified in the initial search, of which, seven articles met the inclusion criteria. There was an apparent protective effect for leukemia (odds ratio (OR)=0.61, 95% confidence interval (CI)=0.50-0.74), pediatric brain tumors (OR=0.73, 95% CI=0.60-0.88) and neuroblastoma (OR=0.53, 95% CI=0.42-0.68). In conclusion, maternal ingestion of prenatal multivitamins is associated with a decreased risk for pediatric brain tumors, neuroblastoma, and leukemia. Presently, it is not known which constituent(s) among the multivitamins confer this protective effect.

Pregnancy outcome following use of large doses of vitamin B6 in the first trimester.

Vitamin B6 is often prescribed for the treatment of nausea and vomiting of pregnancy (NVP), at much higher doses than initially recommended. Large doses of vitamin B6 have been associated with cases of neuropathy. We set out to assess whether higher than standard doses of vitamin B6 during the first trimester of pregnancy were associated with a risk of maternal adverse events, major malformations, miscarriages or low birth weight. This was a prospective comparative observational study. The study group included women who were exposed to >50 mg/day of vitamin B6 during the first trimester; the control group included pregnant women with a non-teratogen exposure. A total of 192 pregnancies were followed-up. The mean dose of B6 used in the study group was 132.3 mg/day (median 110 mg/day, range 50 - 510 mg/day), for a mean period of 9 +/- 4.2 weeks. In this group (n = 96), there were 91 live births, one major malformation and the mean birth weight was 3,542 +/- 512 g. There were no statistical differences in the study endpoints between the vitamin B6 and the control groups. Within the limits of our sample size, higher than standard doses of vitamin B6 do not appear to be associated with an increased risk for major malformations.

Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma.

BACKGROUND: Amifostine protects normal tissues against chemotherapy and radiation-induced toxicity without loss of antitumor effects. Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects. The purpose of this study was to assess the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of twice-daily doses of amifostine with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy for children with refractory malignancies and to determine the pharmacokinetic properties of amifostine, WR-1065, and the disulfide metabolites of amifostine. METHODS: Patients with refractory malignancies were treated with amifostine 15 minutes before and 2 hours after chemotherapy with ifosfamide (3 g/m(2) per dose on Days 1 and 2) and carboplatin (635 mg/m(2) on Day 3). Etoposide was administered on Days 1 and 2 (150 mg/m(2)). The starting dose of amifostine was 740 mg/m(2). Pharmacokinetic studies were performed after the first dose of amifostine. RESULTS: Twelve patients received 23 courses of ICE and amifostine. Dose-limiting toxicities for amifostine at 740 mg/m(2) were somnolence and anxiety. The other Grade 3 and 4 toxicities included asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m(2), amifostine was well tolerated. Hypocalcemia, due to rapid, transient suppression of parathyroid hormone production, required close monitoring and aggressive intravenous calcium supplementation. Pharmacokinetic studies revealed high interpatient variability with rapid plasma clearance of amifostine and WR-1065. The median elimination half-life of amifostine (9.3 minutes) and WR-1065 (15 minutes) was much shorter than the disulfide metabolites (74.4 minutes). CONCLUSIONS: The recommended pediatric dose of amifostine for a twice-daily regimen is 600 mg/m(2) per dose (1200 mg/m(2)/day) with DLTs of anxiety and somnolence, lower than the previously recommended single dose of 1650 mg/m(2).

Can herbal products be used safely during pregnancy? Focus on echinacea.

QUESTION: Many of my patients are now using herbal medicines; some even use them during pregnancy. As we enter the "cold and flu" season, many are inquiring about use of the herb echinacea to prevent these ailments. Is there any evidence to suggest that use of echinacea during pregnancy is safe? ANSWER: Although herbal products have been used in the past during pregnancy and delivery, there is little evidence showing they are safe. Many authoritative reviews of echinacea report that its safety for use during pregnancy has not been established. A recent Motherisk study showed that use of echinacea during the first trimester of pregnancy was not associated with increased risk of major malformations.

Maternal obesity and risk of neural tube defects.

QUESTION: One of my patients is taking olanzapine for schizophrenia. She has gained a lot of weight, which, I understand, often happens with some of the new atypical antipsychotics. Due to her weight gain, she failed to notice she had become pregnant. Is she at risk? ANSWER: Experience with olanzapine is relatively slight, but available prospective data do not show increased teratogenic risk. Adiposity, on the other hand, is associated with increased risk of neural tube defects. Only some of this risk can be reduced by folate supplementation.

Motherisk alert: Folic acid fortification of flour--three years later.

Fortification of flour with folic acid aims to prevent neural tube defects. In Canada, flour fortification began in 1997. The objective of this study was to quantify the changes in women's erythrocyte folic acid levels. Comparing these levels among normocytic women revealed an almost twofold increase (from 517+/-215 nmol/L in 1995 to 901+/-318 nmol/L in 1998) (P<0.00001). While the mean value increased substantially, even now, women at the low range of measured values (367 nmol/L) confer a relative risk of 3.2 for neural tube defects. For these women, higher intake of nutritional folic acid and perinatal supplementation of folic acid tablets continue to be crucial.

Socio-economic disparities in preterm birth: causal pathways and mechanisms.

Preterm birth is the leading cause of infant mortality in industrialised societies. Its incidence is greatly increased among the socially disadvantaged, but the reasons for this excess are unclear and have been relatively unexplored. We hypothesise two distinct sets of causal pathways and mechanisms that may explain social disparities in preterm birth. The first set involves chronic and acute psychosocial stressors, psychological distress caused by those stressors, increased secretion of placental corticotropin releasing hormone (CRH), changes in sexual behaviours or enhanced susceptibility to bacterial vaginosis and chorioamnionitis, cigarette smoking or cocaine use, and decidual vasculopathy. The second hypothesised pathway is a gene-environment interaction based on a highly prevalent mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), combined with low folate intake from the diet and from prenatal vitamin supplements, consequent hyperhomocysteinemia, and decidual vasculopathy. We propose to test these hypothesised pathways and mechanisms in a nested case-control study within a prospectively recruited and followed cohort of pregnant women with singleton pregnancies who deliver at one of four Montreal hospitals that serve an ethnically and socio-economically diverse population. Following recruitment during the late first or early second trimester, participating women are seen at 24-26 weeks, when a research nurse obtains a detailed medical and obstetric history; administers several scales to assess chronic and acute stressors and psychological function; obtains blood samples for CRH, red blood cell and plasma folate, homocysteine, and DNA for the MTHFR mutation; and performs a digital and speculum examination to measure cervical length and vaginal pH and to obtain swabs for bacterial vaginosis and fetal fibronectin. After delivery, each case (delivery at < 37 completed weeks following spontaneous onset of labour or prelabour rupture of membranes) and two controls are selected for placental pathological examination, hair analysis of cotinine, cocaine, and benzoylecgonine, and analysis of stored blood and vaginal specimens. Statistical analysis will be based on multiple logistic regression and structural equation modelling, with sequential construction of models of potential aetiological determinants and covariates to test the hypothesised causal pathways and mechanisms. The research we propose should improve understanding of the factors and processes that mediate social disparities in preterm birth. This improved understanding should help not only in developing strategies to reduce the disparities but also in suggesting preventive interventions applicable across the entire socio-economic spectrum.

Characterization of mice with a combined suppression of I(to) and I(K,slow).

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I(to) and the 4-aminopyridine-sensitive component of I(K,slow) are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I(to) in addition to I(K,slow) in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.

Pregnancy outcome following gestational exposure to echinacea: a prospective controlled study.

BACKGROUND: Echinacea products are among the most popular phytomedicines on the North American market. Since at least half of all pregnancies are unplanned, many women inadvertently use echinacea in their first trimester. Presently, there is a paucity of information regarding the gestational safety of this herb. The primary objective of this study was to evaluate the safety of echinacea in pregnancy when used for upper respiratory tract ailments. PATIENTS AND METHODS: The study group consisted of women who were prospectively followed up after contacting the Motherisk Program regarding the gestational use of echinacea. This cohort was disease-matched to women exposed to nonteratogenic agents by maternal age, alcohol, and cigarette use. Rates of major and minor malformations between the groups were compared. RESULTS: A total of 206 women were enrolled in the study group after using echinacea products during pregnancy; 112 women used the herb in the first trimester. There were a total of 195 live births, including 3 sets of twins, 13 spontaneous abortions, and 1 therapeutic abortion. Six major malformations were reported, including 1 chromosomal abnormality, and 4 of these malformations occurred with echinacea exposure in the first trimester. In the control group, there were 206 women with 198 live births, 7 spontaneous abortions, and 1 therapeutic abortion. Seven major malformations were reported. There were no statistical differences between the study and control groups for any of the end points analyzed. CONCLUSIONS: This first prospective study suggests that gestational use of echinacea during organogenesis is not associated with an increased risk for major malformations.

A randomized prospective crossover trial of amlodipine in pediatric hypertension.

Amlodipine has potential advantages in children since it can be dissolved into a liquid preparation and has a long elimination half-life, allowing for once-daily administration. The objective of this study was to compare the efficacy and compliance of amlodipine with that of standard long-acting calcium channel blockers (felodipine or nifedipine) in hypertensive children. A randomized, prospective, crossover study of 11 hypertensive children (9-17 years of age, 10 renal transplant patients) was performed with electronic monitoring of compliance. Each treatment arm was 30 days. No significant differences were observed in mean systolic (SBP) and diastolic blood pressures (DBP) between amlodipine and the other calcium channel blockers. Using 24-h blood pressure monitoring there were no significant differences over each drug treatment period in both mean day-time and night-time SBP and DBP. Patient compliance was similar in both the amlodipine and the nifedipine/felodipine treatment periods. These data suggest that amlodipine is as effective in pediatric nephrology patients as nifedipine and felodipine. Amlodipine may be optimally suited for treatment of young children because at present it is the only calcium channel blocker which can be administered once daily as a liquid preparation.

Combined analgesia and local anesthesia to minimize pain during circumcision.

BACKGROUND: Pain of circumcision is only partially relieved by single modalities, such as penile nerve block, lidocaine-prilocaine cream, and sucrose pacifiers. OBJECTIVE: To assess the effectiveness of a combination of interventions on the pain response of infants undergoing circumcision. METHODS: Cohort study. Group 1 included infants circumcised using the Mogen clamp and combined analgesics (lidocaine dorsal penile nerve block, lidocaine-prilocaine, acetaminophen, and sugar-coated gauze dipped in grape juice). Group 2 included infants circumcised using the Gomco clamp and lidocaine-prilocaine. Infants were videotaped during circumcision, and pain was assessed using facial activity scores and percentage of time spent crying. RESULTS: There were 57 infants in group 1 and 29 infants in group 2. Birth characteristics did not differ between groups. Infants in group 1 were older than infants in group 2 (17 days vs 2 days) (P < .001). The mean duration of the procedure was 55 seconds and 577 seconds for infants in group 1 and 2, respectively (P < .001). Facial action scores and percentage of time spent crying were significantly lower during circumcision for infants in group 1 (P < .001). The percentage of time spent crying was 18% and 40% for infants in groups 1 and 2, respectively. No adverse effects were observed in infants in group 1; 1 infant in group 2 had a local skin infection. CONCLUSIONS: Infants circumcised with the Mogen clamp and combined analgesia have substantially less pain than those circumcised with the Gomco clamp and lidocaine-prilocaine cream. Because of the immense pain during circumcision, combined local anesthesia and analgesia using the Mogen clamp should be considered.

Caffeine during pregnancy? In moderation.

QUESTION: Many of my female patients, those who plan pregnancy or have conceived, are afraid of any intake of caffeine. This often makes their lives miserable during pregnancy. Is this justified scientifically? ANSWER: Motherisk's recent meta-analysis suggests that the risks for miscarriage and fetal growth retardation increase only with daily doses of caffeine above 150 mg/d, equivalent to six typical cups of coffee a day. It is possible that some of this presumed risk is due to confounders, such as cigarette smoking.

Attitudes and practices of physicians and naturopaths toward herbal products, including use during pregnancy and lactation.

BACKGROUND: The popularity of complementary therapies continues to grow, and physicians are asked increasingly by their patients for information regarding these modalities. PURPOSE: To assess the impact of these trends on physicians and medical students, and compare their attitudes and practices with those of the naturopaths and their students, with particular interest in the use of herbal products during pregnancy and breastfeeding. MATERIALS AND METHODS: A detailed questionnaire was distributed by a medical student and a naturopathic student to a randomly selected group of physicians, medical students, naturopaths and naturopathic students. They were asked a variety of questions about their background, attitudes and practices concerning herbal products. RESULTS: Thirty-eight per cent of the questionnaires were returned, with a total of 242 respondents. Fifty-four per cent of physicians discussed complementary therapies with their patients, whereas 100% of naturopaths discussed conventional medicines with their patients. The most popular product recommended by both medical doctors and naturopaths was echinacea, followed by St John's Wort. Eighty-six per cent of physicians, 74% of medical students, 66% of naturopaths and 50% of naturopathic students think that complementary medical education should be incorporated into the standard medical curriculum. Only one physician actually recommended a herbal product to a pregnant patient compared with 49% of the naturopaths who felt comfortable doing so. CONCLUSIONS: Complementary medicine has become a reality, and physicians are recommending herbal products to their patients, although on a smaller scale than are naturopaths. However, the two most popular herbal products are the same in each group. Physicians are less likely to recommend herbal products to pregnant and breastfeeding women than are naturopaths.

The efficacy of oral deferiprone in acute iron poisoning.

Due to its high cost and need for parenteral administration, the standard iron chelator deferoxamine is not used in many individuals with acute and chronic iron poisoning worldwide. Deferiprone is the first oral iron chelator to be shown to be effective in chronically iron overloaded thalassemia patients. Its efficacy, by oral administration, in acute iron poisoning has not been tested. Our objective was to determine whether orally administered deferiprone can reduce the mortality of rats following acute, toxic, oral doses of iron. Rats were administered 612 mg/kg elemental iron orally, corresponding to LD50 in the species tested. Two other groups received the same oral dose of iron followed by oral deferiprone: 800 mg/kg and 800 mg/kg, followed by another dose of 800 mg/kg 2 hours later. Coadministration of 800 mg/kg deferiprone with the iron decreased mortality from 30% to 6.6% after 2 hours (P = .02), from 40% to 16.6% after 12 hours (P = .04), and from 53.3% to 20% after 24 hours (P = 0.007). Mortality was also significantly decreased among animals coadministrated 2 repeated doses of deferiprone of 800 mg/kg with iron, to 0%, 9%, and 18%, and 2, 12, and 24 hours postdrug administration, respectively (P = .04, .05, .04, respectively). Histologically, there was a dose-dependent decrease in iron accumulation in the gastrointestinal tract. Orally administered deferiprone can decrease morbidity and mortality caused by acute iron overdose in rats. Oral deferiprone holds promise in the treatment of iron poisoning in humans.