The safety of higher than standard dose of doxylamine-pyridoxine (Diclectin) for nausea and vomiting of pregnancy.

A delayed-release combination of doxylamine-pyridoxine (D-P) (Diclectin) is the only approved antiemetic medication for use in pregnancy in Canada. The standard recommended dose is up to 4 tablets a day, regardless of body weight or severity of symptoms. The objective of this study was to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin at the recommended (n = 123) or higher than recommended (n = 102) doses. In this observational, prospective study, one-third (33.6%) of women reported having adverse effects (sleepiness, tiredness, and/or drowsiness) temporally related to the medication. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1-12 tablets). Nausea and vomiting of pregnancy (NVP) was reported as severe by the majority (75.8%) of women. Mean birth weight (BW) was 3,400 g and gestational age (GA) 39 weeks. Multivariate analysis revealed that only prepregnancy weight and GA predicted lower BW, not the dose of D-P or the severity of NVP. There were two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population. It was concluded that the higher than standard dose of Diclectin, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome. If needed, Diclectin can be given at doses higher than 4 tablets/day to normalize for body weight or optimize efficacy.

Determinants of the need for hospital care among women with nausea and vomiting of pregnancy.

OBJECTIVES: To characterize a cohort of pregnant women who required hospital care owing to nausea and vomiting of pregnancy (NVP) and to identify variables that could serve as predictors of the need for hospital care. DESIGN: A retrospective, observational study. METHODS: Between 1996 and 1997, women who suffered from NVP were invited to call the NVP Healthline at The Motherisk Program in Toronto. After obtaining verbal consent, callers were interviewed by trained counsellors through a structured questionnaire about their NVP experience in previous pregnancies. Univariate and multivariate analyses were used to identify factors that could predict the need for hospital care. RESULTS: In total, 3,201 women were recruited;1,348 (43.8%) needed hospital care (treatment in the emergency room, day unit or hospital ward). The following characteristics were significantly associated with the need for hospital care: severity of vomiting (more than 5 times a day), use of more than one antiemetic medication, being primigravid, feeling depressed, having had an obstetrician as the primary health care provider and feeling that NVP had affected the partner's daily life. CONCLUSIONS: Several factors, including the severity of physical symptoms of NVP and psychosocial factors, are associated with the need for hospital care. In addition to treatment of physical symptoms, it is important to address other factors associated with NVP.

A novel method for the evaluation of the severity of nausea and vomiting of pregnancy.

UNLABELLED: The symptomatology of nausea and vomiting of pregnancy (NVP) ranges from mild to very severe. The most advanced method to measure the burden of NVP, the Rhode's scores, incorporates physical signs (length and number of episodes of nausea, number and volume of vomits, and number of retching) with measures of distress caused by these symptoms. However, this system has been validated only for symptoms that occurred in the past 12 h, thus obviating its wide clinical use, and particularly its retrospective use. OBJECTIVE: To examine whether the severity of the physical symptoms of NVP correlate with the degree of stress caused by them, and to develop simple scores that can be used clinically. METHODS AND RESULTS: We prospectively scored 283 women with NVP using the Rhode's system. There was excellent and highly significant correlation between the physical symptoms and their degrees of distress. Subsequently, we examined two simple scoring systems, one with three and one with five physical symptoms. Both yielded distribution of severity of NVP not different from the one found with the use of the full Rhode's score. CONCLUSION: A scoring system based on all five physical symptoms, or only on three (length of nausea, number of episodes of nausea and number of vomits) yielded accurate estimates of severity and changes in severity of NVP. Unlike the Rhode's score, this simple method can be used clinically to evaluate the severity and changes in NVP.

Psychosocial morbidity among women with nausea and vomiting of pregnancy: prevalence and association with anti-emetic therapy.

Unlike severe nausea and vomiting of pregnancy (NVP), it is not known whether milder forms of NVP have been associated with psychosocial morbidity. We undertook the study to explore the prevalence of psychosocial morbidity by severity of NVP, and determine whether, after correction for severity of nausea/vomiting, there is a relationship between psychosocial morbidity and women's decisions to take anti-emetics as a reflection of their distress due to NVP. From 1996-97, an NVP Healthline was advertised. Callers underwent semi-structured interviews about both their NVP and associated psychosocial morbidity in a previous pregnancy. Most of the 3201 callers resided in Canada, worked outside the home, reported on planned pregnancy (a median of) 4 years before, and described severe (> 5 episodes/day of) nausea and vomiting. More severe nausea/vomiting was associated with more frequent feelings of depression, consideration of termination of pregnancy, adverse effects on women's relationships with their partners or their partners' everyday lives, and the perceived likelihood that NVP would harm their baby (p < 0.0001). However, all psychosocial factors were reported by a clinically important proportion of women with mild nausea/vomiting (0-1 episodes/day). The severity of vomiting was most closely related to women's decisions to take anti-emetics, but other psychosocial factors were also independently associated with anti-emetic therapy. We conclude that psychosocial morbidity is evident across the spectrum of severity of nausea and vomiting among women with NVP. The severity of nausea or vomiting does not appear adequately to reflect the distress caused by NVP, as reflected by women's decisions to take anti-emetic therapy.

Critical appraisal of drug therapy for nausea and vomiting of pregnancy: II. Efficacy and safety of diclectin (doxylamine-B6).

Nausea and vomiting of pregnancy is the most common condition in pregnancy and affects up to 80% of all pregnant women. There are a large number of pharmacological agents that are effective for the treatment of nausea and vomiting associated with conditions such as motion sickness and gastrointestinal conditions; however, their use in pregnancy is limited by the lack of sufficient data on their potential teratogenic effects. The efficacy of the delayed-release combination of doxylamine and pyridoxine (Bendectin, Diclectin) has been shown in several randomized, controlled trials. The present review aims to refute the unsubstantiated beliefs that Diclectin is unsafe when used in the treatment of nausea and vomiting of pregnancy.

Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children.

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. The authors sought to determine factors that predict the risk for the development and severity of ifosfamide-induced nephrotoxicity in children and to examine the long-term outcome of this complication. A total of 174 children who had received ifosfamide for various cancers were studied. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score (none, mild, moderate, severe). Patients were assessed 4 to 12 weeks after each ifosfamide course, 3 months after completion of chemotherapy, and 5 years later. Of 174 children, 72 (41.4%) developed tubular dysfunction, whereas only 11 (6.3%) demonstrated glomerular dysfunction; 40 (23.0%) demonstrated mild toxicity, 16 (9.2%) demonstrated moderate toxicity, and 16 (9.2%) developed severe nephrotoxicity. The four severity subgroups (none, mild, moderate, severe) received comparable doses/m2/cycle of ifosfamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild, or no nephrotoxicity (median age: 2.2, 7.0, 8.2, and 10.5 years, respectively; p < 0.001) and received significantly higher cumulative doses of ifosfamide (49.6 +/- 12.3, 46.0 +/- 13.1, 36.2 +/- 9.7, and 33.8 +/- 7.6 g/m2, respectively; p < 0.001). Cumulative doses of cisplatin were higher among children with severe nephrotoxicity compared to those with moderate, mild, or no toxicity, although this difference did not reach statistical significance. Of all risk factors analyzed by multiple regression analysis, age was the most significant predictor for the grade of nephrotoxicity (p < 0.001), followed by the cumulative dose of ifosfamide (p = 0.005). Seven out of 16 children (44.0%) with severe nephrotoxicity and 4 out of 16 children (25.0%) with moderate nephrotoxicity demonstrated severe chronic tubular toxicity over a follow-up period of 5 years. Since severe ifosfamide-induced renal toxicity tends to be chronic in a substantial number of treated children, it should be balanced carefully against efficacy. Cumulative ifosfamide doses of 45 g/m2 and above should be carefully considered, especially in children younger than age 3.

Young women taking isotretinoin still conceive. Role of physicians in preventing disaster.

QUESTION: One of my adolescent patients was prescribed isotretinoin for severe acne by a dermatologist. I was shocked to discover she does not use any means of contraception. The dermatologist insists he told her about the need for contraception. How can we do better? ANSWER: Clearly this dermatologist, like many of his colleagues, does not comply with the Pregnancy Prevention Program. Until physicians become more aware of this program, babies will continue to be born with embryopathy due to isotretinoin.

An investigation into variability in the therapeutic response to deferiprone in patients with thalassemia major.

Data suggest a large variability in the effectiveness of the orally active iron chelator, deferiprone, in inducing a sustained decrease in body iron to concentrations compatible with the avoidance of complications from iron overload. We analyzed 19 patients with thalassemia major who were undergoing long-term therapy with deferiprone (75 mg/kg/day every 8 hours). In seven of the 19 patients, hepatic iron concentration had been reduced or maintained at less than 7 mg/g of dry weight liver tissue, associated with no evidence of iron-induced toxicity (group A). In the remaining 12, hepatic iron concentration had either stabilized at higher than 7 mg/g of dry weight liver tissue, or increased to such concentrations during therapy with deferiprone (group B). We studied in these patients determinants that may explain such variability, including initial hepatic iron concentrations, compliance, transfusion index, pharmacokinetic characteristics of deferiprone, and plasma vitamin C status. Patients in group B showed significantly decreased plasma vitamin C concentrations compared with those in group A, who demonstrated normal levels (0.04 mg/dl [0.04-0.19 mg/dl] and 0.62 mg/day [0.44-1.05 mg/day], respectively; p = 0.02). A significant difference in apparent volume of distribution (Vd/F) had developed between the groups over time, with a higher Vd/F in group B (1.66 [0.681, group A] and 3.16 [0.811, group B]; p = 0.006). Group B had started with hepatic iron concentrations that were significantly higher than those of group A, a difference that became more pronounced over time. In the initial analysis, serum ferritin concentrations were also higher in group B. The two groups did not differ in the remaining factors. The initial hepatic iron concentrations predicted the slope of change in this value. Regression analysis suggested that patients with initial hepatic iron concentration of less than or equal to 7.22 mg/g of dry weight liver tissue are unlikely to further decrease while taking deferiprone 75 mg/kg/day. Vitamin C deficiency developed in patients in group B over time. Vitamin C is an important biologic cofactor that plays a role in the distribution of iron. The trend of increase in Vd/F of deferiprone over time may imply a compartment shift of iron stores to one less accessed by deferiprone. This study confirmed the effectiveness of deferiprone in heavily iron-loaded patients and provided evidence that its effectiveness decreases in proportion to liver iron load.

Deferiprone-Induced Agranulocytosis : A Critical Review of Five Rechallenged Cases.

The most serious adverse effect of deferiprone, the first orally active iron chelator, is agranulocytosis afflicting an estimated 1.6% of patients. Among the 13 reported patients who had experienced deferiprone-induced agranulocytosis or severe neutropenia, 5 were rechallenged. We studied the onset, clinical and rechallenge course of all 5 patients in an attempt to characterise the mechanisms involved in deferiprone-induced agranulocytosis, to verify whether rechallenge in future patients is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agranulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/kg/day, and 31 % with > 90 mg/kg/day. Available data including bone marrow aspiration in some patients support the hypothesis that an early myeloid precursor is the target cell affected by deferiprone. All 5 rechallenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was significantly shorter (13.2 ± 21.7 weeks compared with 46.4 ± 14.2 weeks in the first episode; p < 0.05). All but one of the rechallenged patients re-experienced agranulocytosis or neutropenia 2 to 4 weeks following re-exposure to deferiprone, suggesting a possible immune mechanism. We found that deferiprone was oxidised in vitro by hypochlorous acid, the major neutrophil oxidant to produce a myelotoxic metabolite. This reactive species demonstrated neutrophil toxicity and a dose-dependent lymphotoxic curve. However, we found no differences in the toxicity of this reactive species to neutrophils from 2 patients with a history of deferiprone-induced agranulocytosis when compared with controls. In combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 rechallenged cases ethically preclude the rechallenge of additional cases.