Objective
The objective of the study was to estimate the potential reduction of neural tube defects (NTDs) through the use of Metafolin-fortified oral contraceptives (OCs) in the United States.
Study Design
A population-based decision analytic model was developed to estimate the benefits of increased red blood cell (RBC) folate levels through the use of Metafolin-fortified OCs on NTD risk during pregnancy. We modeled women who began the year taking Metafolin-fortified or traditional OCs. Folate levels were derived from the National Health and Nutrition Examination Survey and clinical trial data. NTD risk was estimated by applying a published risk equation to respective RBC folate levels.
Results
The number of predicted NTD cases declined by 23.7% to 31.4%, depending on median baseline folate levels in women taking a fortified OC compared with taking a traditional OC.
Conclusion
Metafolin-fortified OCs have the potential to reduce the number of folate-dependent NTDs among current and recent OC users.
Neural tube defects (NTDs) are the second most common group of major structural birth defects; they are associated with high mortality and short- and long-term morbidity as well as significant humanistic and economic burdens to society. Spina bifida, anencephaly, and encephalocele are the 3 most common types of NTDs, affecting as many as 1 in 1000 pregnancies each year in the United States.
Infants with anencephaly are stillborn or die within days of birth. Survival rates for infants with spina bifida have improved over the years, but survivors are likely to have long-term physical and psychosocial disabilities, often requiring special education and substantial caregiver time. In addition, the lifetime costs associated with spina bifida were estimated for 2002 to be $279,210 per person in direct cost or $635,210 in direct and indirect costs associated with morbidity and premature mortality.
Low folate levels are associated with increased risk of NTDs. In addition, women who have had a previous NTD-affected pregnancy, are white or Hispanic, are obese, have insulin-dependent diabetes, are taking certain antiseizure medications, or have had high temperatures during early pregnancy are at increased risk for NTDs. Periconceptional use of folic acid to achieve adequate folate levels has been demonstrated to reduce the risk of NTDs by as much as 50-70%.
The US Preventive Services Task Force guidelines recommend that all women capable of pregnancy take an oral supplement containing folic acid (400-800 μg per day) and that women planning pregnancy should initiate daily folic acid supplementation 1 month prior to conception and continue until at least 2-3 months following conception. Unfortunately, estimates based on surveys suggest that only 26-40% of women of child-bearing age are taking oral supplements with rates lower among women aged 18-24 years. Women not on folate supplementation who become pregnant unintentionally might initiate oral supplements too late to achieve adequate folate levels to reduce the risk of folate dependent NTDs, even if they begin oral supplementation as soon as their pregnancy is confirmed.
The United States and Canada are among countries that have instituted mandatory folic acid food-fortification programs that require cereal-grain products to be enriched with folic acid. Evaluation of the mandatory fortification program in the United States suggests that folic acid food fortification is associated with a reduction of 26-27% in the prevalence of NTDs. Despite this, some women consuming fortified foods still fail to achieve folate levels assumed to be associated with minimum NTD risk (red blood cell [RBC] folate levels of ≥906 nmol/L) as demonstrated by Daly et al.
One method targeted specifically to women of child-bearing age for raising folate levels involves the use of Metafolin (Merck & Cie, Schaffhausen, Switzerland; registered trademark, Merck KGaA, Darmstadt, Germany) fortified oral contraceptives (OCs). This approach recognizes that approximately half of all pregnancies in the United States are unplanned and that women who are planning pregnancies may not begin taking folic acid until sometime after the critical first month following conception. A large percentage of women of child-bearing age, who therefore are at risk for becoming pregnant, use OCs prior to becoming pregnant, whether or not the pregnancy was intentional. Approximately 5-8% of women in the United States on OCs become pregnant each year under conditions of typical use, as defined by self-report.
In addition, for women who discontinue OC use to become pregnant, folate levels can be expected to diminish but remain above baseline for some weeks following discontinuation of Metafolin-fortified OCs. Thus, fortifying OCs with Metafolin to raise folate levels would target those women who may become pregnant unintentionally or shortly after discontinuing their fortified OC.
The concept of using OCs as a vehicle for elevating folate levels among women of child-bearing age was unanimously endorsed at a US Food and Drug Administration Advisory Committee for Reproductive Health Drugs meeting in 2003. The committee concluded that increased folate levels could be beneficial to women who become pregnant shortly after discontinuing OCs or who unintentionally become pregnant while taking OCs. With approximately 1 million pregnancies annually among OC users in the United States, fortifying OCs to elevate folate levels may have considerable potential for further reducing the burden of NTDs.
Two products currently approved, Beyaz and Safyral (Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ), combine an ethinylestradiol/drospirenone-containing OC with 0.451 mg levomefolate calcium (Metafolin), a dose equivalent to 0.4 mg of folic acid. Two clinical trials have examined the effects of these Metafolin-fortified OC on RBC folate levels. The European Longterm Folate Study, conducted in Germany, compared the combination of Metafolin in an OC containing drospirenone (3 mg) and ethinyl estradiol (30 μg), given orally in a cyclic regimen for 24 weeks (6 cycles), with the same OC administered separately with folic acid tablets. After the 24 week active treatment phase, women were followed up for an additional 20 weeks to evaluate the elimination of folate from the body over time.
The US Benefit study compared an OC containing drospirenone (3 mg) and ethinyl estradiol (20 μg) plus Metafolin with the non–Metafolin-fortified version of the OC. RBC folate levels were measured every 2 weeks for 24 weeks (6 cycles). Both trials demonstrated significant increases in RBC folate levels associated with the fortified OC. In the European Longterm Folate Study, folate levels were assessed in an additional follow-up phase for 20 weeks after discontinuation during which they were found to diminish but remained elevated over baseline levels.
Mandatory food fortification programs and efforts to promote dietary supplement recommendations have been major factors in the decline of NTD cases in the United States since around 1990. Despite these efforts, NTDs remain an important public health concern. Because of the low incidence of NTDs, it would be impractical to implement a clinical trial to directly assess the impact of Metafolin-fortified OC use on NTD risk.
The objective of this study was to apply clinical trial data derived from Metafolin-fortified OC studies to population-based NTD risk estimates and assess the potential reduction in NTDs through the use of such an OC among women using OCs in the United States.
Materials and Methods
Model overview
We developed a population-based model ( Figure 1 ) to estimate the potential reduction in NTDs in the United States that would occur if women of child-bearing age taking OCs were switched to Metafolin-fortified OCs. The model estimated the risk of NTDs as a function of RBC folate levels, using data for an Irish population reported by Daly et al. The model considered only spina bifida and anencephaly; we judged that the data were too limited to adequately model the occurrence of other NTDs, such as encephalocele. We assumed that adverse events associated with OC use were the same, whether fortified or not; therefore, adverse events were omitted from the analysis.
The model compared outcomes associated with 2 scenarios: one in which all women currently on OCs received a Metafolin-fortified OC and one in which all women received a traditional OC (current practice). The population for this model was all women who were taking OCs in the United States. The model estimated outcomes for women using an OC at the beginning of the year. Women on fortified OCs were assumed to have been on the fortified OC for at least 6 months to assure that they had achieved steady-state folate levels upon entry into the model. Pregnancy outcomes (live birth, stillbirth, or elective termination) were estimated for all women who conceived in the year, even if the pregnancy outcome occurred in the subsequent year.
The model was developed in Microsoft Excel (Microsoft, Redmond, WA) and was quality checked by individuals not directly involved with this project. This study was exempt from an institutional review board because the study did not use human subjects.
Model inputs
Base-case model input values are displayed in Table 1 . We applied age-specific estimates of OC use obtained from the 2002 National Survey of Family Growth to US population estimates for 2008 to estimate the number of women using OCs.
| Model parameter | Base-case value | Reference |
|---|---|---|
| Population of women of child-bearing age using OCs | 12,228,111 | |
| Annual probability of pregnancy with continued typical use of OCs | 5.0% | |
| Annual probability of discontinuing OC use | 23.0% | |
| Percentage of women discontinuing OC use who desire pregnancy | 18.3% | |
| Probability of pregnancy within 20 weeks, given discontinued OC and desired pregnancy | 75.7% | |
| Probability of pregnancy among women who discontinued OC who were not planning on becoming pregnant | 3.3% | |
| Percentage of NTDs that are spina bifida | 57.4% | |
| Spina bifida pregnancy outcomes | ||
| Live birth a | 48.0% | |
| Elective termination | 43.1% | |
| Fetal death | 8.9% | |
| Anencephaly pregnancy outcomes | ||
| Live birth a | 28.7% | |
| Elective termination | 46.1% | |
| Fetal death | 25.2% | |
| Non-NTD pregnancy outcomes | ||
| Live birth a | 77.0% | |
| Elective termination | 22.4% | |
| Fetal death | 0.6% |
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