Inclusion and exclusion criteria for study subjects
Women who called the Motherisk Program at The Hospital for Sick Children in Toronto were included if they were pregnant at the time of the call and had discontinued or had not started any multivitamin due to adverse events such as nausea, vomiting, constipation, diarrhea, heartburn, acid reflux, indigestion, or other GI irritability. Motherisk is a counseling program that provides information to women on the safety or risk to a developing fetus and newborn of maternal exposure to drugs, chemicals, and disease. Women were not included if their pregnancy had progressed beyond 20 weeks gestation. Women were to be excluded if they had hypersensitivities to any of the ingredients available in any of the two multivitamin formulations (either PregVit®, Duchesnay, Laval, Quebec; or Orifer F®, Sanofi-Aventis, Laval, Quebec), if they had hemochromatosis, hemosiderosis, or hemolytic anemia, or if they did not consent to the study protocol. However, no woman who was considered for the study was excluded for these reasons.
Selection of prenatal multivitamins for study comparison
PregVit® is a prenatal multivitamin that contains 35 mg elemental iron, as ferrous fumarate. The multiple vitamins and minerals are formulated into 2 small tablets (one tablet: 16 mm × 9 mm × 4 mm), thus PregVit® is taken as 2 tablets per day. The 2 tablets contain different vitamins and minerals, particularly separating the iron (morning tablet) from the calcium (evening tablet) to optimize iron absorption. The use of PregVit® requires a physician's prescription. Since Materna® (Wyeth Pharmaceuticals, Markham, Ontario; one tablet: 18 mm × 8 mm × 8 mm; contained 60 mg elemental iron as ferrous fumarate at the time of the study) or other generic products are the most commonly used non-prescription (i.e. over-the-counter) prenatal multivitamins, they were not selected for comparison in the study because enrolled subjects who had discontinued a prenatal multivitamin most likely had discontinued any one of them. Ethically, subjects in this situation cannot be randomized to resume Materna® or another generic prenatal multivitamin.
Instead, Orifer F® was selected as the small-tablet (one tablet: 5 mm radius, 5 mm thickness) prenatal multivitamin, containing a high iron content (60 mg elemental iron as ferrous sulphate). It is taken daily as a single tablet and the use of Orifer F® does not require a physician's prescription (i.e. over-the-counter). Comparing PregVit® to Orifer F® would address separation of the potential effect of iron content from that of tablet size on multivitamin tolerability among pregnant women.
Subject recruitment and data collection
Between October 2004 and October 2006, women who called either the Motherisk General Information line or the Motherisk Nausea and Vomiting of Pregnancy (NVP) Helpline were introduced to the study by a Motherisk counselor, based on the inclusion and exclusion criteria. If the caller was interested in study participation, the counselor referred the caller to the research coordinator. The research coordinator explained the study and proceeded with enrolment after obtaining oral consent.
Based on a computer-generated randomization table, women were randomized to one of two groups. Women randomized to the '35 mg' group would commence supplementation with PregVit® (low iron content, small size), and women randomized to the '60 mg' group would commence supplementation with Orifer F® (high iron content, small size). An information package was mailed to each woman, instructing her to commence supplementation with her assigned prenatal multivitamin, according to the product's standard dosing (twice daily for '35 mg' group, once daily for '60 mg' group). Subjects were responsible for obtaining their own multivitamin supply through their health care providers. Information regarding the study was faxed to the physician or other health care provider of each subject.
After enrolment, subjects received a one-week follow-up telephone call and then were interviewed by telephone on a monthly basis until the end of pregnancy. Each interview documented obstetrical and medical information, adherence based on pill intake recall, and any reported adverse events. Discontinuation of the assigned multivitamin was defined as intentionally not taking the supplement and most likely not resuming the supplement. The date(s) of discontinuation at any time(s) during study participation was documented as the date(s) reported by the subject during a monthly interview.
Study completion was defined as completing monthly telephone interviews (when possible) to document pill intake and adverse events up until the end of pregnancy (i.e. 36 weeks gestation or further). Overall adherence was defined as the percentage of pill intake out of the prescribed (i.e. she ingested 200 of the 300 prescribed pills, thus her overall adherence was 67%). Standard adherence was defined as pill intake (out of the prescribed) of at least 80% (i.e. woman A ingested 82% of her pills, thus she adhered to the study intervention, while woman B ingested 67% of her pills, thus she was not adherent to study intervention). Prenatal multivitamins are intended for daily consumption during pregnancy, thus the number of pills prescribed was defined as the expected number of pills to be consumed for the assigned multivitamin for the time of study participation. For example, women in the '35 mg' group were prescribed 2 tablets per day and in a month of 30 days, were expected to take 60 tablets, while women in the '60 mg' group (although the multivitamin was non-prescription) would be expected to take 30 tablets for that same month. The study was approved by the Research Ethics Board of the Hospital for Sick Children, and all subjects gave oral, informed consent.
Data analysis
Rates of adherence and adverse events were compared using chi-squared tests, as appropriate. Adherence was also compared between the 2 treatment groups through Kaplan-Meier survival curves in 2 ways. The first survival curve analysis compared the proportion of women with standard adherence (i.e. at least 80% pill intake over time), after having commenced supplementation with the assigned multivitamin, and the p-value was determined by the Wilcoxon (Peto-Prentice) test. The second survival curve analysis compared overall adherence among women who commenced supplementation with the assigned multivitamin, at any percentage of pill intake over time, and the p-value was determined by the log rank statistic. All curves were plotted from the coordinates of 100% (y-axis point of 1.0) at time zero (x-axis point of 0) to represent that at the beginning of the study, all subjects who commenced supplementation in each multivitamin group were adherent. Instead of fatality as the event which causes the curves to decline (as commonly used in survival curve analysis), the events were modified for the present analyses and defined as the following: a) standard adherence (i.e. at least 80% pill intake) not achieved once supplementation was initiated (first survival curve analysis), and b) discontinuation of assigned multivitamin after having commenced supplementation, at any percentage of pill intake (second survival curve analysis).