There were 13.4 million women (ages 20 and older) with either type 1 or type 2 diabetes in the United States in 2012, according to the CDC.¹ By 2050, overall prevalence of dia­betes is expected to double or triple.² Since the number of women with diabetes will continue to increase, it is important for clinicians to familiarize themselves with management of the condition in those of childbearing age—particularly with regard to medication selection.

Diabetes management in women of childbearing age pre­sents multiple complexities. First, strict glucose control from preconception through pregnancy is necessary to reduce the risk for complications in mother and ­fetus. The American Diabetes Association (ADA) recommends an A1C of less than 7% during the preconception period, if achievable without hypoglycemia.³ Full glycemic targets for women are outlined in Table 1.

Continue for medication classes with pregnancy category >>

Second, many medications used to manage diabetes and pregnancy-associated comorbidities can be fetotoxic. The FDA assigns all drugs to a pregnancy category, the definitions of which are available at http://chemm.nlm.nih.gov/pregnancycategories.htm.⁴ The ADA recommends that sexually active women of childbearing age avoid any potentially teratogenic medications (see Table 2) if they are not using reliable contraception.³

Excellent control of diabetes is necessary to decrease risk for birth defects. Infants born to mothers with preconception diabetes have been shown to have higher rates of morbidity and mortality.⁵ Infants born to women with diabetes are generally large for gestational age and experience hypoglycemia in the first 24 to 48 hours of life.⁶ Large-for-gestational-age babies are at increased risk for trauma at birth, including orthopedic injuries (eg, shoulder dislocation) and brachial plexus injuries. There is also an increased risk for fetal cardiac defects and congenital congestive heart failure.⁶

This article will review four cases of diabetes management in women of childbearing age. The ADA guidelines form the basis for all recommendations.

Continue for case 1 >>

Case 1 A 32-year-old obese woman with type 2 diabetes mellitus (T2DM) presents for routine follow-up. Recent lab results reveal an A1C of 6.4%; GFR > 100 mL/min/1.73 m2; and microalbuminuria (110 mg/d). She is currently taking lisinopril (2.5 mg once daily), metformin (1,000 mg bid), and glyburide (5 mg bid). She plans to become pregnant in the next six months and wants advice.

Discussion
This patient should be counseled on preconception glycemic targets and switched to pregnancy-safe medications. She should also be advised that the recommended weight gain in pregnancy for women with T2DM is 15 to 25 lb in overweight women and 10 to 20 lb in obese women.³

The ADA recommends a target A1C < 7%, in the absence of severe hypoglycemia, prior to conception in patients with type 1 diabetes mellitus (T1DM) or T2DM.³ For women with preconception diabetes who become pregnant, it is recommended that their premeal, bedtime, and overnight glucose be maintained at 60 to 99 mg/dL, their peak postprandial glucose at 100 to 129 mg/dL, and their A1C < 6% during pregnancy (all without excessive hypoglycemia), due to increases in red blood cell turnover.³ It is also recommended that they avoid statins, ACE inhibitors, angiotensin II receptor blockers (ARBs), certain beta blockers, and most noninsulin therapies.³

This patient is currently taking lisinopril, a medication with a pregnancy category of X. The ACE inhibitor class of medications is known to cause oligohydramnios, intrauterine growth retardation, structural malformation, premature birth, fetal renal dysplasia, and other congenital abnormalities, and use of these drugs should be avoided in women trying to conceive.⁷

Safer options for blood pressure control include clonidine, diltiazam, labetalol, methyldopa, or prazosin.³ Diuretics can reduce placental blood perfusion and should be avoided.⁸ An alternative for management of microalbuminuria in women of childbearing age is nifedipine.⁹ In multiple studies, this medication was not only safer in pregnancy, with no major teratogenic risk, but also effectively reduced urine microalbumin levels.^10,11

For T2DM management, metformin (pregnancy category B) and glyburide (pregnancy category B/C, depending on manufacturer) can be used.^12,13 Glyburide, the most studied sulfonylurea, is recommended as the drug of choice in its class.^14-16 While insulin is the standard for managing diabetes in pregnancy—earlier research supported a switch from oral medications to insulin in women interested in becoming pregnant—recent studies have demonstrated that oral medications can be safely used.¹⁷ In addition, lifestyle changes (eg, carbohydrate counting, limited meal portions, and regular moderate exercise) prior to and during pregnancy can be beneficial for diabetes management.^18,19

Also remind the patient to take regular prenatal vitamins. The US Preventive Services Task Force recommends that all women planning to become or capable of becoming pregnant take 400 to 800 µg supplements of folic acid daily.²⁰ For women at high risk for neural tube defects or who have had a previous pregnancy with neural tube defects, 4 mg/d is recommended.²¹ In women with diabetes who are trying to conceive, a folic acid supplement of 5 mg/d is recommended, beginning three months prior to conception.²²

Research shows that diabetic women are less likely to take folic acid supplementation during pregnancy. A study of 6,835 obese or overweight women with diabetes showed that only 35% reported daily folic acid supplementation.²³ The study authors recommended all women of childbearing age, especially those who are obese or have diabetes, take folic acid daily.²³ Encourage all women intending to become pregnant to start prenatal vitamin supplementation.

Continue for case 2 >>

Case 2 A 26-year-old obese patient, 28 weeks primigravida, presents for follow-up on her 3-hour glucose tolerance test. Results indicate a 3-hour glucose level of 148 mg/dL. The patient has a family history of T2DM and gestational diabetes.

Discussion
Gestational diabetes is defined by the ADA as diabetes diagnosed during the second or third trimester of pregnancy that is not T1DM or T2DM.³ The ADA recommends lifestyle management of gestational diabetes before medications are introduced. A1C should be maintained at 6% or less without hypoglycemia. In general, insulin is preferred over oral agents for treatment of gestational diabetes.³

There tends to be a spike in insulin resistance in the second or third trimester; women with preconception diabetes, for example, may require frequent increases in daily insulin dose to maintain glycemic levels, compared to the first trimester.³ A baseline ophthalmology exam should be performed in the first trimester for patients with preconception diabetes, with additional monitoring as needed.³

Following pregnancy, screening should be conducted for diabetes or prediabetes at six to 12 weeks’ postpartum and every one to three years afterward.³ The cumulative incidence of T2DM varies considerably among studies, ranging from 17% to 63% in five to 16 years postpartum.^24,25 Thus, women with gestational diabetes should maintain lifestyle changes, including diet and exercise, to reduce the risk for T2DM later in life.

Continue for case 3 >>

Case 3 A 43-year-old woman with T1DM becomes pregnant while taking atorvastatin (20 mg), insulin detemir (18 units qhs), and insulin aspart with meals, as per her calculated insulin-to-carbohydrate ratio (ICR; 1 U aspart for 18 g carbohydrates) and insulin sensitivity factor (ISF; 1 U aspart for every 60 mg/dL above 130 mg/dL). Her biggest concern today is her medication list and potential adverse effects on the fetus. Her most recent A1C, two months ago, was 6.5%. She senses hypoglycemia at glucose levels of about 60 mg/dL and admits to having such measurements about twice per week.

Discussion
In this case, the patient needs to stop taking her statin and check her blood glucose regularly, as she is at increased risk for hypoglycemia. In their 2013 guidelines, the American College of Cardiology/American Heart Association stated that statins “should not be used in women of childbearing potential unless these women are using effective contraception and are not nursing.”²⁶ This presents a major problem for many women of childbearing age with diabetes.

Statins are associated with a variety of congenital abnormalities, including fetal growth restriction and structural abnormalities in the fetus.²⁷ It is advised that women planning for pregnancy avoid use of statins.²⁸ If the patient has severe hypertriglyceridemia that puts her at risk for acute pancreatitis, fenofibrate (pregnancy category C) can be considered in the second and third trimesters.^29,30

With T1DM in pregnancy, there is an increased risk for hypoglycemia in the first trimester.³ This risk increases as women adapt to more strict blood glucose control. Frequent recalculation of the ICR and ISF may be needed as the pregnancy progresses and weight gain occurs. Most insulin formulations are pregnancy class B, with the exception of glargine, degludec, and glulisine, which are pregnancy category C.³

Continue for case 4 >>

Case 4 A 21-year-old woman with T1DM wishes to start contraception but has concerns about long-term options. She seeks your advice in making a decision.

Discussion
For long-term pregnancy prevention, either the copper or progesterone-containing intrauterine device (IUD) is safe and effective for women with T1DM or T2DM.³¹ While the levonor­gestrel IUD does not produce ­metabolic changes in T1DM, it has not yet been adequately studied in T2DM. Demographics suggest that young women with T2DM could become viable candidates for intrauterine contraception.³¹

The hormone-releasing “ring” has been found to be reliable and safe for women of late reproductive age with T1DM.³² Combined hormonal contraceptives and the transdermal contraceptive patch are best avoided to reduce risk for complications associated with estrogen-containing contraceptives (eg, venous thromboembolism and myocardial infarction).³³

Continue for the conclusion >>

Conclusion
All women with diabetes should be counseled on glucose control prior to pregnancy. Achieving a goal A1C below 6% in the absence of hypoglycemia is recommended by the ADA.³ Long-term contraception options should be considered in women of childbearing age with diabetes to prevent pregnancy. Clinicians should carefully select medications for management of diabetes and its comorbidities in women planning to become pregnant. Healthy dietary habits and regular exercise should be encouraged in all patients with diabetes, especially prior to pregnancy.

References
1. CDC. National Diabetes Statistics Report, 2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed January 12, 2016.
2. CDC. Number of Americans with diabetes projected to double or triple by 2050. 2010. www.cdc.gov/media/pressrel/2010/r101022.html. Accessed January 12, 2016.
3. American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care. 2015;38(suppl 1):S1-S93.
4. Chemical Hazards Emergency Medical Management. FDA pregnancy categories. http://chemm.nlm.nih.gov/pregnancycategories.htm. Accessed January 12, 2016.
5. Weindling AM. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med. 2009;14(2):111-118.
6. Kaneshiro NK. Infant of diabetic mother (2013). Medline Plus. www.nlm.nih.gov/medlineplus/ency/article/001597.htm. Accessed January 12, 2016.
7. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med. 1994;96(5):451-456.
8. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med. 1996;335 (4):257-265.
9. Ismail AA, Medhat I, Tawfic TA, Kholeif A. Evaluation of calcium-antagonists (nifedipine) in the treatment of pre-eclampsia. Int J Gynaecol Obstet. 1993;40:39-43.
10. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol. 1996;174(3):823-828.
11. Kattah AG, Garovic VD. The management of hypertension in pregnancy. Adv Chronic Kidney Dis. 2013;20(3):229-239.
12. Carroll DG, Kelley KW. Review of metformin and glyburide in the management of gestational diabetes. Pharm Pract (Granada). 2014;12(4):528.
13. Koren G. Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol. 2001;15(3):227-229.
14. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165:807-812.
15. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2):S209-S213.
16. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.
17. Kalra B, Gupta Y, Singla R, Kalra S. Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. N Am J Med Sci. 2015; 7(1):6-12.
18. Zhang C, Ning Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am J Clin Nutr. 2011;94(6 suppl):1975S-1979S.
19. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(suppl 2):S251-S260.
20. US Preventive Services Task Force. Folic acid to prevent neural tube defects: preventive medication, 2015. www.uspreventiveservices taskforce.org/Page/Document/Update SummaryFinal/folic-acid-to-prevent-neural-tube-defects-preventive-medication. Ac­cessed January 12, 2016.
21. Cheschier N; ACOG Committee on Practice Bulletins—Obstetrics. Neural tube defects. ACOG Practice Bulletin no 44. Int J Gynaecol Obstet. 2003;83(1):123-133.
22. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.
23. Case AP, Ramadhani TA, Canfield MA, et al. Folic acid supplementation among diabetic, overweight, or obese women of childbearing age. J Obstet Gynecol Neonatal Nurs. 2007;36(4):335-341.
24. Hanna FWF, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med. 2002;19:351-358. 
25. Ben-haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med. 2004;21(2):103-113.
26. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1-S45.
27. Patel C, Edgerton L, Flake D. What precautions should we use with statins for women of childbearing age? J Fam Pract. 2006; 55(1):75-77.
28. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can. 2007;29(11):906-908.
29. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97(9):2969-2989.
30. Saadi HF, Kurlander DJ, Erkins JM, Hoogwerf BJ. Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil. Endocr Pract. 1999;5(1):33-36.
31. Goldstuck ND, Steyn PS. The intrauterine device in women with diabetes mellitus type I and II: a systematic review. ISRN Obstet Gynecol. 2013;2013:814062.
32. Grigoryan OR, Grodnitskaya EE, Andreeva EN, et al. Use of the NuvaRing hormone-releasing system in late reproductive-age women with type 1 diabetes mellitus. Gynecol Endocrinol. 2008;24(2):99-104.
33. Bonnema RA, McNamara MC, Spencer AL. Contraception choices in women with underlying medical conditions. Am Fam Physician. 2010;82(6):621-628.

There were 13.4 million women (ages 20 and older) with either type 1 or type 2 diabetes in the United States in 2012, according to the CDC.¹ By 2050, overall prevalence of dia­betes is expected to double or triple.² Since the number of women with diabetes will continue to increase, it is important for clinicians to familiarize themselves with management of the condition in those of childbearing age—particularly with regard to medication selection.

Diabetes management in women of childbearing age pre­sents multiple complexities. First, strict glucose control from preconception through pregnancy is necessary to reduce the risk for complications in mother and ­fetus. The American Diabetes Association (ADA) recommends an A1C of less than 7% during the preconception period, if achievable without hypoglycemia.³ Full glycemic targets for women are outlined in Table 1.

Continue for medication classes with pregnancy category >>

Second, many medications used to manage diabetes and pregnancy-associated comorbidities can be fetotoxic. The FDA assigns all drugs to a pregnancy category, the definitions of which are available at http://chemm.nlm.nih.gov/pregnancycategories.htm.⁴ The ADA recommends that sexually active women of childbearing age avoid any potentially teratogenic medications (see Table 2) if they are not using reliable contraception.³

Excellent control of diabetes is necessary to decrease risk for birth defects. Infants born to mothers with preconception diabetes have been shown to have higher rates of morbidity and mortality.⁵ Infants born to women with diabetes are generally large for gestational age and experience hypoglycemia in the first 24 to 48 hours of life.⁶ Large-for-gestational-age babies are at increased risk for trauma at birth, including orthopedic injuries (eg, shoulder dislocation) and brachial plexus injuries. There is also an increased risk for fetal cardiac defects and congenital congestive heart failure.⁶

This article will review four cases of diabetes management in women of childbearing age. The ADA guidelines form the basis for all recommendations.

Continue for case 1 >>

Case 1 A 32-year-old obese woman with type 2 diabetes mellitus (T2DM) presents for routine follow-up. Recent lab results reveal an A1C of 6.4%; GFR > 100 mL/min/1.73 m2; and microalbuminuria (110 mg/d). She is currently taking lisinopril (2.5 mg once daily), metformin (1,000 mg bid), and glyburide (5 mg bid). She plans to become pregnant in the next six months and wants advice.

Discussion
This patient should be counseled on preconception glycemic targets and switched to pregnancy-safe medications. She should also be advised that the recommended weight gain in pregnancy for women with T2DM is 15 to 25 lb in overweight women and 10 to 20 lb in obese women.³

The ADA recommends a target A1C < 7%, in the absence of severe hypoglycemia, prior to conception in patients with type 1 diabetes mellitus (T1DM) or T2DM.³ For women with preconception diabetes who become pregnant, it is recommended that their premeal, bedtime, and overnight glucose be maintained at 60 to 99 mg/dL, their peak postprandial glucose at 100 to 129 mg/dL, and their A1C < 6% during pregnancy (all without excessive hypoglycemia), due to increases in red blood cell turnover.³ It is also recommended that they avoid statins, ACE inhibitors, angiotensin II receptor blockers (ARBs), certain beta blockers, and most noninsulin therapies.³

This patient is currently taking lisinopril, a medication with a pregnancy category of X. The ACE inhibitor class of medications is known to cause oligohydramnios, intrauterine growth retardation, structural malformation, premature birth, fetal renal dysplasia, and other congenital abnormalities, and use of these drugs should be avoided in women trying to conceive.⁷

Safer options for blood pressure control include clonidine, diltiazam, labetalol, methyldopa, or prazosin.³ Diuretics can reduce placental blood perfusion and should be avoided.⁸ An alternative for management of microalbuminuria in women of childbearing age is nifedipine.⁹ In multiple studies, this medication was not only safer in pregnancy, with no major teratogenic risk, but also effectively reduced urine microalbumin levels.^10,11

For T2DM management, metformin (pregnancy category B) and glyburide (pregnancy category B/C, depending on manufacturer) can be used.^12,13 Glyburide, the most studied sulfonylurea, is recommended as the drug of choice in its class.^14-16 While insulin is the standard for managing diabetes in pregnancy—earlier research supported a switch from oral medications to insulin in women interested in becoming pregnant—recent studies have demonstrated that oral medications can be safely used.¹⁷ In addition, lifestyle changes (eg, carbohydrate counting, limited meal portions, and regular moderate exercise) prior to and during pregnancy can be beneficial for diabetes management.^18,19

Also remind the patient to take regular prenatal vitamins. The US Preventive Services Task Force recommends that all women planning to become or capable of becoming pregnant take 400 to 800 µg supplements of folic acid daily.²⁰ For women at high risk for neural tube defects or who have had a previous pregnancy with neural tube defects, 4 mg/d is recommended.²¹ In women with diabetes who are trying to conceive, a folic acid supplement of 5 mg/d is recommended, beginning three months prior to conception.²²

Research shows that diabetic women are less likely to take folic acid supplementation during pregnancy. A study of 6,835 obese or overweight women with diabetes showed that only 35% reported daily folic acid supplementation.²³ The study authors recommended all women of childbearing age, especially those who are obese or have diabetes, take folic acid daily.²³ Encourage all women intending to become pregnant to start prenatal vitamin supplementation.

Continue for case 2 >>

Case 2 A 26-year-old obese patient, 28 weeks primigravida, presents for follow-up on her 3-hour glucose tolerance test. Results indicate a 3-hour glucose level of 148 mg/dL. The patient has a family history of T2DM and gestational diabetes.

Discussion
Gestational diabetes is defined by the ADA as diabetes diagnosed during the second or third trimester of pregnancy that is not T1DM or T2DM.³ The ADA recommends lifestyle management of gestational diabetes before medications are introduced. A1C should be maintained at 6% or less without hypoglycemia. In general, insulin is preferred over oral agents for treatment of gestational diabetes.³

There tends to be a spike in insulin resistance in the second or third trimester; women with preconception diabetes, for example, may require frequent increases in daily insulin dose to maintain glycemic levels, compared to the first trimester.³ A baseline ophthalmology exam should be performed in the first trimester for patients with preconception diabetes, with additional monitoring as needed.³

Following pregnancy, screening should be conducted for diabetes or prediabetes at six to 12 weeks’ postpartum and every one to three years afterward.³ The cumulative incidence of T2DM varies considerably among studies, ranging from 17% to 63% in five to 16 years postpartum.^24,25 Thus, women with gestational diabetes should maintain lifestyle changes, including diet and exercise, to reduce the risk for T2DM later in life.

Continue for case 3 >>

Case 3 A 43-year-old woman with T1DM becomes pregnant while taking atorvastatin (20 mg), insulin detemir (18 units qhs), and insulin aspart with meals, as per her calculated insulin-to-carbohydrate ratio (ICR; 1 U aspart for 18 g carbohydrates) and insulin sensitivity factor (ISF; 1 U aspart for every 60 mg/dL above 130 mg/dL). Her biggest concern today is her medication list and potential adverse effects on the fetus. Her most recent A1C, two months ago, was 6.5%. She senses hypoglycemia at glucose levels of about 60 mg/dL and admits to having such measurements about twice per week.

Discussion
In this case, the patient needs to stop taking her statin and check her blood glucose regularly, as she is at increased risk for hypoglycemia. In their 2013 guidelines, the American College of Cardiology/American Heart Association stated that statins “should not be used in women of childbearing potential unless these women are using effective contraception and are not nursing.”²⁶ This presents a major problem for many women of childbearing age with diabetes.

Statins are associated with a variety of congenital abnormalities, including fetal growth restriction and structural abnormalities in the fetus.²⁷ It is advised that women planning for pregnancy avoid use of statins.²⁸ If the patient has severe hypertriglyceridemia that puts her at risk for acute pancreatitis, fenofibrate (pregnancy category C) can be considered in the second and third trimesters.^29,30

With T1DM in pregnancy, there is an increased risk for hypoglycemia in the first trimester.³ This risk increases as women adapt to more strict blood glucose control. Frequent recalculation of the ICR and ISF may be needed as the pregnancy progresses and weight gain occurs. Most insulin formulations are pregnancy class B, with the exception of glargine, degludec, and glulisine, which are pregnancy category C.³

Continue for case 4 >>

Case 4 A 21-year-old woman with T1DM wishes to start contraception but has concerns about long-term options. She seeks your advice in making a decision.

Discussion
For long-term pregnancy prevention, either the copper or progesterone-containing intrauterine device (IUD) is safe and effective for women with T1DM or T2DM.³¹ While the levonor­gestrel IUD does not produce ­metabolic changes in T1DM, it has not yet been adequately studied in T2DM. Demographics suggest that young women with T2DM could become viable candidates for intrauterine contraception.³¹

The hormone-releasing “ring” has been found to be reliable and safe for women of late reproductive age with T1DM.³² Combined hormonal contraceptives and the transdermal contraceptive patch are best avoided to reduce risk for complications associated with estrogen-containing contraceptives (eg, venous thromboembolism and myocardial infarction).³³

Continue for the conclusion >>

Conclusion
All women with diabetes should be counseled on glucose control prior to pregnancy. Achieving a goal A1C below 6% in the absence of hypoglycemia is recommended by the ADA.³ Long-term contraception options should be considered in women of childbearing age with diabetes to prevent pregnancy. Clinicians should carefully select medications for management of diabetes and its comorbidities in women planning to become pregnant. Healthy dietary habits and regular exercise should be encouraged in all patients with diabetes, especially prior to pregnancy.

References
1. CDC. National Diabetes Statistics Report, 2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed January 12, 2016.
2. CDC. Number of Americans with diabetes projected to double or triple by 2050. 2010. www.cdc.gov/media/pressrel/2010/r101022.html. Accessed January 12, 2016.
3. American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care. 2015;38(suppl 1):S1-S93.
4. Chemical Hazards Emergency Medical Management. FDA pregnancy categories. http://chemm.nlm.nih.gov/pregnancycategories.htm. Accessed January 12, 2016.
5. Weindling AM. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med. 2009;14(2):111-118.
6. Kaneshiro NK. Infant of diabetic mother (2013). Medline Plus. www.nlm.nih.gov/medlineplus/ency/article/001597.htm. Accessed January 12, 2016.
7. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med. 1994;96(5):451-456.
8. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med. 1996;335 (4):257-265.
9. Ismail AA, Medhat I, Tawfic TA, Kholeif A. Evaluation of calcium-antagonists (nifedipine) in the treatment of pre-eclampsia. Int J Gynaecol Obstet. 1993;40:39-43.
10. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol. 1996;174(3):823-828.
11. Kattah AG, Garovic VD. The management of hypertension in pregnancy. Adv Chronic Kidney Dis. 2013;20(3):229-239.
12. Carroll DG, Kelley KW. Review of metformin and glyburide in the management of gestational diabetes. Pharm Pract (Granada). 2014;12(4):528.
13. Koren G. Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol. 2001;15(3):227-229.
14. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165:807-812.
15. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2):S209-S213.
16. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.
17. Kalra B, Gupta Y, Singla R, Kalra S. Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. N Am J Med Sci. 2015; 7(1):6-12.
18. Zhang C, Ning Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am J Clin Nutr. 2011;94(6 suppl):1975S-1979S.
19. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(suppl 2):S251-S260.
20. US Preventive Services Task Force. Folic acid to prevent neural tube defects: preventive medication, 2015. www.uspreventiveservices taskforce.org/Page/Document/Update SummaryFinal/folic-acid-to-prevent-neural-tube-defects-preventive-medication. Ac­cessed January 12, 2016.
21. Cheschier N; ACOG Committee on Practice Bulletins—Obstetrics. Neural tube defects. ACOG Practice Bulletin no 44. Int J Gynaecol Obstet. 2003;83(1):123-133.
22. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.
23. Case AP, Ramadhani TA, Canfield MA, et al. Folic acid supplementation among diabetic, overweight, or obese women of childbearing age. J Obstet Gynecol Neonatal Nurs. 2007;36(4):335-341.
24. Hanna FWF, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med. 2002;19:351-358. 
25. Ben-haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med. 2004;21(2):103-113.
26. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1-S45.
27. Patel C, Edgerton L, Flake D. What precautions should we use with statins for women of childbearing age? J Fam Pract. 2006; 55(1):75-77.
28. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can. 2007;29(11):906-908.
29. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97(9):2969-2989.
30. Saadi HF, Kurlander DJ, Erkins JM, Hoogwerf BJ. Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil. Endocr Pract. 1999;5(1):33-36.
31. Goldstuck ND, Steyn PS. The intrauterine device in women with diabetes mellitus type I and II: a systematic review. ISRN Obstet Gynecol. 2013;2013:814062.
32. Grigoryan OR, Grodnitskaya EE, Andreeva EN, et al. Use of the NuvaRing hormone-releasing system in late reproductive-age women with type 1 diabetes mellitus. Gynecol Endocrinol. 2008;24(2):99-104.
33. Bonnema RA, McNamara MC, Spencer AL. Contraception choices in women with underlying medical conditions. Am Fam Physician. 2010;82(6):621-628.

There were 13.4 million women (ages 20 and older) with either type 1 or type 2 diabetes in the United States in 2012, according to the CDC.¹ By 2050, overall prevalence of dia­betes is expected to double or triple.² Since the number of women with diabetes will continue to increase, it is important for clinicians to familiarize themselves with management of the condition in those of childbearing age—particularly with regard to medication selection.

Diabetes management in women of childbearing age pre­sents multiple complexities. First, strict glucose control from preconception through pregnancy is necessary to reduce the risk for complications in mother and ­fetus. The American Diabetes Association (ADA) recommends an A1C of less than 7% during the preconception period, if achievable without hypoglycemia.³ Full glycemic targets for women are outlined in Table 1.

Continue for medication classes with pregnancy category >>

Second, many medications used to manage diabetes and pregnancy-associated comorbidities can be fetotoxic. The FDA assigns all drugs to a pregnancy category, the definitions of which are available at http://chemm.nlm.nih.gov/pregnancycategories.htm.⁴ The ADA recommends that sexually active women of childbearing age avoid any potentially teratogenic medications (see Table 2) if they are not using reliable contraception.³

Excellent control of diabetes is necessary to decrease risk for birth defects. Infants born to mothers with preconception diabetes have been shown to have higher rates of morbidity and mortality.⁵ Infants born to women with diabetes are generally large for gestational age and experience hypoglycemia in the first 24 to 48 hours of life.⁶ Large-for-gestational-age babies are at increased risk for trauma at birth, including orthopedic injuries (eg, shoulder dislocation) and brachial plexus injuries. There is also an increased risk for fetal cardiac defects and congenital congestive heart failure.⁶

This article will review four cases of diabetes management in women of childbearing age. The ADA guidelines form the basis for all recommendations.

Continue for case 1 >>

Case 1 A 32-year-old obese woman with type 2 diabetes mellitus (T2DM) presents for routine follow-up. Recent lab results reveal an A1C of 6.4%; GFR > 100 mL/min/1.73 m2; and microalbuminuria (110 mg/d). She is currently taking lisinopril (2.5 mg once daily), metformin (1,000 mg bid), and glyburide (5 mg bid). She plans to become pregnant in the next six months and wants advice.

Discussion
This patient should be counseled on preconception glycemic targets and switched to pregnancy-safe medications. She should also be advised that the recommended weight gain in pregnancy for women with T2DM is 15 to 25 lb in overweight women and 10 to 20 lb in obese women.³

The ADA recommends a target A1C < 7%, in the absence of severe hypoglycemia, prior to conception in patients with type 1 diabetes mellitus (T1DM) or T2DM.³ For women with preconception diabetes who become pregnant, it is recommended that their premeal, bedtime, and overnight glucose be maintained at 60 to 99 mg/dL, their peak postprandial glucose at 100 to 129 mg/dL, and their A1C < 6% during pregnancy (all without excessive hypoglycemia), due to increases in red blood cell turnover.³ It is also recommended that they avoid statins, ACE inhibitors, angiotensin II receptor blockers (ARBs), certain beta blockers, and most noninsulin therapies.³

This patient is currently taking lisinopril, a medication with a pregnancy category of X. The ACE inhibitor class of medications is known to cause oligohydramnios, intrauterine growth retardation, structural malformation, premature birth, fetal renal dysplasia, and other congenital abnormalities, and use of these drugs should be avoided in women trying to conceive.⁷

Safer options for blood pressure control include clonidine, diltiazam, labetalol, methyldopa, or prazosin.³ Diuretics can reduce placental blood perfusion and should be avoided.⁸ An alternative for management of microalbuminuria in women of childbearing age is nifedipine.⁹ In multiple studies, this medication was not only safer in pregnancy, with no major teratogenic risk, but also effectively reduced urine microalbumin levels.^10,11

For T2DM management, metformin (pregnancy category B) and glyburide (pregnancy category B/C, depending on manufacturer) can be used.^12,13 Glyburide, the most studied sulfonylurea, is recommended as the drug of choice in its class.^14-16 While insulin is the standard for managing diabetes in pregnancy—earlier research supported a switch from oral medications to insulin in women interested in becoming pregnant—recent studies have demonstrated that oral medications can be safely used.¹⁷ In addition, lifestyle changes (eg, carbohydrate counting, limited meal portions, and regular moderate exercise) prior to and during pregnancy can be beneficial for diabetes management.^18,19

Also remind the patient to take regular prenatal vitamins. The US Preventive Services Task Force recommends that all women planning to become or capable of becoming pregnant take 400 to 800 µg supplements of folic acid daily.²⁰ For women at high risk for neural tube defects or who have had a previous pregnancy with neural tube defects, 4 mg/d is recommended.²¹ In women with diabetes who are trying to conceive, a folic acid supplement of 5 mg/d is recommended, beginning three months prior to conception.²²

Research shows that diabetic women are less likely to take folic acid supplementation during pregnancy. A study of 6,835 obese or overweight women with diabetes showed that only 35% reported daily folic acid supplementation.²³ The study authors recommended all women of childbearing age, especially those who are obese or have diabetes, take folic acid daily.²³ Encourage all women intending to become pregnant to start prenatal vitamin supplementation.

Continue for case 2 >>

Case 2 A 26-year-old obese patient, 28 weeks primigravida, presents for follow-up on her 3-hour glucose tolerance test. Results indicate a 3-hour glucose level of 148 mg/dL. The patient has a family history of T2DM and gestational diabetes.

Discussion
Gestational diabetes is defined by the ADA as diabetes diagnosed during the second or third trimester of pregnancy that is not T1DM or T2DM.³ The ADA recommends lifestyle management of gestational diabetes before medications are introduced. A1C should be maintained at 6% or less without hypoglycemia. In general, insulin is preferred over oral agents for treatment of gestational diabetes.³

There tends to be a spike in insulin resistance in the second or third trimester; women with preconception diabetes, for example, may require frequent increases in daily insulin dose to maintain glycemic levels, compared to the first trimester.³ A baseline ophthalmology exam should be performed in the first trimester for patients with preconception diabetes, with additional monitoring as needed.³

Following pregnancy, screening should be conducted for diabetes or prediabetes at six to 12 weeks’ postpartum and every one to three years afterward.³ The cumulative incidence of T2DM varies considerably among studies, ranging from 17% to 63% in five to 16 years postpartum.^24,25 Thus, women with gestational diabetes should maintain lifestyle changes, including diet and exercise, to reduce the risk for T2DM later in life.

Continue for case 3 >>

Case 3 A 43-year-old woman with T1DM becomes pregnant while taking atorvastatin (20 mg), insulin detemir (18 units qhs), and insulin aspart with meals, as per her calculated insulin-to-carbohydrate ratio (ICR; 1 U aspart for 18 g carbohydrates) and insulin sensitivity factor (ISF; 1 U aspart for every 60 mg/dL above 130 mg/dL). Her biggest concern today is her medication list and potential adverse effects on the fetus. Her most recent A1C, two months ago, was 6.5%. She senses hypoglycemia at glucose levels of about 60 mg/dL and admits to having such measurements about twice per week.

Discussion
In this case, the patient needs to stop taking her statin and check her blood glucose regularly, as she is at increased risk for hypoglycemia. In their 2013 guidelines, the American College of Cardiology/American Heart Association stated that statins “should not be used in women of childbearing potential unless these women are using effective contraception and are not nursing.”²⁶ This presents a major problem for many women of childbearing age with diabetes.

Statins are associated with a variety of congenital abnormalities, including fetal growth restriction and structural abnormalities in the fetus.²⁷ It is advised that women planning for pregnancy avoid use of statins.²⁸ If the patient has severe hypertriglyceridemia that puts her at risk for acute pancreatitis, fenofibrate (pregnancy category C) can be considered in the second and third trimesters.^29,30

With T1DM in pregnancy, there is an increased risk for hypoglycemia in the first trimester.³ This risk increases as women adapt to more strict blood glucose control. Frequent recalculation of the ICR and ISF may be needed as the pregnancy progresses and weight gain occurs. Most insulin formulations are pregnancy class B, with the exception of glargine, degludec, and glulisine, which are pregnancy category C.³

Continue for case 4 >>

Case 4 A 21-year-old woman with T1DM wishes to start contraception but has concerns about long-term options. She seeks your advice in making a decision.

Discussion
For long-term pregnancy prevention, either the copper or progesterone-containing intrauterine device (IUD) is safe and effective for women with T1DM or T2DM.³¹ While the levonor­gestrel IUD does not produce ­metabolic changes in T1DM, it has not yet been adequately studied in T2DM. Demographics suggest that young women with T2DM could become viable candidates for intrauterine contraception.³¹

The hormone-releasing “ring” has been found to be reliable and safe for women of late reproductive age with T1DM.³² Combined hormonal contraceptives and the transdermal contraceptive patch are best avoided to reduce risk for complications associated with estrogen-containing contraceptives (eg, venous thromboembolism and myocardial infarction).³³

Continue for the conclusion >>

Conclusion
All women with diabetes should be counseled on glucose control prior to pregnancy. Achieving a goal A1C below 6% in the absence of hypoglycemia is recommended by the ADA.³ Long-term contraception options should be considered in women of childbearing age with diabetes to prevent pregnancy. Clinicians should carefully select medications for management of diabetes and its comorbidities in women planning to become pregnant. Healthy dietary habits and regular exercise should be encouraged in all patients with diabetes, especially prior to pregnancy.

References
1. CDC. National Diabetes Statistics Report, 2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed January 12, 2016.
2. CDC. Number of Americans with diabetes projected to double or triple by 2050. 2010. www.cdc.gov/media/pressrel/2010/r101022.html. Accessed January 12, 2016.
3. American Diabetes Association. Standards of medical care in diabetes—2015. Diabetes Care. 2015;38(suppl 1):S1-S93.
4. Chemical Hazards Emergency Medical Management. FDA pregnancy categories. http://chemm.nlm.nih.gov/pregnancycategories.htm. Accessed January 12, 2016.
5. Weindling AM. Offspring of diabetic pregnancy: short-term outcomes. Semin Fetal Neonatal Med. 2009;14(2):111-118.
6. Kaneshiro NK. Infant of diabetic mother (2013). Medline Plus. www.nlm.nih.gov/medlineplus/ency/article/001597.htm. Accessed January 12, 2016.
7. Shotan A, Widerhorn J, Hurst A, Elkayam U. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med. 1994;96(5):451-456.
8. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med. 1996;335 (4):257-265.
9. Ismail AA, Medhat I, Tawfic TA, Kholeif A. Evaluation of calcium-antagonists (nifedipine) in the treatment of pre-eclampsia. Int J Gynaecol Obstet. 1993;40:39-43.
10. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol. 1996;174(3):823-828.
11. Kattah AG, Garovic VD. The management of hypertension in pregnancy. Adv Chronic Kidney Dis. 2013;20(3):229-239.
12. Carroll DG, Kelley KW. Review of metformin and glyburide in the management of gestational diabetes. Pharm Pract (Granada). 2014;12(4):528.
13. Koren G. Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol. 2001;15(3):227-229.
14. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165:807-812.
15. Moore TR. Glyburide for the treatment of gestational diabetes: a critical appraisal. Diabetes Care. 2007;30(suppl 2):S209-S213.
16. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.
17. Kalra B, Gupta Y, Singla R, Kalra S. Use of oral anti-diabetic agents in pregnancy: a pragmatic approach. N Am J Med Sci. 2015; 7(1):6-12.
18. Zhang C, Ning Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am J Clin Nutr. 2011;94(6 suppl):1975S-1979S.
19. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(suppl 2):S251-S260.
20. US Preventive Services Task Force. Folic acid to prevent neural tube defects: preventive medication, 2015. www.uspreventiveservices taskforce.org/Page/Document/Update SummaryFinal/folic-acid-to-prevent-neural-tube-defects-preventive-medication. Ac­cessed January 12, 2016.
21. Cheschier N; ACOG Committee on Practice Bulletins—Obstetrics. Neural tube defects. ACOG Practice Bulletin no 44. Int J Gynaecol Obstet. 2003;83(1):123-133.
22. Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.
23. Case AP, Ramadhani TA, Canfield MA, et al. Folic acid supplementation among diabetic, overweight, or obese women of childbearing age. J Obstet Gynecol Neonatal Nurs. 2007;36(4):335-341.
24. Hanna FWF, Peters JR. Screening for gestational diabetes; past, present and future. Diabet Med. 2002;19:351-358. 
25. Ben-haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med. 2004;21(2):103-113.
26. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1-S45.
27. Patel C, Edgerton L, Flake D. What precautions should we use with statins for women of childbearing age? J Fam Pract. 2006; 55(1):75-77.
28. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can. 2007;29(11):906-908.
29. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97(9):2969-2989.
30. Saadi HF, Kurlander DJ, Erkins JM, Hoogwerf BJ. Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil. Endocr Pract. 1999;5(1):33-36.
31. Goldstuck ND, Steyn PS. The intrauterine device in women with diabetes mellitus type I and II: a systematic review. ISRN Obstet Gynecol. 2013;2013:814062.
32. Grigoryan OR, Grodnitskaya EE, Andreeva EN, et al. Use of the NuvaRing hormone-releasing system in late reproductive-age women with type 1 diabetes mellitus. Gynecol Endocrinol. 2008;24(2):99-104.
33. Bonnema RA, McNamara MC, Spencer AL. Contraception choices in women with underlying medical conditions. Am Fam Physician. 2010;82(6):621-628.

Answer
The radiograph shows a compression deformity of the C6 vertebral body. In addition, there is a displaced fracture fragment along the anterior superior endplate. Alignment is adequate, with no evidence of subluxation. The disc space of C6-7 also appears slightly distracted, suggesting possible acute injury.

Given the clinical and radiographic presentation, this patient warranted further workup. He was admitted for CT and MRI of the cervical spine, which demonstrated disc herniation at both the C5-6 and C6-7 levels, as well as interspinous ligament injury.

The patient subsequently underwent a two-level anterior cervical disc­ectomy and fusion. His symptoms resolved, and he was discharged home the next day.

Answer
The radiograph shows a compression deformity of the C6 vertebral body. In addition, there is a displaced fracture fragment along the anterior superior endplate. Alignment is adequate, with no evidence of subluxation. The disc space of C6-7 also appears slightly distracted, suggesting possible acute injury.

Given the clinical and radiographic presentation, this patient warranted further workup. He was admitted for CT and MRI of the cervical spine, which demonstrated disc herniation at both the C5-6 and C6-7 levels, as well as interspinous ligament injury.

The patient subsequently underwent a two-level anterior cervical disc­ectomy and fusion. His symptoms resolved, and he was discharged home the next day.

Answer
The radiograph shows a compression deformity of the C6 vertebral body. In addition, there is a displaced fracture fragment along the anterior superior endplate. Alignment is adequate, with no evidence of subluxation. The disc space of C6-7 also appears slightly distracted, suggesting possible acute injury.

Given the clinical and radiographic presentation, this patient warranted further workup. He was admitted for CT and MRI of the cervical spine, which demonstrated disc herniation at both the C5-6 and C6-7 levels, as well as interspinous ligament injury.

The patient subsequently underwent a two-level anterior cervical disc­ectomy and fusion. His symptoms resolved, and he was discharged home the next day.

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

PRACTICE CHANGER
Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.^1,2

Strength of recommendation
A: Based on multiple large, multicenter cohort studies.^1,2

A 28-year-old woman (gravida 2, para 1001) at 10 weeks’ gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities, and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk for fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments.

It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011, after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However, until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are two large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The two groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the firstline approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA be discussed with all patients.⁸

Continue for study summaries >>

STUDY SUMMARIES
CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of ­cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2,042 pregnant patients ages 18 to 49 (mean, 29.6) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes, thyroid disorders, and other comorbidities. cfDNA testing was done on 1,909 maternal blood samples for trisomy 21 and 1,905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and nonlive births, the incidence of trisomy 21 was 5 of 1,909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1,905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly 1 in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false-positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false-positive rate was 0.3% compared to 3.6% for standard screening (P < .001); for trisomy 18, the cfDNA false-positive rate was 0.2% compared to 0.6% for standard screening (P = .03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in six countries.

This study enrolled 18,955 women ages 18 to 48 (mean, 31) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1 – specificity; < .700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages < 35).

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P = .001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P < .001) and a lower false-positive rate (0.06% vs 5.4%; P < .001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing versus standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false-positive rates for cfDNA, compared with traditional screening.

WHAT’S NEW
Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false-positive rates than standard fetal aneuploidy screening for the general obstetric population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetric population, according to ACOG and SMFM, the two groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

Continue for caveats >>

CAVEATS
Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to FDA approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false-negative results. Further testing has shown that such false-negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malig­nancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false-positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing, such as chorionic villus sampling or amniocentesis, before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their ­aneuploidy screening method also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
cfDNA testing is validated only for singleton pregnancies. Clinicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family practice clinicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, clinicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

References
1. Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.
2. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372: 1589-1597.
3. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401.
4. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204:205.e1-11.
5. Bianchi DW, Platt LD, Goldberg JD, et al; MatERNal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) Study Group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119:890-901.
6. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;207: 137.e1-e8.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120:1532-1534.
8. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 640: Cell-free DNA screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31-e37.
9. Wang Y, Zhu J, Chen Y, et al. Two cases of placental T21 mosaicism: challenging the detection limits of non-invasive prenatal testing. Prenat Diagn. 2013;33:1207-1210.
10. Choi H, Lau TK, Jiang FM, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn. 2013; 33:198-200.
11. Norton ME, Jelliffe-Pawlowski LL, Currier RJ. Chromosome abnormalities detected by current prenatal screening and noninvasive prenatal testing. Obstet Gynecol. 2014;124:979-986.
12. Agarwal A, Sayres LC, Cho MK, et al. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33:521-531.

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 © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(1):49-52.

1. The patient had just recovered from a sore throat and noticed discrete red nodules, which eventually coalesced into a single large edematous plaque over the right anterior tibia. The deep intradermal and subdermal edema is exquisitely tender to touch, considerably warmer than the surrounding skin, and highly blanchable.

Diagnosis: Erythema nodosum is a reactive form of septal panniculitis with many potential triggers. Notable triggers include Crohn disease flares and use of drugs such as sulfa, gold salts, and oral contraceptives. Several infections have been identified as triggers, including strep, mycoplasma, and campylobacter, as well as deep fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). More unusual causes include pregnancy and diseases such as sarcoidosis, tuberculosis, Behçet disease, and leukemia/lymphoma.

For more information, see “Painful Lesion Hasn’t Responded to Antibiotics.” Clin Rev. 2015;25(11):10,12.

For the next photograph, proceed to the next page >>

2. A 16-year-old high school student joins her friends in a 2K run one morning. The next day, her shins are so painful she can hardly walk. She applied ice packs to her legs, using elastic bandages to hold them in place until the ice cubes melt. As her legs rewarm, a rash appears where the ice packs contacted the skin.

Diagnosis: This condition is urticarial in nature—albeit an unusual form, triggered by cold. Though it appears counterintuitive, cold uriticaria typically appears only on rewarming of the affected area and is marked by the sudden appearance of “welts” or “hives” that usually clear (with or without treatment) within hours.

Uncomplicated urticaria resolves without leaving any signs (eg, purpura, ecchymosis) that might otherwise suggest the presence of a vasculitic component, such as that seen with lupus or other autoimmune diseases. Blanchability on digital pressure is one way to confirm benignancy, since blood tends to leak from vessels damaged by vasculitis, emptying into the surrounding interstitial spaces and presenting as nonblanchable petechiae, purpura, or ecchymosis. The relatively benign nature of this patient’s urticaria was also suggested by additional history taking, in which she denied having fever, malaise, or arthralgia. These are all symptoms we might have seen with more serious underlying causes.

Cold urticaria is one of the so-called physical urticarias, a group that includes urticaria caused by vibration, pressure, heat, sun, and even exposure to water. Thought to comprise up to 20% of all urticarias, the physical urticarias occur most frequently in persons ages 17 to 40. Dermatographism is the most common form, occurring in the linear track of a vigorous scratch as a wheal that manifests rapidly, lasts a few minutes, then disappears without a trace. Its presence is purposely sought by the examiner to confirm the diagnosis of urticaria (most often the chronic idiopathic variety).

For more information, see “Inexperienced runner develops leg rash.” Clin Rev. 2012;22(8):W3 

For the next photograph, proceed to the next page >>

Source: PhotoStock-Israel / Science Source

3. Typically manifesting with edema, pruritus, warmth, and tenderness, this lesion is usually associated with a history of recent trauma or pharyngitis followed by malaise, chills, and high fever. The lesion is usually raised with a clear line of demarcation at the edge.

Diagnosis: Erysipelas, an acute infection of the skin and subcutaneous tissue, is caused by beta-hemolytic streptococci invading tissues via a disruption to the skin barrier. Streptococcus strains are susceptible to penicillin and 99.5% are susceptible to clindamycin. Associated comorbidities in erysipelas include diabetes mellitus, as well as hypertension, chronic venous insufficiency, and other cardiovascular diseases.

For more information, see “Painful rash on face.” J Fam Pract. 2010;59(8):459-462.

For the next photograph, proceed to the next page >>

Source: CDC Public Health Image Library.

4. This patient presented with a red, expanding rash on the lateral aspect of the left thigh. Affecting any part of the body, this illness may present with fever, chills, sweats, muscle aches, fatigue, nausea and joint pain. Some patients have a rash or Bell’s palsy.

Diagnosis: Lyme disease, caused by B. burgdorferi bacteria, is transmitted to humans through the bite of infected Ixodes ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system.

Because its symptoms mimic many other diseases, diagnosing Lyme disease can be difficult. The diagnosis is based on symptoms, physical findings, eg, rash, and the possibility of exposure to infected ticks; laboratory testing is helpful if used correctly and performed with validated methods.

Treatment choice depends on the whether the disease is early or late. Most cases of early Lyme disease can be treated successfully with a few weeks of antibiotics.

For more information, see “Lyme Disease Presents Differently in Men and Women.”

1. The patient had just recovered from a sore throat and noticed discrete red nodules, which eventually coalesced into a single large edematous plaque over the right anterior tibia. The deep intradermal and subdermal edema is exquisitely tender to touch, considerably warmer than the surrounding skin, and highly blanchable.

Diagnosis: Erythema nodosum is a reactive form of septal panniculitis with many potential triggers. Notable triggers include Crohn disease flares and use of drugs such as sulfa, gold salts, and oral contraceptives. Several infections have been identified as triggers, including strep, mycoplasma, and campylobacter, as well as deep fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). More unusual causes include pregnancy and diseases such as sarcoidosis, tuberculosis, Behçet disease, and leukemia/lymphoma.

For more information, see “Painful Lesion Hasn’t Responded to Antibiotics.” Clin Rev. 2015;25(11):10,12.

For the next photograph, proceed to the next page >>

2. A 16-year-old high school student joins her friends in a 2K run one morning. The next day, her shins are so painful she can hardly walk. She applied ice packs to her legs, using elastic bandages to hold them in place until the ice cubes melt. As her legs rewarm, a rash appears where the ice packs contacted the skin.

Diagnosis: This condition is urticarial in nature—albeit an unusual form, triggered by cold. Though it appears counterintuitive, cold uriticaria typically appears only on rewarming of the affected area and is marked by the sudden appearance of “welts” or “hives” that usually clear (with or without treatment) within hours.

Uncomplicated urticaria resolves without leaving any signs (eg, purpura, ecchymosis) that might otherwise suggest the presence of a vasculitic component, such as that seen with lupus or other autoimmune diseases. Blanchability on digital pressure is one way to confirm benignancy, since blood tends to leak from vessels damaged by vasculitis, emptying into the surrounding interstitial spaces and presenting as nonblanchable petechiae, purpura, or ecchymosis. The relatively benign nature of this patient’s urticaria was also suggested by additional history taking, in which she denied having fever, malaise, or arthralgia. These are all symptoms we might have seen with more serious underlying causes.

Cold urticaria is one of the so-called physical urticarias, a group that includes urticaria caused by vibration, pressure, heat, sun, and even exposure to water. Thought to comprise up to 20% of all urticarias, the physical urticarias occur most frequently in persons ages 17 to 40. Dermatographism is the most common form, occurring in the linear track of a vigorous scratch as a wheal that manifests rapidly, lasts a few minutes, then disappears without a trace. Its presence is purposely sought by the examiner to confirm the diagnosis of urticaria (most often the chronic idiopathic variety).

For more information, see “Inexperienced runner develops leg rash.” Clin Rev. 2012;22(8):W3 

For the next photograph, proceed to the next page >>

Source: PhotoStock-Israel / Science Source

3. Typically manifesting with edema, pruritus, warmth, and tenderness, this lesion is usually associated with a history of recent trauma or pharyngitis followed by malaise, chills, and high fever. The lesion is usually raised with a clear line of demarcation at the edge.

Diagnosis: Erysipelas, an acute infection of the skin and subcutaneous tissue, is caused by beta-hemolytic streptococci invading tissues via a disruption to the skin barrier. Streptococcus strains are susceptible to penicillin and 99.5% are susceptible to clindamycin. Associated comorbidities in erysipelas include diabetes mellitus, as well as hypertension, chronic venous insufficiency, and other cardiovascular diseases.

For more information, see “Painful rash on face.” J Fam Pract. 2010;59(8):459-462.

For the next photograph, proceed to the next page >>

Source: CDC Public Health Image Library.

4. This patient presented with a red, expanding rash on the lateral aspect of the left thigh. Affecting any part of the body, this illness may present with fever, chills, sweats, muscle aches, fatigue, nausea and joint pain. Some patients have a rash or Bell’s palsy.

Diagnosis: Lyme disease, caused by B. burgdorferi bacteria, is transmitted to humans through the bite of infected Ixodes ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system.

Because its symptoms mimic many other diseases, diagnosing Lyme disease can be difficult. The diagnosis is based on symptoms, physical findings, eg, rash, and the possibility of exposure to infected ticks; laboratory testing is helpful if used correctly and performed with validated methods.

Treatment choice depends on the whether the disease is early or late. Most cases of early Lyme disease can be treated successfully with a few weeks of antibiotics.

For more information, see “Lyme Disease Presents Differently in Men and Women.”

1. The patient had just recovered from a sore throat and noticed discrete red nodules, which eventually coalesced into a single large edematous plaque over the right anterior tibia. The deep intradermal and subdermal edema is exquisitely tender to touch, considerably warmer than the surrounding skin, and highly blanchable.

Diagnosis: Erythema nodosum is a reactive form of septal panniculitis with many potential triggers. Notable triggers include Crohn disease flares and use of drugs such as sulfa, gold salts, and oral contraceptives. Several infections have been identified as triggers, including strep, mycoplasma, and campylobacter, as well as deep fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). More unusual causes include pregnancy and diseases such as sarcoidosis, tuberculosis, Behçet disease, and leukemia/lymphoma.

For more information, see “Painful Lesion Hasn’t Responded to Antibiotics.” Clin Rev. 2015;25(11):10,12.

For the next photograph, proceed to the next page >>

2. A 16-year-old high school student joins her friends in a 2K run one morning. The next day, her shins are so painful she can hardly walk. She applied ice packs to her legs, using elastic bandages to hold them in place until the ice cubes melt. As her legs rewarm, a rash appears where the ice packs contacted the skin.

Diagnosis: This condition is urticarial in nature—albeit an unusual form, triggered by cold. Though it appears counterintuitive, cold uriticaria typically appears only on rewarming of the affected area and is marked by the sudden appearance of “welts” or “hives” that usually clear (with or without treatment) within hours.

Uncomplicated urticaria resolves without leaving any signs (eg, purpura, ecchymosis) that might otherwise suggest the presence of a vasculitic component, such as that seen with lupus or other autoimmune diseases. Blanchability on digital pressure is one way to confirm benignancy, since blood tends to leak from vessels damaged by vasculitis, emptying into the surrounding interstitial spaces and presenting as nonblanchable petechiae, purpura, or ecchymosis. The relatively benign nature of this patient’s urticaria was also suggested by additional history taking, in which she denied having fever, malaise, or arthralgia. These are all symptoms we might have seen with more serious underlying causes.

Cold urticaria is one of the so-called physical urticarias, a group that includes urticaria caused by vibration, pressure, heat, sun, and even exposure to water. Thought to comprise up to 20% of all urticarias, the physical urticarias occur most frequently in persons ages 17 to 40. Dermatographism is the most common form, occurring in the linear track of a vigorous scratch as a wheal that manifests rapidly, lasts a few minutes, then disappears without a trace. Its presence is purposely sought by the examiner to confirm the diagnosis of urticaria (most often the chronic idiopathic variety).

For more information, see “Inexperienced runner develops leg rash.” Clin Rev. 2012;22(8):W3 

For the next photograph, proceed to the next page >>

Source: PhotoStock-Israel / Science Source

3. Typically manifesting with edema, pruritus, warmth, and tenderness, this lesion is usually associated with a history of recent trauma or pharyngitis followed by malaise, chills, and high fever. The lesion is usually raised with a clear line of demarcation at the edge.

Diagnosis: Erysipelas, an acute infection of the skin and subcutaneous tissue, is caused by beta-hemolytic streptococci invading tissues via a disruption to the skin barrier. Streptococcus strains are susceptible to penicillin and 99.5% are susceptible to clindamycin. Associated comorbidities in erysipelas include diabetes mellitus, as well as hypertension, chronic venous insufficiency, and other cardiovascular diseases.

For more information, see “Painful rash on face.” J Fam Pract. 2010;59(8):459-462.

For the next photograph, proceed to the next page >>

Source: CDC Public Health Image Library.

4. This patient presented with a red, expanding rash on the lateral aspect of the left thigh. Affecting any part of the body, this illness may present with fever, chills, sweats, muscle aches, fatigue, nausea and joint pain. Some patients have a rash or Bell’s palsy.

Diagnosis: Lyme disease, caused by B. burgdorferi bacteria, is transmitted to humans through the bite of infected Ixodes ticks. Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. If left untreated, infection can spread to joints, the heart, and the nervous system.

Because its symptoms mimic many other diseases, diagnosing Lyme disease can be difficult. The diagnosis is based on symptoms, physical findings, eg, rash, and the possibility of exposure to infected ticks; laboratory testing is helpful if used correctly and performed with validated methods.

Treatment choice depends on the whether the disease is early or late. Most cases of early Lyme disease can be treated successfully with a few weeks of antibiotics.

For more information, see “Lyme Disease Presents Differently in Men and Women.”

ANSWER
The correct answer is normal sinus rhythm, acute anterior myocardial infarction, and inferolateral injury.

A P wave for every QRS and a QRS for every P wave at a rate between 60 and 100 beats/min are indicative of normal sinus rhythm.

Acute anterior myocardial infarction is evidenced by the significant Q waves and ST elevations in leads I and V₂ to V₄ and inferolateral injury by ST elevations in limb leads II, III, and aVF and precordial leads V₅ and V₆.

Subsequent cardiac catheterization revealed an occlusion of the proximal left anterior descending coronary artery, as well as significant lesions in the posterior descending artery and a marginal branch of the circumflex coronary artery.

ANSWER
The correct answer is normal sinus rhythm, acute anterior myocardial infarction, and inferolateral injury.

A P wave for every QRS and a QRS for every P wave at a rate between 60 and 100 beats/min are indicative of normal sinus rhythm.

Acute anterior myocardial infarction is evidenced by the significant Q waves and ST elevations in leads I and V₂ to V₄ and inferolateral injury by ST elevations in limb leads II, III, and aVF and precordial leads V₅ and V₆.

Subsequent cardiac catheterization revealed an occlusion of the proximal left anterior descending coronary artery, as well as significant lesions in the posterior descending artery and a marginal branch of the circumflex coronary artery.

ANSWER
The correct answer is normal sinus rhythm, acute anterior myocardial infarction, and inferolateral injury.

A P wave for every QRS and a QRS for every P wave at a rate between 60 and 100 beats/min are indicative of normal sinus rhythm.

Acute anterior myocardial infarction is evidenced by the significant Q waves and ST elevations in leads I and V₂ to V₄ and inferolateral injury by ST elevations in limb leads II, III, and aVF and precordial leads V₅ and V₆.

Subsequent cardiac catheterization revealed an occlusion of the proximal left anterior descending coronary artery, as well as significant lesions in the posterior descending artery and a marginal branch of the circumflex coronary artery.

ANSWER
The correct answer is food (choice “a”), which for many generations has been blamed for worsening acne (along with other nonfactors, such as makeup). All the others are demonstrably involved in the genesis and perpetuation of acne.

DISCUSSION
Teenagers have a hard enough time dealing with acne and other vicissitudes of puberty, and then they get blamed for eating the wrong kinds of food …. Would that it could be that simple! I think it’s important for us as providers to set the record straight by making sure parents and patients know what matters and what doesn’t.

When we’ve done that, the patient (or occasionally a parent) might say, “Well, every time I eat (insert item here), my acne flares.” To which we of course reply, “Well then, don’t do that!” After all, we certainly wouldn’t object to the patient consuming a better diet.

Once the unimportance of pizza, makeup, and soft drinks has been established, there remains the opportunity to enlighten the patient (and family) about the factors that do play a significant role—all but one of which can be addressed. (The exception, of course, is heredity; still, I believe it’s important to recognize its role in acne.) We can reduce the amount of sebum through use of retinoids and cut down on bacteria by using oral or topical antibiotics (though erythromycin is not especially effective). Hormonal therapy can be accomplished with oral contraceptives or oral spironolactone, though neither is perfect.

Treatment
This particular patient was prescribed a six-month course of isotretinoin (40 mg/d), after which her acne was completely and permanently gone. This is the result in about 70% of cases when this medicine is used correctly.

Proper procedure, including pregnancy tests and blood work, was followed before the patient was placed on the medication. The decision to use it was made after a careful discussion of other options, most of which she had already exhausted, and of the risks versus benefits of all available choices.

The biggest obstacle to starting the patient on isotretinoin was the perception that the drug is dangerous. It certainly must be used with caution, in carefully selected patients, and after a full disclosure of the associated risks. But when used appropriately, it is an effective treatment for acne that has failed to respond to other medications.

Summary
Acne is an extremely common complaint and happens to be exceedingly well studied. There are numerous treatment options, although none is perfect. Our job is to guide patients and families through the maze of information to plan a course of action acceptable to all.

ANSWER
The correct answer is food (choice “a”), which for many generations has been blamed for worsening acne (along with other nonfactors, such as makeup). All the others are demonstrably involved in the genesis and perpetuation of acne.

DISCUSSION
Teenagers have a hard enough time dealing with acne and other vicissitudes of puberty, and then they get blamed for eating the wrong kinds of food …. Would that it could be that simple! I think it’s important for us as providers to set the record straight by making sure parents and patients know what matters and what doesn’t.

When we’ve done that, the patient (or occasionally a parent) might say, “Well, every time I eat (insert item here), my acne flares.” To which we of course reply, “Well then, don’t do that!” After all, we certainly wouldn’t object to the patient consuming a better diet.

Once the unimportance of pizza, makeup, and soft drinks has been established, there remains the opportunity to enlighten the patient (and family) about the factors that do play a significant role—all but one of which can be addressed. (The exception, of course, is heredity; still, I believe it’s important to recognize its role in acne.) We can reduce the amount of sebum through use of retinoids and cut down on bacteria by using oral or topical antibiotics (though erythromycin is not especially effective). Hormonal therapy can be accomplished with oral contraceptives or oral spironolactone, though neither is perfect.

Treatment
This particular patient was prescribed a six-month course of isotretinoin (40 mg/d), after which her acne was completely and permanently gone. This is the result in about 70% of cases when this medicine is used correctly.

Proper procedure, including pregnancy tests and blood work, was followed before the patient was placed on the medication. The decision to use it was made after a careful discussion of other options, most of which she had already exhausted, and of the risks versus benefits of all available choices.

The biggest obstacle to starting the patient on isotretinoin was the perception that the drug is dangerous. It certainly must be used with caution, in carefully selected patients, and after a full disclosure of the associated risks. But when used appropriately, it is an effective treatment for acne that has failed to respond to other medications.

Summary
Acne is an extremely common complaint and happens to be exceedingly well studied. There are numerous treatment options, although none is perfect. Our job is to guide patients and families through the maze of information to plan a course of action acceptable to all.

ANSWER
The correct answer is food (choice “a”), which for many generations has been blamed for worsening acne (along with other nonfactors, such as makeup). All the others are demonstrably involved in the genesis and perpetuation of acne.

DISCUSSION
Teenagers have a hard enough time dealing with acne and other vicissitudes of puberty, and then they get blamed for eating the wrong kinds of food …. Would that it could be that simple! I think it’s important for us as providers to set the record straight by making sure parents and patients know what matters and what doesn’t.

When we’ve done that, the patient (or occasionally a parent) might say, “Well, every time I eat (insert item here), my acne flares.” To which we of course reply, “Well then, don’t do that!” After all, we certainly wouldn’t object to the patient consuming a better diet.

Once the unimportance of pizza, makeup, and soft drinks has been established, there remains the opportunity to enlighten the patient (and family) about the factors that do play a significant role—all but one of which can be addressed. (The exception, of course, is heredity; still, I believe it’s important to recognize its role in acne.) We can reduce the amount of sebum through use of retinoids and cut down on bacteria by using oral or topical antibiotics (though erythromycin is not especially effective). Hormonal therapy can be accomplished with oral contraceptives or oral spironolactone, though neither is perfect.

Treatment
This particular patient was prescribed a six-month course of isotretinoin (40 mg/d), after which her acne was completely and permanently gone. This is the result in about 70% of cases when this medicine is used correctly.

Proper procedure, including pregnancy tests and blood work, was followed before the patient was placed on the medication. The decision to use it was made after a careful discussion of other options, most of which she had already exhausted, and of the risks versus benefits of all available choices.

The biggest obstacle to starting the patient on isotretinoin was the perception that the drug is dangerous. It certainly must be used with caution, in carefully selected patients, and after a full disclosure of the associated risks. But when used appropriately, it is an effective treatment for acne that has failed to respond to other medications.

Summary
Acne is an extremely common complaint and happens to be exceedingly well studied. There are numerous treatment options, although none is perfect. Our job is to guide patients and families through the maze of information to plan a course of action acceptable to all.

The prevalence of psychiatric disorders is high among people with skin-restricted lupus (SRL), compared with the general population, yet most do not receive specialist mental health care or appropriate psychotropic treatment, researchers report.

Investigators led by psychiatrist Isabelle Jalenques of the Clermont-Ferrand (France) University Hospital noted that psychiatric disorders had been extensively reported in patients with systemic lupus erythematosus (SLE), but no data existed on patients with skin-restricted disease (Br J Dermatol. 2016. doi: 10.1111/bjd.14392).

A previous exploratory study by the research group had shown that 60% of the 20 patients with subacute cutaneous lupus erythematosus and discoid lupus erythematosus studied had at least one psychiatric disorder. However the study was limited by its size and lack of a control group.

In the current multicenter study, the researchers compared 75 outpatients with SRL with 150 controls. Mean age of patients was 46 years and mean duration of disease was 10 years. They discovered that almost 49% of the patients with SRL fulfilled criteria for at least one current Axis I psychiatric disorder, compared with 13% of controls (OR, 5.0; P less than .001). Furthermore, 73% of patients fulfilled criteria for at least one lifetime Axis I psychiatric disorder, compared with 43% of controls (OR, 4.4; P less than .001).

The rates were close to that of patients with SLE for both current (42.2 and 46.7%) and lifetime psychiatric disorders (72%), Dr. Jalenques and her associates noted.

Patients with SRL were at a particularly high risk of the following psychiatric disorders, compared with controls:

• Major depressive disorder: current (9% vs. 0%; P = .0007) and lifetime (44% vs. 26%; P = .01).

• Generalized anxiety disorder: current (23% vs. 3%; P less than .001) and lifetime (35% vs. 19%; P = .03).

• Panic disorder: current (7% vs. 0%; P = .004) and lifetime (21 % vs. 3 %; P less than .001).

• Suicide risk: current (24% vs. 7%; P = .003).

• Alcohol dependence: current (7% vs. 0%; P = .004).

• Lifetime agoraphobia: (20% vs. 9%; P = .01).

Many patients were not receiving specialist mental health care or appropriate psychotropic treatment despite psychiatric disorders being a well-known cause of psychological distress, excess mortality, impaired global functioning, and poor compliance with medical treatment, Dr. Jalenques and her associates noted.

“Clinicians should be aware of the high prevalence of these disorders among SRL patients and not hesitate to refer such patients for psychiatric evaluation,” they concluded.

This study was supported by a grant from the French Ministry of Health and from Société Française de Dermatologie. The authors declared they have no conflicts of interest.

[email protected]

The prevalence of psychiatric disorders is high among people with skin-restricted lupus (SRL), compared with the general population, yet most do not receive specialist mental health care or appropriate psychotropic treatment, researchers report.

Investigators led by psychiatrist Isabelle Jalenques of the Clermont-Ferrand (France) University Hospital noted that psychiatric disorders had been extensively reported in patients with systemic lupus erythematosus (SLE), but no data existed on patients with skin-restricted disease (Br J Dermatol. 2016. doi: 10.1111/bjd.14392).

A previous exploratory study by the research group had shown that 60% of the 20 patients with subacute cutaneous lupus erythematosus and discoid lupus erythematosus studied had at least one psychiatric disorder. However the study was limited by its size and lack of a control group.

In the current multicenter study, the researchers compared 75 outpatients with SRL with 150 controls. Mean age of patients was 46 years and mean duration of disease was 10 years. They discovered that almost 49% of the patients with SRL fulfilled criteria for at least one current Axis I psychiatric disorder, compared with 13% of controls (OR, 5.0; P less than .001). Furthermore, 73% of patients fulfilled criteria for at least one lifetime Axis I psychiatric disorder, compared with 43% of controls (OR, 4.4; P less than .001).

The rates were close to that of patients with SLE for both current (42.2 and 46.7%) and lifetime psychiatric disorders (72%), Dr. Jalenques and her associates noted.

Patients with SRL were at a particularly high risk of the following psychiatric disorders, compared with controls:

• Major depressive disorder: current (9% vs. 0%; P = .0007) and lifetime (44% vs. 26%; P = .01).

• Generalized anxiety disorder: current (23% vs. 3%; P less than .001) and lifetime (35% vs. 19%; P = .03).

• Panic disorder: current (7% vs. 0%; P = .004) and lifetime (21 % vs. 3 %; P less than .001).

• Suicide risk: current (24% vs. 7%; P = .003).

• Alcohol dependence: current (7% vs. 0%; P = .004).

• Lifetime agoraphobia: (20% vs. 9%; P = .01).

Many patients were not receiving specialist mental health care or appropriate psychotropic treatment despite psychiatric disorders being a well-known cause of psychological distress, excess mortality, impaired global functioning, and poor compliance with medical treatment, Dr. Jalenques and her associates noted.

“Clinicians should be aware of the high prevalence of these disorders among SRL patients and not hesitate to refer such patients for psychiatric evaluation,” they concluded.

This study was supported by a grant from the French Ministry of Health and from Société Française de Dermatologie. The authors declared they have no conflicts of interest.

[email protected]

The prevalence of psychiatric disorders is high among people with skin-restricted lupus (SRL), compared with the general population, yet most do not receive specialist mental health care or appropriate psychotropic treatment, researchers report.

Investigators led by psychiatrist Isabelle Jalenques of the Clermont-Ferrand (France) University Hospital noted that psychiatric disorders had been extensively reported in patients with systemic lupus erythematosus (SLE), but no data existed on patients with skin-restricted disease (Br J Dermatol. 2016. doi: 10.1111/bjd.14392).

A previous exploratory study by the research group had shown that 60% of the 20 patients with subacute cutaneous lupus erythematosus and discoid lupus erythematosus studied had at least one psychiatric disorder. However the study was limited by its size and lack of a control group.

In the current multicenter study, the researchers compared 75 outpatients with SRL with 150 controls. Mean age of patients was 46 years and mean duration of disease was 10 years. They discovered that almost 49% of the patients with SRL fulfilled criteria for at least one current Axis I psychiatric disorder, compared with 13% of controls (OR, 5.0; P less than .001). Furthermore, 73% of patients fulfilled criteria for at least one lifetime Axis I psychiatric disorder, compared with 43% of controls (OR, 4.4; P less than .001).

The rates were close to that of patients with SLE for both current (42.2 and 46.7%) and lifetime psychiatric disorders (72%), Dr. Jalenques and her associates noted.

Patients with SRL were at a particularly high risk of the following psychiatric disorders, compared with controls:

• Major depressive disorder: current (9% vs. 0%; P = .0007) and lifetime (44% vs. 26%; P = .01).

• Generalized anxiety disorder: current (23% vs. 3%; P less than .001) and lifetime (35% vs. 19%; P = .03).

• Panic disorder: current (7% vs. 0%; P = .004) and lifetime (21 % vs. 3 %; P less than .001).

• Suicide risk: current (24% vs. 7%; P = .003).

• Alcohol dependence: current (7% vs. 0%; P = .004).

• Lifetime agoraphobia: (20% vs. 9%; P = .01).

Many patients were not receiving specialist mental health care or appropriate psychotropic treatment despite psychiatric disorders being a well-known cause of psychological distress, excess mortality, impaired global functioning, and poor compliance with medical treatment, Dr. Jalenques and her associates noted.

“Clinicians should be aware of the high prevalence of these disorders among SRL patients and not hesitate to refer such patients for psychiatric evaluation,” they concluded.

This study was supported by a grant from the French Ministry of Health and from Société Française de Dermatologie. The authors declared they have no conflicts of interest.

[email protected]

Recipients of a solid organ transplant face up to a sixfold increase in the risk of developing a basal cell carcinoma – a risk that seems to increase as time passes.

A pretransplant history of squamous cell carcinoma (SCC) increased this risk to 55 times that seen in the general population, Dr. Britta Krynitz and her colleagues reported (Br J Dermatol. 2015. doi: 10.1111/bjd.14153).

©Kelly Nelson/National Cancer Institute

But even when the pretransplant SCC group was removed from the final analysis, the risk of basal cell carcinoma after transplant was five times that of the general population, “indicating that a pretransplant SCC has limited effect on BCC risk overall and that organ transplantation per se is a strong driver of posttransplant BCC risk,” wrote Dr. Krynitz of Karolinska Institute, Stockholm, and her coauthors.

“Our results strongly suggest tumor promoter effects of the immunosuppressive drugs in the pathogenesis of post-transplantation BCC,” the team said. “We speculate that calcineurin inhibitors and also antiproliferative drugs, often used in combination with corticosteroids, play a role.”

The researchers investigated the incidence of both BCC and SCC in a cohort of 4,023 patients who underwent solid organ transplant from 2004 to 2011. Their median age at the time of transplant was 53 years; most (59%) received a kidney. Other organs transplanted were liver (22%), heart and/or lung (15%), and other organs (4%). The median follow-up time was 3.4 years; the longest follow-up was 5.5 years.

Only 17 of patients had a history of melanoma, and 19 patients a history of SCC – less than 1% for each skin cancer. Seven percent (301) of patients had experienced some form of nonskin cancer.

By the end of follow-up, 341 BCCs had developed among 175 patients – an incidence of 6.7%. About half developed more than one BCC.

The researchers compared these patients to a group of almost 200,000 nontransplant patients who had developed BCC. Among these, the median age at BCC appearance was significantly older (71 years); 39% had more than one lesion.

The overall relative risk of BCC was increased sixfold in transplant recipients and was similar between the genders. However, the risk varied according to the type of organ received. Kidney recipients were at the highest risk (relative risk, 7.2), and those who received other organs had a lower risk (heart/lung: RR, 5.8; liver: RR, 2.6).

The risk also appeared to increase over time, the authors noted. From 0 to 2 years, it was 5.8; from 3 to 5 years, it increased to 7.0.

Among men, 54% of lesions appeared in the head/neck area and 35% on the trunk – a similar distribution to that seen in the nontransplant control group. Among women, there were differences between transplant patients and controls: 44% of lesions appeared on patients’ head/neck, compared with 60% in the control group, and 34% appeared on the truck, compared with 24% in the control group.

Histology was similar, as were the proportions of aggressive type II and highly aggressive type III lesions.

A total of 199 SCCs developed among 87 patients during follow-up, a ratio to BCC of 1:1.7. “The low ratio was probably due to the short follow-up in our study,” the authors noted.

The Welander Foundation, the Westerberg Foundation, and the Strategic Research Program in Epidemiology at Karolinska Institute sponsored the study. None of the authors had any financial declarations.

[email protected]

Recipients of a solid organ transplant face up to a sixfold increase in the risk of developing a basal cell carcinoma – a risk that seems to increase as time passes.

A pretransplant history of squamous cell carcinoma (SCC) increased this risk to 55 times that seen in the general population, Dr. Britta Krynitz and her colleagues reported (Br J Dermatol. 2015. doi: 10.1111/bjd.14153).

©Kelly Nelson/National Cancer Institute

But even when the pretransplant SCC group was removed from the final analysis, the risk of basal cell carcinoma after transplant was five times that of the general population, “indicating that a pretransplant SCC has limited effect on BCC risk overall and that organ transplantation per se is a strong driver of posttransplant BCC risk,” wrote Dr. Krynitz of Karolinska Institute, Stockholm, and her coauthors.

“Our results strongly suggest tumor promoter effects of the immunosuppressive drugs in the pathogenesis of post-transplantation BCC,” the team said. “We speculate that calcineurin inhibitors and also antiproliferative drugs, often used in combination with corticosteroids, play a role.”

The researchers investigated the incidence of both BCC and SCC in a cohort of 4,023 patients who underwent solid organ transplant from 2004 to 2011. Their median age at the time of transplant was 53 years; most (59%) received a kidney. Other organs transplanted were liver (22%), heart and/or lung (15%), and other organs (4%). The median follow-up time was 3.4 years; the longest follow-up was 5.5 years.

Only 17 of patients had a history of melanoma, and 19 patients a history of SCC – less than 1% for each skin cancer. Seven percent (301) of patients had experienced some form of nonskin cancer.

By the end of follow-up, 341 BCCs had developed among 175 patients – an incidence of 6.7%. About half developed more than one BCC.

The researchers compared these patients to a group of almost 200,000 nontransplant patients who had developed BCC. Among these, the median age at BCC appearance was significantly older (71 years); 39% had more than one lesion.

The overall relative risk of BCC was increased sixfold in transplant recipients and was similar between the genders. However, the risk varied according to the type of organ received. Kidney recipients were at the highest risk (relative risk, 7.2), and those who received other organs had a lower risk (heart/lung: RR, 5.8; liver: RR, 2.6).

The risk also appeared to increase over time, the authors noted. From 0 to 2 years, it was 5.8; from 3 to 5 years, it increased to 7.0.

Among men, 54% of lesions appeared in the head/neck area and 35% on the trunk – a similar distribution to that seen in the nontransplant control group. Among women, there were differences between transplant patients and controls: 44% of lesions appeared on patients’ head/neck, compared with 60% in the control group, and 34% appeared on the truck, compared with 24% in the control group.

Histology was similar, as were the proportions of aggressive type II and highly aggressive type III lesions.

A total of 199 SCCs developed among 87 patients during follow-up, a ratio to BCC of 1:1.7. “The low ratio was probably due to the short follow-up in our study,” the authors noted.

The Welander Foundation, the Westerberg Foundation, and the Strategic Research Program in Epidemiology at Karolinska Institute sponsored the study. None of the authors had any financial declarations.

[email protected]

Recipients of a solid organ transplant face up to a sixfold increase in the risk of developing a basal cell carcinoma – a risk that seems to increase as time passes.

A pretransplant history of squamous cell carcinoma (SCC) increased this risk to 55 times that seen in the general population, Dr. Britta Krynitz and her colleagues reported (Br J Dermatol. 2015. doi: 10.1111/bjd.14153).

©Kelly Nelson/National Cancer Institute

But even when the pretransplant SCC group was removed from the final analysis, the risk of basal cell carcinoma after transplant was five times that of the general population, “indicating that a pretransplant SCC has limited effect on BCC risk overall and that organ transplantation per se is a strong driver of posttransplant BCC risk,” wrote Dr. Krynitz of Karolinska Institute, Stockholm, and her coauthors.

“Our results strongly suggest tumor promoter effects of the immunosuppressive drugs in the pathogenesis of post-transplantation BCC,” the team said. “We speculate that calcineurin inhibitors and also antiproliferative drugs, often used in combination with corticosteroids, play a role.”

The researchers investigated the incidence of both BCC and SCC in a cohort of 4,023 patients who underwent solid organ transplant from 2004 to 2011. Their median age at the time of transplant was 53 years; most (59%) received a kidney. Other organs transplanted were liver (22%), heart and/or lung (15%), and other organs (4%). The median follow-up time was 3.4 years; the longest follow-up was 5.5 years.

Only 17 of patients had a history of melanoma, and 19 patients a history of SCC – less than 1% for each skin cancer. Seven percent (301) of patients had experienced some form of nonskin cancer.

By the end of follow-up, 341 BCCs had developed among 175 patients – an incidence of 6.7%. About half developed more than one BCC.

The researchers compared these patients to a group of almost 200,000 nontransplant patients who had developed BCC. Among these, the median age at BCC appearance was significantly older (71 years); 39% had more than one lesion.

The overall relative risk of BCC was increased sixfold in transplant recipients and was similar between the genders. However, the risk varied according to the type of organ received. Kidney recipients were at the highest risk (relative risk, 7.2), and those who received other organs had a lower risk (heart/lung: RR, 5.8; liver: RR, 2.6).

The risk also appeared to increase over time, the authors noted. From 0 to 2 years, it was 5.8; from 3 to 5 years, it increased to 7.0.

Among men, 54% of lesions appeared in the head/neck area and 35% on the trunk – a similar distribution to that seen in the nontransplant control group. Among women, there were differences between transplant patients and controls: 44% of lesions appeared on patients’ head/neck, compared with 60% in the control group, and 34% appeared on the truck, compared with 24% in the control group.

Histology was similar, as were the proportions of aggressive type II and highly aggressive type III lesions.

A total of 199 SCCs developed among 87 patients during follow-up, a ratio to BCC of 1:1.7. “The low ratio was probably due to the short follow-up in our study,” the authors noted.

The Welander Foundation, the Westerberg Foundation, and the Strategic Research Program in Epidemiology at Karolinska Institute sponsored the study. None of the authors had any financial declarations.

[email protected]

SAN ANTONIO – A new pain relief option for multiple rib fractures means that you might not have to wait around anymore for anesthesiology to place thoracic epidurals.

It’s called posterior paramedian subrhomboidal (PoPS) analgesia. A skin incision is made below the lowest fractured rib just paramedian to the spinus processes; a tunneling device is then used to work a catheter upwards under the rhomboids just past the highest fractured rib. The catheter has multiple openings along its length – like a sprinkler hose – so analgesic bathes the intercostal nerves as it runs down from a reservoir into the patient. The reservoir can be set to a desired flow rate or for on-demand use (ON-Q Pain Relief System – Halyard).

A pilot study at the University of Kansas, Kansas City, found that pain control from PoPS was at least equivalent to standard thoracic epidural analgesia (TEA), and that the system can be placed by a variety of hospital staff, not just anesthesiologists.

The 11 PoPS patients also used fewer rescue narcotics than the 19 TEA patients and had less hypotension. Because they weren’t at risk for epidural hematomas, they started venous thromboembolism prophylaxis without delay and at full dose.

“Our results are very promising. PoPS provides pain control similar to that of TEA,” with several “other benefits. You are not relying on one specialty for pain control,” so patients probably get faster relief. “PoPS can also be placed in patients whose injuries prohibit TEA, such as those with spinal cord injuries or increased intracranial pressure,” said investigator Dr. Casey Shelley, a University of Kansas general surgery resident.

PoPS was placed in the study either by anesthesiologists or by a trauma surgeon who practiced placement beforehand in the cadaver lab. The do-it-yourself potential for surgeons “is key. Most of us trauma surgeons are sick of begging anesthesiologists to come place thoracic epidurals,” said an audience member after Dr. Shelley’s presentation at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

Courtesy of Dr. Michael Truitt, Methodist Dallas Medical Center

Ropivacaine 0.2% was used in both PoPS and TEA patients, all of whom had at least three broken ribs.

Median pain scores dropped from 8.5 to 2.5 on a 10-point scale an hour after PoPS placement, versus a median drop from 8 to 5 points an hour after TEA (P = .03). Although not statistically significant, median pain scores were about 1.5 points better with PoPS over the next several days, hovering around 3.5 versus around 5 points with TEA. Anesthesiology “usually won’t place high thoracic epidurals. With PoPS, you can tunnel up as far as you need to go to get to higher ribs,” which might explain the better pain control, Dr. Shelley said.

PoPS patients used about 70 mg/day oral morphine equivalents versus about 90 mg/day with TEA through day 6, but again the difference was not statistically significant. Even so, it might explain why six TEA patients (32%) were hypotensive over that time, compared with two PoPS patients (18%).

PoPS patients were a little older on average (mean 63 versus 55 years), with more fractured ribs (mean eight versus seven), and higher Injury Severity Scale scores (mean 20 versus 16). They were also more likely to have bilateral fractures, longer ICU stays (mean 4.9 versus 3.1 days), and longer overall lengths of stay (mean 14.8 versus 9.8 days), but none of those trends were statistically significant.

Both groups had mean chest Abbreviated Injury Scale scores of 3, and there were no statistical differences in daily spirometry readings. The majority of patients in both groups were men.

Favorable results were also reported in 2010 for ON-Q rib pain control, but the investigators did not compare the system to TEA (World J Surg. 2010 Oct;34:2359-62).

Dr. Shelley said Halyard was not involved in the study, and that she has no disclosures.

[email protected]

SAN ANTONIO – A new pain relief option for multiple rib fractures means that you might not have to wait around anymore for anesthesiology to place thoracic epidurals.

It’s called posterior paramedian subrhomboidal (PoPS) analgesia. A skin incision is made below the lowest fractured rib just paramedian to the spinus processes; a tunneling device is then used to work a catheter upwards under the rhomboids just past the highest fractured rib. The catheter has multiple openings along its length – like a sprinkler hose – so analgesic bathes the intercostal nerves as it runs down from a reservoir into the patient. The reservoir can be set to a desired flow rate or for on-demand use (ON-Q Pain Relief System – Halyard).

A pilot study at the University of Kansas, Kansas City, found that pain control from PoPS was at least equivalent to standard thoracic epidural analgesia (TEA), and that the system can be placed by a variety of hospital staff, not just anesthesiologists.

The 11 PoPS patients also used fewer rescue narcotics than the 19 TEA patients and had less hypotension. Because they weren’t at risk for epidural hematomas, they started venous thromboembolism prophylaxis without delay and at full dose.

“Our results are very promising. PoPS provides pain control similar to that of TEA,” with several “other benefits. You are not relying on one specialty for pain control,” so patients probably get faster relief. “PoPS can also be placed in patients whose injuries prohibit TEA, such as those with spinal cord injuries or increased intracranial pressure,” said investigator Dr. Casey Shelley, a University of Kansas general surgery resident.

PoPS was placed in the study either by anesthesiologists or by a trauma surgeon who practiced placement beforehand in the cadaver lab. The do-it-yourself potential for surgeons “is key. Most of us trauma surgeons are sick of begging anesthesiologists to come place thoracic epidurals,” said an audience member after Dr. Shelley’s presentation at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

Courtesy of Dr. Michael Truitt, Methodist Dallas Medical Center

Ropivacaine 0.2% was used in both PoPS and TEA patients, all of whom had at least three broken ribs.

Median pain scores dropped from 8.5 to 2.5 on a 10-point scale an hour after PoPS placement, versus a median drop from 8 to 5 points an hour after TEA (P = .03). Although not statistically significant, median pain scores were about 1.5 points better with PoPS over the next several days, hovering around 3.5 versus around 5 points with TEA. Anesthesiology “usually won’t place high thoracic epidurals. With PoPS, you can tunnel up as far as you need to go to get to higher ribs,” which might explain the better pain control, Dr. Shelley said.

PoPS patients used about 70 mg/day oral morphine equivalents versus about 90 mg/day with TEA through day 6, but again the difference was not statistically significant. Even so, it might explain why six TEA patients (32%) were hypotensive over that time, compared with two PoPS patients (18%).

PoPS patients were a little older on average (mean 63 versus 55 years), with more fractured ribs (mean eight versus seven), and higher Injury Severity Scale scores (mean 20 versus 16). They were also more likely to have bilateral fractures, longer ICU stays (mean 4.9 versus 3.1 days), and longer overall lengths of stay (mean 14.8 versus 9.8 days), but none of those trends were statistically significant.

Both groups had mean chest Abbreviated Injury Scale scores of 3, and there were no statistical differences in daily spirometry readings. The majority of patients in both groups were men.

Favorable results were also reported in 2010 for ON-Q rib pain control, but the investigators did not compare the system to TEA (World J Surg. 2010 Oct;34:2359-62).

Dr. Shelley said Halyard was not involved in the study, and that she has no disclosures.

[email protected]

SAN ANTONIO – A new pain relief option for multiple rib fractures means that you might not have to wait around anymore for anesthesiology to place thoracic epidurals.

It’s called posterior paramedian subrhomboidal (PoPS) analgesia. A skin incision is made below the lowest fractured rib just paramedian to the spinus processes; a tunneling device is then used to work a catheter upwards under the rhomboids just past the highest fractured rib. The catheter has multiple openings along its length – like a sprinkler hose – so analgesic bathes the intercostal nerves as it runs down from a reservoir into the patient. The reservoir can be set to a desired flow rate or for on-demand use (ON-Q Pain Relief System – Halyard).

A pilot study at the University of Kansas, Kansas City, found that pain control from PoPS was at least equivalent to standard thoracic epidural analgesia (TEA), and that the system can be placed by a variety of hospital staff, not just anesthesiologists.

The 11 PoPS patients also used fewer rescue narcotics than the 19 TEA patients and had less hypotension. Because they weren’t at risk for epidural hematomas, they started venous thromboembolism prophylaxis without delay and at full dose.

“Our results are very promising. PoPS provides pain control similar to that of TEA,” with several “other benefits. You are not relying on one specialty for pain control,” so patients probably get faster relief. “PoPS can also be placed in patients whose injuries prohibit TEA, such as those with spinal cord injuries or increased intracranial pressure,” said investigator Dr. Casey Shelley, a University of Kansas general surgery resident.

PoPS was placed in the study either by anesthesiologists or by a trauma surgeon who practiced placement beforehand in the cadaver lab. The do-it-yourself potential for surgeons “is key. Most of us trauma surgeons are sick of begging anesthesiologists to come place thoracic epidurals,” said an audience member after Dr. Shelley’s presentation at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

Courtesy of Dr. Michael Truitt, Methodist Dallas Medical Center

Ropivacaine 0.2% was used in both PoPS and TEA patients, all of whom had at least three broken ribs.

Median pain scores dropped from 8.5 to 2.5 on a 10-point scale an hour after PoPS placement, versus a median drop from 8 to 5 points an hour after TEA (P = .03). Although not statistically significant, median pain scores were about 1.5 points better with PoPS over the next several days, hovering around 3.5 versus around 5 points with TEA. Anesthesiology “usually won’t place high thoracic epidurals. With PoPS, you can tunnel up as far as you need to go to get to higher ribs,” which might explain the better pain control, Dr. Shelley said.

PoPS patients used about 70 mg/day oral morphine equivalents versus about 90 mg/day with TEA through day 6, but again the difference was not statistically significant. Even so, it might explain why six TEA patients (32%) were hypotensive over that time, compared with two PoPS patients (18%).

PoPS patients were a little older on average (mean 63 versus 55 years), with more fractured ribs (mean eight versus seven), and higher Injury Severity Scale scores (mean 20 versus 16). They were also more likely to have bilateral fractures, longer ICU stays (mean 4.9 versus 3.1 days), and longer overall lengths of stay (mean 14.8 versus 9.8 days), but none of those trends were statistically significant.

Both groups had mean chest Abbreviated Injury Scale scores of 3, and there were no statistical differences in daily spirometry readings. The majority of patients in both groups were men.

Favorable results were also reported in 2010 for ON-Q rib pain control, but the investigators did not compare the system to TEA (World J Surg. 2010 Oct;34:2359-62).

Dr. Shelley said Halyard was not involved in the study, and that she has no disclosures.

[email protected]

EVIDENCE SUMMARY

A Cochrane systematic review of 5 RCTs with a total of 7314 patients evaluated cardiovascular outcomes after 4.7 years follow-up in patients with diabetes who were treated for hypertension to either “lower” or “standard” target blood pressures.¹ One trial in the review (ACCORD, 4734 patients) compared outcomes from significantly lower and standard systolic blood pressures (119/64 mm Hg vs 134/71 mm Hg; P<.0001) in patients with diabetes and either cardiovascular disease or 2 risk factors for cardiovascular disease. The authors evaluated outcomes based on achieved systolic blood pressures rather than intention to treat.

They found a reduced incidence of stroke (risk ratio [RR]=0.58; 95% confidence interval [CI], 0.39-0.88; P=.009; number needed to treat [NNT]=91) but no change in mortality (RR=1.05; 95% CI, 0.84-1.30) at lower blood pressures. Achieving the lower systolic blood pressure increased the number of serious adverse effects, however (RR=2.58; 95% CI, 1.70-3.91; P<.0001; absolute risk increase=2%; number needed to harm=50).

Four RCTs (2580 patients) in the systematic review compared clinical outcomes produced by achieving significantly lower or standard diastolic blood pressure targets (128/76 mm Hg vs 135/83 mm Hg; P<.0001). The trials found no significant difference in total mortality (RR=0.73; 95% CI, 0.53-1.01), stroke (RR=0.67; 95% CI, 0.42-1.05), myocardial infarction (RR=0.95; 95% CI, 0.64-1.40), or congestive heart failure (RR=1.06; 95% CI, 0.58-1.92). Sensitivity analysis of trials comparing diastolic blood pressure targets below 80 mm Hg and below 90 mm Hg showed similar results.

The 4 RCTs didn’t report end-stage renal failure or total serious adverse events. The authors stated that there was a high risk of selection bias in favor of lower blood pressure targets.

Patients with CKD

A systematic review and meta-analysis of 11 RCTs (9287 patients) compared outcomes of achieving lower blood pressure targets or standard targets in patients with CKD. Intensive blood pressure treatment reduced the risk of kidney failure only in patients with proteinuria at baseline (hazard ratio [HR]=0.73; 95% CI, 0.62-0.86; 5 trials, 1703 patients).² Investigators didn’t report the degree of proteinuria for all the trials, but in one trial, patients had proteinuria of 1 to 3 g/d.

Achieved blood pressures in the intensive therapy group averaged 7.7/4.9 mm Hg lower, with pressures typically ranging from 75 to 80 mm Hg diastolic and 125 to 135 mm Hg systolic. Intensive blood pressure lowering didn’t reduce kidney failure in patients without baseline proteinuria (HR=1.12; 95% CI, 0.67-1.87; 3 trials, 1218 patients). Nor did it reduce death (RR=0.94; 95% CI, 0.84-1.05; 10 trials, 6788 patients) or major cardiovascular outcomes (RR=1.09; 95% CI, 0.83-1.42; 5 trials, 5308 patients).

Patients with coronary artery disease

A meta-analysis of 15 RCTs (66,504 patients) that evaluated tight control of hypertension (≤130/80 mm Hg) compared with standard control (<140/90 mm Hg) in patients with coronary artery disease found reduced rates of heart failure (RR=0.73; 95% CI, 0.64-0.84; 10 trials, 37,990 patients) and stroke (RR=0.82; 95% CI, 0.69-0.98; 9 trials, 8344 patients) but increased rates of hypotension (RR=2.19; 95% CI, 1.80-2.66; 6 trials, 17,836 patients).³

Achieving lower blood pressure targets didn’t reduce all-cause mortality (RR=0.96; 95% CI, 0.89-1.04; 13 trials, 39,262 patients), cardiovascular mortality (RR=0.96; 95% CI, 0.86-1.07; 11 trials, 38,452 patients), myocardial infarction (RR=0.92; 95% CI, 0.85-1.00; 14 trials, 39,696 patients), or angina (RR=0.92; 95% CI, 0.84-1.0; 11 trials, 28,007 patients).  But it slightly increased the need for revascularization (RR=1.06; 95% CI, 1.01-1.12; 11 trials, 38,450 patients).

The SPRINT trial: Promising results for intensive treatment of some patients

The Systolic Blood Pressure Intervention Trial (SPRINT), a large RCT, found that targeting systolic blood pressures below 120 mm Hg (compared with a target below 140 mm Hg) in middle-aged and older patients with increased cardiovascular risk reduced a composite outcome that included cardiovascular death by 25%.⁴

Researchers recruited 9361 patients older than 50 years (mean age 68 years; >28% older than 75 years) with systolic blood pressure between 130 and 180 mm Hg and increased cardiovascular risk defined by one or more of the following: preexisting cardiovascular disease, CKD with estimated glomerular filtration rate between 20 and 60 mL/min/1.73 m², age >75 years, and Framingham 10-year risk of 15% or more. They excluded patients with diabetes or previous stroke.

Patients were randomized to intensive treatment (target systolic BP <120; mean achieved 121.4) or standard treatment (target systolic BP <140; mean achieved 136.2). Treatment typically comprised 3 (intensive) or 2 (standard) agents. The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or cardiovascular death.

The study, which was originally intended to run for 5 years, was stopped at 3.26 years based on positive results. Intensive treatment improved the primary composite outcome overall (1.65% vs 2.19%; HR=0.75; 95% CI, 0.64-0.89; P<.001; NNT=61 over 3.26 years), all-cause mortality (HR=0.73; 95% CI, 0.60-0.90; P=.003; NNT=90), and cardiovascular death (HR=0.57; 95% CI, 0.38-0.85; P=.005; NNT=172).

However, intensive treatment didn’t significantly improve the primary composite outcome in these subgroups:

• female patients (HR=0.84; 95% CI, 0.62-1.14)
• black patients (HR=0.77; 95% CI, 0.55-1.06)
• patients with preexisting CKD (HR=0.82; 95% CI, 0.63-1.07) or cardiovascular disease (HR=0.83; 95% CI, 0.62-1.09)
• patients younger than 75 years (HR=0.80; 95% CI, 0.64-1.00)
• patients with systolic blood pressures higher than 132 mm Hg (BP >132 to <145 mm Hg, HR=0.77; 95% CI, 0.57-1.03; BP ≥145 mm Hg, HR=0.83; 95% CI, 0.63-1.09).

While the SPRINT study found that targeting systolic BP below 120 mm Hg reduced a composite outcome that included cardiovascular death, it didn’t improve this outcome in certain patient subgroups.

Intensive treatment also produced more net serious adverse events (HR=1.88; 4.7% vs 2.5%; P<.001), including: ≥30% decrease of glomerular filtration rates to values below 60 mL/min/1.73 m² (HR=3.49; 95% CI, 2.44-5.10; P<.001), syncope (HR=1.44; 3.5% vs 2.4%; P=.003), hypotension (HR=1.70; 3.4% vs 2.0%; P<.001), and electrolyte abnormalities (HR=1.38; 3.8% vs 2.8%; P=.006). It didn’t cause injurious falls (HR=1.00; P=.97) or orthostatic hypotension in clinic (HR=0.88; 16.6% vs 18.3%; P=.01).

Guidelines for patients with peripheral artery disease, previous stroke

A national guideline by an expert panel recommended treating patients with hypertension who have peripheral artery disease or previous stroke to standard values for the general population: <140/90 mm Hg if ages 60 years or younger, <150/90 mm Hg if older than 60 years.⁵ 

EVIDENCE SUMMARY

A Cochrane systematic review of 5 RCTs with a total of 7314 patients evaluated cardiovascular outcomes after 4.7 years follow-up in patients with diabetes who were treated for hypertension to either “lower” or “standard” target blood pressures.¹ One trial in the review (ACCORD, 4734 patients) compared outcomes from significantly lower and standard systolic blood pressures (119/64 mm Hg vs 134/71 mm Hg; P<.0001) in patients with diabetes and either cardiovascular disease or 2 risk factors for cardiovascular disease. The authors evaluated outcomes based on achieved systolic blood pressures rather than intention to treat.

They found a reduced incidence of stroke (risk ratio [RR]=0.58; 95% confidence interval [CI], 0.39-0.88; P=.009; number needed to treat [NNT]=91) but no change in mortality (RR=1.05; 95% CI, 0.84-1.30) at lower blood pressures. Achieving the lower systolic blood pressure increased the number of serious adverse effects, however (RR=2.58; 95% CI, 1.70-3.91; P<.0001; absolute risk increase=2%; number needed to harm=50).

Four RCTs (2580 patients) in the systematic review compared clinical outcomes produced by achieving significantly lower or standard diastolic blood pressure targets (128/76 mm Hg vs 135/83 mm Hg; P<.0001). The trials found no significant difference in total mortality (RR=0.73; 95% CI, 0.53-1.01), stroke (RR=0.67; 95% CI, 0.42-1.05), myocardial infarction (RR=0.95; 95% CI, 0.64-1.40), or congestive heart failure (RR=1.06; 95% CI, 0.58-1.92). Sensitivity analysis of trials comparing diastolic blood pressure targets below 80 mm Hg and below 90 mm Hg showed similar results.

The 4 RCTs didn’t report end-stage renal failure or total serious adverse events. The authors stated that there was a high risk of selection bias in favor of lower blood pressure targets.

Patients with CKD

A systematic review and meta-analysis of 11 RCTs (9287 patients) compared outcomes of achieving lower blood pressure targets or standard targets in patients with CKD. Intensive blood pressure treatment reduced the risk of kidney failure only in patients with proteinuria at baseline (hazard ratio [HR]=0.73; 95% CI, 0.62-0.86; 5 trials, 1703 patients).² Investigators didn’t report the degree of proteinuria for all the trials, but in one trial, patients had proteinuria of 1 to 3 g/d.

Achieved blood pressures in the intensive therapy group averaged 7.7/4.9 mm Hg lower, with pressures typically ranging from 75 to 80 mm Hg diastolic and 125 to 135 mm Hg systolic. Intensive blood pressure lowering didn’t reduce kidney failure in patients without baseline proteinuria (HR=1.12; 95% CI, 0.67-1.87; 3 trials, 1218 patients). Nor did it reduce death (RR=0.94; 95% CI, 0.84-1.05; 10 trials, 6788 patients) or major cardiovascular outcomes (RR=1.09; 95% CI, 0.83-1.42; 5 trials, 5308 patients).

Patients with coronary artery disease

A meta-analysis of 15 RCTs (66,504 patients) that evaluated tight control of hypertension (≤130/80 mm Hg) compared with standard control (<140/90 mm Hg) in patients with coronary artery disease found reduced rates of heart failure (RR=0.73; 95% CI, 0.64-0.84; 10 trials, 37,990 patients) and stroke (RR=0.82; 95% CI, 0.69-0.98; 9 trials, 8344 patients) but increased rates of hypotension (RR=2.19; 95% CI, 1.80-2.66; 6 trials, 17,836 patients).³

Achieving lower blood pressure targets didn’t reduce all-cause mortality (RR=0.96; 95% CI, 0.89-1.04; 13 trials, 39,262 patients), cardiovascular mortality (RR=0.96; 95% CI, 0.86-1.07; 11 trials, 38,452 patients), myocardial infarction (RR=0.92; 95% CI, 0.85-1.00; 14 trials, 39,696 patients), or angina (RR=0.92; 95% CI, 0.84-1.0; 11 trials, 28,007 patients).  But it slightly increased the need for revascularization (RR=1.06; 95% CI, 1.01-1.12; 11 trials, 38,450 patients).

The SPRINT trial: Promising results for intensive treatment of some patients

The Systolic Blood Pressure Intervention Trial (SPRINT), a large RCT, found that targeting systolic blood pressures below 120 mm Hg (compared with a target below 140 mm Hg) in middle-aged and older patients with increased cardiovascular risk reduced a composite outcome that included cardiovascular death by 25%.⁴

Researchers recruited 9361 patients older than 50 years (mean age 68 years; >28% older than 75 years) with systolic blood pressure between 130 and 180 mm Hg and increased cardiovascular risk defined by one or more of the following: preexisting cardiovascular disease, CKD with estimated glomerular filtration rate between 20 and 60 mL/min/1.73 m², age >75 years, and Framingham 10-year risk of 15% or more. They excluded patients with diabetes or previous stroke.

Patients were randomized to intensive treatment (target systolic BP <120; mean achieved 121.4) or standard treatment (target systolic BP <140; mean achieved 136.2). Treatment typically comprised 3 (intensive) or 2 (standard) agents. The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or cardiovascular death.

The study, which was originally intended to run for 5 years, was stopped at 3.26 years based on positive results. Intensive treatment improved the primary composite outcome overall (1.65% vs 2.19%; HR=0.75; 95% CI, 0.64-0.89; P<.001; NNT=61 over 3.26 years), all-cause mortality (HR=0.73; 95% CI, 0.60-0.90; P=.003; NNT=90), and cardiovascular death (HR=0.57; 95% CI, 0.38-0.85; P=.005; NNT=172).

However, intensive treatment didn’t significantly improve the primary composite outcome in these subgroups:

• female patients (HR=0.84; 95% CI, 0.62-1.14)
• black patients (HR=0.77; 95% CI, 0.55-1.06)
• patients with preexisting CKD (HR=0.82; 95% CI, 0.63-1.07) or cardiovascular disease (HR=0.83; 95% CI, 0.62-1.09)
• patients younger than 75 years (HR=0.80; 95% CI, 0.64-1.00)
• patients with systolic blood pressures higher than 132 mm Hg (BP >132 to <145 mm Hg, HR=0.77; 95% CI, 0.57-1.03; BP ≥145 mm Hg, HR=0.83; 95% CI, 0.63-1.09).

While the SPRINT study found that targeting systolic BP below 120 mm Hg reduced a composite outcome that included cardiovascular death, it didn’t improve this outcome in certain patient subgroups.

Intensive treatment also produced more net serious adverse events (HR=1.88; 4.7% vs 2.5%; P<.001), including: ≥30% decrease of glomerular filtration rates to values below 60 mL/min/1.73 m² (HR=3.49; 95% CI, 2.44-5.10; P<.001), syncope (HR=1.44; 3.5% vs 2.4%; P=.003), hypotension (HR=1.70; 3.4% vs 2.0%; P<.001), and electrolyte abnormalities (HR=1.38; 3.8% vs 2.8%; P=.006). It didn’t cause injurious falls (HR=1.00; P=.97) or orthostatic hypotension in clinic (HR=0.88; 16.6% vs 18.3%; P=.01).

Guidelines for patients with peripheral artery disease, previous stroke

A national guideline by an expert panel recommended treating patients with hypertension who have peripheral artery disease or previous stroke to standard values for the general population: <140/90 mm Hg if ages 60 years or younger, <150/90 mm Hg if older than 60 years.⁵ 

EVIDENCE SUMMARY

A Cochrane systematic review of 5 RCTs with a total of 7314 patients evaluated cardiovascular outcomes after 4.7 years follow-up in patients with diabetes who were treated for hypertension to either “lower” or “standard” target blood pressures.¹ One trial in the review (ACCORD, 4734 patients) compared outcomes from significantly lower and standard systolic blood pressures (119/64 mm Hg vs 134/71 mm Hg; P<.0001) in patients with diabetes and either cardiovascular disease or 2 risk factors for cardiovascular disease. The authors evaluated outcomes based on achieved systolic blood pressures rather than intention to treat.

They found a reduced incidence of stroke (risk ratio [RR]=0.58; 95% confidence interval [CI], 0.39-0.88; P=.009; number needed to treat [NNT]=91) but no change in mortality (RR=1.05; 95% CI, 0.84-1.30) at lower blood pressures. Achieving the lower systolic blood pressure increased the number of serious adverse effects, however (RR=2.58; 95% CI, 1.70-3.91; P<.0001; absolute risk increase=2%; number needed to harm=50).

Four RCTs (2580 patients) in the systematic review compared clinical outcomes produced by achieving significantly lower or standard diastolic blood pressure targets (128/76 mm Hg vs 135/83 mm Hg; P<.0001). The trials found no significant difference in total mortality (RR=0.73; 95% CI, 0.53-1.01), stroke (RR=0.67; 95% CI, 0.42-1.05), myocardial infarction (RR=0.95; 95% CI, 0.64-1.40), or congestive heart failure (RR=1.06; 95% CI, 0.58-1.92). Sensitivity analysis of trials comparing diastolic blood pressure targets below 80 mm Hg and below 90 mm Hg showed similar results.

The 4 RCTs didn’t report end-stage renal failure or total serious adverse events. The authors stated that there was a high risk of selection bias in favor of lower blood pressure targets.

Patients with CKD

A systematic review and meta-analysis of 11 RCTs (9287 patients) compared outcomes of achieving lower blood pressure targets or standard targets in patients with CKD. Intensive blood pressure treatment reduced the risk of kidney failure only in patients with proteinuria at baseline (hazard ratio [HR]=0.73; 95% CI, 0.62-0.86; 5 trials, 1703 patients).² Investigators didn’t report the degree of proteinuria for all the trials, but in one trial, patients had proteinuria of 1 to 3 g/d.

Achieved blood pressures in the intensive therapy group averaged 7.7/4.9 mm Hg lower, with pressures typically ranging from 75 to 80 mm Hg diastolic and 125 to 135 mm Hg systolic. Intensive blood pressure lowering didn’t reduce kidney failure in patients without baseline proteinuria (HR=1.12; 95% CI, 0.67-1.87; 3 trials, 1218 patients). Nor did it reduce death (RR=0.94; 95% CI, 0.84-1.05; 10 trials, 6788 patients) or major cardiovascular outcomes (RR=1.09; 95% CI, 0.83-1.42; 5 trials, 5308 patients).

Patients with coronary artery disease

A meta-analysis of 15 RCTs (66,504 patients) that evaluated tight control of hypertension (≤130/80 mm Hg) compared with standard control (<140/90 mm Hg) in patients with coronary artery disease found reduced rates of heart failure (RR=0.73; 95% CI, 0.64-0.84; 10 trials, 37,990 patients) and stroke (RR=0.82; 95% CI, 0.69-0.98; 9 trials, 8344 patients) but increased rates of hypotension (RR=2.19; 95% CI, 1.80-2.66; 6 trials, 17,836 patients).³

Achieving lower blood pressure targets didn’t reduce all-cause mortality (RR=0.96; 95% CI, 0.89-1.04; 13 trials, 39,262 patients), cardiovascular mortality (RR=0.96; 95% CI, 0.86-1.07; 11 trials, 38,452 patients), myocardial infarction (RR=0.92; 95% CI, 0.85-1.00; 14 trials, 39,696 patients), or angina (RR=0.92; 95% CI, 0.84-1.0; 11 trials, 28,007 patients).  But it slightly increased the need for revascularization (RR=1.06; 95% CI, 1.01-1.12; 11 trials, 38,450 patients).

The SPRINT trial: Promising results for intensive treatment of some patients

The Systolic Blood Pressure Intervention Trial (SPRINT), a large RCT, found that targeting systolic blood pressures below 120 mm Hg (compared with a target below 140 mm Hg) in middle-aged and older patients with increased cardiovascular risk reduced a composite outcome that included cardiovascular death by 25%.⁴

Researchers recruited 9361 patients older than 50 years (mean age 68 years; >28% older than 75 years) with systolic blood pressure between 130 and 180 mm Hg and increased cardiovascular risk defined by one or more of the following: preexisting cardiovascular disease, CKD with estimated glomerular filtration rate between 20 and 60 mL/min/1.73 m², age >75 years, and Framingham 10-year risk of 15% or more. They excluded patients with diabetes or previous stroke.

Patients were randomized to intensive treatment (target systolic BP <120; mean achieved 121.4) or standard treatment (target systolic BP <140; mean achieved 136.2). Treatment typically comprised 3 (intensive) or 2 (standard) agents. The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or cardiovascular death.

The study, which was originally intended to run for 5 years, was stopped at 3.26 years based on positive results. Intensive treatment improved the primary composite outcome overall (1.65% vs 2.19%; HR=0.75; 95% CI, 0.64-0.89; P<.001; NNT=61 over 3.26 years), all-cause mortality (HR=0.73; 95% CI, 0.60-0.90; P=.003; NNT=90), and cardiovascular death (HR=0.57; 95% CI, 0.38-0.85; P=.005; NNT=172).

However, intensive treatment didn’t significantly improve the primary composite outcome in these subgroups:

• female patients (HR=0.84; 95% CI, 0.62-1.14)
• black patients (HR=0.77; 95% CI, 0.55-1.06)
• patients with preexisting CKD (HR=0.82; 95% CI, 0.63-1.07) or cardiovascular disease (HR=0.83; 95% CI, 0.62-1.09)
• patients younger than 75 years (HR=0.80; 95% CI, 0.64-1.00)
• patients with systolic blood pressures higher than 132 mm Hg (BP >132 to <145 mm Hg, HR=0.77; 95% CI, 0.57-1.03; BP ≥145 mm Hg, HR=0.83; 95% CI, 0.63-1.09).

While the SPRINT study found that targeting systolic BP below 120 mm Hg reduced a composite outcome that included cardiovascular death, it didn’t improve this outcome in certain patient subgroups.

Intensive treatment also produced more net serious adverse events (HR=1.88; 4.7% vs 2.5%; P<.001), including: ≥30% decrease of glomerular filtration rates to values below 60 mL/min/1.73 m² (HR=3.49; 95% CI, 2.44-5.10; P<.001), syncope (HR=1.44; 3.5% vs 2.4%; P=.003), hypotension (HR=1.70; 3.4% vs 2.0%; P<.001), and electrolyte abnormalities (HR=1.38; 3.8% vs 2.8%; P=.006). It didn’t cause injurious falls (HR=1.00; P=.97) or orthostatic hypotension in clinic (HR=0.88; 16.6% vs 18.3%; P=.01).

Guidelines for patients with peripheral artery disease, previous stroke

A national guideline by an expert panel recommended treating patients with hypertension who have peripheral artery disease or previous stroke to standard values for the general population: <140/90 mm Hg if ages 60 years or younger, <150/90 mm Hg if older than 60 years.⁵