Article

Key clinical point: The addition of venetoclax to lenalidomide plus rituximab therapy may provide an effective and safe combination for the treatment of unselected patients with untreated mantle cell lymphoma (MCL).

Major finding: All patients were escalated to the maximum tolerated dose of venetoclax (400 mg daily). The overall response and complete remission rates were 96% and 86%, respectively. After a median follow-up of 27.5 months, the median overall survival and progression-free survival were not reached. No dose-limiting toxicity event was observed.

Study details: This multicenter phase 1 study included 28 unselected adult patients with untreated MCL who received induction therapy with lenalidomide (daily on days 1-21 of each cycle), rituximab (weekly during cycle 1 until cycle 2 day 1), and venetoclax (escalated weekly up to 400 mg daily) for 6-12 cycles followed by maintenance therapy.

Disclosures: This study was funded by AbbVie and the University of Michigan Rogel Cancer Center. Some authors reported ties with various organizations, including AbbVie.

Source: Phillips TJ et al. Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023 (Apr 4). Doi: 10.1182/bloodadvances.2023009992

Key clinical point: The addition of venetoclax to lenalidomide plus rituximab therapy may provide an effective and safe combination for the treatment of unselected patients with untreated mantle cell lymphoma (MCL).

Major finding: All patients were escalated to the maximum tolerated dose of venetoclax (400 mg daily). The overall response and complete remission rates were 96% and 86%, respectively. After a median follow-up of 27.5 months, the median overall survival and progression-free survival were not reached. No dose-limiting toxicity event was observed.

Study details: This multicenter phase 1 study included 28 unselected adult patients with untreated MCL who received induction therapy with lenalidomide (daily on days 1-21 of each cycle), rituximab (weekly during cycle 1 until cycle 2 day 1), and venetoclax (escalated weekly up to 400 mg daily) for 6-12 cycles followed by maintenance therapy.

Disclosures: This study was funded by AbbVie and the University of Michigan Rogel Cancer Center. Some authors reported ties with various organizations, including AbbVie.

Source: Phillips TJ et al. Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023 (Apr 4). Doi: 10.1182/bloodadvances.2023009992

Key clinical point: The addition of venetoclax to lenalidomide plus rituximab therapy may provide an effective and safe combination for the treatment of unselected patients with untreated mantle cell lymphoma (MCL).

Major finding: All patients were escalated to the maximum tolerated dose of venetoclax (400 mg daily). The overall response and complete remission rates were 96% and 86%, respectively. After a median follow-up of 27.5 months, the median overall survival and progression-free survival were not reached. No dose-limiting toxicity event was observed.

Study details: This multicenter phase 1 study included 28 unselected adult patients with untreated MCL who received induction therapy with lenalidomide (daily on days 1-21 of each cycle), rituximab (weekly during cycle 1 until cycle 2 day 1), and venetoclax (escalated weekly up to 400 mg daily) for 6-12 cycles followed by maintenance therapy.

Disclosures: This study was funded by AbbVie and the University of Michigan Rogel Cancer Center. Some authors reported ties with various organizations, including AbbVie.

Source: Phillips TJ et al. Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023 (Apr 4). Doi: 10.1182/bloodadvances.2023009992

Key clinical point: Compared with matched control individuals, patients with mantle cell lymphoma (MCL) treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) had higher hospitalization rates and relative risks for blood disorders and infections.

Major finding: Patients with MCL vs control individuals had a significantly increased incidence rate of outpatient (incidence rate ratio [IRR] 2.0; 95% CI 1.8-2.2) and inpatient (IRR 7.2; 95% CI 6.3-8.3) visits and relative risks for blood disorders (non-HD-ASCT: hazard ratio [HR] 9.84; 95% CI 6.91-14.00; HD-ASCT: HR 5.80; 95% CI 3.42-9.84) and infections (non-HD-ASCT: HR 4.66; 95% CI 3.62-5.99; HD-ASCT: HR 5.62; 95% CI 4.20-7.52).

Study details: Findings are from a population-based study including 620 adult patients with MCL who did (n = 247) or did not (n = 373) receive HD-ASCT and 6200 matched control individuals without MCL.

Disclosures: This study was supported by the Swedish Cancer Society. The authors reported ties with various organizations.

Source: Ekberg S et al. Late effects in patients with mantle cell lymphoma treated with or without autologous stem cell transplantation. Blood Adv. 2023;7(5):866-874 (Mar 14). Doi: 10.1182/bloodadvances.2022007241

Key clinical point: Compared with matched control individuals, patients with mantle cell lymphoma (MCL) treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) had higher hospitalization rates and relative risks for blood disorders and infections.

Major finding: Patients with MCL vs control individuals had a significantly increased incidence rate of outpatient (incidence rate ratio [IRR] 2.0; 95% CI 1.8-2.2) and inpatient (IRR 7.2; 95% CI 6.3-8.3) visits and relative risks for blood disorders (non-HD-ASCT: hazard ratio [HR] 9.84; 95% CI 6.91-14.00; HD-ASCT: HR 5.80; 95% CI 3.42-9.84) and infections (non-HD-ASCT: HR 4.66; 95% CI 3.62-5.99; HD-ASCT: HR 5.62; 95% CI 4.20-7.52).

Study details: Findings are from a population-based study including 620 adult patients with MCL who did (n = 247) or did not (n = 373) receive HD-ASCT and 6200 matched control individuals without MCL.

Disclosures: This study was supported by the Swedish Cancer Society. The authors reported ties with various organizations.

Source: Ekberg S et al. Late effects in patients with mantle cell lymphoma treated with or without autologous stem cell transplantation. Blood Adv. 2023;7(5):866-874 (Mar 14). Doi: 10.1182/bloodadvances.2022007241

Key clinical point: Compared with matched control individuals, patients with mantle cell lymphoma (MCL) treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) had higher hospitalization rates and relative risks for blood disorders and infections.

Major finding: Patients with MCL vs control individuals had a significantly increased incidence rate of outpatient (incidence rate ratio [IRR] 2.0; 95% CI 1.8-2.2) and inpatient (IRR 7.2; 95% CI 6.3-8.3) visits and relative risks for blood disorders (non-HD-ASCT: hazard ratio [HR] 9.84; 95% CI 6.91-14.00; HD-ASCT: HR 5.80; 95% CI 3.42-9.84) and infections (non-HD-ASCT: HR 4.66; 95% CI 3.62-5.99; HD-ASCT: HR 5.62; 95% CI 4.20-7.52).

Study details: Findings are from a population-based study including 620 adult patients with MCL who did (n = 247) or did not (n = 373) receive HD-ASCT and 6200 matched control individuals without MCL.

Disclosures: This study was supported by the Swedish Cancer Society. The authors reported ties with various organizations.

Source: Ekberg S et al. Late effects in patients with mantle cell lymphoma treated with or without autologous stem cell transplantation. Blood Adv. 2023;7(5):866-874 (Mar 14). Doi: 10.1182/bloodadvances.2022007241

Key clinical point: Compared with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), ibrutinib plus bendamustine and rituximab (Ibru+BR) prolongs progression-free survival (PFS) in patients with newly diagnosed mantle cell lymphoma (MCL) who are ineligible for intensive therapy.

Major finding: Ibru+BR significantly improved PFS compared with VR-CAP (hazard ratio [HR] 0.55; P  =  .03) and R-CHOP (HR 0.35; P < .001). Adverse event risks were not significantly different in the Ibru+BR, VR-CAP, R-CHOP, and BR treatment arms.

Study details: The data come from a network meta-analysis of 3 studies involving 1459 patients with newly diagnosed MCL who were ineligible for intensive therapy and received first-line Ibru+BR, VR-CAP, R-CHOP, or BR.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Sheng Z and Wang L. Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. Eur J Haematol. 2023 (Mar 14). Doi: 10.1111/ejh.13953

Key clinical point: Compared with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), ibrutinib plus bendamustine and rituximab (Ibru+BR) prolongs progression-free survival (PFS) in patients with newly diagnosed mantle cell lymphoma (MCL) who are ineligible for intensive therapy.

Major finding: Ibru+BR significantly improved PFS compared with VR-CAP (hazard ratio [HR] 0.55; P  =  .03) and R-CHOP (HR 0.35; P < .001). Adverse event risks were not significantly different in the Ibru+BR, VR-CAP, R-CHOP, and BR treatment arms.

Study details: The data come from a network meta-analysis of 3 studies involving 1459 patients with newly diagnosed MCL who were ineligible for intensive therapy and received first-line Ibru+BR, VR-CAP, R-CHOP, or BR.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Sheng Z and Wang L. Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. Eur J Haematol. 2023 (Mar 14). Doi: 10.1111/ejh.13953

Key clinical point: Compared with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), ibrutinib plus bendamustine and rituximab (Ibru+BR) prolongs progression-free survival (PFS) in patients with newly diagnosed mantle cell lymphoma (MCL) who are ineligible for intensive therapy.

Major finding: Ibru+BR significantly improved PFS compared with VR-CAP (hazard ratio [HR] 0.55; P  =  .03) and R-CHOP (HR 0.35; P < .001). Adverse event risks were not significantly different in the Ibru+BR, VR-CAP, R-CHOP, and BR treatment arms.

Study details: The data come from a network meta-analysis of 3 studies involving 1459 patients with newly diagnosed MCL who were ineligible for intensive therapy and received first-line Ibru+BR, VR-CAP, R-CHOP, or BR.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Sheng Z and Wang L. Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. Eur J Haematol. 2023 (Mar 14). Doi: 10.1111/ejh.13953

Key clinical point: Compared with chemoimmunotherapy, second-line targeted therapies improved treatment-free survival (TFS) and tended to improve overall survival (OS) in patients with chronic lymphocytic leukemia (CLL), including those who were frail and had comorbidities.

Major finding: The 3-year TFS and estimated OS rates were higher in patients receiving targeted therapies (63%, 95% CI 50%-76%; and 79%, 95% CI 68%-91%, respectively) vs fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab (FCR/BR; 37%,; 95% CI 26%-48%; and 70%, 95% CI 60%-81%, respectively) or chlorambucil+/−CD20-antibody (CD20Clb/Clb; 22%, 95% CI 10%-33%; and 60%, 95% CI 47%-74%, respectively). The grade ≥3 adverse event rate was similar with targeted treatment and FCR/BR.

Study details: This retrospective population-based real-world study included 286 patients with CLL who relapsed or were refractory to first-line treatment and received second-line targeted treatment (ibrutinib+venetoclax, venetoclax, venetoclax+rituximab/obinutuzumab, idelalisib, or idelalisib+rituximab), FCR/BR, or CD20Clb/Clb.

Disclosures: This study was partly supported by grants from Rigshospitalets Foundation. Some authors reported ties with various sources.

Source: Vainer N et al. Real-world outcomes upon second-line treatment in patients with chronic lymphocytic leukaemia. Br J Haematol. 2023 (Mar 10). Doi: 10.1111/bjh.18715

Key clinical point: Compared with chemoimmunotherapy, second-line targeted therapies improved treatment-free survival (TFS) and tended to improve overall survival (OS) in patients with chronic lymphocytic leukemia (CLL), including those who were frail and had comorbidities.

Major finding: The 3-year TFS and estimated OS rates were higher in patients receiving targeted therapies (63%, 95% CI 50%-76%; and 79%, 95% CI 68%-91%, respectively) vs fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab (FCR/BR; 37%,; 95% CI 26%-48%; and 70%, 95% CI 60%-81%, respectively) or chlorambucil+/−CD20-antibody (CD20Clb/Clb; 22%, 95% CI 10%-33%; and 60%, 95% CI 47%-74%, respectively). The grade ≥3 adverse event rate was similar with targeted treatment and FCR/BR.

Study details: This retrospective population-based real-world study included 286 patients with CLL who relapsed or were refractory to first-line treatment and received second-line targeted treatment (ibrutinib+venetoclax, venetoclax, venetoclax+rituximab/obinutuzumab, idelalisib, or idelalisib+rituximab), FCR/BR, or CD20Clb/Clb.

Disclosures: This study was partly supported by grants from Rigshospitalets Foundation. Some authors reported ties with various sources.

Source: Vainer N et al. Real-world outcomes upon second-line treatment in patients with chronic lymphocytic leukaemia. Br J Haematol. 2023 (Mar 10). Doi: 10.1111/bjh.18715

Key clinical point: Compared with chemoimmunotherapy, second-line targeted therapies improved treatment-free survival (TFS) and tended to improve overall survival (OS) in patients with chronic lymphocytic leukemia (CLL), including those who were frail and had comorbidities.

Major finding: The 3-year TFS and estimated OS rates were higher in patients receiving targeted therapies (63%, 95% CI 50%-76%; and 79%, 95% CI 68%-91%, respectively) vs fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab (FCR/BR; 37%,; 95% CI 26%-48%; and 70%, 95% CI 60%-81%, respectively) or chlorambucil+/−CD20-antibody (CD20Clb/Clb; 22%, 95% CI 10%-33%; and 60%, 95% CI 47%-74%, respectively). The grade ≥3 adverse event rate was similar with targeted treatment and FCR/BR.

Study details: This retrospective population-based real-world study included 286 patients with CLL who relapsed or were refractory to first-line treatment and received second-line targeted treatment (ibrutinib+venetoclax, venetoclax, venetoclax+rituximab/obinutuzumab, idelalisib, or idelalisib+rituximab), FCR/BR, or CD20Clb/Clb.

Disclosures: This study was partly supported by grants from Rigshospitalets Foundation. Some authors reported ties with various sources.

Source: Vainer N et al. Real-world outcomes upon second-line treatment in patients with chronic lymphocytic leukaemia. Br J Haematol. 2023 (Mar 10). Doi: 10.1111/bjh.18715

As Parkinson's disease progresses, dopamine and dopamine agonists that control tremor and stiffness can wear off too early or cause dyskinesia when they peak in the bloodstream.  

In this ReCAP, Dr Michael Okun, professor and chair of neurology at the University of Florida, explains that adjustments to dose, timing, or delivery mode of these medications can smooth out some fluctuations. He reports that catechol-O-methyltransferase inhibitors, such as opicapone, tolcapone, and entacapone, can extend the effect of dopamine and the addition of amantadine or istradefylline can suppress dyskinesia. 

He points out that for other patients, surgical options, such as deep brain stimulation or focused ultrasound, can alter how the brain controls disordered movement or implanted pumps can better regulate the delivery of medication either subcutaneously or directly into the gut. 

--

Michael S. Okun, MD, Chair of Neurology, College of Medicine; Director Norman Fixel Institute, University of Florida, Gainesville, Florida 

Michael S. Okun, MD, has disclosed no relevant financial relationships

As Parkinson's disease progresses, dopamine and dopamine agonists that control tremor and stiffness can wear off too early or cause dyskinesia when they peak in the bloodstream.  

In this ReCAP, Dr Michael Okun, professor and chair of neurology at the University of Florida, explains that adjustments to dose, timing, or delivery mode of these medications can smooth out some fluctuations. He reports that catechol-O-methyltransferase inhibitors, such as opicapone, tolcapone, and entacapone, can extend the effect of dopamine and the addition of amantadine or istradefylline can suppress dyskinesia. 

He points out that for other patients, surgical options, such as deep brain stimulation or focused ultrasound, can alter how the brain controls disordered movement or implanted pumps can better regulate the delivery of medication either subcutaneously or directly into the gut. 

--

Michael S. Okun, MD, Chair of Neurology, College of Medicine; Director Norman Fixel Institute, University of Florida, Gainesville, Florida 

Michael S. Okun, MD, has disclosed no relevant financial relationships

As Parkinson's disease progresses, dopamine and dopamine agonists that control tremor and stiffness can wear off too early or cause dyskinesia when they peak in the bloodstream.  

In this ReCAP, Dr Michael Okun, professor and chair of neurology at the University of Florida, explains that adjustments to dose, timing, or delivery mode of these medications can smooth out some fluctuations. He reports that catechol-O-methyltransferase inhibitors, such as opicapone, tolcapone, and entacapone, can extend the effect of dopamine and the addition of amantadine or istradefylline can suppress dyskinesia. 

He points out that for other patients, surgical options, such as deep brain stimulation or focused ultrasound, can alter how the brain controls disordered movement or implanted pumps can better regulate the delivery of medication either subcutaneously or directly into the gut. 

--

Michael S. Okun, MD, Chair of Neurology, College of Medicine; Director Norman Fixel Institute, University of Florida, Gainesville, Florida 

Michael S. Okun, MD, has disclosed no relevant financial relationships

Bipolar disorder  is a multifaceted condition associated with an increased risk for hospitalization and suicide as well as high costs to society and family. 

In this ReCAP, Dr Martha Sajatovic, of the University Hospitals of Cleveland, discusses evidence of the short- and long-term consequences of bipolar disorder, including progressive neurologic impact such as changes in brain structure.  

She discusses two FDA-approved long-acting injectables  for bipolar disorder and considerations for their use, including their potential for first-line maintenance treatment and benefits for medication adherence.  

Finally, she considers challenges in the clinical use of the long-acting injectables, including insufficient caregiver involvement and lack of awareness of the drugs' availability. 

--

Martha Sajatovic, MD, Director, Neurological and Behavioral Outcomes Center, University Hospitals of Cleveland, Cleveland, Ohio 

Martha Sajatovic, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Otsuka; International Society for Bipolar Disorders; National Institutes of Health 

Received income in an amount equal to or greater than $250 from: Otsuka; Janssen; Lundbeck; Teva; Neurelis 

Received royalties from: Springer Press; Johns Hopkins University Press 

Bipolar disorder  is a multifaceted condition associated with an increased risk for hospitalization and suicide as well as high costs to society and family. 

In this ReCAP, Dr Martha Sajatovic, of the University Hospitals of Cleveland, discusses evidence of the short- and long-term consequences of bipolar disorder, including progressive neurologic impact such as changes in brain structure.  

She discusses two FDA-approved long-acting injectables  for bipolar disorder and considerations for their use, including their potential for first-line maintenance treatment and benefits for medication adherence.  

Finally, she considers challenges in the clinical use of the long-acting injectables, including insufficient caregiver involvement and lack of awareness of the drugs' availability. 

--

Martha Sajatovic, MD, Director, Neurological and Behavioral Outcomes Center, University Hospitals of Cleveland, Cleveland, Ohio 

Martha Sajatovic, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Otsuka; International Society for Bipolar Disorders; National Institutes of Health 

Received income in an amount equal to or greater than $250 from: Otsuka; Janssen; Lundbeck; Teva; Neurelis 

Received royalties from: Springer Press; Johns Hopkins University Press 

Bipolar disorder  is a multifaceted condition associated with an increased risk for hospitalization and suicide as well as high costs to society and family. 

In this ReCAP, Dr Martha Sajatovic, of the University Hospitals of Cleveland, discusses evidence of the short- and long-term consequences of bipolar disorder, including progressive neurologic impact such as changes in brain structure.  

She discusses two FDA-approved long-acting injectables  for bipolar disorder and considerations for their use, including their potential for first-line maintenance treatment and benefits for medication adherence.  

Finally, she considers challenges in the clinical use of the long-acting injectables, including insufficient caregiver involvement and lack of awareness of the drugs' availability. 

--

Martha Sajatovic, MD, Director, Neurological and Behavioral Outcomes Center, University Hospitals of Cleveland, Cleveland, Ohio 

Martha Sajatovic, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Otsuka; International Society for Bipolar Disorders; National Institutes of Health 

Received income in an amount equal to or greater than $250 from: Otsuka; Janssen; Lundbeck; Teva; Neurelis 

Received royalties from: Springer Press; Johns Hopkins University Press 

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

 

 

Mifepristone-misoprostol versus misoprostol

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

 

 

Expectant management versus misoprostol

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

 

 

Mifepristone-misoprostol versus misoprostol

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

 

 

Expectant management versus misoprostol

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

First trimester miscarriage, the presence of a nonviable intrauterine pregnancy before 13 weeks’ gestation, is a common complication occurring in approximately 15% of clinical pregnancies.^1,2 The goals for the holistic management of first-trimester miscarriage are to 1) reduce the risk of complications such as excessive bleeding and infection, 2) ensure that the patient is supported during a time of great distress, and 3) optimally counsel the patient about treatment options and elicit the patient’s preferences for care.³ To resolve a miscarriage, the intrauterine pregnancy tissue must be expelled, restoring normal reproductive function.

The options for the management of a nonviable intrauterine pregnancy include expectant management, medication treatment with mifepristone plus misoprostol or misoprostol-alone, or uterine aspiration. In the absence of uterine hemorrhage, infection, or another severe complication of miscarriage, the patient’s preferences should guide the choice of treatment. Many patients with miscarriage prioritize avoiding medical interventions and may prefer expectant management. A patient who prefers rapid and reliable completion of the pregnancy loss process may prefer uterine aspiration. If the patient prefers to avoid uterine aspiration but desires control over the time and location of the expulsion process, medication treatment may be optimal. Many other factors influence a patient’s choice of miscarriage treatment, including balancing work and childcare issues and the ease of scheduling a uterine aspiration. In counseling patients about the options for miscarriage treatment it is helpful to know the success rate of each treatment option.⁴ This editorial reviews miscarriage treatment outcomes as summarized in a recent Cochrane network meta-analysis.⁵

Uterine aspiration versus mifepristone-misoprostol

In 2 clinical trials that included 899 patients with miscarriage, successful treatment with uterine aspira-tion versus mifepristone-misoprostolwas reported in 95% and 66% of cases, respectively.^6,7

In the largest clinical trial comparing uterine aspiration to mifepristone-misoprostol, 801 patients with first-trimester miscarriage were randomly assigned to uterine aspiration or mifepristone-misoprostol.⁶ Uterine aspiration and mifepristone-misoprostol were associated with successful miscarriage treatment in 95% and 64% of cases, respectively. In the uterine aspiration group, a second uterine aspiration occurred in 5% of patients. Two patients in the uterine aspiration group needed a third uterine aspiration to resolve the miscarriage. In the mifepristone-misoprostol group, 36% of patients had a uterine aspiration. It should be noted that the trial protocol guided patients having a medication abortion to uterine aspiration if expulsion of miscarriage tissue had not occurred within 8 hours of receiving misoprostol. If the trial protocol permitted 1 to 4 weeks of monitoring after mifepristone-misoprostol treatment, the success rate with medication treatment would be greater. Six to 8 weeks following miscarriage treatment, patient-reported anxiety and depression symptoms were similar in both groups.⁶

Uterine aspiration versus misoprostol

Among 3 clinical trials that limited enrollment to patients with missed miscarriage, involving 308 patients, the success rates for uterine aspiration and misoprostol treatment was 95% and 62%, respectively.⁵

In a study sponsored by the National Institutes of Health, 652 patients with missed miscarriage or incomplete miscarriage were randomly assigned in a 1:3 ratioto uterine aspiration or misoprostol treatment (800 µg vaginally). After 8 days of follow-up, successful treatment rates among the patients treated with uterine evacuation or misoprostol was 97% and 84%, respectively.⁸ Of note, with misoprostol treatment the success rate increased from day 3 to day 8 of follow-up—from 71% to 84%.⁸

Continue to: Mifepristone-misoprostol versus misoprostol...

 

 

Mifepristone-misoprostol versus misoprostol

The combined results of 7 clinical trials of medication management of missed miscarriage that included 1,812 patients showed that successful treatment with mifepristone-misoprostol or misoprostol alone occurred in 80% and 70% of cases, respectively.⁵

Schreiber and colleagues⁹ reported a study of 300 patients with an anembryonic gestation or embryonic demise that were between 5 and 12 completed weeks of gestation and randomly assigned to treatment with mifepristone (200 mg) plus vaginal misoprostol (800 µg) administered 24 to 48 hours after mifepristone or vaginal misoprostol (800 µg) alone. Ultrasonography was performed 1 to 4 days after misoprostol administration. Successful treatment was defined as expulsion of the gestational sac plus no additional surgical or medical intervention within 30 days after treatment. In this study, the dual-medication regimen of mifepristone-misoprostol was more successful than misoprostol alone in resolving the miscarriage, 84% and 67%, respectively (relative risk [RR], 1.25; 95% CI, 1.09–1.43). Surgical evacuation of the uterus occurred less often with mifepristone-misoprostol treatment (9%) than with misoprostol monotherapy (24%) (RR, 0.37; 95% CI, 0.21 ̶ 0.68). Pelvic infection occurred in 2 patients (1.3%) in each group. Uterine bleeding managed with blood transfusion occurred in 3 patients who received mifepristone-misoprostol and 1 patient who received misoprostol alone. In this study, clinical factors, including active bleeding, parity, and gestational age did not influence treatment success with the mifepristone-misoprostol regimen.¹⁰ The mifepristone-misoprostol regimen was reported to be more cost-effective than misoprostol alone.¹¹Chu and colleagues¹² reporteda study of medication treatmentof missed miscarriage that included more than 700 patients randomly assigned to treatment with mifepristone-misoprostol or placebo-misoprostol. Missed miscarriage was diagnosed by an ultrasound demonstrating a gestational sac and a nonviable pregnancy. The doses of mifepristone and misoprostol were 200 mg and 800 µg, respectively. In this study, the misoprostol was administered 48 hours following mifepristone or placebo using a vaginal, oral, or buccal route; 90% of patients used the vaginal route. Treatment was considered successful if the patient passed the gestational sac as determined by an ultrasound performed 7 days after entry into the study. If the gestational sac was passed, the patients were asked to do a urine pregnancy test 3 weeks after entering the study to conclude their care episode. If patients did not pass the gestational sac, they were offered a second dose of misoprostol or surgical evacuation. At 7 days of follow-up, the success rates in the mifepristone-misoprostol and misoprostol-alone groups were 83% and 76%, respectively. Surgical intervention was performed in 25% of patients treated with placebo-misoprostol and 17% of patients treated with mifepristone-misoprostol (RR, 0.73; 95% CI, 0.53 ̶ 0.95; P=.021).¹² A cost-effectiveness analysis of the trial results reported that the combination of mifepristone-misoprostol was less costly than misoprostolalone for the management of missed miscarriages.¹³

Photo: Getty Images

Expectant management versus uterine aspiration

The combined results of 7 clinical trials that included a total of 1,693 patients showed that successful treatment of miscarriage with expectant management or uterine aspiration occurred in 68% and 93% of cases, respectively.⁵ In one study, 700 patients with miscarriage were randomly assigned to expectant management or uterine aspiration. Treatment was successful for 56% and 95% of patients in the expectant management and uterine aspiration groups, respectively.⁶

The Cochrane network meta-analysis concluded that cervical preparation followed by uterine aspiration may be more effective than expectant management, with a reported risk ratio (RR) of 2.12 (95% CI, 1.41–3.20) with low-certainty evidence.⁵ In addition, uterine aspiration compared with expectant management may reduce the risk of serious complications (RR, 0.55; 95% CI, 0.23–1.32), with a wide range of treatment effects in reported trials and low-certainty evidence.⁵

In the treatment of miscarriage, the efficacy of expectant management may vary by the type of miscarriage. In one study, following the identification of a miscarriage, the percent of patients who have completed the expulsion of pregnancy tissue by 14 days was reported to be 84% for incomplete miscarriage, 59% for pregnancy loss with no expulsion of tissue, and 52% with ultrasound detection of a nonviable pregnancy with a gestational sac.¹⁴

Expectant management versus mifepristone-misoprostol

Aggregated data from 3 clinical trials that included a total of 910 patients showed that successful treatment with expectant management or mifepristone-misoprostol was reported in 48% and 68% of cases, respectively.⁵ The Cochrane network meta-analysis concluded that mifepristone-misoprostol may be more effective than expectant management, with a risk ratio of 1.42 (95% CI, 1.22–1.66) with low-certainty evidence. In addition, mifepristone-misoprostol compared with expectant management may reduce the risk for serious complications (RR, 0.76; 95% CI, 0.31–1.84) with wide range of treatment effects and low-certainty evidence.⁵

Continue to: Expectant management versus misoprostol...

 

 

Expectant management versus misoprostol

The combined results of 10 clinical trials that included a total of 838 patients with miscarriage, showed that successful treatment with expectant management or misoprostol-alone occurred in 44% and 75% of cases, respectively.⁵ Among 3 studies limiting enrollment to patients with missed miscarriage, successful treatment with expectant management or misoprostol-alone occurred in 32% and 70%, respectively.⁵

The Cochrane analysis concluded that misoprostol-alone may be more effective than expectant management, with a reported risk ratio of 1.30 (95% CI, 1.16–1.46) with low-certainty evidence. In addition, misoprostol-alone compared with expectant management may reduce the risk of serious complications (RR, 0.50; 95% CI, 0.22–1.15) with a wide range of treatment effects and low-certainty evidence.⁵

Patient experience of miscarriage care

Pregnancy loss is often a distressing experience, which is associated with grief, anxiety, depression, and guilt, lasting up to 2 years for some patients.^15,16 Patient dissatisfaction with miscarriage care often focuses on 4 issues: a perceived lack of emotional support, failure to elicit patient preferences for treatment, insufficient provision of information, and inconsistent posttreatment follow-up.^17-19 When caring for patients with miscarriage, key goals are to communicate medical information with empathy and to provide emotional support. In the setting of a miscarriage, it is easy for patients to perceive that the clinician is insensitive and cold.¹⁵ Expressions of sympathy, compassion, and condolence help build an emotional connection and improve trust with the patient. Communications that may be helpful include: “I am sorry for your loss,” “I wish the outcome could be different,” “Our clinical team wants to provide you the best care possible,” and “May I ask how you are feeling?” Many patients report that they would like to have been offered mental health services as part of their miscarriage care.¹⁵

The Cochrane network meta-analysis of miscarriage concluded that uterine aspiration, misoprostol-mifepristone, and misoprostol-alone were likely more effective in resolving a miscarriage than expectant management.⁵ The strength of the conclusion was limited because of significant heterogeneity among studies, including different inclusion criteria, definition of success, and length of follow-up. Clinical trials with follow-up intervals more than 7 days generally reported greater success rates with expectant¹⁴ and medication management⁸ than studies with short follow-up intervals. Generally, expectant or medication management treatment is more likely to be successful in cases of incomplete abortion than in cases of missed miscarriage.⁵

In a rank analysis of treatment efficacy, uterine aspiration was top-ranked, followed by medication management. Expectant management had the greatest probability of being associated with unplanned uterine aspiration. Based on my analysis of available miscarriage studies, I estimate that the treatment success rates are approximately:

• uterine aspiration (93% to 99%)
• misoprostol-mifepristone (66% to 84%)
• misoprostol-alone (62% to 76%)
• expectant management (32% to 68%).

Although there may be significant differences in efficacy among the treatment options, offering patients all available approaches to treatment, providing information about the relative success of each approach, and eliciting the patient preference for care ensures an optimal patient experience during a major life event. ●
 

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The abnormal upward curve to the fingernails was consistent with a diagnosis of koilonychia—otherwise known as spoon nails.

Koilonychia is an abnormal nail growth pattern where the distal nail matrix is depressed below its normal level, resulting in the spoon shape. The reverse, where the distal nail matrix is elevated in contrast to the proximal nail matrix, results in clubbing.¹

There are multiple factors and diseases that result in koilonychia, including lichen planus, psoriasis, nutritional deficiencies (including iron deficiency anemia), and endocrinopathies.¹ Lichen planus, which can cause koilonychia, often affects multiple nails and can also cause an associated central ridge pattern. Psoriasis may display a range of nail abnormalities; these include koilonychia, pitting onycholysis, and oil staining.

This patient did not have any signs or symptoms of psoriasis or lichen planus of her nails or skin. A review of her laboratory tests on file made no mention of anemia. Her chemistry profile—including liver tests, renal function tests, and protein levels—were all normal except for glucose levels, which was consistent with her prediabetes. Her thyroid function was also normal. No additional testing was performed since she had no symptoms, physical exam findings, or laboratory clues that pointed to other diseases or systemic processes.

The patient was advised to pick up over-the-counter nail strengtheners and to keep her fingernails trimmed short to minimize the likelihood of painful distal splitting that often occurs with brittle nails. Her physician advised her to follow up with the primary care team if she developed any new signs or symptoms.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.