Women's Health

Yes, anti-tumor necrosis factor (anti-TNF) therapy for inflammatory bowel disease (IBD) can be continued during pregnancy.

IBD is often diagnosed and treated in women during their reproductive years. Consequently, these patients face important decisions about the management of their disease and the safety of their baby. Clinicians should be prepared to offer guidance by discussing the risks and benefits of anti-TNF agents with their pregnant patients who have IBD, as well as with those considering pregnancy.

STUDIES OF THE POTENTIAL RISKS

Anti-TNF agents are monoclonal antibodies. Infliximab, adalimumab, and golimumab are actively transported into the fetal circulation via the placenta, mainly during the second and third trimesters. Certolizumab crosses the placenta only by passive means, because it lacks the fragment crystallizable (Fc) region required for placental transfer.¹

Effects on pregnancy outcomes

In a 2016 meta-analysis,² of 1,242 pregnancies in women with IBD, 482 were in women on anti-TNF therapy. It found no statistically significant difference in rates of adverse pregnancy outcomes including congenital abnormality, preterm birth, and low birth weight.

A meta-analysis of 1,216 pregnant women with IBD found no statistically significant differences in rates of spontaneous or elective abortion, preterm birth, low birth weight, or congenital malformation in those on anti-TNF therapy vs controls.³

A systematic review of 58 studies including more than 1,500 pregnant women with IBD who were exposed to anti-TNF agents concluded that there was no association with adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, stillbirth, low birth weight, congenital malformation, or infection.⁴

A retrospective cohort study of 66 pregnant patients with IBD from several centers in Spain found that anti-TNF or thiopurine therapy during pregnancy did not increase the risk of pregnancy complications or neonatal complications.⁵

Effects on newborns

Cord blood studies have shown that maternal use of infliximab and adalimumab results in a detectable serum level in newborns, while cord blood levels of certolizumab are much lower.^1,6 In some studies, anti-TNF drugs were detectable in infants for up to 6 months after birth, whereas other studies found that detectable serum levels dropped soon after birth.^1,7

Addressing concern about an increased risk of infection or dysfunctional immune development in newborns exposed to anti-TNF drugs in utero, a systematic review found no increased risk.⁴ A retrospective multicenter cohort study of 841 children also reported no association between in utero exposure to anti-TNF agents and risk of severe infection in the short term or long term (mean of 4 years).⁸ Additional studies are under way to determine long-term risk to the newborn.⁷

The Toronto consensus guidelines strongly recommend continuing anti-TNF therapy during pregnancy in women with IBD who began maintenance therapy before conception.⁶

If a patient strongly prefers to stop therapy during pregnancy to limit fetal exposure, the Toronto consensus recommends giving the last dose at 22 to 24 weeks of gestation. However, this should only be considered in patients whose IBD is in remission and at low risk of relapse.^6,9

Although anti-TNF drugs may differ in terms of placental transfer, agents should not be switched in stable patients, as switching increases the risk of relapse.¹⁰

BENEFITS OF CONTINUING THERAPY

Active IBD poses a significantly greater risk to the mother and the baby than continuing anti-TNF therapy during pregnancy.^1,7 The primary benefit of continuing therapy is to maintain disease remission.

Among women with active IBD at the time of conception, one-third will have improvement in disease activity during the course of their pregnancy, one-third will have no change, and one-third will have worsening of disease activity. But if IBD is in remission at the time of conception, it will remain in remission in nearly 80% of women during pregnancy.¹

Women with active IBD are at increased risk of preterm delivery, low birth weight, and intrauterine growth restriction.^1,2,5 Also, women with IBD have an increased risk of venous thromboembolism, particularly if they have active disease during pregnancy.¹ Therefore, achieving and maintaining remission are vital in the management of the pregnant patient with IBD.

CONSIDERATIONS AFTER BIRTH: BREAST-FEEDING AND VACCINATION

Breast-feeding is considered safe. Minuscule amounts of infliximab or adalimumab are transferred in breast milk but are unlikely to result in systemic immune suppression in the infant.⁷

Live-attenuated vaccines should be avoided for the first 6 months in infants exposed to anti-TNF agents in utero.^1,7,11 All other vaccines, including hepatitis B virus vaccine, should be given according to standard schedules.⁶

OUR RECOMMENDATIONS

The goal of managing IBD in women of reproductive age is to minimize the risk of adverse outcomes for both mother and baby. We recommend a team approach, working closely with a gastroenterologist and a high-risk-pregnancy obstetrician, if available.

Patients should continue anti-TNF therapy during pregnancy because evidence supports its safety. If a woman wants to stop therapy and is at low risk of relapse, we recommend giving the last dose at 22 to 24 weeks of gestation, then promptly resuming therapy postpartum.

Live-attenuated vaccines (eg, influenza, rotavirus) should be avoided for the first 6 months in babies born to mothers on anti-TNF therapy.

Yes, anti-tumor necrosis factor (anti-TNF) therapy for inflammatory bowel disease (IBD) can be continued during pregnancy.

IBD is often diagnosed and treated in women during their reproductive years. Consequently, these patients face important decisions about the management of their disease and the safety of their baby. Clinicians should be prepared to offer guidance by discussing the risks and benefits of anti-TNF agents with their pregnant patients who have IBD, as well as with those considering pregnancy.

STUDIES OF THE POTENTIAL RISKS

Anti-TNF agents are monoclonal antibodies. Infliximab, adalimumab, and golimumab are actively transported into the fetal circulation via the placenta, mainly during the second and third trimesters. Certolizumab crosses the placenta only by passive means, because it lacks the fragment crystallizable (Fc) region required for placental transfer.¹

Effects on pregnancy outcomes

In a 2016 meta-analysis,² of 1,242 pregnancies in women with IBD, 482 were in women on anti-TNF therapy. It found no statistically significant difference in rates of adverse pregnancy outcomes including congenital abnormality, preterm birth, and low birth weight.

A meta-analysis of 1,216 pregnant women with IBD found no statistically significant differences in rates of spontaneous or elective abortion, preterm birth, low birth weight, or congenital malformation in those on anti-TNF therapy vs controls.³

A systematic review of 58 studies including more than 1,500 pregnant women with IBD who were exposed to anti-TNF agents concluded that there was no association with adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, stillbirth, low birth weight, congenital malformation, or infection.⁴

A retrospective cohort study of 66 pregnant patients with IBD from several centers in Spain found that anti-TNF or thiopurine therapy during pregnancy did not increase the risk of pregnancy complications or neonatal complications.⁵

Effects on newborns

Cord blood studies have shown that maternal use of infliximab and adalimumab results in a detectable serum level in newborns, while cord blood levels of certolizumab are much lower.^1,6 In some studies, anti-TNF drugs were detectable in infants for up to 6 months after birth, whereas other studies found that detectable serum levels dropped soon after birth.^1,7

Addressing concern about an increased risk of infection or dysfunctional immune development in newborns exposed to anti-TNF drugs in utero, a systematic review found no increased risk.⁴ A retrospective multicenter cohort study of 841 children also reported no association between in utero exposure to anti-TNF agents and risk of severe infection in the short term or long term (mean of 4 years).⁸ Additional studies are under way to determine long-term risk to the newborn.⁷

The Toronto consensus guidelines strongly recommend continuing anti-TNF therapy during pregnancy in women with IBD who began maintenance therapy before conception.⁶

If a patient strongly prefers to stop therapy during pregnancy to limit fetal exposure, the Toronto consensus recommends giving the last dose at 22 to 24 weeks of gestation. However, this should only be considered in patients whose IBD is in remission and at low risk of relapse.^6,9

Although anti-TNF drugs may differ in terms of placental transfer, agents should not be switched in stable patients, as switching increases the risk of relapse.¹⁰

BENEFITS OF CONTINUING THERAPY

Active IBD poses a significantly greater risk to the mother and the baby than continuing anti-TNF therapy during pregnancy.^1,7 The primary benefit of continuing therapy is to maintain disease remission.

Among women with active IBD at the time of conception, one-third will have improvement in disease activity during the course of their pregnancy, one-third will have no change, and one-third will have worsening of disease activity. But if IBD is in remission at the time of conception, it will remain in remission in nearly 80% of women during pregnancy.¹

Women with active IBD are at increased risk of preterm delivery, low birth weight, and intrauterine growth restriction.^1,2,5 Also, women with IBD have an increased risk of venous thromboembolism, particularly if they have active disease during pregnancy.¹ Therefore, achieving and maintaining remission are vital in the management of the pregnant patient with IBD.

CONSIDERATIONS AFTER BIRTH: BREAST-FEEDING AND VACCINATION

Breast-feeding is considered safe. Minuscule amounts of infliximab or adalimumab are transferred in breast milk but are unlikely to result in systemic immune suppression in the infant.⁷

Live-attenuated vaccines should be avoided for the first 6 months in infants exposed to anti-TNF agents in utero.^1,7,11 All other vaccines, including hepatitis B virus vaccine, should be given according to standard schedules.⁶

OUR RECOMMENDATIONS

The goal of managing IBD in women of reproductive age is to minimize the risk of adverse outcomes for both mother and baby. We recommend a team approach, working closely with a gastroenterologist and a high-risk-pregnancy obstetrician, if available.

Patients should continue anti-TNF therapy during pregnancy because evidence supports its safety. If a woman wants to stop therapy and is at low risk of relapse, we recommend giving the last dose at 22 to 24 weeks of gestation, then promptly resuming therapy postpartum.

Live-attenuated vaccines (eg, influenza, rotavirus) should be avoided for the first 6 months in babies born to mothers on anti-TNF therapy.

Yes, anti-tumor necrosis factor (anti-TNF) therapy for inflammatory bowel disease (IBD) can be continued during pregnancy.

IBD is often diagnosed and treated in women during their reproductive years. Consequently, these patients face important decisions about the management of their disease and the safety of their baby. Clinicians should be prepared to offer guidance by discussing the risks and benefits of anti-TNF agents with their pregnant patients who have IBD, as well as with those considering pregnancy.

STUDIES OF THE POTENTIAL RISKS

Anti-TNF agents are monoclonal antibodies. Infliximab, adalimumab, and golimumab are actively transported into the fetal circulation via the placenta, mainly during the second and third trimesters. Certolizumab crosses the placenta only by passive means, because it lacks the fragment crystallizable (Fc) region required for placental transfer.¹

Effects on pregnancy outcomes

In a 2016 meta-analysis,² of 1,242 pregnancies in women with IBD, 482 were in women on anti-TNF therapy. It found no statistically significant difference in rates of adverse pregnancy outcomes including congenital abnormality, preterm birth, and low birth weight.

A meta-analysis of 1,216 pregnant women with IBD found no statistically significant differences in rates of spontaneous or elective abortion, preterm birth, low birth weight, or congenital malformation in those on anti-TNF therapy vs controls.³

A systematic review of 58 studies including more than 1,500 pregnant women with IBD who were exposed to anti-TNF agents concluded that there was no association with adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, stillbirth, low birth weight, congenital malformation, or infection.⁴

A retrospective cohort study of 66 pregnant patients with IBD from several centers in Spain found that anti-TNF or thiopurine therapy during pregnancy did not increase the risk of pregnancy complications or neonatal complications.⁵

Effects on newborns

Cord blood studies have shown that maternal use of infliximab and adalimumab results in a detectable serum level in newborns, while cord blood levels of certolizumab are much lower.^1,6 In some studies, anti-TNF drugs were detectable in infants for up to 6 months after birth, whereas other studies found that detectable serum levels dropped soon after birth.^1,7

Addressing concern about an increased risk of infection or dysfunctional immune development in newborns exposed to anti-TNF drugs in utero, a systematic review found no increased risk.⁴ A retrospective multicenter cohort study of 841 children also reported no association between in utero exposure to anti-TNF agents and risk of severe infection in the short term or long term (mean of 4 years).⁸ Additional studies are under way to determine long-term risk to the newborn.⁷

The Toronto consensus guidelines strongly recommend continuing anti-TNF therapy during pregnancy in women with IBD who began maintenance therapy before conception.⁶

If a patient strongly prefers to stop therapy during pregnancy to limit fetal exposure, the Toronto consensus recommends giving the last dose at 22 to 24 weeks of gestation. However, this should only be considered in patients whose IBD is in remission and at low risk of relapse.^6,9

Although anti-TNF drugs may differ in terms of placental transfer, agents should not be switched in stable patients, as switching increases the risk of relapse.¹⁰

BENEFITS OF CONTINUING THERAPY

Active IBD poses a significantly greater risk to the mother and the baby than continuing anti-TNF therapy during pregnancy.^1,7 The primary benefit of continuing therapy is to maintain disease remission.

Among women with active IBD at the time of conception, one-third will have improvement in disease activity during the course of their pregnancy, one-third will have no change, and one-third will have worsening of disease activity. But if IBD is in remission at the time of conception, it will remain in remission in nearly 80% of women during pregnancy.¹

Women with active IBD are at increased risk of preterm delivery, low birth weight, and intrauterine growth restriction.^1,2,5 Also, women with IBD have an increased risk of venous thromboembolism, particularly if they have active disease during pregnancy.¹ Therefore, achieving and maintaining remission are vital in the management of the pregnant patient with IBD.

CONSIDERATIONS AFTER BIRTH: BREAST-FEEDING AND VACCINATION

Breast-feeding is considered safe. Minuscule amounts of infliximab or adalimumab are transferred in breast milk but are unlikely to result in systemic immune suppression in the infant.⁷

Live-attenuated vaccines should be avoided for the first 6 months in infants exposed to anti-TNF agents in utero.^1,7,11 All other vaccines, including hepatitis B virus vaccine, should be given according to standard schedules.⁶

OUR RECOMMENDATIONS

The goal of managing IBD in women of reproductive age is to minimize the risk of adverse outcomes for both mother and baby. We recommend a team approach, working closely with a gastroenterologist and a high-risk-pregnancy obstetrician, if available.

Patients should continue anti-TNF therapy during pregnancy because evidence supports its safety. If a woman wants to stop therapy and is at low risk of relapse, we recommend giving the last dose at 22 to 24 weeks of gestation, then promptly resuming therapy postpartum.

Live-attenuated vaccines (eg, influenza, rotavirus) should be avoided for the first 6 months in babies born to mothers on anti-TNF therapy.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

CE/CME No: CR-1812

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the epidemiology and underlying pathogenesis of premenstrual dysphoric disorder (PMDD).
• Describe PMDD diagnostic criteria established by DSM-5.
• Differentiate PMDD from other conditions in order to provide appropriate treatment.
• Identify effective evidence-based treatment modalities for PMDD.
• Discuss PMDD treatment challenges and importance of individualizing PMDD treatment.

FACULTY
Jovanka Rajic is a recent graduate of the Master of Science in Nursing–Family Nurse Practitioner program at the Patricia A. Chin School of Nursing at California State University, Los Angeles. Stefanie A. Varela is adjunct faculty in the Patricia A. Chin School of Nursing at California State University, Los Angeles, and practices in the Obstetrics and Gynecology Department at Kaiser Permanente in Ontario, California.

The authors reported no conflicts of interest related to this article.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through November 30, 2019.

Article begins on next page >>

The severe psychiatric and somatic symptoms of premenstrual dysphoric disorder (PMDD) can be debilitating and place women at increased risk for other psychiatric disorders (including major depression and generalized anxiety) and for suicidal ideation. While PMDD’s complex nature makes it an underdiagnosed condition, there are clear diagnostic criteria for clinicians to ensure their patients receive timely and appropriate treatment—thus reducing the risk for serious sequelae.

Premenstrual dysphoric disorder (PMDD) is categorized as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).¹ The hallmarks of this unique disorder are chronic, severe psychiatric and somatic symptoms that occur only during the late luteal phase of the menstrual cycle and dissipate soon after the onset of menstruation.² Symptoms are generally disruptive and often associated with significant distress and impaired quality of life.²

PMDD occurs in 3%-8% of women of childbearing age; it affects women worldwide and is not influenced by geography or culture.² Genetic susceptibility, stress, obesity, and a history of trauma or sexual abuse have been implicated as risk factors.^2-6 The impact of PMDD on health-related quality of life is greater than that of chronic back pain but comparable to that of rheumatoid arthritis and osteoarthritis.^2,7 Significantly, women with PMDD have a 50%-78% lifetime risk for psychiatric disorders, such as major depressive, dysthymic, seasonal affective, and generalized anxiety disorders, and suicidality.²

PMDD can be challenging for primary care providers to diagnose and treat, due to the lack of standardized screening methods, unfamiliarity with evidence-based practices for diagnosis, and the need to tailor treatment to each patient’s individual needs.^3,8 But the increased risk for psychiatric sequelae, including suicidality, make timely diagnosis and treatment of PMDD critical.^2,9

PATHOGENESIS

The pathogenesis of PMDD is not completely understood. The prevailing theory is that PMDD is underlined by increased sensitivity to normal fluctuations in ovarian steroid hormone levels (see the Figure) during the luteal phase of the menstrual cycle.^2-4,6

This sensitivity involves the progeste­rone metabolite allopregnanolone (ALLO), which acts as a modulator of central GABA-A receptors that have anxiolytic and sedative effects.^2,3 It has been postulated that women with PMDD have impaired production of ALLO or decreased sensitivity of GABA-A receptors to ALLO during the luteal phase.^2,3 In addition, women with PMDD exhibit a paradoxical anxiety and irritability response to ALLO.^2,3 Recent research suggests that PMDD is precipitated by changing ALLO levels during the luteal phase and that treatment directed at reducing ALLO availability during this phase can alleviate PMDD symptoms.¹⁰

Hormonal fluctuations have been associated with impaired serotonergic system function in women with PMDD, which results in dysregulation of mood, cognition, sleep, and eating behavior.^2-4,6 Hormonal fluctuations have also been implicated in the alteration of emotional and cognitive circuits.^2,3,6,11,12 Brain imaging studies have revealed that women with PMDD demonstrate enhanced reactivity to amygdala, which processes emotional and cognitive stimuli, as well as impaired control of amygdala by the prefrontal cortex during the luteal phase.^3,7,12

Continue to: PATIENT PRESENTATION/HISTORY

PMDD is an individual experience for each woman.^3,4 However, women with PMDD generally present with a history of various psychiatric and somatic symptoms that significantly interfere with their occupational or social functions (to be discussed in the Diagnosis section, page 42).^1-4 The reported symptoms occur in predictable patterns that are associated with the menstrual cycle, intensifying around the time of menstruation and resolving immediately after onset of menstruation in most cases.^1-4

Many psychiatric and medical conditions may be exacerbated during the luteal phase of the menstrual cycle and thus may mimic the signs and symptoms of PMDD (see Table 1).^1,4 Therefore, the pattern and severity of symptoms should always be considered when differentiating PMDD from other underlying conditions.^1,2,4,5

It is also important to distinguish PMDD from PMS, a condition with which it is frequently confused. The latter manifests with at least one affective or somatic symptom that is bothersome but not disabling.^4,5 An accurate differential diagnosis is important, as the management of these two conditions differs significantly.^4,5

ASSESSMENT

PMDD assessment should include thorough history taking, with emphasis on medical, gynecologic, and psychiatric history as well as social and familial history (including PMDD and other psychiatric disorders); and physical examination, including gynecologic and mental status assessment and depression screening using the Patient Health Questionnaire (PHQ-9).^2,4,13,14 The physical exam is usually unremarkable.¹⁴ The most common physical findings during the luteal phase include mild swelling in the lower extremities and breast tenderness.¹⁴ Mental status examination, however, may be abnormal during the late luteal phase—albeit with orientation, memory, thoughts, and perceptions intact.^13,14

LABORATORY WORKUP

There is no specific laboratory test for PMDD; rather, testing is aimed at ruling out alternative diagnoses.^4,14 Relevant studies may include a complete blood count to exclude anemia, a thyroid function test to exclude thyroid disorders, a blood glucose test to exclude diabetes or hypoglycemia, and a ß hCG test to exclude possible pregnancy.^4,14 Hormonal tests (eg, for FSH) may be considered for younger women with irregular cycles or for those younger than 40 with suspected premature menopause.^4,14

Continue to: DIAGNOSIS

Diagnosis of PMDD is guided by the DSM-5 criteria, which include the following components

• Content (presence of specific symptoms)
• Cyclicity (premenstrual onset and postmenstrual resolution)
• Severity (significant distress)
• Chronicity (occurrence in the past year).¹⁵

DSM-5 has established seven criteria (labeled A-G) for a PMDD diagnosis.¹ First and foremost, a woman must experience a minimum of five of the 11 listed symptoms, with a minimum of one symptom being related to mood, during most menstrual cycles over the previous 12 months (Criterion A).¹ The symptoms must occur during the week before the onset of menses, must improve within a few days of onset of menses, and must resolve in the week following menses.¹

Mood-related symptoms (outlined in Criterion B) include

1. Notable depressed mood, hopelessness, or self-deprecation
2. Notable tension and/or anxiety
3. Notable affective lability (eg, mood swings, sudden sadness, tearfulness, or increased sensitivity to rejection)
4. Notable anger or irritability or increased interpersonal conflicts.¹

Somatic or functional symptoms associated with PMDD (Criterion C) include:

5. Low interest in common activities (eg, those related to friends, work, school, and/or hobbies)
6. Difficulty concentrating
7. Lethargy, fatigue, or increased lack of energy
8. Notable change in appetite
9. Insomnia or hypersomnia
10. Feeling overwhelmed or out of control
11. Physical symptoms, such as breast tenderness or swelling, joint or muscle pain, headache, weight gain, or bloating.¹

Again, patients must report at least one symptom from Criterion B and at least one from Criterion C—but a minimum of five symptoms overall—to receive a diagnosis of PMDD.¹

Continue to: Additionally, the symptoms must...

Additionally, the symptoms must cause clinically significant distress or impair daily functioning, including occupational, social, academic, and sexual activities (Criterion D). They must not represent exacerbation of another underlying psychiatric disorder, such as major depressive, dysthymic, panic, or personality disorders (Criterion E), although PMDD may co-occur with psychiatric disorders.¹

The above-mentioned symptom profile must be confirmed by prospective daily ratings of a minimum of two consecutive symptomatic menstrual cycles (Criterion F), although a provisional diagnosis of PMDD may be made prior to confirmation.¹ The Daily Record of Severity of Problems is the most widely used instrument for prospective daily rating of PMDD symptoms listed in the DSM-5 criteria.^5,15

Finally, the symptoms must not be evoked by the use of a substance (eg, medications, alcohol, and illicit drugs) or another medical condition (Criterion G).¹

TREATMENT/MANAGEMENT

The goal of PMDD treatment is to relieve psychiatric and physical symptoms and improve the patient's ability to function.³ Treatment is primarily directed at pharmacologic neuromodulation using selective serotonin reuptake inhibitors (SSRIs) or ovulation suppression using oral contraceptives and hormones.²

Pharmacotherapy

SSRIs are the firstline treatment for PMDD.⁵ Fluoxetine, paroxetine, and sertraline are the only serotonergic medications approved by the FDA for treatment of PMDD.² SSRIs act within one to two days when used for PMDD, thereby allowing different modes of dosing.² SSRI dosing may be continuous (daily administration), intermittent (administration from ovulation to first day of menses), or symptomatic (administration from symptom onset until first day of menses).³ Although data on continuous and intermittent dosing are available for fluoxetine, paroxetine, and sertraline, symptom-onset data are currently available only for sertraline (see Table 2).^16-19

Continue to: Combined oral contraceptives...

Combined oral contraceptives (COCs) containing estrogen and progesterone are considered secondline treatment for PMDD—specifically, COCs containing 20 µg of ethinyl estradiol and 3 mg of drospirenone administered as a 24/4 regimen.^2,3,5,6 This combination has been approved by the FDA for women with PMDD who seek oral contraception.³ Although drospirenone-containing products have been associated with increased risk for venous thromboembolism (VTE), this risk is lower than that for VTE during pregnancy or in the postpartum period.³ Currently, no strong evidence exists regarding the effectiveness of other oral contraceptives for PMDD.⁶

Gonadotropin-releasing hormone agonists are the thirdline treatment for PMDD.⁶ They eliminate symptoms of the luteal phase by suppressing ovarian release of estrogen and ovulation.⁶ However, use of these agents is not recommended for more than one year due to the increased risk for cardiovascular events.^5,6 In addition, long-term users need add-back therapy (adding back small amounts of the hormone) to counteract the effects of low estrogen, such as bone loss; providers should be aware that this may lead to the recurrence of PMDD.^3,5,6 The use of estrogen and progesterone formulations for PMDD is currently not strongly supported by research.⁶

Complementary treatment

Cognitive behavioral therapy has been shown to improve functioning and reduce depression in women with PMDD and may be a useful adjunct.^2,20 Regular aerobic exercise, a diet high in protein and complex carbohydrates to increase tryptophan ­(serotonin precursor) levels, and reduced intake of caffeine, sugar, and alcohol are some commonly recommended lifestyle changes.²

Calcium carbonate supplementation (500 mg/d) has demonstrated effectiveness in alleviating premenstrual mood and physical symptoms.²¹ There is currently no strong evidence regarding the benefits of acupuncture, Qi therapy, reflexology, and herbal preparations for managing PMDD.²²

Surgery

Bilateral oophorectomy, usually with concomitant hysterectomy, is the last resort for women with severe PMDD who do not respond to or cannot tolerate the standard treatments.⁶ This surgical procedure results in premature menopause, which may lead to complications related to a hypoestrogenic state—including vasomotor symptoms (flushes/flashes), vaginal atrophy, osteopenia, osteoporosis, and cardiovascular disease.² Therefore, it is important to implement estrogen replacement therapy after surgery until the age of natural menopause is reached.² If hysterectomy is not performed, the administration of progesterone is necessary to prevent endometrial hyperplasia and therefore reduce the risk for endometrial cancer.² However, the addition of progesterone may lead to recurrence of symptoms.²

^{Continue to: Treatment challenges}

Treatment challenges

PMDD treatment differs for each patient.³ Severity of symptoms, response to treatment, treatment preference, conception plans, and reproductive age need to be considered.³

Women with prominent depressive or physical symptoms may respond better to continuous dosing of SSRIs, whereas those with prominent irritability, anger, and mood swings may respond better to a symptom-onset SSRI regimen that reduces availability and function of ALLO.³ Women who develop tolerance to SSRIs may need to have their dosage increased or be switched to another medication.³Quetiapine is used as an adjunct to SSRIs for women who do not respond to SSRIs alone and has shown to improve mood swings, anxiety, and irritability.⁵ However, women experiencing persistent adverse effects of SSRIs, such as sexual dysfunction, may benefit from intermittent dosing.³

Adolescents and women in their early 20s should be treated with OCs or nonpharmacologic modalities due to concerns about SSRI use and increased risk for suicidality in this population.³ The risks related to SSRI use during pregnancy and breastfeeding should be considered and discussed with women of childbearing age who use SSRIs to treat PMDD.³ Perimenopausal women with irregular menses on intermittent ­SSRIs may have to switch to symptom-onset or continuous dosing due to the difficulty of tracking the menstrual period and lack of significant benchmarks regarding when to start the treatment.³

Patient education/follow-up

Patients should be educated on PMDD etiology, diagnostic process, and available treatment options.⁴ The importance of prospective record-keeping—for confirmation of the diagnosis and evaluation of individual response to a specific treatment—should be emphasized.⁴ Patients should be encouraged to follow up with their health care provider to monitor treatment effectiveness, possible adverse effects, and need for treatment adjustment.⁴

CONCLUSION

The symptoms of PMDD can have a debilitating and life-disrupting impact on affected women—and put them at risk for other serious psychiatric disorders and suicide. The DSM-5 criteria provide diagnostic guidance to help distinguish PMDD from other underlying conditions, ensuring that patients can receive timely and appropriate treatment. While SSRIs are regarded as the most effective option, other evidence-based treatments should be considered, since PMDD requires individualized treatment to ensure optimal clinical outcomes.

CE/CME No: CR-1812

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the epidemiology and underlying pathogenesis of premenstrual dysphoric disorder (PMDD).
• Describe PMDD diagnostic criteria established by DSM-5.
• Differentiate PMDD from other conditions in order to provide appropriate treatment.
• Identify effective evidence-based treatment modalities for PMDD.
• Discuss PMDD treatment challenges and importance of individualizing PMDD treatment.

FACULTY
Jovanka Rajic is a recent graduate of the Master of Science in Nursing–Family Nurse Practitioner program at the Patricia A. Chin School of Nursing at California State University, Los Angeles. Stefanie A. Varela is adjunct faculty in the Patricia A. Chin School of Nursing at California State University, Los Angeles, and practices in the Obstetrics and Gynecology Department at Kaiser Permanente in Ontario, California.

The authors reported no conflicts of interest related to this article.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through November 30, 2019.

Article begins on next page >>

The severe psychiatric and somatic symptoms of premenstrual dysphoric disorder (PMDD) can be debilitating and place women at increased risk for other psychiatric disorders (including major depression and generalized anxiety) and for suicidal ideation. While PMDD’s complex nature makes it an underdiagnosed condition, there are clear diagnostic criteria for clinicians to ensure their patients receive timely and appropriate treatment—thus reducing the risk for serious sequelae.

Premenstrual dysphoric disorder (PMDD) is categorized as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).¹ The hallmarks of this unique disorder are chronic, severe psychiatric and somatic symptoms that occur only during the late luteal phase of the menstrual cycle and dissipate soon after the onset of menstruation.² Symptoms are generally disruptive and often associated with significant distress and impaired quality of life.²

PMDD occurs in 3%-8% of women of childbearing age; it affects women worldwide and is not influenced by geography or culture.² Genetic susceptibility, stress, obesity, and a history of trauma or sexual abuse have been implicated as risk factors.^2-6 The impact of PMDD on health-related quality of life is greater than that of chronic back pain but comparable to that of rheumatoid arthritis and osteoarthritis.^2,7 Significantly, women with PMDD have a 50%-78% lifetime risk for psychiatric disorders, such as major depressive, dysthymic, seasonal affective, and generalized anxiety disorders, and suicidality.²

PMDD can be challenging for primary care providers to diagnose and treat, due to the lack of standardized screening methods, unfamiliarity with evidence-based practices for diagnosis, and the need to tailor treatment to each patient’s individual needs.^3,8 But the increased risk for psychiatric sequelae, including suicidality, make timely diagnosis and treatment of PMDD critical.^2,9

PATHOGENESIS

The pathogenesis of PMDD is not completely understood. The prevailing theory is that PMDD is underlined by increased sensitivity to normal fluctuations in ovarian steroid hormone levels (see the Figure) during the luteal phase of the menstrual cycle.^2-4,6

This sensitivity involves the progeste­rone metabolite allopregnanolone (ALLO), which acts as a modulator of central GABA-A receptors that have anxiolytic and sedative effects.^2,3 It has been postulated that women with PMDD have impaired production of ALLO or decreased sensitivity of GABA-A receptors to ALLO during the luteal phase.^2,3 In addition, women with PMDD exhibit a paradoxical anxiety and irritability response to ALLO.^2,3 Recent research suggests that PMDD is precipitated by changing ALLO levels during the luteal phase and that treatment directed at reducing ALLO availability during this phase can alleviate PMDD symptoms.¹⁰

Hormonal fluctuations have been associated with impaired serotonergic system function in women with PMDD, which results in dysregulation of mood, cognition, sleep, and eating behavior.^2-4,6 Hormonal fluctuations have also been implicated in the alteration of emotional and cognitive circuits.^2,3,6,11,12 Brain imaging studies have revealed that women with PMDD demonstrate enhanced reactivity to amygdala, which processes emotional and cognitive stimuli, as well as impaired control of amygdala by the prefrontal cortex during the luteal phase.^3,7,12

Continue to: PATIENT PRESENTATION/HISTORY

PMDD is an individual experience for each woman.^3,4 However, women with PMDD generally present with a history of various psychiatric and somatic symptoms that significantly interfere with their occupational or social functions (to be discussed in the Diagnosis section, page 42).^1-4 The reported symptoms occur in predictable patterns that are associated with the menstrual cycle, intensifying around the time of menstruation and resolving immediately after onset of menstruation in most cases.^1-4

Many psychiatric and medical conditions may be exacerbated during the luteal phase of the menstrual cycle and thus may mimic the signs and symptoms of PMDD (see Table 1).^1,4 Therefore, the pattern and severity of symptoms should always be considered when differentiating PMDD from other underlying conditions.^1,2,4,5

It is also important to distinguish PMDD from PMS, a condition with which it is frequently confused. The latter manifests with at least one affective or somatic symptom that is bothersome but not disabling.^4,5 An accurate differential diagnosis is important, as the management of these two conditions differs significantly.^4,5

ASSESSMENT

PMDD assessment should include thorough history taking, with emphasis on medical, gynecologic, and psychiatric history as well as social and familial history (including PMDD and other psychiatric disorders); and physical examination, including gynecologic and mental status assessment and depression screening using the Patient Health Questionnaire (PHQ-9).^2,4,13,14 The physical exam is usually unremarkable.¹⁴ The most common physical findings during the luteal phase include mild swelling in the lower extremities and breast tenderness.¹⁴ Mental status examination, however, may be abnormal during the late luteal phase—albeit with orientation, memory, thoughts, and perceptions intact.^13,14

LABORATORY WORKUP

There is no specific laboratory test for PMDD; rather, testing is aimed at ruling out alternative diagnoses.^4,14 Relevant studies may include a complete blood count to exclude anemia, a thyroid function test to exclude thyroid disorders, a blood glucose test to exclude diabetes or hypoglycemia, and a ß hCG test to exclude possible pregnancy.^4,14 Hormonal tests (eg, for FSH) may be considered for younger women with irregular cycles or for those younger than 40 with suspected premature menopause.^4,14

Continue to: DIAGNOSIS

Diagnosis of PMDD is guided by the DSM-5 criteria, which include the following components

• Content (presence of specific symptoms)
• Cyclicity (premenstrual onset and postmenstrual resolution)
• Severity (significant distress)
• Chronicity (occurrence in the past year).¹⁵

DSM-5 has established seven criteria (labeled A-G) for a PMDD diagnosis.¹ First and foremost, a woman must experience a minimum of five of the 11 listed symptoms, with a minimum of one symptom being related to mood, during most menstrual cycles over the previous 12 months (Criterion A).¹ The symptoms must occur during the week before the onset of menses, must improve within a few days of onset of menses, and must resolve in the week following menses.¹

Mood-related symptoms (outlined in Criterion B) include

1. Notable depressed mood, hopelessness, or self-deprecation
2. Notable tension and/or anxiety
3. Notable affective lability (eg, mood swings, sudden sadness, tearfulness, or increased sensitivity to rejection)
4. Notable anger or irritability or increased interpersonal conflicts.¹

Somatic or functional symptoms associated with PMDD (Criterion C) include:

5. Low interest in common activities (eg, those related to friends, work, school, and/or hobbies)
6. Difficulty concentrating
7. Lethargy, fatigue, or increased lack of energy
8. Notable change in appetite
9. Insomnia or hypersomnia
10. Feeling overwhelmed or out of control
11. Physical symptoms, such as breast tenderness or swelling, joint or muscle pain, headache, weight gain, or bloating.¹

Again, patients must report at least one symptom from Criterion B and at least one from Criterion C—but a minimum of five symptoms overall—to receive a diagnosis of PMDD.¹

Continue to: Additionally, the symptoms must...

Additionally, the symptoms must cause clinically significant distress or impair daily functioning, including occupational, social, academic, and sexual activities (Criterion D). They must not represent exacerbation of another underlying psychiatric disorder, such as major depressive, dysthymic, panic, or personality disorders (Criterion E), although PMDD may co-occur with psychiatric disorders.¹

The above-mentioned symptom profile must be confirmed by prospective daily ratings of a minimum of two consecutive symptomatic menstrual cycles (Criterion F), although a provisional diagnosis of PMDD may be made prior to confirmation.¹ The Daily Record of Severity of Problems is the most widely used instrument for prospective daily rating of PMDD symptoms listed in the DSM-5 criteria.^5,15

Finally, the symptoms must not be evoked by the use of a substance (eg, medications, alcohol, and illicit drugs) or another medical condition (Criterion G).¹

TREATMENT/MANAGEMENT

The goal of PMDD treatment is to relieve psychiatric and physical symptoms and improve the patient's ability to function.³ Treatment is primarily directed at pharmacologic neuromodulation using selective serotonin reuptake inhibitors (SSRIs) or ovulation suppression using oral contraceptives and hormones.²

Pharmacotherapy

SSRIs are the firstline treatment for PMDD.⁵ Fluoxetine, paroxetine, and sertraline are the only serotonergic medications approved by the FDA for treatment of PMDD.² SSRIs act within one to two days when used for PMDD, thereby allowing different modes of dosing.² SSRI dosing may be continuous (daily administration), intermittent (administration from ovulation to first day of menses), or symptomatic (administration from symptom onset until first day of menses).³ Although data on continuous and intermittent dosing are available for fluoxetine, paroxetine, and sertraline, symptom-onset data are currently available only for sertraline (see Table 2).^16-19

Continue to: Combined oral contraceptives...

Combined oral contraceptives (COCs) containing estrogen and progesterone are considered secondline treatment for PMDD—specifically, COCs containing 20 µg of ethinyl estradiol and 3 mg of drospirenone administered as a 24/4 regimen.^2,3,5,6 This combination has been approved by the FDA for women with PMDD who seek oral contraception.³ Although drospirenone-containing products have been associated with increased risk for venous thromboembolism (VTE), this risk is lower than that for VTE during pregnancy or in the postpartum period.³ Currently, no strong evidence exists regarding the effectiveness of other oral contraceptives for PMDD.⁶

Gonadotropin-releasing hormone agonists are the thirdline treatment for PMDD.⁶ They eliminate symptoms of the luteal phase by suppressing ovarian release of estrogen and ovulation.⁶ However, use of these agents is not recommended for more than one year due to the increased risk for cardiovascular events.^5,6 In addition, long-term users need add-back therapy (adding back small amounts of the hormone) to counteract the effects of low estrogen, such as bone loss; providers should be aware that this may lead to the recurrence of PMDD.^3,5,6 The use of estrogen and progesterone formulations for PMDD is currently not strongly supported by research.⁶

Complementary treatment

Cognitive behavioral therapy has been shown to improve functioning and reduce depression in women with PMDD and may be a useful adjunct.^2,20 Regular aerobic exercise, a diet high in protein and complex carbohydrates to increase tryptophan ­(serotonin precursor) levels, and reduced intake of caffeine, sugar, and alcohol are some commonly recommended lifestyle changes.²

Calcium carbonate supplementation (500 mg/d) has demonstrated effectiveness in alleviating premenstrual mood and physical symptoms.²¹ There is currently no strong evidence regarding the benefits of acupuncture, Qi therapy, reflexology, and herbal preparations for managing PMDD.²²

Surgery

Bilateral oophorectomy, usually with concomitant hysterectomy, is the last resort for women with severe PMDD who do not respond to or cannot tolerate the standard treatments.⁶ This surgical procedure results in premature menopause, which may lead to complications related to a hypoestrogenic state—including vasomotor symptoms (flushes/flashes), vaginal atrophy, osteopenia, osteoporosis, and cardiovascular disease.² Therefore, it is important to implement estrogen replacement therapy after surgery until the age of natural menopause is reached.² If hysterectomy is not performed, the administration of progesterone is necessary to prevent endometrial hyperplasia and therefore reduce the risk for endometrial cancer.² However, the addition of progesterone may lead to recurrence of symptoms.²

^{Continue to: Treatment challenges}

Treatment challenges

PMDD treatment differs for each patient.³ Severity of symptoms, response to treatment, treatment preference, conception plans, and reproductive age need to be considered.³

Women with prominent depressive or physical symptoms may respond better to continuous dosing of SSRIs, whereas those with prominent irritability, anger, and mood swings may respond better to a symptom-onset SSRI regimen that reduces availability and function of ALLO.³ Women who develop tolerance to SSRIs may need to have their dosage increased or be switched to another medication.³Quetiapine is used as an adjunct to SSRIs for women who do not respond to SSRIs alone and has shown to improve mood swings, anxiety, and irritability.⁵ However, women experiencing persistent adverse effects of SSRIs, such as sexual dysfunction, may benefit from intermittent dosing.³

Adolescents and women in their early 20s should be treated with OCs or nonpharmacologic modalities due to concerns about SSRI use and increased risk for suicidality in this population.³ The risks related to SSRI use during pregnancy and breastfeeding should be considered and discussed with women of childbearing age who use SSRIs to treat PMDD.³ Perimenopausal women with irregular menses on intermittent ­SSRIs may have to switch to symptom-onset or continuous dosing due to the difficulty of tracking the menstrual period and lack of significant benchmarks regarding when to start the treatment.³

Patient education/follow-up

Patients should be educated on PMDD etiology, diagnostic process, and available treatment options.⁴ The importance of prospective record-keeping—for confirmation of the diagnosis and evaluation of individual response to a specific treatment—should be emphasized.⁴ Patients should be encouraged to follow up with their health care provider to monitor treatment effectiveness, possible adverse effects, and need for treatment adjustment.⁴

CONCLUSION

The symptoms of PMDD can have a debilitating and life-disrupting impact on affected women—and put them at risk for other serious psychiatric disorders and suicide. The DSM-5 criteria provide diagnostic guidance to help distinguish PMDD from other underlying conditions, ensuring that patients can receive timely and appropriate treatment. While SSRIs are regarded as the most effective option, other evidence-based treatments should be considered, since PMDD requires individualized treatment to ensure optimal clinical outcomes.

CE/CME No: CR-1812

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the epidemiology and underlying pathogenesis of premenstrual dysphoric disorder (PMDD).
• Describe PMDD diagnostic criteria established by DSM-5.
• Differentiate PMDD from other conditions in order to provide appropriate treatment.
• Identify effective evidence-based treatment modalities for PMDD.
• Discuss PMDD treatment challenges and importance of individualizing PMDD treatment.

FACULTY
Jovanka Rajic is a recent graduate of the Master of Science in Nursing–Family Nurse Practitioner program at the Patricia A. Chin School of Nursing at California State University, Los Angeles. Stefanie A. Varela is adjunct faculty in the Patricia A. Chin School of Nursing at California State University, Los Angeles, and practices in the Obstetrics and Gynecology Department at Kaiser Permanente in Ontario, California.

The authors reported no conflicts of interest related to this article.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through November 30, 2019.

Article begins on next page >>

The severe psychiatric and somatic symptoms of premenstrual dysphoric disorder (PMDD) can be debilitating and place women at increased risk for other psychiatric disorders (including major depression and generalized anxiety) and for suicidal ideation. While PMDD’s complex nature makes it an underdiagnosed condition, there are clear diagnostic criteria for clinicians to ensure their patients receive timely and appropriate treatment—thus reducing the risk for serious sequelae.

Premenstrual dysphoric disorder (PMDD) is categorized as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).¹ The hallmarks of this unique disorder are chronic, severe psychiatric and somatic symptoms that occur only during the late luteal phase of the menstrual cycle and dissipate soon after the onset of menstruation.² Symptoms are generally disruptive and often associated with significant distress and impaired quality of life.²

PMDD occurs in 3%-8% of women of childbearing age; it affects women worldwide and is not influenced by geography or culture.² Genetic susceptibility, stress, obesity, and a history of trauma or sexual abuse have been implicated as risk factors.^2-6 The impact of PMDD on health-related quality of life is greater than that of chronic back pain but comparable to that of rheumatoid arthritis and osteoarthritis.^2,7 Significantly, women with PMDD have a 50%-78% lifetime risk for psychiatric disorders, such as major depressive, dysthymic, seasonal affective, and generalized anxiety disorders, and suicidality.²

PMDD can be challenging for primary care providers to diagnose and treat, due to the lack of standardized screening methods, unfamiliarity with evidence-based practices for diagnosis, and the need to tailor treatment to each patient’s individual needs.^3,8 But the increased risk for psychiatric sequelae, including suicidality, make timely diagnosis and treatment of PMDD critical.^2,9

PATHOGENESIS

The pathogenesis of PMDD is not completely understood. The prevailing theory is that PMDD is underlined by increased sensitivity to normal fluctuations in ovarian steroid hormone levels (see the Figure) during the luteal phase of the menstrual cycle.^2-4,6

This sensitivity involves the progeste­rone metabolite allopregnanolone (ALLO), which acts as a modulator of central GABA-A receptors that have anxiolytic and sedative effects.^2,3 It has been postulated that women with PMDD have impaired production of ALLO or decreased sensitivity of GABA-A receptors to ALLO during the luteal phase.^2,3 In addition, women with PMDD exhibit a paradoxical anxiety and irritability response to ALLO.^2,3 Recent research suggests that PMDD is precipitated by changing ALLO levels during the luteal phase and that treatment directed at reducing ALLO availability during this phase can alleviate PMDD symptoms.¹⁰

Hormonal fluctuations have been associated with impaired serotonergic system function in women with PMDD, which results in dysregulation of mood, cognition, sleep, and eating behavior.^2-4,6 Hormonal fluctuations have also been implicated in the alteration of emotional and cognitive circuits.^2,3,6,11,12 Brain imaging studies have revealed that women with PMDD demonstrate enhanced reactivity to amygdala, which processes emotional and cognitive stimuli, as well as impaired control of amygdala by the prefrontal cortex during the luteal phase.^3,7,12

Continue to: PATIENT PRESENTATION/HISTORY

PMDD is an individual experience for each woman.^3,4 However, women with PMDD generally present with a history of various psychiatric and somatic symptoms that significantly interfere with their occupational or social functions (to be discussed in the Diagnosis section, page 42).^1-4 The reported symptoms occur in predictable patterns that are associated with the menstrual cycle, intensifying around the time of menstruation and resolving immediately after onset of menstruation in most cases.^1-4

Many psychiatric and medical conditions may be exacerbated during the luteal phase of the menstrual cycle and thus may mimic the signs and symptoms of PMDD (see Table 1).^1,4 Therefore, the pattern and severity of symptoms should always be considered when differentiating PMDD from other underlying conditions.^1,2,4,5

It is also important to distinguish PMDD from PMS, a condition with which it is frequently confused. The latter manifests with at least one affective or somatic symptom that is bothersome but not disabling.^4,5 An accurate differential diagnosis is important, as the management of these two conditions differs significantly.^4,5

ASSESSMENT

PMDD assessment should include thorough history taking, with emphasis on medical, gynecologic, and psychiatric history as well as social and familial history (including PMDD and other psychiatric disorders); and physical examination, including gynecologic and mental status assessment and depression screening using the Patient Health Questionnaire (PHQ-9).^2,4,13,14 The physical exam is usually unremarkable.¹⁴ The most common physical findings during the luteal phase include mild swelling in the lower extremities and breast tenderness.¹⁴ Mental status examination, however, may be abnormal during the late luteal phase—albeit with orientation, memory, thoughts, and perceptions intact.^13,14

LABORATORY WORKUP

There is no specific laboratory test for PMDD; rather, testing is aimed at ruling out alternative diagnoses.^4,14 Relevant studies may include a complete blood count to exclude anemia, a thyroid function test to exclude thyroid disorders, a blood glucose test to exclude diabetes or hypoglycemia, and a ß hCG test to exclude possible pregnancy.^4,14 Hormonal tests (eg, for FSH) may be considered for younger women with irregular cycles or for those younger than 40 with suspected premature menopause.^4,14

Continue to: DIAGNOSIS

Diagnosis of PMDD is guided by the DSM-5 criteria, which include the following components

• Content (presence of specific symptoms)
• Cyclicity (premenstrual onset and postmenstrual resolution)
• Severity (significant distress)
• Chronicity (occurrence in the past year).¹⁵

DSM-5 has established seven criteria (labeled A-G) for a PMDD diagnosis.¹ First and foremost, a woman must experience a minimum of five of the 11 listed symptoms, with a minimum of one symptom being related to mood, during most menstrual cycles over the previous 12 months (Criterion A).¹ The symptoms must occur during the week before the onset of menses, must improve within a few days of onset of menses, and must resolve in the week following menses.¹

Mood-related symptoms (outlined in Criterion B) include

1. Notable depressed mood, hopelessness, or self-deprecation
2. Notable tension and/or anxiety
3. Notable affective lability (eg, mood swings, sudden sadness, tearfulness, or increased sensitivity to rejection)
4. Notable anger or irritability or increased interpersonal conflicts.¹

Somatic or functional symptoms associated with PMDD (Criterion C) include:

5. Low interest in common activities (eg, those related to friends, work, school, and/or hobbies)
6. Difficulty concentrating
7. Lethargy, fatigue, or increased lack of energy
8. Notable change in appetite
9. Insomnia or hypersomnia
10. Feeling overwhelmed or out of control
11. Physical symptoms, such as breast tenderness or swelling, joint or muscle pain, headache, weight gain, or bloating.¹

Again, patients must report at least one symptom from Criterion B and at least one from Criterion C—but a minimum of five symptoms overall—to receive a diagnosis of PMDD.¹

Continue to: Additionally, the symptoms must...

Additionally, the symptoms must cause clinically significant distress or impair daily functioning, including occupational, social, academic, and sexual activities (Criterion D). They must not represent exacerbation of another underlying psychiatric disorder, such as major depressive, dysthymic, panic, or personality disorders (Criterion E), although PMDD may co-occur with psychiatric disorders.¹

The above-mentioned symptom profile must be confirmed by prospective daily ratings of a minimum of two consecutive symptomatic menstrual cycles (Criterion F), although a provisional diagnosis of PMDD may be made prior to confirmation.¹ The Daily Record of Severity of Problems is the most widely used instrument for prospective daily rating of PMDD symptoms listed in the DSM-5 criteria.^5,15

Finally, the symptoms must not be evoked by the use of a substance (eg, medications, alcohol, and illicit drugs) or another medical condition (Criterion G).¹

TREATMENT/MANAGEMENT

The goal of PMDD treatment is to relieve psychiatric and physical symptoms and improve the patient's ability to function.³ Treatment is primarily directed at pharmacologic neuromodulation using selective serotonin reuptake inhibitors (SSRIs) or ovulation suppression using oral contraceptives and hormones.²

Pharmacotherapy

SSRIs are the firstline treatment for PMDD.⁵ Fluoxetine, paroxetine, and sertraline are the only serotonergic medications approved by the FDA for treatment of PMDD.² SSRIs act within one to two days when used for PMDD, thereby allowing different modes of dosing.² SSRI dosing may be continuous (daily administration), intermittent (administration from ovulation to first day of menses), or symptomatic (administration from symptom onset until first day of menses).³ Although data on continuous and intermittent dosing are available for fluoxetine, paroxetine, and sertraline, symptom-onset data are currently available only for sertraline (see Table 2).^16-19

Continue to: Combined oral contraceptives...

Combined oral contraceptives (COCs) containing estrogen and progesterone are considered secondline treatment for PMDD—specifically, COCs containing 20 µg of ethinyl estradiol and 3 mg of drospirenone administered as a 24/4 regimen.^2,3,5,6 This combination has been approved by the FDA for women with PMDD who seek oral contraception.³ Although drospirenone-containing products have been associated with increased risk for venous thromboembolism (VTE), this risk is lower than that for VTE during pregnancy or in the postpartum period.³ Currently, no strong evidence exists regarding the effectiveness of other oral contraceptives for PMDD.⁶

Gonadotropin-releasing hormone agonists are the thirdline treatment for PMDD.⁶ They eliminate symptoms of the luteal phase by suppressing ovarian release of estrogen and ovulation.⁶ However, use of these agents is not recommended for more than one year due to the increased risk for cardiovascular events.^5,6 In addition, long-term users need add-back therapy (adding back small amounts of the hormone) to counteract the effects of low estrogen, such as bone loss; providers should be aware that this may lead to the recurrence of PMDD.^3,5,6 The use of estrogen and progesterone formulations for PMDD is currently not strongly supported by research.⁶

Complementary treatment

Cognitive behavioral therapy has been shown to improve functioning and reduce depression in women with PMDD and may be a useful adjunct.^2,20 Regular aerobic exercise, a diet high in protein and complex carbohydrates to increase tryptophan ­(serotonin precursor) levels, and reduced intake of caffeine, sugar, and alcohol are some commonly recommended lifestyle changes.²

Calcium carbonate supplementation (500 mg/d) has demonstrated effectiveness in alleviating premenstrual mood and physical symptoms.²¹ There is currently no strong evidence regarding the benefits of acupuncture, Qi therapy, reflexology, and herbal preparations for managing PMDD.²²

Surgery

Bilateral oophorectomy, usually with concomitant hysterectomy, is the last resort for women with severe PMDD who do not respond to or cannot tolerate the standard treatments.⁶ This surgical procedure results in premature menopause, which may lead to complications related to a hypoestrogenic state—including vasomotor symptoms (flushes/flashes), vaginal atrophy, osteopenia, osteoporosis, and cardiovascular disease.² Therefore, it is important to implement estrogen replacement therapy after surgery until the age of natural menopause is reached.² If hysterectomy is not performed, the administration of progesterone is necessary to prevent endometrial hyperplasia and therefore reduce the risk for endometrial cancer.² However, the addition of progesterone may lead to recurrence of symptoms.²

^{Continue to: Treatment challenges}

Treatment challenges

PMDD treatment differs for each patient.³ Severity of symptoms, response to treatment, treatment preference, conception plans, and reproductive age need to be considered.³

Women with prominent depressive or physical symptoms may respond better to continuous dosing of SSRIs, whereas those with prominent irritability, anger, and mood swings may respond better to a symptom-onset SSRI regimen that reduces availability and function of ALLO.³ Women who develop tolerance to SSRIs may need to have their dosage increased or be switched to another medication.³Quetiapine is used as an adjunct to SSRIs for women who do not respond to SSRIs alone and has shown to improve mood swings, anxiety, and irritability.⁵ However, women experiencing persistent adverse effects of SSRIs, such as sexual dysfunction, may benefit from intermittent dosing.³

Adolescents and women in their early 20s should be treated with OCs or nonpharmacologic modalities due to concerns about SSRI use and increased risk for suicidality in this population.³ The risks related to SSRI use during pregnancy and breastfeeding should be considered and discussed with women of childbearing age who use SSRIs to treat PMDD.³ Perimenopausal women with irregular menses on intermittent ­SSRIs may have to switch to symptom-onset or continuous dosing due to the difficulty of tracking the menstrual period and lack of significant benchmarks regarding when to start the treatment.³

Patient education/follow-up

Patients should be educated on PMDD etiology, diagnostic process, and available treatment options.⁴ The importance of prospective record-keeping—for confirmation of the diagnosis and evaluation of individual response to a specific treatment—should be emphasized.⁴ Patients should be encouraged to follow up with their health care provider to monitor treatment effectiveness, possible adverse effects, and need for treatment adjustment.⁴

CONCLUSION

The symptoms of PMDD can have a debilitating and life-disrupting impact on affected women—and put them at risk for other serious psychiatric disorders and suicide. The DSM-5 criteria provide diagnostic guidance to help distinguish PMDD from other underlying conditions, ensuring that patients can receive timely and appropriate treatment. While SSRIs are regarded as the most effective option, other evidence-based treatments should be considered, since PMDD requires individualized treatment to ensure optimal clinical outcomes.

A diagnosis of polycystic ovarian syndrome was associated with an increased risk of several cancers, based on an analysis of nearly 3.5 million women in a large Swedish database.

Women with PCOS had a sixfold increased risk of endometrial cancer, a tripling of endocrine gland cancers, and more than a doubling in the risk of ovarian and pancreatic cancers. Once women reached menopausal status, however, their cancer risk was comparable to that of women without a history of PCOS.

“Several carcinogenic processes are associated with PCOS, including dyslipidemia, hyperinsulinemia, and chronic inflammation,” wrote Weimin Ye, MD, PhD, of the Karolinska Institutet, Stockholm, and his colleagues. “Our study indicates that cancer may need to be added to the spectrum of long-term health consequences of PCOS and warrants increased surveillance among those patients.”

The research letter was published online in JAMA Oncology.

The team examined the relationship between PCOS and primary cancers in about 3.5 million women over a span of up to 24 years (1985-2009), although the mean follow-up time was not mentioned. To examine the potential impact of menopause, they conducted separate multivariate logistic regression analyses for those younger than 51 years, and those aged 51 years or older. The analyses controlled for use of some medications (metformin, oral contraceptives, and hormone therapy); as well as educational level (a proxy for socioeconomic status); smoking; parity (a proxy for fertility); parental cancers; and diabetes.

Overall, 14,764 women had been diagnosed with PCOS; they were a mean of 28 years at baseline and 182 developed a primary cancer 1 year or more after PCOS diagnosis.

These women had a 15% overall increased risk of cancer, compared with women without PCOS.

The risks for specific cancers also were increased, compared with women without PCOS, including endometrial (hazard ratio, 2.62), ovarian (HR, 2.16), endocrine (HR, 1.92), pancreatic (HR, 3.4), kidney (HR, 3.0), and skeletal and hematopoietic (HR, 1.69) cancers.

The risks were associated with younger age, however. In the group under age 51 years, the overall risk was 22% higher. The increased risk of specific cancers were endometrial (HR, 6.45), ovarian (HR, 2.55), pancreatic (HR, 6.68), kidney (HR, 4.57), and endocrine (not thyroid) gland (HR, 2.9) cancers.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Yin W et al. JAMA Oncol. 2018 Nov 29. doi:10.1001/jamaoncol.2018.5188.

A diagnosis of polycystic ovarian syndrome was associated with an increased risk of several cancers, based on an analysis of nearly 3.5 million women in a large Swedish database.

Women with PCOS had a sixfold increased risk of endometrial cancer, a tripling of endocrine gland cancers, and more than a doubling in the risk of ovarian and pancreatic cancers. Once women reached menopausal status, however, their cancer risk was comparable to that of women without a history of PCOS.

“Several carcinogenic processes are associated with PCOS, including dyslipidemia, hyperinsulinemia, and chronic inflammation,” wrote Weimin Ye, MD, PhD, of the Karolinska Institutet, Stockholm, and his colleagues. “Our study indicates that cancer may need to be added to the spectrum of long-term health consequences of PCOS and warrants increased surveillance among those patients.”

The research letter was published online in JAMA Oncology.

The team examined the relationship between PCOS and primary cancers in about 3.5 million women over a span of up to 24 years (1985-2009), although the mean follow-up time was not mentioned. To examine the potential impact of menopause, they conducted separate multivariate logistic regression analyses for those younger than 51 years, and those aged 51 years or older. The analyses controlled for use of some medications (metformin, oral contraceptives, and hormone therapy); as well as educational level (a proxy for socioeconomic status); smoking; parity (a proxy for fertility); parental cancers; and diabetes.

Overall, 14,764 women had been diagnosed with PCOS; they were a mean of 28 years at baseline and 182 developed a primary cancer 1 year or more after PCOS diagnosis.

These women had a 15% overall increased risk of cancer, compared with women without PCOS.

The risks for specific cancers also were increased, compared with women without PCOS, including endometrial (hazard ratio, 2.62), ovarian (HR, 2.16), endocrine (HR, 1.92), pancreatic (HR, 3.4), kidney (HR, 3.0), and skeletal and hematopoietic (HR, 1.69) cancers.

The risks were associated with younger age, however. In the group under age 51 years, the overall risk was 22% higher. The increased risk of specific cancers were endometrial (HR, 6.45), ovarian (HR, 2.55), pancreatic (HR, 6.68), kidney (HR, 4.57), and endocrine (not thyroid) gland (HR, 2.9) cancers.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Yin W et al. JAMA Oncol. 2018 Nov 29. doi:10.1001/jamaoncol.2018.5188.

A diagnosis of polycystic ovarian syndrome was associated with an increased risk of several cancers, based on an analysis of nearly 3.5 million women in a large Swedish database.

Women with PCOS had a sixfold increased risk of endometrial cancer, a tripling of endocrine gland cancers, and more than a doubling in the risk of ovarian and pancreatic cancers. Once women reached menopausal status, however, their cancer risk was comparable to that of women without a history of PCOS.

“Several carcinogenic processes are associated with PCOS, including dyslipidemia, hyperinsulinemia, and chronic inflammation,” wrote Weimin Ye, MD, PhD, of the Karolinska Institutet, Stockholm, and his colleagues. “Our study indicates that cancer may need to be added to the spectrum of long-term health consequences of PCOS and warrants increased surveillance among those patients.”

The research letter was published online in JAMA Oncology.

The team examined the relationship between PCOS and primary cancers in about 3.5 million women over a span of up to 24 years (1985-2009), although the mean follow-up time was not mentioned. To examine the potential impact of menopause, they conducted separate multivariate logistic regression analyses for those younger than 51 years, and those aged 51 years or older. The analyses controlled for use of some medications (metformin, oral contraceptives, and hormone therapy); as well as educational level (a proxy for socioeconomic status); smoking; parity (a proxy for fertility); parental cancers; and diabetes.

Overall, 14,764 women had been diagnosed with PCOS; they were a mean of 28 years at baseline and 182 developed a primary cancer 1 year or more after PCOS diagnosis.

These women had a 15% overall increased risk of cancer, compared with women without PCOS.

The risks for specific cancers also were increased, compared with women without PCOS, including endometrial (hazard ratio, 2.62), ovarian (HR, 2.16), endocrine (HR, 1.92), pancreatic (HR, 3.4), kidney (HR, 3.0), and skeletal and hematopoietic (HR, 1.69) cancers.

The risks were associated with younger age, however. In the group under age 51 years, the overall risk was 22% higher. The increased risk of specific cancers were endometrial (HR, 6.45), ovarian (HR, 2.55), pancreatic (HR, 6.68), kidney (HR, 4.57), and endocrine (not thyroid) gland (HR, 2.9) cancers.

The authors had no relevant financial disclosures.

[email protected]

SOURCE: Yin W et al. JAMA Oncol. 2018 Nov 29. doi:10.1001/jamaoncol.2018.5188.

Infant mortality in the United Sates dropped very slightly from 2015 to 2016 and has not changed significantly since 2011, according to the National Center for Health Statistics.

Overall infant mortality was 5.87 per 1,000 live births in 2016, which was not significantly less than the 2015 rate of 5.90 per 1,000 or the rate of 6.07 per 1,000 recorded in 2011, the NCHS said in a recent Data Brief. The rate for 2016 works out to 3.88 per 1,000 for the neonatal period (0-27 days) and 1.99 per 1,000 during the postneonatal period (28-364 days).

Maternal age had a significant effect on infant mortality in 2016. The rate was lowest for mothers aged 30-34 years (4.86 per 1,000) and highest for those under 20 years (8.69). All overall rates by maternal age were significantly different from each other, except for those of mothers aged 20-24 years (7.13) and those aged 40 years and over (7.27). Neonatal mortality was highest for the under-20 group and the 40-and-over group at 5.32 per 1,000, with the difference between them coming during the postneonatal period: 3.36 for those under 20 and 1.95 for the 40-and-overs, the NCHS investigators reported based on data from the National Vital Statistics System.

The leading cause of death during the neonatal period in 2016 was low birth weight at 98 per 1,000 live births, with congenital malformations second at 86 per 1,000. The leading cause of death in the postneonatal period was congenital malformations at 36 per 1,000, followed by sudden infant death syndrome (35 per 1,000), unintentional injuries (27 per 1,000), diseases of the circulatory system (9 per 1,000), and homicide (6 per 1,000), they added.

[email protected]

Infant mortality in the United Sates dropped very slightly from 2015 to 2016 and has not changed significantly since 2011, according to the National Center for Health Statistics.

Overall infant mortality was 5.87 per 1,000 live births in 2016, which was not significantly less than the 2015 rate of 5.90 per 1,000 or the rate of 6.07 per 1,000 recorded in 2011, the NCHS said in a recent Data Brief. The rate for 2016 works out to 3.88 per 1,000 for the neonatal period (0-27 days) and 1.99 per 1,000 during the postneonatal period (28-364 days).

Maternal age had a significant effect on infant mortality in 2016. The rate was lowest for mothers aged 30-34 years (4.86 per 1,000) and highest for those under 20 years (8.69). All overall rates by maternal age were significantly different from each other, except for those of mothers aged 20-24 years (7.13) and those aged 40 years and over (7.27). Neonatal mortality was highest for the under-20 group and the 40-and-over group at 5.32 per 1,000, with the difference between them coming during the postneonatal period: 3.36 for those under 20 and 1.95 for the 40-and-overs, the NCHS investigators reported based on data from the National Vital Statistics System.

The leading cause of death during the neonatal period in 2016 was low birth weight at 98 per 1,000 live births, with congenital malformations second at 86 per 1,000. The leading cause of death in the postneonatal period was congenital malformations at 36 per 1,000, followed by sudden infant death syndrome (35 per 1,000), unintentional injuries (27 per 1,000), diseases of the circulatory system (9 per 1,000), and homicide (6 per 1,000), they added.

[email protected]

Infant mortality in the United Sates dropped very slightly from 2015 to 2016 and has not changed significantly since 2011, according to the National Center for Health Statistics.

Overall infant mortality was 5.87 per 1,000 live births in 2016, which was not significantly less than the 2015 rate of 5.90 per 1,000 or the rate of 6.07 per 1,000 recorded in 2011, the NCHS said in a recent Data Brief. The rate for 2016 works out to 3.88 per 1,000 for the neonatal period (0-27 days) and 1.99 per 1,000 during the postneonatal period (28-364 days).

Maternal age had a significant effect on infant mortality in 2016. The rate was lowest for mothers aged 30-34 years (4.86 per 1,000) and highest for those under 20 years (8.69). All overall rates by maternal age were significantly different from each other, except for those of mothers aged 20-24 years (7.13) and those aged 40 years and over (7.27). Neonatal mortality was highest for the under-20 group and the 40-and-over group at 5.32 per 1,000, with the difference between them coming during the postneonatal period: 3.36 for those under 20 and 1.95 for the 40-and-overs, the NCHS investigators reported based on data from the National Vital Statistics System.

The leading cause of death during the neonatal period in 2016 was low birth weight at 98 per 1,000 live births, with congenital malformations second at 86 per 1,000. The leading cause of death in the postneonatal period was congenital malformations at 36 per 1,000, followed by sudden infant death syndrome (35 per 1,000), unintentional injuries (27 per 1,000), diseases of the circulatory system (9 per 1,000), and homicide (6 per 1,000), they added.

[email protected]

CHICAGO – It’s clear that there’s a dose-dependent relationship between hypertension in pregnancy and poor outcomes, but, even so, treatment usually doesn’t begin until women hit 160/105 mm Hg or higher, according to Mark Santillan, MD, PhD, an assistant professor of obstetrics and gynecology – maternal fetal medicine at the University of Iowa, Iowa City.

M. Alexander Otto/MDedge News

That might soon change. The National Institutes of Health–funded CHAPS (Chronic Hypertension and Pregnancy) trial is testing whether earlier intervention improves outcomes, and it hopes to define proper treatment targets, which are uncertain at this point. Results are expected as soon as 2020.

What’s already changed is that the old treatment standby – methyldopa – has fallen out of favor for labetalol and nifedipine, which have been shown to work better. “Sometimes, we will throw on hydrochlorothiazide after we max out our beta- and calcium channel blockers,” Dr. Santillan said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension (Cochrane Database Syst Rev. 2018 Oct 1;10:CD002252).

For severe hypertension, “most of the time we start off with IV hydralazine or IV labetalol” in the hospital. “You give a dose and check blood pressure in 10 or 20 minutes,” he said. If it hasn’t dropped, “give another dose until you reach your max dose.” When intravenous access is an issue, oral nifedipine is a good option (Obstet Gynecol. 2017 Apr;129[4]:e90-e95).

Delivery date is key; babies exposed to chronic hypertension are more likely to be stillborn. For hypertension without symptoms, delivery is at around 38 weeks. For mild preeclampsia – hypertension with only minor symptoms – it’s at 37 weeks.

In more severe cases – hypertension with pulmonary edema, renal insufficiency, and other problems – “the general gestalt is to stabilize and deliver when you can. See if you can get up to at least 34 weeks,” Dr. Santillan said. However, when women “have full-on HELLP syndrome [hemolysis, elevated liver enzymes, low platelet count], we often just deliver [immediately] because there’s not a lot of stabilization” that can be done. “We give magnesium after delivery to help decrease the risk of seizure,” he added.

Guidelines still use 140/90 mm Hg to define hypertension in pregnancy. When that level is reached, “you don’t need proteinuria anymore to diagnose preeclampsia. You need to have hypertension and something that looks like HELLP,” such as impaired liver function or neurologic symptoms, he said. Onset before 34 weeks portends more severe disease.

Daily baby aspirin 81 mg is known to help prevent preeclampsia, if only a little bit, so anyone with a history of preeclampsia or twin pregnancy, chronic hypertension, diabetes, renal disease, or autoimmune disease should automatically be put on aspirin prophylaxis. Women with two or more moderate risk factors – first pregnancy, obesity, preeclamptic family history, or aged 35 years or older – also should also get baby aspirin. Vitamin C, bed rest, and other preventative measures haven’t panned out in trials.

Investigators are looking for better predictors of preeclampsia; uterine artery blood flow is among the promising markers. However, it and other options are “expensive ventures” if you’re just going to end up in the same place, giving baby aspirin, Dr. Santillan said.

Dr. Santillan reported that he holds three patents; two on copeptin to predict preeclampsia and one on vasopressin receptor antagonists to treat it.

[email protected]

CHICAGO – It’s clear that there’s a dose-dependent relationship between hypertension in pregnancy and poor outcomes, but, even so, treatment usually doesn’t begin until women hit 160/105 mm Hg or higher, according to Mark Santillan, MD, PhD, an assistant professor of obstetrics and gynecology – maternal fetal medicine at the University of Iowa, Iowa City.

M. Alexander Otto/MDedge News

That might soon change. The National Institutes of Health–funded CHAPS (Chronic Hypertension and Pregnancy) trial is testing whether earlier intervention improves outcomes, and it hopes to define proper treatment targets, which are uncertain at this point. Results are expected as soon as 2020.

What’s already changed is that the old treatment standby – methyldopa – has fallen out of favor for labetalol and nifedipine, which have been shown to work better. “Sometimes, we will throw on hydrochlorothiazide after we max out our beta- and calcium channel blockers,” Dr. Santillan said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension (Cochrane Database Syst Rev. 2018 Oct 1;10:CD002252).

For severe hypertension, “most of the time we start off with IV hydralazine or IV labetalol” in the hospital. “You give a dose and check blood pressure in 10 or 20 minutes,” he said. If it hasn’t dropped, “give another dose until you reach your max dose.” When intravenous access is an issue, oral nifedipine is a good option (Obstet Gynecol. 2017 Apr;129[4]:e90-e95).

Delivery date is key; babies exposed to chronic hypertension are more likely to be stillborn. For hypertension without symptoms, delivery is at around 38 weeks. For mild preeclampsia – hypertension with only minor symptoms – it’s at 37 weeks.

In more severe cases – hypertension with pulmonary edema, renal insufficiency, and other problems – “the general gestalt is to stabilize and deliver when you can. See if you can get up to at least 34 weeks,” Dr. Santillan said. However, when women “have full-on HELLP syndrome [hemolysis, elevated liver enzymes, low platelet count], we often just deliver [immediately] because there’s not a lot of stabilization” that can be done. “We give magnesium after delivery to help decrease the risk of seizure,” he added.

Guidelines still use 140/90 mm Hg to define hypertension in pregnancy. When that level is reached, “you don’t need proteinuria anymore to diagnose preeclampsia. You need to have hypertension and something that looks like HELLP,” such as impaired liver function or neurologic symptoms, he said. Onset before 34 weeks portends more severe disease.

Daily baby aspirin 81 mg is known to help prevent preeclampsia, if only a little bit, so anyone with a history of preeclampsia or twin pregnancy, chronic hypertension, diabetes, renal disease, or autoimmune disease should automatically be put on aspirin prophylaxis. Women with two or more moderate risk factors – first pregnancy, obesity, preeclamptic family history, or aged 35 years or older – also should also get baby aspirin. Vitamin C, bed rest, and other preventative measures haven’t panned out in trials.

Investigators are looking for better predictors of preeclampsia; uterine artery blood flow is among the promising markers. However, it and other options are “expensive ventures” if you’re just going to end up in the same place, giving baby aspirin, Dr. Santillan said.

Dr. Santillan reported that he holds three patents; two on copeptin to predict preeclampsia and one on vasopressin receptor antagonists to treat it.

[email protected]

CHICAGO – It’s clear that there’s a dose-dependent relationship between hypertension in pregnancy and poor outcomes, but, even so, treatment usually doesn’t begin until women hit 160/105 mm Hg or higher, according to Mark Santillan, MD, PhD, an assistant professor of obstetrics and gynecology – maternal fetal medicine at the University of Iowa, Iowa City.

M. Alexander Otto/MDedge News

That might soon change. The National Institutes of Health–funded CHAPS (Chronic Hypertension and Pregnancy) trial is testing whether earlier intervention improves outcomes, and it hopes to define proper treatment targets, which are uncertain at this point. Results are expected as soon as 2020.

What’s already changed is that the old treatment standby – methyldopa – has fallen out of favor for labetalol and nifedipine, which have been shown to work better. “Sometimes, we will throw on hydrochlorothiazide after we max out our beta- and calcium channel blockers,” Dr. Santillan said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension (Cochrane Database Syst Rev. 2018 Oct 1;10:CD002252).

For severe hypertension, “most of the time we start off with IV hydralazine or IV labetalol” in the hospital. “You give a dose and check blood pressure in 10 or 20 minutes,” he said. If it hasn’t dropped, “give another dose until you reach your max dose.” When intravenous access is an issue, oral nifedipine is a good option (Obstet Gynecol. 2017 Apr;129[4]:e90-e95).

Delivery date is key; babies exposed to chronic hypertension are more likely to be stillborn. For hypertension without symptoms, delivery is at around 38 weeks. For mild preeclampsia – hypertension with only minor symptoms – it’s at 37 weeks.

In more severe cases – hypertension with pulmonary edema, renal insufficiency, and other problems – “the general gestalt is to stabilize and deliver when you can. See if you can get up to at least 34 weeks,” Dr. Santillan said. However, when women “have full-on HELLP syndrome [hemolysis, elevated liver enzymes, low platelet count], we often just deliver [immediately] because there’s not a lot of stabilization” that can be done. “We give magnesium after delivery to help decrease the risk of seizure,” he added.

Guidelines still use 140/90 mm Hg to define hypertension in pregnancy. When that level is reached, “you don’t need proteinuria anymore to diagnose preeclampsia. You need to have hypertension and something that looks like HELLP,” such as impaired liver function or neurologic symptoms, he said. Onset before 34 weeks portends more severe disease.

Daily baby aspirin 81 mg is known to help prevent preeclampsia, if only a little bit, so anyone with a history of preeclampsia or twin pregnancy, chronic hypertension, diabetes, renal disease, or autoimmune disease should automatically be put on aspirin prophylaxis. Women with two or more moderate risk factors – first pregnancy, obesity, preeclamptic family history, or aged 35 years or older – also should also get baby aspirin. Vitamin C, bed rest, and other preventative measures haven’t panned out in trials.

Investigators are looking for better predictors of preeclampsia; uterine artery blood flow is among the promising markers. However, it and other options are “expensive ventures” if you’re just going to end up in the same place, giving baby aspirin, Dr. Santillan said.

Dr. Santillan reported that he holds three patents; two on copeptin to predict preeclampsia and one on vasopressin receptor antagonists to treat it.

[email protected]

The National Institutes of Health is deeply concerned about the work just presented at the Second International Summit on Human Genome Editing in Hong Kong by Dr. He Jiankui, who described his effort using CRISPR-Cas9 on human embryos to disable the CCR5 gene. He claims that the two embryos were subsequently implanted, and infant twins have been born.

This work represents a deeply disturbing willingness by Dr. He and his team to flout international ethical norms. The project was largely carried out in secret, the medical necessity for inactivation of CCR5 in these infants is utterly unconvincing, the informed consent process appears highly questionable, and the possibility of damaging off-target effects has not been satisfactorily explored. It is profoundly unfortunate that the first apparent application of this powerful technique to the human germline has been carried out so irresponsibly.

The need for development of binding international consensus on setting limits for this kind of research, now being debated in Hong Kong, has never been more apparent. Without such limits, the world will face the serious risk of a deluge of similarly ill-considered and unethical projects.

Should such epic scientific misadventures proceed, a technology with enormous promise for prevention and treatment of disease will be overshadowed by justifiable public outrage, fear, and disgust.

Lest there be any doubt, and as we have stated previously, NIH does not support the use of gene-editing technologies in human embryos.

Francis S. Collins, M.D., Ph.D. is director of the National Institutes of Health. His comments were made in a statement Nov. 28.

The National Institutes of Health is deeply concerned about the work just presented at the Second International Summit on Human Genome Editing in Hong Kong by Dr. He Jiankui, who described his effort using CRISPR-Cas9 on human embryos to disable the CCR5 gene. He claims that the two embryos were subsequently implanted, and infant twins have been born.

This work represents a deeply disturbing willingness by Dr. He and his team to flout international ethical norms. The project was largely carried out in secret, the medical necessity for inactivation of CCR5 in these infants is utterly unconvincing, the informed consent process appears highly questionable, and the possibility of damaging off-target effects has not been satisfactorily explored. It is profoundly unfortunate that the first apparent application of this powerful technique to the human germline has been carried out so irresponsibly.

The need for development of binding international consensus on setting limits for this kind of research, now being debated in Hong Kong, has never been more apparent. Without such limits, the world will face the serious risk of a deluge of similarly ill-considered and unethical projects.

Should such epic scientific misadventures proceed, a technology with enormous promise for prevention and treatment of disease will be overshadowed by justifiable public outrage, fear, and disgust.

Lest there be any doubt, and as we have stated previously, NIH does not support the use of gene-editing technologies in human embryos.

Francis S. Collins, M.D., Ph.D. is director of the National Institutes of Health. His comments were made in a statement Nov. 28.

The National Institutes of Health is deeply concerned about the work just presented at the Second International Summit on Human Genome Editing in Hong Kong by Dr. He Jiankui, who described his effort using CRISPR-Cas9 on human embryos to disable the CCR5 gene. He claims that the two embryos were subsequently implanted, and infant twins have been born.

This work represents a deeply disturbing willingness by Dr. He and his team to flout international ethical norms. The project was largely carried out in secret, the medical necessity for inactivation of CCR5 in these infants is utterly unconvincing, the informed consent process appears highly questionable, and the possibility of damaging off-target effects has not been satisfactorily explored. It is profoundly unfortunate that the first apparent application of this powerful technique to the human germline has been carried out so irresponsibly.

The need for development of binding international consensus on setting limits for this kind of research, now being debated in Hong Kong, has never been more apparent. Without such limits, the world will face the serious risk of a deluge of similarly ill-considered and unethical projects.

Should such epic scientific misadventures proceed, a technology with enormous promise for prevention and treatment of disease will be overshadowed by justifiable public outrage, fear, and disgust.

Lest there be any doubt, and as we have stated previously, NIH does not support the use of gene-editing technologies in human embryos.

Francis S. Collins, M.D., Ph.D. is director of the National Institutes of Health. His comments were made in a statement Nov. 28.

Taking omega-3 long-chain polyunsaturated fatty acids during pregnancy was associated with reduced risk of preterm birth, and also may reduce the risk of babies born at a low birth weight and risk of requiring neonatal intensive care, according to a Cochrane review of 70 randomized controlled trials.

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“There are not many options for preventing premature birth, so these new findings are very important for pregnant women, babies, and the health professionals who care for them,” Philippa Middleton, MPH, PhD, of Cochrane Pregnancy and Childbirth Group and the South Australian Health and Medical Research Institute, in Adelaide, stated in a press release. “We don’t yet fully understand the causes of premature labor, so predicting and preventing early birth has always been a challenge. This is one of the reasons omega-3 supplementation in pregnancy is of such great interest to researchers around the world.”

Dr. Middleton and her colleagues performed a search of the Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform and identified 70 randomized controlled trials (RCTs) where 19,927 women at varying levels of risk for preterm birth received omega-3 long-chain polyunsaturated fatty acids (LCPUFA), placebo, or no omega-3.

“Many pregnant women in the UK are already taking omega-3 supplements by personal choice rather than as a result of advice from health professionals,” Dr. Middleton said in the release. “It’s worth noting though that many supplements currently on the market don’t contain the optimal dose or type of omega-3 for preventing premature birth. Our review found the optimum dose was a daily supplement containing between 500 and 1,000 milligrams of long-chain omega-3 fats (containing at least 500 mg of DHA [docosahexaenoic acid]) starting at 12 weeks of pregnancy.”

In 26 RCTs (10,304 women), the risk of preterm birth under 37 weeks was 11% lower for women who took omega-3 LCPUFA compared with women who did not take omega-3 (relative risk, 0.89; 95% confidence interval, 0.81-0.97), while the risk for preterm birth under 34 weeks in 9 RCTs (5,204 women) was 42% lower for women compared with women who did not take omega-3 (RR, 0.58; 95% CI, 0.44-0.77).

With regard to infant health, use of omega-3 LCPUFA during pregnancy was associated in 10 RCTs (7,416 women) with a potential reduced risk of perinatal mortality (RR, 0.75; 95% CI, 0.54-1.03) and, in 9 RCTs (6,920 women), a reduced risk of neonatal intensive care admission (RR, 0.92; 95% CI, 0.83-1.03). The researchers noted that omega-3 use in 15 trials (8,449 women) was potentially associated with a reduced number of babies with low birth weight (RR, 0.90; 95% CI, 0.82-0.99), but an increase in babies who were large for their gestational age in 3,722 women from 6 RCTs (RR, 1.15; 95% CI, 0.97-1.36). There was no significant difference among groups with regard to babies who were born small for their gestational age or in uterine growth restriction, they said.

While maternal outcomes were examined, Dr. Middleton and her colleagues found no significant differences between groups in factors such as postterm induction, serious adverse events, admission to intensive care, and postnatal depression.

“Ultimately, we hope this review will make a real contribution to the evidence base we need to reduce premature births, which continue to be one of the most pressing and intractable maternal and child health problems in every country around the world,” Dr. Middleton said.

The National Institutes of Health funded the review. The authors reported no conflicts of interest.

SOURCE: Middleton P et al. Cochrane Database Syst Rev. 2018; doi: 10.1002/14651858.CD003402.pub3.

Taking omega-3 long-chain polyunsaturated fatty acids during pregnancy was associated with reduced risk of preterm birth, and also may reduce the risk of babies born at a low birth weight and risk of requiring neonatal intensive care, according to a Cochrane review of 70 randomized controlled trials.

Creatas Images

“There are not many options for preventing premature birth, so these new findings are very important for pregnant women, babies, and the health professionals who care for them,” Philippa Middleton, MPH, PhD, of Cochrane Pregnancy and Childbirth Group and the South Australian Health and Medical Research Institute, in Adelaide, stated in a press release. “We don’t yet fully understand the causes of premature labor, so predicting and preventing early birth has always been a challenge. This is one of the reasons omega-3 supplementation in pregnancy is of such great interest to researchers around the world.”

Dr. Middleton and her colleagues performed a search of the Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform and identified 70 randomized controlled trials (RCTs) where 19,927 women at varying levels of risk for preterm birth received omega-3 long-chain polyunsaturated fatty acids (LCPUFA), placebo, or no omega-3.

“Many pregnant women in the UK are already taking omega-3 supplements by personal choice rather than as a result of advice from health professionals,” Dr. Middleton said in the release. “It’s worth noting though that many supplements currently on the market don’t contain the optimal dose or type of omega-3 for preventing premature birth. Our review found the optimum dose was a daily supplement containing between 500 and 1,000 milligrams of long-chain omega-3 fats (containing at least 500 mg of DHA [docosahexaenoic acid]) starting at 12 weeks of pregnancy.”

In 26 RCTs (10,304 women), the risk of preterm birth under 37 weeks was 11% lower for women who took omega-3 LCPUFA compared with women who did not take omega-3 (relative risk, 0.89; 95% confidence interval, 0.81-0.97), while the risk for preterm birth under 34 weeks in 9 RCTs (5,204 women) was 42% lower for women compared with women who did not take omega-3 (RR, 0.58; 95% CI, 0.44-0.77).

With regard to infant health, use of omega-3 LCPUFA during pregnancy was associated in 10 RCTs (7,416 women) with a potential reduced risk of perinatal mortality (RR, 0.75; 95% CI, 0.54-1.03) and, in 9 RCTs (6,920 women), a reduced risk of neonatal intensive care admission (RR, 0.92; 95% CI, 0.83-1.03). The researchers noted that omega-3 use in 15 trials (8,449 women) was potentially associated with a reduced number of babies with low birth weight (RR, 0.90; 95% CI, 0.82-0.99), but an increase in babies who were large for their gestational age in 3,722 women from 6 RCTs (RR, 1.15; 95% CI, 0.97-1.36). There was no significant difference among groups with regard to babies who were born small for their gestational age or in uterine growth restriction, they said.

While maternal outcomes were examined, Dr. Middleton and her colleagues found no significant differences between groups in factors such as postterm induction, serious adverse events, admission to intensive care, and postnatal depression.

“Ultimately, we hope this review will make a real contribution to the evidence base we need to reduce premature births, which continue to be one of the most pressing and intractable maternal and child health problems in every country around the world,” Dr. Middleton said.

The National Institutes of Health funded the review. The authors reported no conflicts of interest.

SOURCE: Middleton P et al. Cochrane Database Syst Rev. 2018; doi: 10.1002/14651858.CD003402.pub3.

Taking omega-3 long-chain polyunsaturated fatty acids during pregnancy was associated with reduced risk of preterm birth, and also may reduce the risk of babies born at a low birth weight and risk of requiring neonatal intensive care, according to a Cochrane review of 70 randomized controlled trials.

Creatas Images

“There are not many options for preventing premature birth, so these new findings are very important for pregnant women, babies, and the health professionals who care for them,” Philippa Middleton, MPH, PhD, of Cochrane Pregnancy and Childbirth Group and the South Australian Health and Medical Research Institute, in Adelaide, stated in a press release. “We don’t yet fully understand the causes of premature labor, so predicting and preventing early birth has always been a challenge. This is one of the reasons omega-3 supplementation in pregnancy is of such great interest to researchers around the world.”

Dr. Middleton and her colleagues performed a search of the Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform and identified 70 randomized controlled trials (RCTs) where 19,927 women at varying levels of risk for preterm birth received omega-3 long-chain polyunsaturated fatty acids (LCPUFA), placebo, or no omega-3.

“Many pregnant women in the UK are already taking omega-3 supplements by personal choice rather than as a result of advice from health professionals,” Dr. Middleton said in the release. “It’s worth noting though that many supplements currently on the market don’t contain the optimal dose or type of omega-3 for preventing premature birth. Our review found the optimum dose was a daily supplement containing between 500 and 1,000 milligrams of long-chain omega-3 fats (containing at least 500 mg of DHA [docosahexaenoic acid]) starting at 12 weeks of pregnancy.”

In 26 RCTs (10,304 women), the risk of preterm birth under 37 weeks was 11% lower for women who took omega-3 LCPUFA compared with women who did not take omega-3 (relative risk, 0.89; 95% confidence interval, 0.81-0.97), while the risk for preterm birth under 34 weeks in 9 RCTs (5,204 women) was 42% lower for women compared with women who did not take omega-3 (RR, 0.58; 95% CI, 0.44-0.77).

With regard to infant health, use of omega-3 LCPUFA during pregnancy was associated in 10 RCTs (7,416 women) with a potential reduced risk of perinatal mortality (RR, 0.75; 95% CI, 0.54-1.03) and, in 9 RCTs (6,920 women), a reduced risk of neonatal intensive care admission (RR, 0.92; 95% CI, 0.83-1.03). The researchers noted that omega-3 use in 15 trials (8,449 women) was potentially associated with a reduced number of babies with low birth weight (RR, 0.90; 95% CI, 0.82-0.99), but an increase in babies who were large for their gestational age in 3,722 women from 6 RCTs (RR, 1.15; 95% CI, 0.97-1.36). There was no significant difference among groups with regard to babies who were born small for their gestational age or in uterine growth restriction, they said.

While maternal outcomes were examined, Dr. Middleton and her colleagues found no significant differences between groups in factors such as postterm induction, serious adverse events, admission to intensive care, and postnatal depression.

“Ultimately, we hope this review will make a real contribution to the evidence base we need to reduce premature births, which continue to be one of the most pressing and intractable maternal and child health problems in every country around the world,” Dr. Middleton said.

The National Institutes of Health funded the review. The authors reported no conflicts of interest.

SOURCE: Middleton P et al. Cochrane Database Syst Rev. 2018; doi: 10.1002/14651858.CD003402.pub3.

Women who have a healthier lifestyle during the menopausal transition could significantly reduce their risk of cardiovascular disease, new research suggests.

kali9/E+

Because women experience a steeper increase in CVD risk during and after the menopausal transition, researchers analyzed data from the Study of Women’s Health Across the Nation (SWAN), a prospective longitudinal cohort study of 1,143 women aged 42-52 years. The report is in JAHA: Journal of the American Heart Association.

The analysis revealed that women with the highest average Healthy Lifestyle Score – a composite score of dietary quality, levels of physical activity, and smoking – over 10 years of follow-up had a 0.024-mm smaller common carotid artery intima-media thickness and 0.16-mm smaller adventitial diameter, compared to those with the lowest average score. This was after adjustment for confounders and physiological risk factors such as ethnicity, age, menopausal status, body mass index, and cholesterol levels.

“Smoking, unhealthy diet, and lack of physical activity are three well-known modifiable behavioral risk factors for CVD,” wrote Dongqing Wang of the University of Michigan, Ann Arbor, and his coauthors. “Even after adjusting for the lifestyle-related physiological risk factors, the adherence to a healthy lifestyle composed of abstinence from smoking, healthy diet, and regular engagement in physical activity is inversely associated with atherosclerosis in midlife women.”

Women with higher average health lifestyle score also had lower levels of carotid plaque after adjustment for confounding factors, but this was no longer significant after adjustment for physiological risk factors.

The authors analyzed the three components of the healthy lifestyle score separately, and found that not smoking was strongly and significantly associated with lower scores for all three measures of subclinical atherosclerosis. Women who never smoked across the duration of the study had a 49% lower odds of having a high carotid plaque index compared with women who smoked at some point during the follow-up period.

The analysis showed an inverse association between average Alternate Healthy Eating Index score – a measure of diet quality – and smaller common carotid artery adventitial diameter, although after adjustment for BMI this association was no longer statistically significant. Likewise, the association between dietary quality and intima-media thickness was only marginally significant and lost that significance after adjustment for BMI.

Long-term physical activity was only marginally significantly associated with common carotid artery intima-media thickness, but this was not significant after adjustment for physiological risk factors. No association was found between physical activity and common carotid artery adventitial diameter or carotid plaque.

The authors said that 1.7% of the study population managed to stay in the top category for all three components of healthy lifestyle at all three follow-up time points in the study.

“The low prevalence of a healthy lifestyle in midlife women highlights the potential for lifestyle interventions aimed at this vulnerable population,” they wrote.

In particular, they highlighted abstinence from smoking as having the strongest impact on all three measures of subclinical atherosclerosis, which is known to affect women more than men. However, the outcomes from diet and physical activity weren’t so strong: The authors suggested that BMI could partly mediate the effects of healthier diet and greater levels of physical activity.

One strength of the study was its ethnically diverse population, which included African American, Chinese, and Hispanic women in addition to non-Hispanic white women. However, the study was not powered to examine the impacts ethnicity may have had on outcomes, the researchers wrote.

The Study of Women’s Health Across the Nation is supported by the National Institutes of Health. No conflicts of interest were declared.

SOURCE: Wang D et al. JAHA 2018 Nov. 28.

Women who have a healthier lifestyle during the menopausal transition could significantly reduce their risk of cardiovascular disease, new research suggests.

kali9/E+

Because women experience a steeper increase in CVD risk during and after the menopausal transition, researchers analyzed data from the Study of Women’s Health Across the Nation (SWAN), a prospective longitudinal cohort study of 1,143 women aged 42-52 years. The report is in JAHA: Journal of the American Heart Association.

The analysis revealed that women with the highest average Healthy Lifestyle Score – a composite score of dietary quality, levels of physical activity, and smoking – over 10 years of follow-up had a 0.024-mm smaller common carotid artery intima-media thickness and 0.16-mm smaller adventitial diameter, compared to those with the lowest average score. This was after adjustment for confounders and physiological risk factors such as ethnicity, age, menopausal status, body mass index, and cholesterol levels.

“Smoking, unhealthy diet, and lack of physical activity are three well-known modifiable behavioral risk factors for CVD,” wrote Dongqing Wang of the University of Michigan, Ann Arbor, and his coauthors. “Even after adjusting for the lifestyle-related physiological risk factors, the adherence to a healthy lifestyle composed of abstinence from smoking, healthy diet, and regular engagement in physical activity is inversely associated with atherosclerosis in midlife women.”

Women with higher average health lifestyle score also had lower levels of carotid plaque after adjustment for confounding factors, but this was no longer significant after adjustment for physiological risk factors.

The authors analyzed the three components of the healthy lifestyle score separately, and found that not smoking was strongly and significantly associated with lower scores for all three measures of subclinical atherosclerosis. Women who never smoked across the duration of the study had a 49% lower odds of having a high carotid plaque index compared with women who smoked at some point during the follow-up period.

The analysis showed an inverse association between average Alternate Healthy Eating Index score – a measure of diet quality – and smaller common carotid artery adventitial diameter, although after adjustment for BMI this association was no longer statistically significant. Likewise, the association between dietary quality and intima-media thickness was only marginally significant and lost that significance after adjustment for BMI.

Long-term physical activity was only marginally significantly associated with common carotid artery intima-media thickness, but this was not significant after adjustment for physiological risk factors. No association was found between physical activity and common carotid artery adventitial diameter or carotid plaque.

The authors said that 1.7% of the study population managed to stay in the top category for all three components of healthy lifestyle at all three follow-up time points in the study.

“The low prevalence of a healthy lifestyle in midlife women highlights the potential for lifestyle interventions aimed at this vulnerable population,” they wrote.

In particular, they highlighted abstinence from smoking as having the strongest impact on all three measures of subclinical atherosclerosis, which is known to affect women more than men. However, the outcomes from diet and physical activity weren’t so strong: The authors suggested that BMI could partly mediate the effects of healthier diet and greater levels of physical activity.

One strength of the study was its ethnically diverse population, which included African American, Chinese, and Hispanic women in addition to non-Hispanic white women. However, the study was not powered to examine the impacts ethnicity may have had on outcomes, the researchers wrote.

The Study of Women’s Health Across the Nation is supported by the National Institutes of Health. No conflicts of interest were declared.

SOURCE: Wang D et al. JAHA 2018 Nov. 28.

Women who have a healthier lifestyle during the menopausal transition could significantly reduce their risk of cardiovascular disease, new research suggests.

kali9/E+

Because women experience a steeper increase in CVD risk during and after the menopausal transition, researchers analyzed data from the Study of Women’s Health Across the Nation (SWAN), a prospective longitudinal cohort study of 1,143 women aged 42-52 years. The report is in JAHA: Journal of the American Heart Association.

The analysis revealed that women with the highest average Healthy Lifestyle Score – a composite score of dietary quality, levels of physical activity, and smoking – over 10 years of follow-up had a 0.024-mm smaller common carotid artery intima-media thickness and 0.16-mm smaller adventitial diameter, compared to those with the lowest average score. This was after adjustment for confounders and physiological risk factors such as ethnicity, age, menopausal status, body mass index, and cholesterol levels.

“Smoking, unhealthy diet, and lack of physical activity are three well-known modifiable behavioral risk factors for CVD,” wrote Dongqing Wang of the University of Michigan, Ann Arbor, and his coauthors. “Even after adjusting for the lifestyle-related physiological risk factors, the adherence to a healthy lifestyle composed of abstinence from smoking, healthy diet, and regular engagement in physical activity is inversely associated with atherosclerosis in midlife women.”

Women with higher average health lifestyle score also had lower levels of carotid plaque after adjustment for confounding factors, but this was no longer significant after adjustment for physiological risk factors.

The authors analyzed the three components of the healthy lifestyle score separately, and found that not smoking was strongly and significantly associated with lower scores for all three measures of subclinical atherosclerosis. Women who never smoked across the duration of the study had a 49% lower odds of having a high carotid plaque index compared with women who smoked at some point during the follow-up period.

The analysis showed an inverse association between average Alternate Healthy Eating Index score – a measure of diet quality – and smaller common carotid artery adventitial diameter, although after adjustment for BMI this association was no longer statistically significant. Likewise, the association between dietary quality and intima-media thickness was only marginally significant and lost that significance after adjustment for BMI.

Long-term physical activity was only marginally significantly associated with common carotid artery intima-media thickness, but this was not significant after adjustment for physiological risk factors. No association was found between physical activity and common carotid artery adventitial diameter or carotid plaque.

The authors said that 1.7% of the study population managed to stay in the top category for all three components of healthy lifestyle at all three follow-up time points in the study.

“The low prevalence of a healthy lifestyle in midlife women highlights the potential for lifestyle interventions aimed at this vulnerable population,” they wrote.

In particular, they highlighted abstinence from smoking as having the strongest impact on all three measures of subclinical atherosclerosis, which is known to affect women more than men. However, the outcomes from diet and physical activity weren’t so strong: The authors suggested that BMI could partly mediate the effects of healthier diet and greater levels of physical activity.

One strength of the study was its ethnically diverse population, which included African American, Chinese, and Hispanic women in addition to non-Hispanic white women. However, the study was not powered to examine the impacts ethnicity may have had on outcomes, the researchers wrote.

The Study of Women’s Health Across the Nation is supported by the National Institutes of Health. No conflicts of interest were declared.

SOURCE: Wang D et al. JAHA 2018 Nov. 28.