Patrice Wendling

LISBON – A large observational study found no increased risk of preterm birth or low birth weight following in vitro fertilization within acceptable limits of ovarian stimulation compared with unstimulated IVF.

“These findings support that ovarian stimulation is safe for maximizing live birth rates when you use acceptable limits of ovarian stimulation such as less than 20 oocytes,” Dr. Sesh Kamal Sunkara said at the annual meeting of the European Society of Human Reproduction and Embryology.

Epigenetic modifications resulting from ovarian stimulation or embryo culture are under increasing scrutiny as possible contributory factors to adverse perinatal outcomes.

A recent analysis of almost 66,000 singleton births by Dr. Sunkara and her associates showed a significantly higher risk of preterm birth (PTB) and low birth weight (LBW) in women with an excessive response (> 20 oocytes) to ovarian stimulation versus those with a normal response (10-15 oocytes) (Hum. Reprod. 2015; 30:1473-80).

A 2013 systematic review and meta-analysis also identified a higher risk of PTB and early PTB among singletons born after blastocyst- versus cleavage-stage embryo transfer in IVF (Fertil. Steril. 2013; 100: 1615-21.e10).

Both of these confounding factors were taken into account in the current analysis, reported Dr. Sunkara, of Aberdeen Fertility Centre, Aberdeen Maternity Hospital, University of Aberdeen, Scotland.

Using the Human Fertilisation and Embryology Authority database, which includes data for all IVF cycles performed in the United Kingdom from 1991 to 2012, the investigators examined 719,220 fresh IVF stimulated cycles and 135,570 fresh IVF unstimulated cycles, resulting in 105,374 and 10,668 singleton live births, respectively. Surprisingly, most women in either group were aged 18-34 years at the time of treatment, Dr. Sunkara said.

A large proportion of the unstimulated cycles did not have any oocytes retrieved compared with the stimulated group (41.7% vs. ~7%).

The overall birth rate per cycle was significantly higher with stimulation than without stimulation (19.4% vs. 8%), as was the multiple birth rate (24.4% vs. 2.1%), she said.

In the unadjusted analyses, the stimulated versus unstimulated group had significantly higher rates of PTB (9.2% vs. 5.5%; odds ratio, 1.72; 95% confidence interval 1.58-1.88), early PTB (1.7% vs. 0.7%; OR, 2.36; CI, 1.88-2.96), LBW (9.3% vs. 5.1%; OR, 1.91; CI, 1.75-2.09), and very LBW (1.8% vs. 0.8%; OR, 2.23; CI, 1.80-2.77).

No significant differences were observed, however, for each outcome between stimulated and unstimulated cycles following logistic regression and adjustment for maternal age, year of treatment, previous IVF cycles, previous live birth, number of oocytes retrieved (≤ 20 or > 20), and day of embryo transfer (cleavage or blastocyst stage), Dr. Sunkara said.

The adjusted odds ratios were: PTB (aOR, 1.04; C.I. 0.60-1.80), early PTB (aOR, 1.60; C.I. 0.51-5.01), LBW (aOR, 1.93; C.I. 0.95-3.94), and very LBW (aOR, 1.01; C.I. 0.55-4.22).

“The results demonstrated that safe stimulation within acceptable limits does not increase the risk of PTB and LBW,” she said.

Dr. Sunkara reported no having no financial conflicts.

[email protected]

LISBON – A large observational study found no increased risk of preterm birth or low birth weight following in vitro fertilization within acceptable limits of ovarian stimulation compared with unstimulated IVF.

“These findings support that ovarian stimulation is safe for maximizing live birth rates when you use acceptable limits of ovarian stimulation such as less than 20 oocytes,” Dr. Sesh Kamal Sunkara said at the annual meeting of the European Society of Human Reproduction and Embryology.

Epigenetic modifications resulting from ovarian stimulation or embryo culture are under increasing scrutiny as possible contributory factors to adverse perinatal outcomes.

A recent analysis of almost 66,000 singleton births by Dr. Sunkara and her associates showed a significantly higher risk of preterm birth (PTB) and low birth weight (LBW) in women with an excessive response (> 20 oocytes) to ovarian stimulation versus those with a normal response (10-15 oocytes) (Hum. Reprod. 2015; 30:1473-80).

A 2013 systematic review and meta-analysis also identified a higher risk of PTB and early PTB among singletons born after blastocyst- versus cleavage-stage embryo transfer in IVF (Fertil. Steril. 2013; 100: 1615-21.e10).

Both of these confounding factors were taken into account in the current analysis, reported Dr. Sunkara, of Aberdeen Fertility Centre, Aberdeen Maternity Hospital, University of Aberdeen, Scotland.

Using the Human Fertilisation and Embryology Authority database, which includes data for all IVF cycles performed in the United Kingdom from 1991 to 2012, the investigators examined 719,220 fresh IVF stimulated cycles and 135,570 fresh IVF unstimulated cycles, resulting in 105,374 and 10,668 singleton live births, respectively. Surprisingly, most women in either group were aged 18-34 years at the time of treatment, Dr. Sunkara said.

A large proportion of the unstimulated cycles did not have any oocytes retrieved compared with the stimulated group (41.7% vs. ~7%).

The overall birth rate per cycle was significantly higher with stimulation than without stimulation (19.4% vs. 8%), as was the multiple birth rate (24.4% vs. 2.1%), she said.

In the unadjusted analyses, the stimulated versus unstimulated group had significantly higher rates of PTB (9.2% vs. 5.5%; odds ratio, 1.72; 95% confidence interval 1.58-1.88), early PTB (1.7% vs. 0.7%; OR, 2.36; CI, 1.88-2.96), LBW (9.3% vs. 5.1%; OR, 1.91; CI, 1.75-2.09), and very LBW (1.8% vs. 0.8%; OR, 2.23; CI, 1.80-2.77).

No significant differences were observed, however, for each outcome between stimulated and unstimulated cycles following logistic regression and adjustment for maternal age, year of treatment, previous IVF cycles, previous live birth, number of oocytes retrieved (≤ 20 or > 20), and day of embryo transfer (cleavage or blastocyst stage), Dr. Sunkara said.

The adjusted odds ratios were: PTB (aOR, 1.04; C.I. 0.60-1.80), early PTB (aOR, 1.60; C.I. 0.51-5.01), LBW (aOR, 1.93; C.I. 0.95-3.94), and very LBW (aOR, 1.01; C.I. 0.55-4.22).

“The results demonstrated that safe stimulation within acceptable limits does not increase the risk of PTB and LBW,” she said.

Dr. Sunkara reported no having no financial conflicts.

[email protected]

LISBON – A large observational study found no increased risk of preterm birth or low birth weight following in vitro fertilization within acceptable limits of ovarian stimulation compared with unstimulated IVF.

“These findings support that ovarian stimulation is safe for maximizing live birth rates when you use acceptable limits of ovarian stimulation such as less than 20 oocytes,” Dr. Sesh Kamal Sunkara said at the annual meeting of the European Society of Human Reproduction and Embryology.

Epigenetic modifications resulting from ovarian stimulation or embryo culture are under increasing scrutiny as possible contributory factors to adverse perinatal outcomes.

A recent analysis of almost 66,000 singleton births by Dr. Sunkara and her associates showed a significantly higher risk of preterm birth (PTB) and low birth weight (LBW) in women with an excessive response (> 20 oocytes) to ovarian stimulation versus those with a normal response (10-15 oocytes) (Hum. Reprod. 2015; 30:1473-80).

A 2013 systematic review and meta-analysis also identified a higher risk of PTB and early PTB among singletons born after blastocyst- versus cleavage-stage embryo transfer in IVF (Fertil. Steril. 2013; 100: 1615-21.e10).

Both of these confounding factors were taken into account in the current analysis, reported Dr. Sunkara, of Aberdeen Fertility Centre, Aberdeen Maternity Hospital, University of Aberdeen, Scotland.

Using the Human Fertilisation and Embryology Authority database, which includes data for all IVF cycles performed in the United Kingdom from 1991 to 2012, the investigators examined 719,220 fresh IVF stimulated cycles and 135,570 fresh IVF unstimulated cycles, resulting in 105,374 and 10,668 singleton live births, respectively. Surprisingly, most women in either group were aged 18-34 years at the time of treatment, Dr. Sunkara said.

A large proportion of the unstimulated cycles did not have any oocytes retrieved compared with the stimulated group (41.7% vs. ~7%).

The overall birth rate per cycle was significantly higher with stimulation than without stimulation (19.4% vs. 8%), as was the multiple birth rate (24.4% vs. 2.1%), she said.

In the unadjusted analyses, the stimulated versus unstimulated group had significantly higher rates of PTB (9.2% vs. 5.5%; odds ratio, 1.72; 95% confidence interval 1.58-1.88), early PTB (1.7% vs. 0.7%; OR, 2.36; CI, 1.88-2.96), LBW (9.3% vs. 5.1%; OR, 1.91; CI, 1.75-2.09), and very LBW (1.8% vs. 0.8%; OR, 2.23; CI, 1.80-2.77).

No significant differences were observed, however, for each outcome between stimulated and unstimulated cycles following logistic regression and adjustment for maternal age, year of treatment, previous IVF cycles, previous live birth, number of oocytes retrieved (≤ 20 or > 20), and day of embryo transfer (cleavage or blastocyst stage), Dr. Sunkara said.

The adjusted odds ratios were: PTB (aOR, 1.04; C.I. 0.60-1.80), early PTB (aOR, 1.60; C.I. 0.51-5.01), LBW (aOR, 1.93; C.I. 0.95-3.94), and very LBW (aOR, 1.01; C.I. 0.55-4.22).

“The results demonstrated that safe stimulation within acceptable limits does not increase the risk of PTB and LBW,” she said.

Dr. Sunkara reported no having no financial conflicts.

[email protected]

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Dilation and curettage increases the risk for prematurity in subsequent pregnancy, according to a systematic review and meta-analysis of nearly 2 million women.

Overall, D&C for first-trimester miscarriage or pregnancy termination increased the risk for preterm birth (< 37 weeks) by 29% (Odds ratio, 1.29; 95% confidence interval 1.17-1.42).

Subgroup and sensitivity analyses performed to test the robustness of the finding showed D&C upped the risk for very preterm birth (< 32 weeks) by 69% (OR, 1.69; C.I. 1.20-2.38) and critical preterm birth (< 28 weeks) by 68% (OR, 1.68; C.I. 1.47-1.92).

Patrice Wendling/Frontline Medical News

A dose-response relationship was also identified, with multiple D&C procedures raising the risk of preterm birth even higher (OR, 1.74; C.I. 1.10-2.76), Dr. Marike Lemmers reported at the annual meeting of the European Society of Human Reproduction and Embryology.

“This really questions the use of dilation and curettage as first-line treatment for women with a miscarriage or termination of pregnancy since other treatment options are non-invasive, safe, well-tolerated, cheap, and accessible,” Dr. Lemmers, of the Academic Medical Center, Amsterdam, the Netherlands, said.

The increasing popularity of misoprostol as an alternative to D&C or for cervical priming prior to curettage would suggest that D&C use is declining. Still, gynecologists in the Netherlands treat half of all miscarriages with D&C, a figure that likely reflects practice elsewhere, Dr. Willem Ankum, the principal investigator, said during a press briefing.

The authors hypothesize that the mechanism behind the increased risk from D&C is that dilation may damage the cervix and affect cervical tightness or may damage the endometrial lining, leading to a malpresentation.

The systematic review and meta-analysis included 21 studies (7 prospective cohort studies, 11 retrospective cohort studies, and 3 case-control studies) involving 66,003 women with a history of D&C for first trimester miscarriage or termination, and 1,781,786 controls with a medically managed miscarriage or termination or no such events. The quality of the studies varied from 7 to 29 based on the Strobe score.

The primary outcome of risk of preterm birth was significantly increased with D&C regardless of whether the analysis relied only on the prospective studies (OR, 1.28; C.I. 1.01-1.60), retrospective studies (OR, 1.27; C.I. 1.12-1.45), or case-control studies (OR, 1.44; C.I. 1.18-1.77), Dr. Lemmers said.

Several audience members questioned the inclusion of older trials dating back to the late 1970s before prostoglandins had been introduced for cycle priming. One attendee cited a recent Scottish cohort study showing a declining preterm birth rate in women with previous miscarriage, possibly attributable to the increasing use of misoprostol (Cytotec) for miscarriage or termination and cervical priming before D&C (PLoS. Med. 2013; 10: e1001481 [doi:10.1371/journal.pmed.1001481]).

Dr. Lemmers was aware of the Scottish study and said a funnel plot they performed showed “the exact same results” between older and newer studies. Further, a subgroup analysis of 38,905 women from studies dating from 1999 forward also showed an increased risk of preterm birth with D&C versus medical treatment (OR, 1.19; C.I. 1.10-1.28).

She added that it’s unlikely that the use of hysteroscopy with minimal dilation before in-vitro fertilization impacted results, but that outcomes may differ between women with a miscarriage versus termination of an attached pregnancy, although this calculation wasn’t possible based on the available data.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Lemmers and Dr. Ankum reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Expectant management is a safe and effective treatment for incomplete miscarriage after misoprostol, results of the MisoREST trial show.

“Because it is non-invasive, we think it should be considered as first-line treatment and to reserve curettage only for specific patients,” Dr. Marianne Verschoor said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

Misoprostol (Cytotec) is an inexpensive and effective treatment for miscarriage, but about 30% of women are left with an incomplete evacuation of the uterus. Curettage is often performed in these typically asymptomatic women, but carries both short- and long-term risks, said Dr. Verschoor of the Academic Medical Center, Amsterdam.

No study had directly compared the effectiveness of curettage and expectant management, she said. To fill this void, the researchers performed a randomized controlled trial (RCT) and parallel observational cohort study at 27 community and academic hospitals. Women who had sonographic findings of intrauterine remnants and/or a thick endometrium (> 10 mm) 1-2 weeks after misoprostol treatment for first-trimester miscarriage were randomly assigned to curettage within 3 days of diagnosis or expectant management. Women who declined randomization were prospectively followed.

The primary outcome was sonographic evidence of an empty uterine cavity at 6 weeks or an uneventful clinical course at 3 months in the absence of sonography.

Because of strong preferences for expectant management (EM), 59 women were randomized in the RCT (30 curettage, 29 EM) and 197 women were followed prospectively (65 curettage, 132 EM). All groups were comparable at baseline with regard to age, gestational age, and previous miscarriage or curettage.

In the RCT, 93% of women had an empty cavity or uneventful clinical course with curettage vs. 76% with EM. This difference was not statistically significant (relative risk, 1.23; 95% confidence interval, 0.098-1.54), Dr. Verschoor said.

In the observational cohort, 95% of patients choosing curettage had a successful outcome vs. 83% choosing EM. This difference was statistically significant (RR, 1.14; CI, 1.04-1.26).

When the two populations were pooled, 95% of patients (90/95) treated with curettage reached the primary end point vs. 82% of patients (132/161) with EM, which was statistically different (RR, 1.16; CI, 1.06-1.26), she said.

There were no significant differences in secondary outcomes in the RCT between the curettage and EM groups, including intrauterine infection (each 1 patient), excessive blood loss defined as > 500 mL (1 patient vs. 2 patients), or duration of bleeding (mean 5.4 days vs. 5.5 days).

However, one patient had already developed Asherman syndrome in the curettage group within 3 months of follow-up, Dr. Verschoor said. Two patients in each arm underwent reintervention with hysteroscopy and 5 EM patients underwent curettage.

Secondary outcomes in the observational cohort were also comparable between the curettage and EM groups for intrauterine infection (3 vs. 2), excessive blood loss (0 vs. 1), and duration of bleeding (mean 5.7 days vs. 7.1 days). One patient who underwent curettage developed Asherman syndrome vs. none in the EM group, she said. There were 11 reinterventions in the curettage group (7 hysteroscopy, 4 recurettage), compared with 30 in the EM group (12 hysteroscopy, 18 curettage).

A closer look at the EM patients who underwent reintervention revealed that “the interventions were primarily elective,” Dr. Vershcoor said. “Only in 26% of cases was there a medical reason for performing the intervention like bleeding, fever, or excessive abdominal pain.” Histology performed in these patients found no pregnancy tissue in 46%.

A separate quality of life analysis of the MisoREST participants found no statistical differences at baseline, 2, 4, and 12 weeks for the Short Form 36 Health Survey mental and physical score in all four treatment arms. Anxiety and depression measured with the Hospital Anxiety and Depression Scale were also not statistically different at any time, study coauthor Dr. Marike Lemmers, also of the Academic Medical Center, Amsterdam, reported in a poster at the meeting.

ZonMw, a Dutch organization for health research and development, funded the study. Dr. Verschoor reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Advanced age appears to trump disease activity or antirheumatic drug treatment as the driving force behind miscarriage in women with rheumatoid arthritis.

“The risk for miscarriage in rheumatoid arthritis is age dependent,” Dr. Jenny Brouwer said at the annual meeting of the European Society of Human Reproduction and Embryology.

Patrice Wendling/Frontline Medical News

She reported on 162 evaluable pregnancies in 239 Dutch women enrolled during 2002-2010 in the nationwide Pregnancy-Induced Amelioration of Rheumatoid Arthritis (PARA) study, the world’s largest prospective cohort of pregnant RA patients. They had a mean age of 32.3 years and a mean RA duration of 4.9 years. Overall, 49.4% were nulliparous and 13.6% had suffered a previous miscarriage.

Prednisone (37%), sulfasalazine (33%), and NSAIDs (29%) were most commonly used in the periconceptional period. Women eligible for PARA had to have stopped methotrexate for at least 3 months prior to attempting to conceive, a parameter included because it is an indicator for more severe disease.

Varying reports have shown no increased miscarriage rate in women with RA, while others have reported a significantly higher risk. These studies, however, were cross-sectional or retrospective in nature and lacked detailed information on preconception disease activity and antirheumatic drug use, observed Dr. Brouwer of Erasmus Medical Center, Rotterdam, the Netherlands.

Among the 162 pregnancies, 28 miscarriages occurred (17.3%), roughly half in weeks 5-9.

Reassuringly, the miscarriage rate is comparable with that in the general population, she said. Indeed, a recent study from the Nurses Health Study II also reported a miscarriage rate of 17.3%.

Disease Activity Score based on 28 joints (DAS28) was higher 6 and 12 weeks after miscarriage than before pregnancy, with 33% of women having a disease flare after miscarriage.

“This can be a sign that women who have more active disease have a higher risk for miscarriage and should be monitored more closely when their disease activity in the preconceptional period increases,” Dr. Brouwer said.

Women who miscarried were significantly older than were women with an ongoing pregnancy (mean 33.9 years vs. 32 years; P = .022). They also were more likely to be positive for anti-citrullinated protein antibodies (ACPA) (82% vs. 60%; P = .058), have higher DAS28 scores (3.92 vs. 3.59; P = .166), and have used methotrexate in the past (82% vs. 68%; P = .174).

No significant association was observed between miscarriage and corticosteroids, anti-inflammatories, or biological therapies, she said.

Because of the low frequency of miscarriages in the study, logistic regression showed only a trend toward higher miscarriage risk in association with increasing age (OR, 1.12; P = .065 per year of age increase) and ACPA positivity (OR, 2.47; P = .092), Dr. Brouwer said.

“Since the confidence interval is 0.99-1.25, there clearly seems to be a trend toward a higher risk for occurrence of miscarriage with increasing age, which is only logical since in the general population we also see an increase in miscarriage rate with increasing age,” she said in an interview. “My expectation is that, in a larger RA cohort, with a larger absolute number of miscarriages, the association will be significant.”

Follow-up revealed that, within 1 year of miscarriage, 68% of women became pregnant again, 14% stopped trying to conceive, and 11% were lost to follow-up. The live birth rate in the subsequent pregnancy was 90%. A follow-up study of these children did not find an increased rate of congenital malformations, despite the use of RA medications during pregnancy, Dr. Brouwer said.

The audience questioned whether the investigators are suggesting that rheumatoid arthritis has no role in miscarriage, observing that the study outcomes look very similar to patients without RA. Dr. Brouwer responded that there seems to be a higher sensitivity in patients with ACPA using methotrexate in the past but that this failed to reach significance.

“The results found in this study: some association with more severe disease – ACPA positivity and past methotrexate use – although not significant are a confirmation to us that extra care should be given to suppressing active disease already before actively trying to achieve a pregnancy,” she told this publication.

For more details, the full manuscript has been published (Arthritis Rheumatol. 2015;67:1738-43).

Reumafond, the Dutch Arthritis Foundation, funded the study. Dr. Brouwer reported no financial conflicts.

[email protected]

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

LISBON – Women undergoing assisted reproduction had similar pregnancy rates with gonadotropin-releasing hormone agonist and antagonist protocols, but less ovarian hyperstimulation syndrome with the GnRH-antagonist protocol in a large randomized trial.

Severe ovarian hyperstimulation syndrome (OHSS) was roughly halved with the GnRH-antagonist vs. the GnRH-agonist protocol (3.2% vs. 6.1%; P = .03), as were ascites punctures (0 vs. 2%: P = .001) and treatment changes due to risk of OHSS (5.7% vs. 10.3%; P = .006).

Patrice Wendling/Frontline Medical News

Hospital admissions for OHSS also favored the GnRH antagonist protocol (1.7% vs. 3.6%; P = .06), Dr. Mette Toftager reported at the annual meeting of the European Society of Human Reproduction and Embryology.

The exact impact of these protocols has been controversial following early reports that GnRH antagonists were associated with lower pregnancy rates.

Two 2006 meta-analyses yielded conflicting results, but were based on small heterogeneous trials that were not powered for OHSS nor pregnancy rates and were conducted in selected populations, said Dr. Toftager of Fertility Clinic, Hvidovre Hospital, Denmark.

The current noninferiority trial used few inclusion criteria – just age 18-40 years and first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle – to prospectively enroll 1,099 women and evenly randomize them to a classic short GnRH-antagonist protocol or a classic long GnRH-agonist protocol.

Women received a fixed dose of either recombinant follicle stimulating hormone 150 IU or 225 IU based on age (≤ 36 years vs. > 36 years) and were given the option to adjust the rFSH dose based on ovarian response at stimulation day 6.

The trial was designed to detect a 2.5% difference in moderate/severe OHSS per Golan OHSS criteria between the two groups, stratified by age, IVF center, and IVF/ICSI.

At baseline, the two groups were comparable in age (mean 32 years), cycle length (mean 28.9 days), and nulliparity (92.3%). The study included women with irregular cycles and polycystic ovary syndrome, who represented about 13% of each group.

Regarding stimulation, significant differences were found between the GnRH-antagonist and GnRH-agonist groups in total rFSH dose (mean 1,522 IU vs. 1,999 IU), days of stimulation (mean 9 vs. 11), and the number of aspirated oocytes (mean 8.5 vs. 10; P < .0001 for all), Dr. Toftager reported.

The GnRH-antagonist and GnRH-agonist groups had the same number of embryos transferred (mean 1.1 vs. 1.2), use of embryo freezing (50% vs. 53%), and number of frozen embryos (mean 3.2 vs. 3.4).

By all measures used, pregnancy outcomes were similar between protocols, she said.

The GnRH-antagonist and GnRH-agonist groups had similar clinical pregnancy rates (35% vs. 35.7%) and clinical pregnancies per embryo transfer (42.6% vs. 41%). There were similar results for ongoing pregnancy rates analyzed per randomization (25.5% vs. 26.4%), if patient started stimulation (24.8% vs. 24.0%), and per embryo transfer (30.7% vs. 29%).

During a discussion of the results, an audience member questioned the high FSH starting doses and suggested they may be the cause of OHSS. Dr. Toftager said the trial was designed in 2007 and that they now use lower FSH doses, but that starting doses were the same in both groups.

Another attendee asked whether OHSS rates remained statistically significant after controlling for the number of oocytes collected and the gonadotropin dose, which were significantly lower in the GnRH-antagonist group and hence, so was OHSS. That analysis will likely be conducted, but the data were just received days before the presentation, Dr. Toftager said.

Merck Sharp & Dohme sponsored the study. Dr. Toftager reported having no financial conflicts.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Autologous engineered skin substitutes (EES) reduce mortality and donor-site harvesting in children with extensive, deep burns, a randomized, paired-site comparison showed.

“Autologous ESS offer an alternative therapy for closure of extensive, excised, full-thickness burns,” Steven Boyce, Ph.D., said at the annual meeting of the American Burn Association.

Patrice Wendling/Frontline Medical News

The skin substitutes were engineered using split-thickness skin biopsies from 16 children with full-thickness burns covering an average total body surface area (TBSA) of 78% and a high of 95%.

The ESS were composed of autologous cultured keratinocytes and dermal fibroblasts attached to a collagen-based, biopolymer scaffold.

Clinicians are increasingly turning to tissue engineering as a way to address the shortfalls associated with the prevailing standard of care, autologous skin grafting, including lack of donor sites in larger burns, increased morbidity from autograft harvesting and skin grafts, and scarring.

At the 2014 ABA meeting, Canadian researchers reported on an autologous skin substitute that had both dermal and epidermal components. It took 2 months to prepare, whereas the Cincinnati model requires about 1 month to prepare and offers greater availability and stability of the closed wounds, Dr. Boyce said in an interview.

For the current study, Dr. Boyce and his associates compared mortality after treatment with ESS in 16 children with data from 1,008 patients from the National Burn Repository who were of similar ages, had 77% full-thickness TBSA burns, and were treated with meshed and expanded split-thickness skin autografts (AG). One patient died before ESS were prepared, leaving 15 patients in whom 2,056 ESS grafts were applied in 59 operations. Their average age was 6.3 years, 13 were male, and the average time to first ESS was 32 days.

Mortality was 6.25% (1/16) with the skin substitutes and 30.3% (305/1,008) with the autografts (P value < .05), said Dr. Boyce, a professor with the University of Cincinnati and director of the Skin Substitute Laboratories, Shriners Hospitals for Children, both in Cincinnati.

Rates of engraftment at postoperative day 14, however, significantly favored the AG group at 96.5 vs. 83.5% for ESS (P < .05).

One major reason for reduced rates of engraftment is lack of blood vessels in current models of engineered skin, he explained.

At day 28, the percentage of TBSA closed was approximately 30% for ESS and 47% for AG, while the ratio of closed-to-donor areas was significantly greater for ESS (108.7 vs. 4.0; P < .001).

The correlation between the percentage TBSA closed with ESS and TBSA burned generated an R-squared value of 0.65 (P < .001), Dr. Boyce said.

Regraftment rates were similar between graft types. Antibody formation to the biopolymer scaffold at postoperative day 28 was similar between patients receiving 1 or multiple ESS.

“Stable wound closure [with ESS] is interpreted to result from preservation of epidermal progenitor cells, formation in vitro of basement membrane between fibroblasts and keratinocytes, and generation of fibrovascular tissue by the biopolymer scaffold,” he said.

Tissue engineering offers patients the opportunity to survive with otherwise statistically lethal burns and “the data are very clear that happens with this product,” session comoderator and past ABA president Dr. David Ahrenholz said in an interview.

That said, “the product is very expensive, so I would not use it for patients in whom I had adequate donor sites, but it’s fairly easy to identify those patients on admission,” he added.

The study was supported by grants from the U.S. Department of Defense, National Institute of General Medical Sciences, and Shriners Hospitals for Children. The authors reported no current relevant financial disclosures.

[email protected]

On Twitter @pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl

WASHINGTON – More intensive treatment with early combined immunosuppression was associated with a longer time to first flare and fewer flares than conventional management during long-term follow-up of patients with Crohn’s disease.

Fewer patients treated with the “top-down” approach required anti–tumor necrosis factor (anti-TNF) agents or corticosteroids during follow-up, Dr. Daniël Hoekman reported during the annual Digestive Disease Week.

Current guidelines advocate an initial “step-up” approach for Crohn’s disease that focuses on controlling symptoms with corticosteroids followed by immunomodulators and then anti-TNF inhibitors to manage the chronic relapsing-remitting course of Crohn’s.

A new strategy has been proposed with the aim of altering the disease course and slow progression by reversing the treatment paradigm from a step-up to a top-down approach. A 2-year, randomized European trial showed that a top-down approach, combining early immunosuppression with infliximab (Remicade) and azathioprine (Imuran in Canada, Azasan in the United States) followed by azathioprine monotherapy and, if necessary, additional infliximab and corticosteroids, was more effective than step-up management for induction of remission and reduction of steroids in the short term (Lancet 2008;371:660-7).

To investigate the long-term outcome of Crohn’s disease, researchers performed a retrospective chart review in 119 of the 133 trial participants followed for 8 years or 16 semesters (mean 14.2 semesters) after the initial 2-year trial period. Management during the study was left to physician discretion. At the start of the extended follow-up, most patients in both the step-up and top-down groups were on immunomodulators (66% vs. 82%) and only a small portion were using infliximab (15% vs. 20%). A total of 164 endoscopy reports were available for 59% of patients.

During follow-up, significantly more patients treated with the step-up approach than the top-down approach required anti-TNF inhibitors (73% vs. 54%; P = .04) and steroids (62% vs. 41%; P = .02), said Dr. Hoekman of the Academic Medical Center, Amsterdam.

There was no difference between the step-up and top-down groups in long-term remission rates (70% vs. 73%; P = .85).

The top-down group, however, had significantly fewer flares than the step-up group (7% vs. 19%; P = .01) and a longer time to first flare (median 9 semesters vs. 5 semesters; P = .02), he said.

There were no differences between groups in rates of hospitalization or surgery for Crohn’s disease, new fistula, or rescue treatment, defined as use of cyclosporine, experimental therapy, or surgery.

A review of the endoscopy reports suggested a trend for fewer large ulcers per patient in the top-down group than the step-up group, but this did not reach statistical significance (14% vs. 24%; P = .11), Dr. Hoekman said. The median proportion of endoscopies with remission also was similar (49% vs. 43%; P = .46).

Rates of adverse events also were similar in the top-down and step-up groups including infusion reactions (14% vs. 10%), serious infection (22% vs. 10%), malignancy (0 vs. 1 event), and dysplastic lesions (0 vs. 2 events), he said.

[email protected]

On Twitter@pwendl