The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and Research Institute, The Hospital for Sick Children, Toronto, Department of Pediatrics, Pharmacology, Pharmacy and Medicine, the University of Toronto, Toronto, Ontario, Canada
Supported by a grant from Duchesnay Inc., Laval, Quebec
* Published in Reproductive Toxicology,1999;13:313-9.
Since the thalidomide disaster of the late 1950s and early 1960s, pharmacological interventions used to treat women suffering from nausea and vomiting of pregnancy (NVP) have been viewed with great trepidation. As a result, "morning sickness" (as it is most commonly known) has been commonly treated with either dietary or lifestyle changes which have been empirically derived. Effective and safe pharmacological therapies have often been avoided; in fact, Bendectin was actually withdrawn from the world market because of unsubstantiated claims of teratogenicity and the unwillingness of the manufacturer to pay litigation costs.1
The Motherisk Program, at the Hospital for Sick Children in Toronto, receives numerous inquiries each month regarding the safety and/or effectiveness of antiemetic medications for NVP. Unlike in the United States, Diclectin (doxylamine/pyridoxine), a generic form of Bendectin, is indicated for the treatment of NVP and is available to patients in Canada suffering from this disorder of pregnancy.
Since the inception of our program, we have investigated the perception of teratogenic risk in patients attending the Motherisk clinic.2 We have shown that women exposed to agents not considered teratogenic believed their risk for malformations was 24%, which is approximately the rate of malformations for in utero exposure to thalidomide.3 After consultation on their specific drug, the women's perception decreased to 14%. These results indicated that reassuring advice concerning environmental exposures during pregnancy can change the perception in a positive manner.4
The objective of the present investigation was to evaluate the type of advice pregnant women in Canada and the United States report receiving regarding pharmacological and non-pharmacological therapy to treat NVP and their malformation risk perception of antiemetic use for NVP. We also wished to determine the change in perception of risk after receiving evidence-based counselling.
From February, 1996 to August, 1997, announcements on radio programs and in Canadian and American women's magazines and newspapers advertised the Hospital for Sick Children's interest in interviewing women with previous or current NVP. The project was approved by the Research Ethics Board of the Hospital for Sick Children in January, 1996.
For the purpose of this study, eligible callers were pregnant women at less than 20 weeks' gestation suffering from recurrent nausea and/or vomiting, not attributable to a cause other than pregnancy. Exclusion criteria included women with severe NVP that would preclude a telephone interview, nausea and/or vomiting due to a condition(s) other than pregnancy, and inadequate cognitive abilities and/or knowledge of English/French to permit a meaningful telephone interview.
Eligible callers were asked for their consent to undergo a 20-minute telephone interview. Interviews were conducted by bilingual (English and French) team members. Semi-structured data collection forms were used to collect the following information: i) maternal demographics, ii) severity of physical symptoms of NVP (including details of admissions to hospital), iii) advice received (and from whom) about antiemetic medication and other treatments for NVP, iv) actual use of drugs or other therapy for NVP, v) other (concurrent) drug/physical exposures, vi) impact of symptoms of NVP on emotional well-being (i.e., depression, emotional support from partner, concerns about NVP and/or antiemetic therapy harming the baby, likelihood of having another pregnancy), vii) impact of symptoms of NVP on social functioning (i.e., time lost from household tasks, time lost from paid work, relationship with partner, effect on partner's day-to-day life), and viii) pre-counselling views on the risk of antiemetic medication on the likelihood of having a baby with a major birth defect. Open-ended questions about the impact of NVP on emotional and social functioning were also included.
Each participant was counselled, in an identical fashion, on the risks associated with pregnancy (i.e., women not having any other teratogenic risks have a 1-5% chance of having a baby with a major birth defect, even in the absence of antiemetics to treat their NVP5) and informed that no antiemetic medication, other than thalidomide, has been proven to cause birth defects when used as indicated in humans. Patients were also informed on the natural course of NVP.
After the initial interview was completed, the interviewer asked the caller for her permission to be contacted at approximately 20 weeks' gestation for a 20-minute telephone follow-up interview. The purpose of this interview was: 1) to determine the women's views on the risk of antiemetic drug use during pregnancy and hence the effectiveness of our counselling, 2) to further characterize symptoms (and their resolution/persistence) in the population studied, and 3) to document drug or other therapies used for NVP. The opportunity was provided for further risk counselling at the patient's request.
Caregiver advice reported by participants was categorized into four possible outcomes: nothing can be done/NVP will resolve on its own; change diet and/or lifestyle; use antiemetic medication; use nonpharmacological interventions. Teratogenic risk perception was categorized as follows: increased risk for malformations (More Likely); unchanged risk for malformations (Unchanged); and decreased risk for malformations (Less Likely). Chi-squared with continuity correction (Fisher's exact test was employed for expected values less than 5) was used to compare risk perception before and after consultation and advice reported compared to teratogenic risk perception. Association between advice and risk perception was analysed by the correlation coefficient, Phi (j), for nominal data. For all tests, the level of statistical significance was set at 5%.
From February, 1996 to August, 1997, 669 women suffering from NVP at the time of interview contacted Motherisk. From this group of patients, 372 were at or beyond 20 weeks' gestation and were excluded from the analysis. The remaining 295 patients were under 20 weeks' gestation and were enrolled in the study. From this cohort, 35 women were lost to follow-up at the 20-week return call.
Maternal demographics for these women are outlined in Table 1. Approximately half of the callers identified Canada as their place of residence, while the remainder identified the United States of America as their place of residence. The mean age of the respondents was 30 years. The majority of women were in their second pregnancy, while one-third were pregnant for the first time. Eleven patients identified a birth defect in a previous pregnancy, representing an incidence of 4.5% in this population. Under three-quarters of the women reported that the pregnancy was planned. Two-thirds were being cared for by an obstetrician, while very few were seeing a midwife or registered nurse. Over two-thirds of the women reported working outside the home environment.
Table 2 lists the drugs used therapeutically in this population for medical conditions not related to NVP. Although one-quarter of the study participants reported use of medications, 34 different products are listed because some patients were taking more than one drug. None of the drugs listed have been associated with an increased risk for congenital malformations in humans.
Table 3 summarizes the severity of NVP symptoms in these patients. Characteristically, the physical symptoms of NVP appeared in the sixth week of gestation. Although a large majority reported severe nausea prior to treatment with antiemetic medication, only 26.2% experienced severe vomiting. Two-thirds of the women reported weight loss, with a median of 2.7 kilograms.
In terms of emotional well-being, an almost equal number of patients reported depression always/most of the time and rarely/never. The vast majority felt emotional support from their partner (91.9%). Thirty-one patients (11.9%) indicated that they considered termination of the pregnancy because of the NVP.
Over three-quarters of the women reported time lost from paid employment, and two-thirds reported obtaining sick leave, i.e., paid time off. About half of the patients indicated that their NVP had an adverse effect on their relationship with their partner, while over half felt that the NVP had an adverse effect on their partner's day-to-day life.
Table 4 summarizes the women's report of their caregivers' advice regarding management of their NVP. Thirty-eight patients had not yet discussed the NVP at the time of contact with the healthline. One hundred thirty-three women reported receiving single advice, while 89 women received multiple options. Of those who reported receiving one recommendation, two-thirds were advised to use antiemetic medication, while one-quarter were advised to change their diet and/or lifestyle, and a small percentage were told that there was nothing to alleviate the NVP (12.8%).
In terms of pharmacological recommendations, over half the women reported being advised to use only the doxylamine/pyridoxine combination, while 10 women were informed to use doxylamine/pyridoxine in combination with other antiemetic medication. The most common phenothiazine recommended was promethazine (22 women). A small number of women were advised to use dimenhydrinate (4.8%) and pyridoxine (10.9%) alone. Sixty-seven percent (77/115) of women advised to take Diclectin (doxylamine/pyridoxine) reported to have used the medication. The proportion was similar for dimenhydrinate (24/42, 57%) and promethazine (26/42, 62%).
Other medications recommended for NVP are listed in Table 5. The majority of the medications listed below were identified by women residing in the United States (U.S.). Doxylamine (Unisom in the U.S.) is listed in combination with pyridoxine not as the Diclectin formulation, but rather as a preparation made specifically by pharmacists in the U.S. for the treatment of NVP.
Table 6 summarizes the reported effect of the various antiemetic medications used by the study participants. Over half of the women felt better after administration of medication for NVP, while a few reported feeling worse for reasons such as increased nausea (ginger), drowsiness (doxylamine/pyridoxine), and extrapyramidal effects (phenothiazines).
Teratogenic risk perception and intervention
Table 7 outlines the perception of teratogenic risk attributed to antiemetics for NVP in the cohort of patients contacting the healthline.
At the initial call, all women responded to the question posed regarding the risk of antiemetic use during their pregnancy. Over two-thirds of the women reported that drug use for NVP was more likely to increase their baby's risk for malformations, while approximately one percent attributed no increased risk to the foetus. At the 20-week gestation follow-up, a statistically significant drop was seen in the "more likely" category (65.8% vs. 42.3%, p < 0.05) concurrent with a statistically significant increase in the "unchanged" category (32.7% vs. 51.9%, p < 0.05). Stratification of the respondents into those using antiemetic medication at the initial call and those not using antiemetics at the initial call produced similar trends (Tables 8 and 9, respectively).
Advice versus risk perception
Table 10 summarizes the distribution in risk perception in the population based on the advice reported. Since the number of individuals reporting non-pharmacological interventions was too small for analysis, it was excluded as one of the outcomes. Advice to change diet and/or lifestyle was significantly associated with an increased teratogenic risk perception (N = 0.23, p = 0.001), whereas recommendation to use antiemetic medication was significantly associated with no change in risk for major malformations (N = 0.22, p = 0.001).
The population of pregnant women collected in this study was similar to what is expected in women of child-bearing age in North American society today, i.e., the 50th percentiles for age, gravidity and parity were 30 years, 2 and 1, respectively. The rate of previous defects also falls within the expected rate of 1-5% in the general population. Given that the average gestational age of the participants was 12 weeks, it was not surprising that two-thirds of the women reported an obstetrician as their primary caregiver.
In terms of the NVP, the data collected were also found to be similar to those documented: the 50th percentile for onset of symptoms was 6 weeks' gestation, and for resolution of NVP was 16 weeks' gestation.6 However, as would be expected, the women who contacted the healthline presented with more severe nausea and vomiting than the average in the population. Therefore, conclusions drawn regarding this cohort of patients should represent the more severe end of the spectrum.
The data identified a number of issues regarding the effects of NVP on women's quality of life. Over 60% of the women reported some degree of depression because of the NVP, and 50% were concerned that their NVP would impact negatively on the health of their child. Moreover, 12% of patients considered termination of their pregnancy because of the severity of their NVP. This possibly reflects the severe nature of the disorder in this population. In terms of lifestyle changes, 78% reported some time lost from outside employment, which is higher than previously reported in a similar study, although the mean number or hours lost was quite similar (52 vs. 62).6 This probably can be attributed to the severer nature of the condition in the group studied here.
Although almost half of the women felt that the NVP adversely affected the relationship with their partner, over 90% felt support from their partner. This seeming contradiction can possibly be explained by the nonspecific nature of the question. Support from a partner can be interpreted as financial, emotional, intimate, or all three.
The current study demonstrates that there is no consensus regarding advice for the treatment of NVP. Although in this cohort, the majority of women reported being told to use antiemetic medication, a substantial number of women continued not to receive advice regarding specific strategies for the management of their NVP. Randomized, placebo controlled trials have shown that all of the following are effective for treatment of varying degrees of NVP: Bendectin/Diclectin (doxylamine/pyridoxine), histamine H1-blockers, phenothiazines (as a group), pyridoxine, and P6 acupressure.7 Small randomized controlled trials have suggested that corticosteroids8 and ondansetron9 may have therapeutic roles to play; however, their foetal safety has not been established.
There are several reasons why some caregivers may or may not prescribe antiemetics for NVP. Less severe forms of NVP may lead the caregiver to attempt a change in diet and lifestyle. Alternatively, the physician's knowledge of his patients' wish to use "natural" products may affect the decision. Thirdly, in the present litigious atmosphere it is conceivable that some physicians will be less inclined to recommend medications in pregnancy. Obviously, one cannot quantify, based on the present study, the proportion of health professionals who believe that antiemetics are harmful to the foetus. However, approximately 13% of patients in this cohort were told that "there was nothing to alleviate the NVP", while a small proportion reported to be told that antiemetics are harmful to the foetus. Moreover, one cannot assume that the advice reported by the women reflects accurately the advice given by the physician. There is considerable evidence of discrepancies between what a health provider says and what a patient hears and remembers.10-12 It is therefore possible that women who believe that all medications taken during pregnancy have substantial potential for harm may be more likely to remember their health provider expressing the same view. While the design of our study does not allow answers to these questions, it is alarming that, overall, women perceive an increased teratogenic risk of antiemetic drugs proven scientifically to be safe in pregnancy.
In general, the women in this cohort considered that antiemetics used to treat NVP would increase the risk for major malformations, whether they used medication or not. Women who were advised to take medication by their primary caregiver were proportionally less likely to attribute an increased risk for major malformations as compared to those not told to use medication. Those who were advised to change their diet and lifestyle were more likely to consider antiemetic medication as a risk factor to the foetus. These results do not necessarily mean that those who received medication were those who were appropriately counselled on their safety. It is also possible that women who are really suffering from NVP, and subsequently find relief through medication, are more willing to believe that these medications will not harm the foetus. However, additional supportive advice received from our service regarding antiemetic management of NVP resulted in reduced numbers of women who considered drug therapy for NVP to increase the risk for major malformations.
A plausible reason for the increased risk-perception of antiemetics may be related, in part, to the thalidomide tragedy. Thalidomide was the first drug to be labelled as a human teratogen and had been used for the relief of morning sickness. The net result of the thalidomide experience was increased scrutiny of antiemetic drugs with potential benefits, such as Bendectin/Diclectin. In fact, even up until 1989, the Canadian media reported Diclectin to be "another thalidomide."13-15 The effect of these reports on potentially beneficial drugs for NVP continue to be felt in the medical community and in the public at large.
Our investigation suggests that there is still misperception, by patients and health professionals alike, about the foetal risks of antiemetic medication. This study also suggests that counselling can decrease the perception of teratogenic risk and support women's use of safe antiemetic drugs. In a previous study, we have shown that such counselling is effective in preventing unnecessary elective terminations among women exposed to drugs during pregnancy.4 A large educational effort, based on evidence-based management, is needed among health professionals and patients to optimize management and eradicate misinformation about NVP. Women with severe forms of NVP may benefit from specialized services focussing on their physical, as well as their psychosocial needs.
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