Women's Health

The rate of chronic hypertension during pregnancy has increased significantly in the United States since 1970 and is more common in older women and in black women, according to a population-based, cross-sectional analysis.

Jovanmandic/Getty Images

Researchers analyzed data from more than 151 million women with delivery-related hospitalizations in the United States between 1970 and 2010 and found that the rate of chronic hypertension in pregnancy increased steadily over time from 1970 to 1990, plateaued from 1990 to 2000, then increased again to 2010.

The analysis revealed an average annual increase of 6% – which was higher among white women than among black women – and an overall 13-fold increase from 1970 to 2010. These increases appeared to be independent of rates of obesity and smoking. The findings were published in Hypertension.

The rates of chronic hypertension also increased with maternal age, among both black and white women.

“The strong association between age and rates of chronic hypertension underscores the potential for both biological and social determinants of health to influence risk,” wrote Cande V. Ananth, PhD, from the Rutgers University, New Brunswick, N.J., and coauthors. “The period effect in chronic hypertension in pregnancy is thus largely a product of the age effect and the increasing mean age at first birth in the U.S.”

The overall prevalence of chronic hypertension in pregnancy was 0.63%, but was twofold higher in black women, compared with white women (1.24% vs. 0.53%). The authors noted that black women experienced disproportionally higher rates of ischemic placental disease, pregestational and gestational diabetes, preterm delivery and perinatal mortality, which may be a consequences of higher rates of obesity, social disadvantage, smoking, and less access to care.

“This disparity may also be related to the higher tendency of black women to develop vascular disease at an earlier age than white women, which may also explain why the age-associated increase in chronic hypertension among black women is relatively smaller than white women,” they wrote. “The persistent race disparity in chronic hypertension is also a cause for continued concern and underscores the role of complex population dynamics that shape risks.”

This was the largest study to evaluate changes in the prevalence of chronic hypertension in pregnancy over time and particularly how the prevalence is influenced by age, period, and birth cohort.

In regard to the 13-fold increase from 1970 to 2010, the researchers suggested that changing diagnostic criteria for hypertension, as well as earlier access to prenatal care, may have played a part. For example, the American College of Cardiology recently modified their guidelines to include patients with systolic and diastolic blood pressures of 130-139 mm Hg and 80-89 mm Hg as stage 1 hypertension, which they noted would increase the prevalence rates of chronic hypertension during pregnancy.

The researchers reported having no outside funding and no conflicts of interest.

SOURCE: Ananth CV et al. Hypertension. 2019 Sept 9. doi: 10.1161/HYPERTENSIONAHA.119.12968.

The rate of chronic hypertension during pregnancy has increased significantly in the United States since 1970 and is more common in older women and in black women, according to a population-based, cross-sectional analysis.

Jovanmandic/Getty Images

Researchers analyzed data from more than 151 million women with delivery-related hospitalizations in the United States between 1970 and 2010 and found that the rate of chronic hypertension in pregnancy increased steadily over time from 1970 to 1990, plateaued from 1990 to 2000, then increased again to 2010.

The analysis revealed an average annual increase of 6% – which was higher among white women than among black women – and an overall 13-fold increase from 1970 to 2010. These increases appeared to be independent of rates of obesity and smoking. The findings were published in Hypertension.

The rates of chronic hypertension also increased with maternal age, among both black and white women.

“The strong association between age and rates of chronic hypertension underscores the potential for both biological and social determinants of health to influence risk,” wrote Cande V. Ananth, PhD, from the Rutgers University, New Brunswick, N.J., and coauthors. “The period effect in chronic hypertension in pregnancy is thus largely a product of the age effect and the increasing mean age at first birth in the U.S.”

The overall prevalence of chronic hypertension in pregnancy was 0.63%, but was twofold higher in black women, compared with white women (1.24% vs. 0.53%). The authors noted that black women experienced disproportionally higher rates of ischemic placental disease, pregestational and gestational diabetes, preterm delivery and perinatal mortality, which may be a consequences of higher rates of obesity, social disadvantage, smoking, and less access to care.

“This disparity may also be related to the higher tendency of black women to develop vascular disease at an earlier age than white women, which may also explain why the age-associated increase in chronic hypertension among black women is relatively smaller than white women,” they wrote. “The persistent race disparity in chronic hypertension is also a cause for continued concern and underscores the role of complex population dynamics that shape risks.”

This was the largest study to evaluate changes in the prevalence of chronic hypertension in pregnancy over time and particularly how the prevalence is influenced by age, period, and birth cohort.

In regard to the 13-fold increase from 1970 to 2010, the researchers suggested that changing diagnostic criteria for hypertension, as well as earlier access to prenatal care, may have played a part. For example, the American College of Cardiology recently modified their guidelines to include patients with systolic and diastolic blood pressures of 130-139 mm Hg and 80-89 mm Hg as stage 1 hypertension, which they noted would increase the prevalence rates of chronic hypertension during pregnancy.

The researchers reported having no outside funding and no conflicts of interest.

SOURCE: Ananth CV et al. Hypertension. 2019 Sept 9. doi: 10.1161/HYPERTENSIONAHA.119.12968.

The rate of chronic hypertension during pregnancy has increased significantly in the United States since 1970 and is more common in older women and in black women, according to a population-based, cross-sectional analysis.

Jovanmandic/Getty Images

Researchers analyzed data from more than 151 million women with delivery-related hospitalizations in the United States between 1970 and 2010 and found that the rate of chronic hypertension in pregnancy increased steadily over time from 1970 to 1990, plateaued from 1990 to 2000, then increased again to 2010.

The analysis revealed an average annual increase of 6% – which was higher among white women than among black women – and an overall 13-fold increase from 1970 to 2010. These increases appeared to be independent of rates of obesity and smoking. The findings were published in Hypertension.

The rates of chronic hypertension also increased with maternal age, among both black and white women.

“The strong association between age and rates of chronic hypertension underscores the potential for both biological and social determinants of health to influence risk,” wrote Cande V. Ananth, PhD, from the Rutgers University, New Brunswick, N.J., and coauthors. “The period effect in chronic hypertension in pregnancy is thus largely a product of the age effect and the increasing mean age at first birth in the U.S.”

The overall prevalence of chronic hypertension in pregnancy was 0.63%, but was twofold higher in black women, compared with white women (1.24% vs. 0.53%). The authors noted that black women experienced disproportionally higher rates of ischemic placental disease, pregestational and gestational diabetes, preterm delivery and perinatal mortality, which may be a consequences of higher rates of obesity, social disadvantage, smoking, and less access to care.

“This disparity may also be related to the higher tendency of black women to develop vascular disease at an earlier age than white women, which may also explain why the age-associated increase in chronic hypertension among black women is relatively smaller than white women,” they wrote. “The persistent race disparity in chronic hypertension is also a cause for continued concern and underscores the role of complex population dynamics that shape risks.”

This was the largest study to evaluate changes in the prevalence of chronic hypertension in pregnancy over time and particularly how the prevalence is influenced by age, period, and birth cohort.

In regard to the 13-fold increase from 1970 to 2010, the researchers suggested that changing diagnostic criteria for hypertension, as well as earlier access to prenatal care, may have played a part. For example, the American College of Cardiology recently modified their guidelines to include patients with systolic and diastolic blood pressures of 130-139 mm Hg and 80-89 mm Hg as stage 1 hypertension, which they noted would increase the prevalence rates of chronic hypertension during pregnancy.

The researchers reported having no outside funding and no conflicts of interest.

SOURCE: Ananth CV et al. Hypertension. 2019 Sept 9. doi: 10.1161/HYPERTENSIONAHA.119.12968.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

EVIDENCE SUMMARY

Efficacy. A 2014 double-blind RCT compared ondansetron with pyridoxine plus doxylamine (standard care) for outpatient treatment of nausea and vomiting in pregnancy.¹ The 36 patients had an average gestational age of 8 weeks and received either 4 mg oral ondansetron plus placebo or 25 mg pyridoxine plus 12.5 mg doxylamine 3 times daily for 5 days. Nausea and vomiting severity was measured using 2 separate 10-cm visual analog scales (VAS) with scores ranging from 0 to 10 (worst nausea or vomiting imaginable). Researchers determined that a VAS score reduction of 2.5 cm was clinically significant.

Patients treated with ondansetron described greater improvements in nausea (mean VAS change −5.1 cm vs −2 cm; P = .019) and vomiting (mean VAS change −4.1 cm vs −1.7 cm; P = .049). No patient required hospitalization. The researchers didn’t report on adverse effects or birth outcomes. The study was limited by the small sample size and a high rate (17%) of patients with missing data or who were lost to follow-up.

IV ondansetron vs metoclopramide: Similar efficacy, fewer adverse effects

A 2014 double-blind RCT compared IV ondansetron with IV metoclopramide (standard care) for treating hyperemesis gravidarum.² The 160 patients had an average gestational age of 9.5 weeks and intractable nausea and vomiting severe enough to cause dehydration, metabolic disturbance, and hospitalization. Patients received either 4 mg ondansetron or 10 mg metoclopramide IV every 8 hours for 24 hours. The primary outcomes were number of episodes of vomiting over 24 hours and self-reported sense of well-being rated on a 10-point scale.

No differences were found between the ondansetron- and metoclopramide-treated groups in terms of vomiting over 24 hours (median episodes 1 and 1; P = .38) or sense of well-being (mean scores 8.7 vs 8.3; P = .13). Patients treated with ondansetron were less likely to have persistent ketonuria at 24 hours (relative risk [RR] = 0.3; 95% confidence interval [CI], 0.1-0.8; number needed to treat [NNT] = 6). They also were less likely to feel drowsy (RR = 0.3; 95% CI, 0.1–0.8; NNT = 6) or complain of dry mouth (RR = 0.4; 95% CI, 0.1-0.9; NNT = 8). The study didn’t report birth outcomes or adverse fetal effects.

Oral ondansetron outperforms oral metoclopramide in small study

A 2013 double-blind RCT compared ondansetron with metoclopramide (standard care) for controlling severe nausea and vomiting.³ The 83 patients, with an average gestational age of 8.7 weeks, had more than 3 vomiting episodes daily, weight loss, and ketonuria. They received either 4 mg oral ondansetron or 10 mg oral metoclopramide for 2 weeks as follows: 3 times daily for 1 week, then twice daily for 3 days, then once daily for 4 days. Patients rated nausea severity using a 10-cm VAS from 0 to 10 (severe nausea) and recorded the number of vomiting episodes.

Women treated with ondansetron had significantly lower VAS scores on Days 3 and 4 of treatment (5.4 vs 6, P = .024 on Day­ 3; 4.1 vs 5.7, P = .023 on Day 4). They also had fewer episodes of vomiting on Days 2, 3, and 4 (3.7 vs 6, P = .006 on Day 2; 3.2 vs 5.3, P = .006 on Day 3; and 3.3 vs 5, P = .013 on Day 4). The study was limited by the small sample size.

Safety. A 2016 systematic review examining the risk of birth defects associated with ondansetron exposure in pregnancy found 8 reports: 5 birth registries, 2 case-control studies, and 1 prospective cohort study.⁴ Investigators compared rates of major malformations—cleft lips, cleft palates, neural tube defects, cardiac defects, and hypospadias—in 5101 women exposed to ondansetron in the first trimester with birth defect rates in more than 3.1 million nonexposed women.

Continue to: No study demonstrated...

No study demonstrated an increased rate of major malformations associated with ondansetron exposure except for 2 disease registry studies with nearly 2.4 million patients that reported a slight increase in the risk of cardiac defects (odds ratio [OR] = 2; 95% CI, 1.3-3.1; OR = 1.6, 95% CI, 1-2.1). Comparisons of other birth defect rates associated with ondansetron exposure were inconsistent, with studies showing small increases, decreases, or no difference in rates between exposed and nonexposed women.

Exposure vs nonexposure: No difference in adverse outcomes

A 2013 retrospective cohort study looked at 608,385 pregnancies among women in Denmark, of whom 1970 (0.3%) had been exposed to ondansetron.⁵ The study found that exposure to ondansetron compared with nonexposure was associated with a lower risk for spontaneous abortion between 7 and 12 weeks’ gestation (1.1% vs 3.7%; hazard ratio [HR] = 0.5; 95% CI, 0.3-0.9).

Oral ondansetron is more effective than pyridoxine plus doxylamine for outpatient treatment of nausea and vomiting in pregnancy.

No significant differences between ­ondansetron exposure and nonexposure were found for the following adverse outcomes: spontaneous abortion between 13 and 22 weeks’ gestation (1% vs 2.1%; HR = 0.6; 95% CI, 0.3-1.2); stillbirth (0.3% vs 0.4%;  HR = 0.4; 95% CI, 0.1-1.7); any major birth defect (2.9% in both exposed and nonexposed women; OR = 1.12; 95% CI, 0.69-1.82); preterm delivery (6.2% vs 5.2%; OR = 0.9; 95% CI, 0.7-1.3), low birth weight infant (4.1% vs 3.7%; OR = 0.8; 95% CI, 0.5-1.1); and small-for-­gestational-age infant (10.4% vs 9.2%; OR = 1.1; 95% CI, 0.9-1.4).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) states that insufficient data exist regarding the safety of ondansetron for the fetus.⁶ ACOG recommends individualizing the use of ondansetron before 10 weeks of pregnancy after weighing the risks and benefits. ACOG also recommends adding ondansetron as third-line treatment for nausea and vomiting unresponsive to first- and second-line treatments.

EDITOR'S TAKEAWAY

Higher-quality studies showed ondansetron to be an effective treatment for hyperemesis gravidarum. Lower-quality studies raised some concerns about adverse fetal effects. Although the adverse effects were rare and the quality of the evidence was lower, the cautionary principle suggests that ondansetron should be a second-line option.

EVIDENCE SUMMARY

Efficacy. A 2014 double-blind RCT compared ondansetron with pyridoxine plus doxylamine (standard care) for outpatient treatment of nausea and vomiting in pregnancy.¹ The 36 patients had an average gestational age of 8 weeks and received either 4 mg oral ondansetron plus placebo or 25 mg pyridoxine plus 12.5 mg doxylamine 3 times daily for 5 days. Nausea and vomiting severity was measured using 2 separate 10-cm visual analog scales (VAS) with scores ranging from 0 to 10 (worst nausea or vomiting imaginable). Researchers determined that a VAS score reduction of 2.5 cm was clinically significant.

Patients treated with ondansetron described greater improvements in nausea (mean VAS change −5.1 cm vs −2 cm; P = .019) and vomiting (mean VAS change −4.1 cm vs −1.7 cm; P = .049). No patient required hospitalization. The researchers didn’t report on adverse effects or birth outcomes. The study was limited by the small sample size and a high rate (17%) of patients with missing data or who were lost to follow-up.

IV ondansetron vs metoclopramide: Similar efficacy, fewer adverse effects

A 2014 double-blind RCT compared IV ondansetron with IV metoclopramide (standard care) for treating hyperemesis gravidarum.² The 160 patients had an average gestational age of 9.5 weeks and intractable nausea and vomiting severe enough to cause dehydration, metabolic disturbance, and hospitalization. Patients received either 4 mg ondansetron or 10 mg metoclopramide IV every 8 hours for 24 hours. The primary outcomes were number of episodes of vomiting over 24 hours and self-reported sense of well-being rated on a 10-point scale.

No differences were found between the ondansetron- and metoclopramide-treated groups in terms of vomiting over 24 hours (median episodes 1 and 1; P = .38) or sense of well-being (mean scores 8.7 vs 8.3; P = .13). Patients treated with ondansetron were less likely to have persistent ketonuria at 24 hours (relative risk [RR] = 0.3; 95% confidence interval [CI], 0.1-0.8; number needed to treat [NNT] = 6). They also were less likely to feel drowsy (RR = 0.3; 95% CI, 0.1–0.8; NNT = 6) or complain of dry mouth (RR = 0.4; 95% CI, 0.1-0.9; NNT = 8). The study didn’t report birth outcomes or adverse fetal effects.

Oral ondansetron outperforms oral metoclopramide in small study

A 2013 double-blind RCT compared ondansetron with metoclopramide (standard care) for controlling severe nausea and vomiting.³ The 83 patients, with an average gestational age of 8.7 weeks, had more than 3 vomiting episodes daily, weight loss, and ketonuria. They received either 4 mg oral ondansetron or 10 mg oral metoclopramide for 2 weeks as follows: 3 times daily for 1 week, then twice daily for 3 days, then once daily for 4 days. Patients rated nausea severity using a 10-cm VAS from 0 to 10 (severe nausea) and recorded the number of vomiting episodes.

Women treated with ondansetron had significantly lower VAS scores on Days 3 and 4 of treatment (5.4 vs 6, P = .024 on Day­ 3; 4.1 vs 5.7, P = .023 on Day 4). They also had fewer episodes of vomiting on Days 2, 3, and 4 (3.7 vs 6, P = .006 on Day 2; 3.2 vs 5.3, P = .006 on Day 3; and 3.3 vs 5, P = .013 on Day 4). The study was limited by the small sample size.

Safety. A 2016 systematic review examining the risk of birth defects associated with ondansetron exposure in pregnancy found 8 reports: 5 birth registries, 2 case-control studies, and 1 prospective cohort study.⁴ Investigators compared rates of major malformations—cleft lips, cleft palates, neural tube defects, cardiac defects, and hypospadias—in 5101 women exposed to ondansetron in the first trimester with birth defect rates in more than 3.1 million nonexposed women.

Continue to: No study demonstrated...

No study demonstrated an increased rate of major malformations associated with ondansetron exposure except for 2 disease registry studies with nearly 2.4 million patients that reported a slight increase in the risk of cardiac defects (odds ratio [OR] = 2; 95% CI, 1.3-3.1; OR = 1.6, 95% CI, 1-2.1). Comparisons of other birth defect rates associated with ondansetron exposure were inconsistent, with studies showing small increases, decreases, or no difference in rates between exposed and nonexposed women.

Exposure vs nonexposure: No difference in adverse outcomes

A 2013 retrospective cohort study looked at 608,385 pregnancies among women in Denmark, of whom 1970 (0.3%) had been exposed to ondansetron.⁵ The study found that exposure to ondansetron compared with nonexposure was associated with a lower risk for spontaneous abortion between 7 and 12 weeks’ gestation (1.1% vs 3.7%; hazard ratio [HR] = 0.5; 95% CI, 0.3-0.9).

Oral ondansetron is more effective than pyridoxine plus doxylamine for outpatient treatment of nausea and vomiting in pregnancy.

No significant differences between ­ondansetron exposure and nonexposure were found for the following adverse outcomes: spontaneous abortion between 13 and 22 weeks’ gestation (1% vs 2.1%; HR = 0.6; 95% CI, 0.3-1.2); stillbirth (0.3% vs 0.4%;  HR = 0.4; 95% CI, 0.1-1.7); any major birth defect (2.9% in both exposed and nonexposed women; OR = 1.12; 95% CI, 0.69-1.82); preterm delivery (6.2% vs 5.2%; OR = 0.9; 95% CI, 0.7-1.3), low birth weight infant (4.1% vs 3.7%; OR = 0.8; 95% CI, 0.5-1.1); and small-for-­gestational-age infant (10.4% vs 9.2%; OR = 1.1; 95% CI, 0.9-1.4).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) states that insufficient data exist regarding the safety of ondansetron for the fetus.⁶ ACOG recommends individualizing the use of ondansetron before 10 weeks of pregnancy after weighing the risks and benefits. ACOG also recommends adding ondansetron as third-line treatment for nausea and vomiting unresponsive to first- and second-line treatments.

EDITOR'S TAKEAWAY

Higher-quality studies showed ondansetron to be an effective treatment for hyperemesis gravidarum. Lower-quality studies raised some concerns about adverse fetal effects. Although the adverse effects were rare and the quality of the evidence was lower, the cautionary principle suggests that ondansetron should be a second-line option.

EVIDENCE SUMMARY

Efficacy. A 2014 double-blind RCT compared ondansetron with pyridoxine plus doxylamine (standard care) for outpatient treatment of nausea and vomiting in pregnancy.¹ The 36 patients had an average gestational age of 8 weeks and received either 4 mg oral ondansetron plus placebo or 25 mg pyridoxine plus 12.5 mg doxylamine 3 times daily for 5 days. Nausea and vomiting severity was measured using 2 separate 10-cm visual analog scales (VAS) with scores ranging from 0 to 10 (worst nausea or vomiting imaginable). Researchers determined that a VAS score reduction of 2.5 cm was clinically significant.

Patients treated with ondansetron described greater improvements in nausea (mean VAS change −5.1 cm vs −2 cm; P = .019) and vomiting (mean VAS change −4.1 cm vs −1.7 cm; P = .049). No patient required hospitalization. The researchers didn’t report on adverse effects or birth outcomes. The study was limited by the small sample size and a high rate (17%) of patients with missing data or who were lost to follow-up.

IV ondansetron vs metoclopramide: Similar efficacy, fewer adverse effects

A 2014 double-blind RCT compared IV ondansetron with IV metoclopramide (standard care) for treating hyperemesis gravidarum.² The 160 patients had an average gestational age of 9.5 weeks and intractable nausea and vomiting severe enough to cause dehydration, metabolic disturbance, and hospitalization. Patients received either 4 mg ondansetron or 10 mg metoclopramide IV every 8 hours for 24 hours. The primary outcomes were number of episodes of vomiting over 24 hours and self-reported sense of well-being rated on a 10-point scale.

No differences were found between the ondansetron- and metoclopramide-treated groups in terms of vomiting over 24 hours (median episodes 1 and 1; P = .38) or sense of well-being (mean scores 8.7 vs 8.3; P = .13). Patients treated with ondansetron were less likely to have persistent ketonuria at 24 hours (relative risk [RR] = 0.3; 95% confidence interval [CI], 0.1-0.8; number needed to treat [NNT] = 6). They also were less likely to feel drowsy (RR = 0.3; 95% CI, 0.1–0.8; NNT = 6) or complain of dry mouth (RR = 0.4; 95% CI, 0.1-0.9; NNT = 8). The study didn’t report birth outcomes or adverse fetal effects.

Oral ondansetron outperforms oral metoclopramide in small study

A 2013 double-blind RCT compared ondansetron with metoclopramide (standard care) for controlling severe nausea and vomiting.³ The 83 patients, with an average gestational age of 8.7 weeks, had more than 3 vomiting episodes daily, weight loss, and ketonuria. They received either 4 mg oral ondansetron or 10 mg oral metoclopramide for 2 weeks as follows: 3 times daily for 1 week, then twice daily for 3 days, then once daily for 4 days. Patients rated nausea severity using a 10-cm VAS from 0 to 10 (severe nausea) and recorded the number of vomiting episodes.

Women treated with ondansetron had significantly lower VAS scores on Days 3 and 4 of treatment (5.4 vs 6, P = .024 on Day­ 3; 4.1 vs 5.7, P = .023 on Day 4). They also had fewer episodes of vomiting on Days 2, 3, and 4 (3.7 vs 6, P = .006 on Day 2; 3.2 vs 5.3, P = .006 on Day 3; and 3.3 vs 5, P = .013 on Day 4). The study was limited by the small sample size.

Safety. A 2016 systematic review examining the risk of birth defects associated with ondansetron exposure in pregnancy found 8 reports: 5 birth registries, 2 case-control studies, and 1 prospective cohort study.⁴ Investigators compared rates of major malformations—cleft lips, cleft palates, neural tube defects, cardiac defects, and hypospadias—in 5101 women exposed to ondansetron in the first trimester with birth defect rates in more than 3.1 million nonexposed women.

Continue to: No study demonstrated...

No study demonstrated an increased rate of major malformations associated with ondansetron exposure except for 2 disease registry studies with nearly 2.4 million patients that reported a slight increase in the risk of cardiac defects (odds ratio [OR] = 2; 95% CI, 1.3-3.1; OR = 1.6, 95% CI, 1-2.1). Comparisons of other birth defect rates associated with ondansetron exposure were inconsistent, with studies showing small increases, decreases, or no difference in rates between exposed and nonexposed women.

Exposure vs nonexposure: No difference in adverse outcomes

A 2013 retrospective cohort study looked at 608,385 pregnancies among women in Denmark, of whom 1970 (0.3%) had been exposed to ondansetron.⁵ The study found that exposure to ondansetron compared with nonexposure was associated with a lower risk for spontaneous abortion between 7 and 12 weeks’ gestation (1.1% vs 3.7%; hazard ratio [HR] = 0.5; 95% CI, 0.3-0.9).

Oral ondansetron is more effective than pyridoxine plus doxylamine for outpatient treatment of nausea and vomiting in pregnancy.

No significant differences between ­ondansetron exposure and nonexposure were found for the following adverse outcomes: spontaneous abortion between 13 and 22 weeks’ gestation (1% vs 2.1%; HR = 0.6; 95% CI, 0.3-1.2); stillbirth (0.3% vs 0.4%;  HR = 0.4; 95% CI, 0.1-1.7); any major birth defect (2.9% in both exposed and nonexposed women; OR = 1.12; 95% CI, 0.69-1.82); preterm delivery (6.2% vs 5.2%; OR = 0.9; 95% CI, 0.7-1.3), low birth weight infant (4.1% vs 3.7%; OR = 0.8; 95% CI, 0.5-1.1); and small-for-­gestational-age infant (10.4% vs 9.2%; OR = 1.1; 95% CI, 0.9-1.4).

RECOMMENDATIONS

The American College of Obstetricians and Gynecologists (ACOG) states that insufficient data exist regarding the safety of ondansetron for the fetus.⁶ ACOG recommends individualizing the use of ondansetron before 10 weeks of pregnancy after weighing the risks and benefits. ACOG also recommends adding ondansetron as third-line treatment for nausea and vomiting unresponsive to first- and second-line treatments.

EDITOR'S TAKEAWAY

Higher-quality studies showed ondansetron to be an effective treatment for hyperemesis gravidarum. Lower-quality studies raised some concerns about adverse fetal effects. Although the adverse effects were rare and the quality of the evidence was lower, the cautionary principle suggests that ondansetron should be a second-line option.

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020

5. More chest compression–only CPR leads to increased survival rates

To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020

5. More chest compression–only CPR leads to increased survival rates

To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020

5. More chest compression–only CPR leads to increased survival rates

To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

Women with postmenopausal osteoporosis who discontinued denosumab treatment after achieving osteopenia maintained bone mineral density at the spine and hip with a single infusion of zoledronate given 6 months after the last infusion of denosumab, according to results from a small, multicenter, randomized trial published in the Journal of Bone and Mineral Research.

ogichobanov/iStock/Getty Images Plus

The cessation of the monoclonal antibody denosumab is typically followed by a “rebound phenomenon” often attributed to an increase in bone turnover above pretreatment values caused by the up-regulation of osteoclastogenesis, according to Athanasios D. Anastasilakis, MD, of 424 General Military Hospital, Thessaloníki, Greece, and colleagues. Guidelines recommend that patients take a bisphosphonate to prevent this effect, but the optimal bisphosphonate regimen is unknown and evidence is inconsistent.

To address this question, the investigators randomized 57 postmenopausal women with osteoporosis who had received six monthly injections of denosumab (for an average of 2.2 years) and had achieved nonosteoporotic bone mineral density (BMD) T scores greater than –2.5 but no greater than –1 at the hip or the spine. A total of 27 received a single IV infusion of zoledronate 5 mg given 6 months after the last denosumab injection with a 3-week window, and 30 continued denosumab and received two additional monthly 60-mg injections. Following either the zoledronate infusion or the last denosumab injection, all women received no treatment and were followed until 2 years from randomization. All women were given vitamin D supplements and were seen in clinic appointments at baseline, 6, 12, 15, 18, and 24 months.

Areal BMD of the lumbar spine and femoral neck of the nondominant hip were measured at baseline, 12, and 24 months by dual-energy x-ray absorptiometry, and least significant changes were 5% or less at the spine and 4% or less at the femoral neck, based on proposals from the International Foundation for Osteoporosis and the National Osteoporosis Foundation USA.

At 24 months, lumbar spine BMD (LS‐BMD) returned to baseline in the zoledronate group, but decreased in the denosumab group by 4.82% from the 12‐month value (P less than .001).

The difference in LS-BMD changes between the two groups from month 12 to 24, the primary endpoint of the study, was statistically significant (–0.018 with zoledronate vs. –0.045 with denosumab; P = .025). Differences in changes of femoral neck BMD were also statistically significant (–0.004 with zoledronate vs. –0.038 with denosumab; P = .005), the researchers reported.

The differences in BMD changes between the two groups 24 and 12 months after discontinuation of denosumab (6 months after the last injection) for the zoledronate and denosumab group respectively were also statistically significant both at the lumbar spine (–0.002 with zoledronate vs. –0.045 with denosumab; P = .03) and at the femoral neck (–0.004 with zoledronate vs. –0.038 with denosumab; P = .007).

The authors observed no relationship between the number of denosumab injections and LS-BMD changes in either group of women; however, they noted that responses of individual patients to zoledronate were variable. For example, three women who took zoledronate experienced decreases of LS-BMD greater than the least significant change observed at 24 months, a finding which could not be explained by the timing of the infusion, baseline rate of bone turnover, or baseline BMD.

“It appears that intrinsic factors that still need to be defined may affect the response of a few individuals,” they wrote.

This was further illustrated by one patient in the zoledronate group who sustained clinical vertebral fractures associated with significant, unexplained decreases of BMD that could not be prevented with the zoledronate infusion.

“In clinical practice, it is, therefore, advisable to measure BMD at 12 months after the zoledronate infusion and decide whether additional treatment may be required,” the authors wrote.

Another significant finding reported by the authors was that neither baseline nor 12‐month bone turnover marker (BTM) values were associated with BMD changes in either group of women during the entire study period.

“Particularly important for clinical practice was the lack of a relationship in zoledronate-treated women; even when women were divided according to baseline median BTM values (below or above) there were no significant difference in BMD changes at 12 or 24 months,” they wrote.

“In a substantial number of women in the denosumab group BTMs were still above the upper limit of normal of the postmenopausal age 18 months after the last Dmab [denosumab] injection but also in 7.4% of patients treated with zoledronate at 2 years,” they added.

“Whether in the latter patients BTMs were also increased before the start of Dmab treatment, as it is known to occur in some patients with osteoporosis, or are due to a prolonged effect of Dmab withdrawal on bone metabolism could not be prevented by zoledronate, is not known because pretreatment data were not available,” the study authors noted.

For adverse events, in addition to the one patient in the zoledronate group with clinical vertebral fractures, three patients in the denosumab group sustained vertebral fractures.

“Prevalent vertebral fractures have been previously reported as the most important risk factor for clinical vertebral fractures following cessation of Dmab therapy [which] strongly suggest that spine x-rays should be performed in all patients in whom discontinuation of Dmab treatment is considered,” the authors wrote.

“In most women with postmenopausal osteoporosis treated with [denosumab] in whom discontinuation of treatment is considered when a nonosteoporotic BMD is achieved, a single intravenous infusion of zoledronate 5 mg given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, as in a few patients treatment might not have the expected effect at 2 years for currently unknown reasons,” they concluded.

The study was funded by institutional funds and the Hellenic Endocrine Society. Several authors reported receiving consulting or lecture fees from Amgen, which markets denosumab, as well as other pharmaceutical companies.

SOURCE: Anastasilakis A et al. J Bone Miner Res. 2019 Aug 21. doi: 10.1002/jbmr.3853.

Women with postmenopausal osteoporosis who discontinued denosumab treatment after achieving osteopenia maintained bone mineral density at the spine and hip with a single infusion of zoledronate given 6 months after the last infusion of denosumab, according to results from a small, multicenter, randomized trial published in the Journal of Bone and Mineral Research.

ogichobanov/iStock/Getty Images Plus

The cessation of the monoclonal antibody denosumab is typically followed by a “rebound phenomenon” often attributed to an increase in bone turnover above pretreatment values caused by the up-regulation of osteoclastogenesis, according to Athanasios D. Anastasilakis, MD, of 424 General Military Hospital, Thessaloníki, Greece, and colleagues. Guidelines recommend that patients take a bisphosphonate to prevent this effect, but the optimal bisphosphonate regimen is unknown and evidence is inconsistent.

To address this question, the investigators randomized 57 postmenopausal women with osteoporosis who had received six monthly injections of denosumab (for an average of 2.2 years) and had achieved nonosteoporotic bone mineral density (BMD) T scores greater than –2.5 but no greater than –1 at the hip or the spine. A total of 27 received a single IV infusion of zoledronate 5 mg given 6 months after the last denosumab injection with a 3-week window, and 30 continued denosumab and received two additional monthly 60-mg injections. Following either the zoledronate infusion or the last denosumab injection, all women received no treatment and were followed until 2 years from randomization. All women were given vitamin D supplements and were seen in clinic appointments at baseline, 6, 12, 15, 18, and 24 months.

Areal BMD of the lumbar spine and femoral neck of the nondominant hip were measured at baseline, 12, and 24 months by dual-energy x-ray absorptiometry, and least significant changes were 5% or less at the spine and 4% or less at the femoral neck, based on proposals from the International Foundation for Osteoporosis and the National Osteoporosis Foundation USA.

At 24 months, lumbar spine BMD (LS‐BMD) returned to baseline in the zoledronate group, but decreased in the denosumab group by 4.82% from the 12‐month value (P less than .001).

The difference in LS-BMD changes between the two groups from month 12 to 24, the primary endpoint of the study, was statistically significant (–0.018 with zoledronate vs. –0.045 with denosumab; P = .025). Differences in changes of femoral neck BMD were also statistically significant (–0.004 with zoledronate vs. –0.038 with denosumab; P = .005), the researchers reported.

The differences in BMD changes between the two groups 24 and 12 months after discontinuation of denosumab (6 months after the last injection) for the zoledronate and denosumab group respectively were also statistically significant both at the lumbar spine (–0.002 with zoledronate vs. –0.045 with denosumab; P = .03) and at the femoral neck (–0.004 with zoledronate vs. –0.038 with denosumab; P = .007).

The authors observed no relationship between the number of denosumab injections and LS-BMD changes in either group of women; however, they noted that responses of individual patients to zoledronate were variable. For example, three women who took zoledronate experienced decreases of LS-BMD greater than the least significant change observed at 24 months, a finding which could not be explained by the timing of the infusion, baseline rate of bone turnover, or baseline BMD.

“It appears that intrinsic factors that still need to be defined may affect the response of a few individuals,” they wrote.

This was further illustrated by one patient in the zoledronate group who sustained clinical vertebral fractures associated with significant, unexplained decreases of BMD that could not be prevented with the zoledronate infusion.

“In clinical practice, it is, therefore, advisable to measure BMD at 12 months after the zoledronate infusion and decide whether additional treatment may be required,” the authors wrote.

Another significant finding reported by the authors was that neither baseline nor 12‐month bone turnover marker (BTM) values were associated with BMD changes in either group of women during the entire study period.

“Particularly important for clinical practice was the lack of a relationship in zoledronate-treated women; even when women were divided according to baseline median BTM values (below or above) there were no significant difference in BMD changes at 12 or 24 months,” they wrote.

“In a substantial number of women in the denosumab group BTMs were still above the upper limit of normal of the postmenopausal age 18 months after the last Dmab [denosumab] injection but also in 7.4% of patients treated with zoledronate at 2 years,” they added.

“Whether in the latter patients BTMs were also increased before the start of Dmab treatment, as it is known to occur in some patients with osteoporosis, or are due to a prolonged effect of Dmab withdrawal on bone metabolism could not be prevented by zoledronate, is not known because pretreatment data were not available,” the study authors noted.

For adverse events, in addition to the one patient in the zoledronate group with clinical vertebral fractures, three patients in the denosumab group sustained vertebral fractures.

“Prevalent vertebral fractures have been previously reported as the most important risk factor for clinical vertebral fractures following cessation of Dmab therapy [which] strongly suggest that spine x-rays should be performed in all patients in whom discontinuation of Dmab treatment is considered,” the authors wrote.

“In most women with postmenopausal osteoporosis treated with [denosumab] in whom discontinuation of treatment is considered when a nonosteoporotic BMD is achieved, a single intravenous infusion of zoledronate 5 mg given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, as in a few patients treatment might not have the expected effect at 2 years for currently unknown reasons,” they concluded.

The study was funded by institutional funds and the Hellenic Endocrine Society. Several authors reported receiving consulting or lecture fees from Amgen, which markets denosumab, as well as other pharmaceutical companies.

SOURCE: Anastasilakis A et al. J Bone Miner Res. 2019 Aug 21. doi: 10.1002/jbmr.3853.

Women with postmenopausal osteoporosis who discontinued denosumab treatment after achieving osteopenia maintained bone mineral density at the spine and hip with a single infusion of zoledronate given 6 months after the last infusion of denosumab, according to results from a small, multicenter, randomized trial published in the Journal of Bone and Mineral Research.

ogichobanov/iStock/Getty Images Plus

The cessation of the monoclonal antibody denosumab is typically followed by a “rebound phenomenon” often attributed to an increase in bone turnover above pretreatment values caused by the up-regulation of osteoclastogenesis, according to Athanasios D. Anastasilakis, MD, of 424 General Military Hospital, Thessaloníki, Greece, and colleagues. Guidelines recommend that patients take a bisphosphonate to prevent this effect, but the optimal bisphosphonate regimen is unknown and evidence is inconsistent.

To address this question, the investigators randomized 57 postmenopausal women with osteoporosis who had received six monthly injections of denosumab (for an average of 2.2 years) and had achieved nonosteoporotic bone mineral density (BMD) T scores greater than –2.5 but no greater than –1 at the hip or the spine. A total of 27 received a single IV infusion of zoledronate 5 mg given 6 months after the last denosumab injection with a 3-week window, and 30 continued denosumab and received two additional monthly 60-mg injections. Following either the zoledronate infusion or the last denosumab injection, all women received no treatment and were followed until 2 years from randomization. All women were given vitamin D supplements and were seen in clinic appointments at baseline, 6, 12, 15, 18, and 24 months.

Areal BMD of the lumbar spine and femoral neck of the nondominant hip were measured at baseline, 12, and 24 months by dual-energy x-ray absorptiometry, and least significant changes were 5% or less at the spine and 4% or less at the femoral neck, based on proposals from the International Foundation for Osteoporosis and the National Osteoporosis Foundation USA.

At 24 months, lumbar spine BMD (LS‐BMD) returned to baseline in the zoledronate group, but decreased in the denosumab group by 4.82% from the 12‐month value (P less than .001).

The difference in LS-BMD changes between the two groups from month 12 to 24, the primary endpoint of the study, was statistically significant (–0.018 with zoledronate vs. –0.045 with denosumab; P = .025). Differences in changes of femoral neck BMD were also statistically significant (–0.004 with zoledronate vs. –0.038 with denosumab; P = .005), the researchers reported.

The differences in BMD changes between the two groups 24 and 12 months after discontinuation of denosumab (6 months after the last injection) for the zoledronate and denosumab group respectively were also statistically significant both at the lumbar spine (–0.002 with zoledronate vs. –0.045 with denosumab; P = .03) and at the femoral neck (–0.004 with zoledronate vs. –0.038 with denosumab; P = .007).

The authors observed no relationship between the number of denosumab injections and LS-BMD changes in either group of women; however, they noted that responses of individual patients to zoledronate were variable. For example, three women who took zoledronate experienced decreases of LS-BMD greater than the least significant change observed at 24 months, a finding which could not be explained by the timing of the infusion, baseline rate of bone turnover, or baseline BMD.

“It appears that intrinsic factors that still need to be defined may affect the response of a few individuals,” they wrote.

This was further illustrated by one patient in the zoledronate group who sustained clinical vertebral fractures associated with significant, unexplained decreases of BMD that could not be prevented with the zoledronate infusion.

“In clinical practice, it is, therefore, advisable to measure BMD at 12 months after the zoledronate infusion and decide whether additional treatment may be required,” the authors wrote.

Another significant finding reported by the authors was that neither baseline nor 12‐month bone turnover marker (BTM) values were associated with BMD changes in either group of women during the entire study period.

“Particularly important for clinical practice was the lack of a relationship in zoledronate-treated women; even when women were divided according to baseline median BTM values (below or above) there were no significant difference in BMD changes at 12 or 24 months,” they wrote.

“In a substantial number of women in the denosumab group BTMs were still above the upper limit of normal of the postmenopausal age 18 months after the last Dmab [denosumab] injection but also in 7.4% of patients treated with zoledronate at 2 years,” they added.

“Whether in the latter patients BTMs were also increased before the start of Dmab treatment, as it is known to occur in some patients with osteoporosis, or are due to a prolonged effect of Dmab withdrawal on bone metabolism could not be prevented by zoledronate, is not known because pretreatment data were not available,” the study authors noted.

For adverse events, in addition to the one patient in the zoledronate group with clinical vertebral fractures, three patients in the denosumab group sustained vertebral fractures.

“Prevalent vertebral fractures have been previously reported as the most important risk factor for clinical vertebral fractures following cessation of Dmab therapy [which] strongly suggest that spine x-rays should be performed in all patients in whom discontinuation of Dmab treatment is considered,” the authors wrote.

“In most women with postmenopausal osteoporosis treated with [denosumab] in whom discontinuation of treatment is considered when a nonosteoporotic BMD is achieved, a single intravenous infusion of zoledronate 5 mg given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, as in a few patients treatment might not have the expected effect at 2 years for currently unknown reasons,” they concluded.

The study was funded by institutional funds and the Hellenic Endocrine Society. Several authors reported receiving consulting or lecture fees from Amgen, which markets denosumab, as well as other pharmaceutical companies.

SOURCE: Anastasilakis A et al. J Bone Miner Res. 2019 Aug 21. doi: 10.1002/jbmr.3853.

Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.

A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.

Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.

The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.

Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.

Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.

Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.

Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.

If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.

Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.

Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder. 

“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.* 


The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.

The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.

SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.

*This article was updated on 9/9/2019.

Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.

A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.

Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.

The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.

Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.

Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.

Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.

Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.

If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.

Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.

Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder. 

“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.* 


The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.

The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.

SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.

*This article was updated on 9/9/2019.

Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.

A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.

Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.

The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.

Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.

Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.

Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.

Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.

If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.

Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.

Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder. 

“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.* 


The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.

The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.

SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.

*This article was updated on 9/9/2019.