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Does Fish Oil During Pregnancy Help Prevent Asthma in Kids?
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma, and she wants to know if there is anything she can do to reduce her second child’s risk for it. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 According to the CDC, 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreases the risk for atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial, by Palmer et al, which included 706 women, showed no benefit for supplementation.8 The second largest, by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR], 0.37; number needed to treat [NNT], 19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until age 3, which is around the time that asthma can be formally diagnosed—potentially leading to underreporting.8 In addition, the diagnosis of asthma was based on parent report of three episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (rate without sensitization was not reported) was 1.8% in both study groups—much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces asthma in children
This single-center, double-blind RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after age 3, persistent wheeze was termed asthma), determined based on daily diary recordings of five episodes of troublesome lung symptoms within the past six months (each lasting for at least three consecutive days); rescue use of inhaled ß2-agonists; and/or relapse after a three-month course of inhaled glucocorticoids. Secondary outcomes included reduced incidence of respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study, with 95.5% follow-up at three years and 93.1% at five. The children had scheduled pediatric visits at 1 week; at one, three, six, 12, 18, 24, 30, and 36 months; and at 4 and 5 years. They also had acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of mothers who took fish oil had a lower risk for persistent wheeze or asthma at ages 3 to 5, compared to those who received placebo (16.9% vs 23.7%; HR, 0.69; NNT, 14.7). But this effect was significant only in the children whose mothers had baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR, 0.46; NNT, 5.6). Similarly, fish oil supplementation had a greater benefit in children whose mothers had consumed the least EPA and DHA before the start of the study (18.5% vs 32.4%; HR, 0.55; NNT, 7.2).
As for the secondary outcomes, only a reduction in lower respiratory infections was associated with fish oil supplementation compared with placebo (38.8% vs 45.5%; HR, 0.77; NNT, 14.9). There was no reduction in asthma exacerbations, eczema, or risk for sensitization in the fish oil group.
WHAT’S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk for asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2,400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2,700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the US.
CAVEATS
Ideal dose? Which women to treat?
The FDA currently recommends 8 to 12 oz of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study, using 900 mg/d of fish oil, did not show a benefit, whereas there did appear to be a benefit in this study (2,400 mg/d) and the Olsen study (2,700 mg/d).1,8,9 Further research is needed to determine the optimal dosage.
The decreased risk for persistent wheeze or asthma was seen only in the children of women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r, 0.32).1 Therefore, additional screening questions to gauge fish consumption would be useful to identify women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills, additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to four additional pills per day for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[2]: 100-102).
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375(26):2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59(5):469-478.
3. CDC . Asthma. www.cdc.gov/asthma/most_recent_data.htm. Accessed February 1, 2018.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64(1):27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42(6):513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17(2):94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22(7): CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88(1): 167-175.
10. Helgi Library. Fish consumption per capita by country. www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed February 1, 2018.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Fed Regist. 2017;82:6571-6574.
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma, and she wants to know if there is anything she can do to reduce her second child’s risk for it. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 According to the CDC, 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreases the risk for atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial, by Palmer et al, which included 706 women, showed no benefit for supplementation.8 The second largest, by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR], 0.37; number needed to treat [NNT], 19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until age 3, which is around the time that asthma can be formally diagnosed—potentially leading to underreporting.8 In addition, the diagnosis of asthma was based on parent report of three episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (rate without sensitization was not reported) was 1.8% in both study groups—much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces asthma in children
This single-center, double-blind RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after age 3, persistent wheeze was termed asthma), determined based on daily diary recordings of five episodes of troublesome lung symptoms within the past six months (each lasting for at least three consecutive days); rescue use of inhaled ß2-agonists; and/or relapse after a three-month course of inhaled glucocorticoids. Secondary outcomes included reduced incidence of respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study, with 95.5% follow-up at three years and 93.1% at five. The children had scheduled pediatric visits at 1 week; at one, three, six, 12, 18, 24, 30, and 36 months; and at 4 and 5 years. They also had acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of mothers who took fish oil had a lower risk for persistent wheeze or asthma at ages 3 to 5, compared to those who received placebo (16.9% vs 23.7%; HR, 0.69; NNT, 14.7). But this effect was significant only in the children whose mothers had baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR, 0.46; NNT, 5.6). Similarly, fish oil supplementation had a greater benefit in children whose mothers had consumed the least EPA and DHA before the start of the study (18.5% vs 32.4%; HR, 0.55; NNT, 7.2).
As for the secondary outcomes, only a reduction in lower respiratory infections was associated with fish oil supplementation compared with placebo (38.8% vs 45.5%; HR, 0.77; NNT, 14.9). There was no reduction in asthma exacerbations, eczema, or risk for sensitization in the fish oil group.
WHAT’S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk for asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2,400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2,700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the US.
CAVEATS
Ideal dose? Which women to treat?
The FDA currently recommends 8 to 12 oz of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study, using 900 mg/d of fish oil, did not show a benefit, whereas there did appear to be a benefit in this study (2,400 mg/d) and the Olsen study (2,700 mg/d).1,8,9 Further research is needed to determine the optimal dosage.
The decreased risk for persistent wheeze or asthma was seen only in the children of women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r, 0.32).1 Therefore, additional screening questions to gauge fish consumption would be useful to identify women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills, additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to four additional pills per day for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[2]: 100-102).
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma, and she wants to know if there is anything she can do to reduce her second child’s risk for it. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 According to the CDC, 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreases the risk for atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial, by Palmer et al, which included 706 women, showed no benefit for supplementation.8 The second largest, by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR], 0.37; number needed to treat [NNT], 19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until age 3, which is around the time that asthma can be formally diagnosed—potentially leading to underreporting.8 In addition, the diagnosis of asthma was based on parent report of three episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (rate without sensitization was not reported) was 1.8% in both study groups—much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces asthma in children
This single-center, double-blind RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after age 3, persistent wheeze was termed asthma), determined based on daily diary recordings of five episodes of troublesome lung symptoms within the past six months (each lasting for at least three consecutive days); rescue use of inhaled ß2-agonists; and/or relapse after a three-month course of inhaled glucocorticoids. Secondary outcomes included reduced incidence of respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study, with 95.5% follow-up at three years and 93.1% at five. The children had scheduled pediatric visits at 1 week; at one, three, six, 12, 18, 24, 30, and 36 months; and at 4 and 5 years. They also had acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of mothers who took fish oil had a lower risk for persistent wheeze or asthma at ages 3 to 5, compared to those who received placebo (16.9% vs 23.7%; HR, 0.69; NNT, 14.7). But this effect was significant only in the children whose mothers had baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR, 0.46; NNT, 5.6). Similarly, fish oil supplementation had a greater benefit in children whose mothers had consumed the least EPA and DHA before the start of the study (18.5% vs 32.4%; HR, 0.55; NNT, 7.2).
As for the secondary outcomes, only a reduction in lower respiratory infections was associated with fish oil supplementation compared with placebo (38.8% vs 45.5%; HR, 0.77; NNT, 14.9). There was no reduction in asthma exacerbations, eczema, or risk for sensitization in the fish oil group.
WHAT’S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk for asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2,400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2,700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the US.
CAVEATS
Ideal dose? Which women to treat?
The FDA currently recommends 8 to 12 oz of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study, using 900 mg/d of fish oil, did not show a benefit, whereas there did appear to be a benefit in this study (2,400 mg/d) and the Olsen study (2,700 mg/d).1,8,9 Further research is needed to determine the optimal dosage.
The decreased risk for persistent wheeze or asthma was seen only in the children of women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r, 0.32).1 Therefore, additional screening questions to gauge fish consumption would be useful to identify women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills, additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to four additional pills per day for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[2]: 100-102).
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375(26):2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59(5):469-478.
3. CDC . Asthma. www.cdc.gov/asthma/most_recent_data.htm. Accessed February 1, 2018.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64(1):27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42(6):513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17(2):94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22(7): CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88(1): 167-175.
10. Helgi Library. Fish consumption per capita by country. www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed February 1, 2018.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Fed Regist. 2017;82:6571-6574.
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375(26):2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59(5):469-478.
3. CDC . Asthma. www.cdc.gov/asthma/most_recent_data.htm. Accessed February 1, 2018.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64(1):27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42(6):513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17(2):94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22(7): CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88(1): 167-175.
10. Helgi Library. Fish consumption per capita by country. www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed February 1, 2018.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Fed Regist. 2017;82:6571-6574.
Does fish oil during pregnancy help prevent asthma in kids?
ILLUSTRATIVE CASE
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.8 The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.8 In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces incidence of asthma in children
This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta2-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).
As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.
WHAT'S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the United States.
CAVEATS
Questions remain: Ideal dose and which women to treat?
The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study,8 using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)1 and the Olsen study (2700 mg/d).9 Further research is needed to determine the optimal dosage.
The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).1 Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills and additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375:2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dessemination Committee Report. Allergy. 2004;59:469-478.
3. Centers for Disease Control and Prevention. Asthma. Available at: https://www.cdc.gov/asthma/most_recent_data.htm. Accessed October 9, 2017.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64:27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42:513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17:94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22:CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88:167-175.
10. Helgi Library. Fish consumption per capita by country. Available at: http://www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed September 27, 2017.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Federal Register.2017;82:6571-6574.
ILLUSTRATIVE CASE
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.8 The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.8 In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces incidence of asthma in children
This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta2-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).
As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.
WHAT'S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the United States.
CAVEATS
Questions remain: Ideal dose and which women to treat?
The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study,8 using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)1 and the Olsen study (2700 mg/d).9 Further research is needed to determine the optimal dosage.
The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).1 Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills and additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?
Asthma is the most common chronic disease in children in resource-rich countries such as the United States.2 The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.3
Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.4 Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.5,6
A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.7 Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.8 The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).9
These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.8 In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.
STUDY SUMMARY
Maternal fish oil supplementation reduces incidence of asthma in children
This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.1
Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.
The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta2-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.
Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).
As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.
WHAT'S NEW?
Study adds fuel to the fire
This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.9 The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.
Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.
Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.10 Thus, the effect of supplementation may be more pronounced in women in the United States.
CAVEATS
Questions remain: Ideal dose and which women to treat?
The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.11 The Palmer study,8 using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)1 and the Olsen study (2700 mg/d).9 Further research is needed to determine the optimal dosage.
The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.
One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).1 Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.
CHALLENGES TO IMPLEMENTATION
Multiple pills and additional cost
Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375:2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dessemination Committee Report. Allergy. 2004;59:469-478.
3. Centers for Disease Control and Prevention. Asthma. Available at: https://www.cdc.gov/asthma/most_recent_data.htm. Accessed October 9, 2017.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64:27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42:513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17:94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22:CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88:167-175.
10. Helgi Library. Fish consumption per capita by country. Available at: http://www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed September 27, 2017.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Federal Register.2017;82:6571-6574.
1. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375:2530-2539.
2. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dessemination Committee Report. Allergy. 2004;59:469-478.
3. Centers for Disease Control and Prevention. Asthma. Available at: https://www.cdc.gov/asthma/most_recent_data.htm. Accessed October 9, 2017.
4. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergol Int. 2015;64:27-34.
5. Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005;42:513-518.
6. Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006;17:94-102.
7. Gunaratne AW, Makrides M, Collins CT. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst Rev. 2015;22:CD010085.
8. Palmer D, Sullivan T, Gold M, et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy. 2013;68:1370-1376.
9. Olsen SF, Østerdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88:167-175.
10. Helgi Library. Fish consumption per capita by country. Available at: http://www.helgilibrary.com/indicators/fish-consumption-per-capita/. Accessed September 27, 2017.
11. FDA Advice About Eating Fish, From the Environmental Protection Agency and Food and Drug Administration; Revised Fish Advice; Availability. Federal Register.2017;82:6571-6574.
Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.
PRACTICE CHANGER
Fish oil supplementation taken by women in the third trimester of pregnancy can reduce the risk of persistent wheeze, asthma, and infections of the lower respiratory tract in their children.1
STRENGTH OF RECOMMENDATION
B: Based on 2 double-blinded randomized controlled trials (RCTs).
Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med. 2016;375:2530-2539.1
An obesity remedy for diabetes
Consider bariatric surgery for patients with diabetes who are obese; surgery is associated with higher remission rates than medical therapy, regardless of the amount of weight lost.1
STRENGTH OF RECOMMENDATION
B: Based on a single nonblinded randomized controlled trial (RCT).
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
ILLUSTRATIVE CASE
A 43-year-old woman with a body mass index (BMI) of 38 kg/m2 and a 5-year history of diabetes has a glycated hemoglobin (HbA1c) of 8.5% despite the use of oral hypoglycemic agents. Should you talk to her about gastric bypass surgery to treat her diabetes?
Diet and exercise are the first steps in addressing diabetes, but these interventions are often unsuccessful. The International Diabetes Federation (IDF) recommends consideration of bariatric surgery for patients who have a BMI >35 kg/m2 and diabetes that lifestyle modification and pharmacotherapy have failed to control.2
Surgery for diabetes: Is there ample evidence?
Until recently, the IDF’s recommendation was based on observational data and a single RCT that found increased resolution of diabetes following various bariatric procedures.3-5 In the study detailed in this PURL, Mingrone et al took another look.
STUDY SUMMARY: Surgery led to higher remission rates
This single-center, nonblinded RCT compared 2 malabsorptive procedures— Roux-en-Y gastric bypass and biliopancreatic diversion, a more complicated procedure not commonly performed—with medical therapy.1 The primary outcome was the rate of diabetes remission at 2 years, defined as a fasting glucose level <100 mg/dL and an HbA1c <6.5%. Changes in BMI and cholesterol levels were among the secondary endpoints.
To be eligible, patients had to be between the ages of 30 and 60 years and have a BMI ≥35 kg/m2, a history of type 2 diabetes ≥5 years, and an HbA1c ≥7.0%. Exclusion criteria included a history of type 1 diabetes, diabetes caused by an underlying disease or steroid treatment, previous bariatric surgery, pregnancy, diabetic complications, other severe medical conditions, and acute hospitalization. Both the gastric bypass and biliopancreatic diversion procedures were performed by independent surgical teams.
Participants (N=60) were evaluated at baseline and at 1, 3, 6, 9, 12, and 24 months after the intervention by a team that included a dietician, a nurse, and a physician. All received a diet plan with daily exercise designed by their team. Those in the medical therapy group had their medications titrated to reach a goal HbA1c <7%. Pharmacotherapy was stopped based on normalization of blood sugars or HbA1c <6.5%.
Within 15 days postsurgery, patients in both surgical arms had their diabetes medications stopped based on their blood glucose levels.
At 2 years, 75% of the patients in the gastric bypass arm and 95% of the patients in the biliopancreatic diversion arm (number needed to treat=1.3 and 1, respectively) were considered to be in diabetes remission, defined as a fasting blood sugar of <100 mg/dL and an HbA1c <6.5% after one year without pharmacotherapy. (Notably, this differs from that of the American Diabetes Association, which requires an HbA1c <6.0% for classification as complete remission.) None of the patients in the medical therapy arm was in remission at the 2-year mark.
On average, blood sugars normalized for gastric bypass patients by 10±2 months, vs 4±1 months for biliopancreatic diversion patients (P=.01). The average HbA1c at the end of 2 years was significantly different among all 3 groups (6.35%±1.42 for those undergoing gastric bypass, 4.95%±0.49 for the biliopancreatic diversion group, and 7.69%±0.57 for the medical therapy group), as was the change in HbA1c from baseline (TABLE). Changes in BMI and the number of patients who achieved normalization of total cholesterol were similar for both surgical groups. Interestingly, neither baseline BMI nor amount of weight lost or pre-enrollment duration of diabetes were predictors of diabetes remission or normalization of fasting glucose levels.
TABLE
Surgery vs medical therapy for diabetes: Gastric bypass and biliopancreatic diversion are more effective
| Gastric bypass (n=20) | Biliopancreatic diversion (n=20) | Medical therapy (n=20) | |
|---|---|---|---|
| HbA1c at 2 years (%) | 6.35±1.42* (n=19) | 4.95±0.49 (n=19) | 7.69±0.57 (n=18) |
| HbA1c change from baseline* (%) | –25.18±20.89 | –43.01±9.64 | –8.39±9.93 |
| BMI change from baseline* (%) | –33.31±7.88 | –33.82±10.17* | –4.73±6.37 |
| Total cholesterol normalization† (%) | 100* | 100* | 27.3 |
| BMI, body mass index. *P<0.01 for post hoc analysis comparing surgical arm to medical therapy. †Normalization of cholesterol was defined as a total cholesterol <201 mg/dL and HDL >40 mg/dL in men and >50 mg/dL in women (personal communication from author). | |||
There were no deaths associated with this study. There were 2 adverse events requiring reoperation: an incisional hernia in a patient in the biliopancreatic diversion group and an intestinal obstruction in a patient in the gastric bypass group. Six patients in the biliopancreatic diversion arm developed metabolic abnormalities, including iron deficiency anemia, hypoalbuminemia, osteopenia, and osteoporosis. In the gastric bypass arm, 2 patients developed iron deficiency anemia.
WHAT’S NEW?: Evidence of efficacy has grown
This is the first RCT to evaluate biliopancreatic diversion and only the second to evaluate gastric bypass as strategies for controlling diabetes. Similar findings were demonstrated at 12 months in an RCT of 150 obese patients with diabetes in which intensive medical therapy was compared with either gastric bypass or sleeve gastrectomy,6 published concurrently with the Mingrone study. Like the Mingrone study, this study found that for select patients with diabetes, surgery may lead to better outcomes than medical management alone.
CAVEATS: Long-term effect is still uncertain
The long-term efficacy of surgery as a way to manage diabetes remains uncertain. Patients in this study were followed for just 2 years and the outcomes were metabolic measures rather than morbidity and mortality. A recent prospective observational study following patients for 6 years after gastric bypass found that the rate of remission for diabetes was 75% (95% confidence interval (CI), 63%-87%) at 2 years but dropped to 62% (95% CI, 49%-75%) at 6 years7
A larger study (N=4047) of longer duration—the Swedish Obese Subjects (SOS) cohort study —found a considerably larger drop: The diabetes remission rate for those who had surgery went from 72% at 2 years to 36% at 10-year follow-up, but that was still higher than the 10-year remission rate (13%) for the matched controls.4 It is still not clear exactly how long diabetic remission lasts after bariatric surgery or what effect a 10-year respite from the disease will have on the long-term morbidity and mortality of patients with diabetes.
Surgical risks. In small studies such as the one by Mingrone et al,1 it can be difficult to see the full extent of surgical complications. The much larger SOS study found low mortality rates (0.25%). But 13% of those who underwent bariatric surgery had postoperative complications (number needed to harm = 8), with 2.2% of patients requiring reoperation.4 Additionally, women who become pregnant after bariatric surgery are at increased risk for internal hernias or bowel obstruction during pregnancy.8
Furthermore, malabsorptive-type surgeries are known to cause nutritional deficiencies, leading to disorders including anemia and osteoporosis.6 Importantly, while women of childbearing-age who undergo bariatric surgery decrease their risk of developing gestational hypertension and gestational diabetes, they are more likely to have nutritional deficiencies during pregnancy and to have children with these deficiencies.8
CHALLENGES TO IMPLEMENTATION: The ideal candidate remains unclear
It is still not clear from this study which patients should be referred for bariatric surgery. Historically, BMI has been used as the main indication for bariatric surgery, but this and other, studies have found that remission of diabetes is independent of BMI and the amount of weight lost.9 A predictive 10-point Diabetes Surgery Score has recently been developed: It uses age, BMI, duration of diabetes, and C-peptide levels to predict the likelihood of diabetes remission after surgery.10 This scoring system has yet to be validated in non-Asian patients, and a threshold for recommending surgery has been not established. However, this tool indicates that younger patients with a shorter duration of diabetes (which was not a factor in the outcome of the Mingrone study) and no baseline use of insulin are most likely to benefit from surgery. Thus, these patients may be the ones we need to consider referring first.
Cost of surgery. Several studies have shown that bariatric surgery is cost-effective for the treatment of diabetes, and saves money after approximately 5 years.11,12 However, patients with diabetes and obesity may be uninsured or underinsured, and have high out-of-pocket costs. One challenge will be to ensure that surgery is a viable option for patients with financial constraints.
Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
2. Dixon JB, Zimmet P, Alberti KG, et al. Bariatric surgery: an IDF statement for obese type 2 diabetes. Diabet Med. 2011;28:628-642.
3. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122:248-256.
4. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-2693.
5. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299:316-323.
6. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1568-1576.
7. Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308:1122-1131.
8. Dalfrà MG, Busetto L, Chilelli NC, et al. Pregnancy and foetal outcome after bariatric surgery: a review of recent studies. J Matern Fetal Neonatal Med. 2012;25:1537-1543.
9. Livingston EH Pitfalls in using BMI as a selection criterion for bariatric surgery. Curr Opin Endocrinol Diabetes Obes. 2012;19:347-351.
10. Lee W-J, Hur K, Lakadawala M, et al. Predicting success of metabolic surgery: age, body mass index, C-peptide, and duration score. Surg Obes Relat Dis. 2012; [Epub ahead of print].
11. Terranova L, Busetto L, Vestri A, et al. Bariatric surgery: cost-effectiveness and budget impact. Obes Surg. 2012;22:646-653.
12. Hoerger TJ, Zhang P, Segel JE, et al. Cost-effectiveness of bariatric surgery for severely obese adults with diabetes. Diabetes Care. 2010;33:1933-1939.
Consider bariatric surgery for patients with diabetes who are obese; surgery is associated with higher remission rates than medical therapy, regardless of the amount of weight lost.1
STRENGTH OF RECOMMENDATION
B: Based on a single nonblinded randomized controlled trial (RCT).
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
ILLUSTRATIVE CASE
A 43-year-old woman with a body mass index (BMI) of 38 kg/m2 and a 5-year history of diabetes has a glycated hemoglobin (HbA1c) of 8.5% despite the use of oral hypoglycemic agents. Should you talk to her about gastric bypass surgery to treat her diabetes?
Diet and exercise are the first steps in addressing diabetes, but these interventions are often unsuccessful. The International Diabetes Federation (IDF) recommends consideration of bariatric surgery for patients who have a BMI >35 kg/m2 and diabetes that lifestyle modification and pharmacotherapy have failed to control.2
Surgery for diabetes: Is there ample evidence?
Until recently, the IDF’s recommendation was based on observational data and a single RCT that found increased resolution of diabetes following various bariatric procedures.3-5 In the study detailed in this PURL, Mingrone et al took another look.
STUDY SUMMARY: Surgery led to higher remission rates
This single-center, nonblinded RCT compared 2 malabsorptive procedures— Roux-en-Y gastric bypass and biliopancreatic diversion, a more complicated procedure not commonly performed—with medical therapy.1 The primary outcome was the rate of diabetes remission at 2 years, defined as a fasting glucose level <100 mg/dL and an HbA1c <6.5%. Changes in BMI and cholesterol levels were among the secondary endpoints.
To be eligible, patients had to be between the ages of 30 and 60 years and have a BMI ≥35 kg/m2, a history of type 2 diabetes ≥5 years, and an HbA1c ≥7.0%. Exclusion criteria included a history of type 1 diabetes, diabetes caused by an underlying disease or steroid treatment, previous bariatric surgery, pregnancy, diabetic complications, other severe medical conditions, and acute hospitalization. Both the gastric bypass and biliopancreatic diversion procedures were performed by independent surgical teams.
Participants (N=60) were evaluated at baseline and at 1, 3, 6, 9, 12, and 24 months after the intervention by a team that included a dietician, a nurse, and a physician. All received a diet plan with daily exercise designed by their team. Those in the medical therapy group had their medications titrated to reach a goal HbA1c <7%. Pharmacotherapy was stopped based on normalization of blood sugars or HbA1c <6.5%.
Within 15 days postsurgery, patients in both surgical arms had their diabetes medications stopped based on their blood glucose levels.
At 2 years, 75% of the patients in the gastric bypass arm and 95% of the patients in the biliopancreatic diversion arm (number needed to treat=1.3 and 1, respectively) were considered to be in diabetes remission, defined as a fasting blood sugar of <100 mg/dL and an HbA1c <6.5% after one year without pharmacotherapy. (Notably, this differs from that of the American Diabetes Association, which requires an HbA1c <6.0% for classification as complete remission.) None of the patients in the medical therapy arm was in remission at the 2-year mark.
On average, blood sugars normalized for gastric bypass patients by 10±2 months, vs 4±1 months for biliopancreatic diversion patients (P=.01). The average HbA1c at the end of 2 years was significantly different among all 3 groups (6.35%±1.42 for those undergoing gastric bypass, 4.95%±0.49 for the biliopancreatic diversion group, and 7.69%±0.57 for the medical therapy group), as was the change in HbA1c from baseline (TABLE). Changes in BMI and the number of patients who achieved normalization of total cholesterol were similar for both surgical groups. Interestingly, neither baseline BMI nor amount of weight lost or pre-enrollment duration of diabetes were predictors of diabetes remission or normalization of fasting glucose levels.
TABLE
Surgery vs medical therapy for diabetes: Gastric bypass and biliopancreatic diversion are more effective
| Gastric bypass (n=20) | Biliopancreatic diversion (n=20) | Medical therapy (n=20) | |
|---|---|---|---|
| HbA1c at 2 years (%) | 6.35±1.42* (n=19) | 4.95±0.49 (n=19) | 7.69±0.57 (n=18) |
| HbA1c change from baseline* (%) | –25.18±20.89 | –43.01±9.64 | –8.39±9.93 |
| BMI change from baseline* (%) | –33.31±7.88 | –33.82±10.17* | –4.73±6.37 |
| Total cholesterol normalization† (%) | 100* | 100* | 27.3 |
| BMI, body mass index. *P<0.01 for post hoc analysis comparing surgical arm to medical therapy. †Normalization of cholesterol was defined as a total cholesterol <201 mg/dL and HDL >40 mg/dL in men and >50 mg/dL in women (personal communication from author). | |||
There were no deaths associated with this study. There were 2 adverse events requiring reoperation: an incisional hernia in a patient in the biliopancreatic diversion group and an intestinal obstruction in a patient in the gastric bypass group. Six patients in the biliopancreatic diversion arm developed metabolic abnormalities, including iron deficiency anemia, hypoalbuminemia, osteopenia, and osteoporosis. In the gastric bypass arm, 2 patients developed iron deficiency anemia.
WHAT’S NEW?: Evidence of efficacy has grown
This is the first RCT to evaluate biliopancreatic diversion and only the second to evaluate gastric bypass as strategies for controlling diabetes. Similar findings were demonstrated at 12 months in an RCT of 150 obese patients with diabetes in which intensive medical therapy was compared with either gastric bypass or sleeve gastrectomy,6 published concurrently with the Mingrone study. Like the Mingrone study, this study found that for select patients with diabetes, surgery may lead to better outcomes than medical management alone.
CAVEATS: Long-term effect is still uncertain
The long-term efficacy of surgery as a way to manage diabetes remains uncertain. Patients in this study were followed for just 2 years and the outcomes were metabolic measures rather than morbidity and mortality. A recent prospective observational study following patients for 6 years after gastric bypass found that the rate of remission for diabetes was 75% (95% confidence interval (CI), 63%-87%) at 2 years but dropped to 62% (95% CI, 49%-75%) at 6 years7
A larger study (N=4047) of longer duration—the Swedish Obese Subjects (SOS) cohort study —found a considerably larger drop: The diabetes remission rate for those who had surgery went from 72% at 2 years to 36% at 10-year follow-up, but that was still higher than the 10-year remission rate (13%) for the matched controls.4 It is still not clear exactly how long diabetic remission lasts after bariatric surgery or what effect a 10-year respite from the disease will have on the long-term morbidity and mortality of patients with diabetes.
Surgical risks. In small studies such as the one by Mingrone et al,1 it can be difficult to see the full extent of surgical complications. The much larger SOS study found low mortality rates (0.25%). But 13% of those who underwent bariatric surgery had postoperative complications (number needed to harm = 8), with 2.2% of patients requiring reoperation.4 Additionally, women who become pregnant after bariatric surgery are at increased risk for internal hernias or bowel obstruction during pregnancy.8
Furthermore, malabsorptive-type surgeries are known to cause nutritional deficiencies, leading to disorders including anemia and osteoporosis.6 Importantly, while women of childbearing-age who undergo bariatric surgery decrease their risk of developing gestational hypertension and gestational diabetes, they are more likely to have nutritional deficiencies during pregnancy and to have children with these deficiencies.8
CHALLENGES TO IMPLEMENTATION: The ideal candidate remains unclear
It is still not clear from this study which patients should be referred for bariatric surgery. Historically, BMI has been used as the main indication for bariatric surgery, but this and other, studies have found that remission of diabetes is independent of BMI and the amount of weight lost.9 A predictive 10-point Diabetes Surgery Score has recently been developed: It uses age, BMI, duration of diabetes, and C-peptide levels to predict the likelihood of diabetes remission after surgery.10 This scoring system has yet to be validated in non-Asian patients, and a threshold for recommending surgery has been not established. However, this tool indicates that younger patients with a shorter duration of diabetes (which was not a factor in the outcome of the Mingrone study) and no baseline use of insulin are most likely to benefit from surgery. Thus, these patients may be the ones we need to consider referring first.
Cost of surgery. Several studies have shown that bariatric surgery is cost-effective for the treatment of diabetes, and saves money after approximately 5 years.11,12 However, patients with diabetes and obesity may be uninsured or underinsured, and have high out-of-pocket costs. One challenge will be to ensure that surgery is a viable option for patients with financial constraints.
Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Consider bariatric surgery for patients with diabetes who are obese; surgery is associated with higher remission rates than medical therapy, regardless of the amount of weight lost.1
STRENGTH OF RECOMMENDATION
B: Based on a single nonblinded randomized controlled trial (RCT).
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
ILLUSTRATIVE CASE
A 43-year-old woman with a body mass index (BMI) of 38 kg/m2 and a 5-year history of diabetes has a glycated hemoglobin (HbA1c) of 8.5% despite the use of oral hypoglycemic agents. Should you talk to her about gastric bypass surgery to treat her diabetes?
Diet and exercise are the first steps in addressing diabetes, but these interventions are often unsuccessful. The International Diabetes Federation (IDF) recommends consideration of bariatric surgery for patients who have a BMI >35 kg/m2 and diabetes that lifestyle modification and pharmacotherapy have failed to control.2
Surgery for diabetes: Is there ample evidence?
Until recently, the IDF’s recommendation was based on observational data and a single RCT that found increased resolution of diabetes following various bariatric procedures.3-5 In the study detailed in this PURL, Mingrone et al took another look.
STUDY SUMMARY: Surgery led to higher remission rates
This single-center, nonblinded RCT compared 2 malabsorptive procedures— Roux-en-Y gastric bypass and biliopancreatic diversion, a more complicated procedure not commonly performed—with medical therapy.1 The primary outcome was the rate of diabetes remission at 2 years, defined as a fasting glucose level <100 mg/dL and an HbA1c <6.5%. Changes in BMI and cholesterol levels were among the secondary endpoints.
To be eligible, patients had to be between the ages of 30 and 60 years and have a BMI ≥35 kg/m2, a history of type 2 diabetes ≥5 years, and an HbA1c ≥7.0%. Exclusion criteria included a history of type 1 diabetes, diabetes caused by an underlying disease or steroid treatment, previous bariatric surgery, pregnancy, diabetic complications, other severe medical conditions, and acute hospitalization. Both the gastric bypass and biliopancreatic diversion procedures were performed by independent surgical teams.
Participants (N=60) were evaluated at baseline and at 1, 3, 6, 9, 12, and 24 months after the intervention by a team that included a dietician, a nurse, and a physician. All received a diet plan with daily exercise designed by their team. Those in the medical therapy group had their medications titrated to reach a goal HbA1c <7%. Pharmacotherapy was stopped based on normalization of blood sugars or HbA1c <6.5%.
Within 15 days postsurgery, patients in both surgical arms had their diabetes medications stopped based on their blood glucose levels.
At 2 years, 75% of the patients in the gastric bypass arm and 95% of the patients in the biliopancreatic diversion arm (number needed to treat=1.3 and 1, respectively) were considered to be in diabetes remission, defined as a fasting blood sugar of <100 mg/dL and an HbA1c <6.5% after one year without pharmacotherapy. (Notably, this differs from that of the American Diabetes Association, which requires an HbA1c <6.0% for classification as complete remission.) None of the patients in the medical therapy arm was in remission at the 2-year mark.
On average, blood sugars normalized for gastric bypass patients by 10±2 months, vs 4±1 months for biliopancreatic diversion patients (P=.01). The average HbA1c at the end of 2 years was significantly different among all 3 groups (6.35%±1.42 for those undergoing gastric bypass, 4.95%±0.49 for the biliopancreatic diversion group, and 7.69%±0.57 for the medical therapy group), as was the change in HbA1c from baseline (TABLE). Changes in BMI and the number of patients who achieved normalization of total cholesterol were similar for both surgical groups. Interestingly, neither baseline BMI nor amount of weight lost or pre-enrollment duration of diabetes were predictors of diabetes remission or normalization of fasting glucose levels.
TABLE
Surgery vs medical therapy for diabetes: Gastric bypass and biliopancreatic diversion are more effective
| Gastric bypass (n=20) | Biliopancreatic diversion (n=20) | Medical therapy (n=20) | |
|---|---|---|---|
| HbA1c at 2 years (%) | 6.35±1.42* (n=19) | 4.95±0.49 (n=19) | 7.69±0.57 (n=18) |
| HbA1c change from baseline* (%) | –25.18±20.89 | –43.01±9.64 | –8.39±9.93 |
| BMI change from baseline* (%) | –33.31±7.88 | –33.82±10.17* | –4.73±6.37 |
| Total cholesterol normalization† (%) | 100* | 100* | 27.3 |
| BMI, body mass index. *P<0.01 for post hoc analysis comparing surgical arm to medical therapy. †Normalization of cholesterol was defined as a total cholesterol <201 mg/dL and HDL >40 mg/dL in men and >50 mg/dL in women (personal communication from author). | |||
There were no deaths associated with this study. There were 2 adverse events requiring reoperation: an incisional hernia in a patient in the biliopancreatic diversion group and an intestinal obstruction in a patient in the gastric bypass group. Six patients in the biliopancreatic diversion arm developed metabolic abnormalities, including iron deficiency anemia, hypoalbuminemia, osteopenia, and osteoporosis. In the gastric bypass arm, 2 patients developed iron deficiency anemia.
WHAT’S NEW?: Evidence of efficacy has grown
This is the first RCT to evaluate biliopancreatic diversion and only the second to evaluate gastric bypass as strategies for controlling diabetes. Similar findings were demonstrated at 12 months in an RCT of 150 obese patients with diabetes in which intensive medical therapy was compared with either gastric bypass or sleeve gastrectomy,6 published concurrently with the Mingrone study. Like the Mingrone study, this study found that for select patients with diabetes, surgery may lead to better outcomes than medical management alone.
CAVEATS: Long-term effect is still uncertain
The long-term efficacy of surgery as a way to manage diabetes remains uncertain. Patients in this study were followed for just 2 years and the outcomes were metabolic measures rather than morbidity and mortality. A recent prospective observational study following patients for 6 years after gastric bypass found that the rate of remission for diabetes was 75% (95% confidence interval (CI), 63%-87%) at 2 years but dropped to 62% (95% CI, 49%-75%) at 6 years7
A larger study (N=4047) of longer duration—the Swedish Obese Subjects (SOS) cohort study —found a considerably larger drop: The diabetes remission rate for those who had surgery went from 72% at 2 years to 36% at 10-year follow-up, but that was still higher than the 10-year remission rate (13%) for the matched controls.4 It is still not clear exactly how long diabetic remission lasts after bariatric surgery or what effect a 10-year respite from the disease will have on the long-term morbidity and mortality of patients with diabetes.
Surgical risks. In small studies such as the one by Mingrone et al,1 it can be difficult to see the full extent of surgical complications. The much larger SOS study found low mortality rates (0.25%). But 13% of those who underwent bariatric surgery had postoperative complications (number needed to harm = 8), with 2.2% of patients requiring reoperation.4 Additionally, women who become pregnant after bariatric surgery are at increased risk for internal hernias or bowel obstruction during pregnancy.8
Furthermore, malabsorptive-type surgeries are known to cause nutritional deficiencies, leading to disorders including anemia and osteoporosis.6 Importantly, while women of childbearing-age who undergo bariatric surgery decrease their risk of developing gestational hypertension and gestational diabetes, they are more likely to have nutritional deficiencies during pregnancy and to have children with these deficiencies.8
CHALLENGES TO IMPLEMENTATION: The ideal candidate remains unclear
It is still not clear from this study which patients should be referred for bariatric surgery. Historically, BMI has been used as the main indication for bariatric surgery, but this and other, studies have found that remission of diabetes is independent of BMI and the amount of weight lost.9 A predictive 10-point Diabetes Surgery Score has recently been developed: It uses age, BMI, duration of diabetes, and C-peptide levels to predict the likelihood of diabetes remission after surgery.10 This scoring system has yet to be validated in non-Asian patients, and a threshold for recommending surgery has been not established. However, this tool indicates that younger patients with a shorter duration of diabetes (which was not a factor in the outcome of the Mingrone study) and no baseline use of insulin are most likely to benefit from surgery. Thus, these patients may be the ones we need to consider referring first.
Cost of surgery. Several studies have shown that bariatric surgery is cost-effective for the treatment of diabetes, and saves money after approximately 5 years.11,12 However, patients with diabetes and obesity may be uninsured or underinsured, and have high out-of-pocket costs. One challenge will be to ensure that surgery is a viable option for patients with financial constraints.
Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
2. Dixon JB, Zimmet P, Alberti KG, et al. Bariatric surgery: an IDF statement for obese type 2 diabetes. Diabet Med. 2011;28:628-642.
3. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122:248-256.
4. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-2693.
5. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299:316-323.
6. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1568-1576.
7. Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308:1122-1131.
8. Dalfrà MG, Busetto L, Chilelli NC, et al. Pregnancy and foetal outcome after bariatric surgery: a review of recent studies. J Matern Fetal Neonatal Med. 2012;25:1537-1543.
9. Livingston EH Pitfalls in using BMI as a selection criterion for bariatric surgery. Curr Opin Endocrinol Diabetes Obes. 2012;19:347-351.
10. Lee W-J, Hur K, Lakadawala M, et al. Predicting success of metabolic surgery: age, body mass index, C-peptide, and duration score. Surg Obes Relat Dis. 2012; [Epub ahead of print].
11. Terranova L, Busetto L, Vestri A, et al. Bariatric surgery: cost-effectiveness and budget impact. Obes Surg. 2012;22:646-653.
12. Hoerger TJ, Zhang P, Segel JE, et al. Cost-effectiveness of bariatric surgery for severely obese adults with diabetes. Diabetes Care. 2010;33:1933-1939.
1. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585.
2. Dixon JB, Zimmet P, Alberti KG, et al. Bariatric surgery: an IDF statement for obese type 2 diabetes. Diabet Med. 2011;28:628-642.
3. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122:248-256.
4. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-2693.
5. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299:316-323.
6. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1568-1576.
7. Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308:1122-1131.
8. Dalfrà MG, Busetto L, Chilelli NC, et al. Pregnancy and foetal outcome after bariatric surgery: a review of recent studies. J Matern Fetal Neonatal Med. 2012;25:1537-1543.
9. Livingston EH Pitfalls in using BMI as a selection criterion for bariatric surgery. Curr Opin Endocrinol Diabetes Obes. 2012;19:347-351.
10. Lee W-J, Hur K, Lakadawala M, et al. Predicting success of metabolic surgery: age, body mass index, C-peptide, and duration score. Surg Obes Relat Dis. 2012; [Epub ahead of print].
11. Terranova L, Busetto L, Vestri A, et al. Bariatric surgery: cost-effectiveness and budget impact. Obes Surg. 2012;22:646-653.
12. Hoerger TJ, Zhang P, Segel JE, et al. Cost-effectiveness of bariatric surgery for severely obese adults with diabetes. Diabetes Care. 2010;33:1933-1939.
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