Obstetrics

WASHINGTON – Universal cervical length screening to prevent preterm birth has been implemented by more two-thirds of institutions with maternal-fetal medicine fellowship programs, but less than half of these programs screen with transvaginal ultrasound, a national survey has found.

The survey of 78 accredited programs also revealed geographic variations in the use of routine screening and the ultrasound approach employed, Dr. Adeeb Khalifeh reported at the annual meeting of the American College of Obstetricians and Gynecologists.

©herjua/Thinkstock

All 78 programs responded to the survey. Fifty-three programs (68%) indicated they had implemented a universal screening program, defined as cervical length screening of women with singleton gestations who had not had a prior spontaneous preterm delivery. Of these, 28 use transabdominal ultrasound (TAU) and 25 use transvaginal ultrasound (TVU) for screening.

While the survey shows that a majority of academic institutions now perform universal cervical length screening, it also reveals that “almost one-third do not,” despite strong evidence of an inverse relationship between cervical length and risk of spontaneous preterm birth, said Dr. Khalifeh, a maternal-fetal medicine fellow at Thomas Jefferson University Hospital in Philadelphia who conducted the survey in 2015 with other physicians there.

Both ACOG and the Society for Maternal-Fetal Medicine recommend transvaginal measurements of cervical length for physicians who decide to implement universal cervical length screening.

ACOG’s 2012 Practice Bulletin on Prediction and Prevention of Preterm Birth, which does not mandate universal screening but supports its consideration, notes that, “if second trimester transabdominal scanning of the lower uterine segment suggests that the cervix may be short or have some other abnormality, it is recommended that a subsequent transvaginal ultrasound examination be performed to better visualize the cervix and establish its length” (Obstet Gynecol. 2012 Oct;120:964-73).

Cervical length assessment performed with TAU is unreliable, and it is less cost effective then assessment using TVU, Dr. Khalifeh said.

Vaginal progesterone as a treatment for short cervix in patients with singleton gestations was assessed and proven to be valuable in studies using TVU, not TAU, he noted.

Institutions in the Midwest had the highest rate of universal screening (94%) and the highest use of TVU (58% of programs with routine screening), while programs in the South had the lowest rate of university screening (58%) and the lowest use of TVU (12.5%).

In the Northeast, universal screening was reported by 60% of institutions, and the use of TVU by 40%. Among institutions in the West, 69% reported performing universal screening, with 40% of these programs using TVU.

Obstetrical volume did not impact the implementation of, or approach to, universal cervical length screening; there were no significant differences between institutions with a higher obstetrical volume (more than 3,000 deliveries annually) and a lower volume.

It’s “hard to extrapolate the practice of academic centers [to the community at large], so the findings might not be representative of what’s happening nationwide,” Dr. Khalifeh said.

He reported that he and his coinvestigators had no relevant financial disclosures.

WASHINGTON – Universal cervical length screening to prevent preterm birth has been implemented by more two-thirds of institutions with maternal-fetal medicine fellowship programs, but less than half of these programs screen with transvaginal ultrasound, a national survey has found.

The survey of 78 accredited programs also revealed geographic variations in the use of routine screening and the ultrasound approach employed, Dr. Adeeb Khalifeh reported at the annual meeting of the American College of Obstetricians and Gynecologists.

©herjua/Thinkstock

All 78 programs responded to the survey. Fifty-three programs (68%) indicated they had implemented a universal screening program, defined as cervical length screening of women with singleton gestations who had not had a prior spontaneous preterm delivery. Of these, 28 use transabdominal ultrasound (TAU) and 25 use transvaginal ultrasound (TVU) for screening.

While the survey shows that a majority of academic institutions now perform universal cervical length screening, it also reveals that “almost one-third do not,” despite strong evidence of an inverse relationship between cervical length and risk of spontaneous preterm birth, said Dr. Khalifeh, a maternal-fetal medicine fellow at Thomas Jefferson University Hospital in Philadelphia who conducted the survey in 2015 with other physicians there.

Both ACOG and the Society for Maternal-Fetal Medicine recommend transvaginal measurements of cervical length for physicians who decide to implement universal cervical length screening.

ACOG’s 2012 Practice Bulletin on Prediction and Prevention of Preterm Birth, which does not mandate universal screening but supports its consideration, notes that, “if second trimester transabdominal scanning of the lower uterine segment suggests that the cervix may be short or have some other abnormality, it is recommended that a subsequent transvaginal ultrasound examination be performed to better visualize the cervix and establish its length” (Obstet Gynecol. 2012 Oct;120:964-73).

Cervical length assessment performed with TAU is unreliable, and it is less cost effective then assessment using TVU, Dr. Khalifeh said.

Vaginal progesterone as a treatment for short cervix in patients with singleton gestations was assessed and proven to be valuable in studies using TVU, not TAU, he noted.

Institutions in the Midwest had the highest rate of universal screening (94%) and the highest use of TVU (58% of programs with routine screening), while programs in the South had the lowest rate of university screening (58%) and the lowest use of TVU (12.5%).

In the Northeast, universal screening was reported by 60% of institutions, and the use of TVU by 40%. Among institutions in the West, 69% reported performing universal screening, with 40% of these programs using TVU.

Obstetrical volume did not impact the implementation of, or approach to, universal cervical length screening; there were no significant differences between institutions with a higher obstetrical volume (more than 3,000 deliveries annually) and a lower volume.

It’s “hard to extrapolate the practice of academic centers [to the community at large], so the findings might not be representative of what’s happening nationwide,” Dr. Khalifeh said.

He reported that he and his coinvestigators had no relevant financial disclosures.

WASHINGTON – Universal cervical length screening to prevent preterm birth has been implemented by more two-thirds of institutions with maternal-fetal medicine fellowship programs, but less than half of these programs screen with transvaginal ultrasound, a national survey has found.

The survey of 78 accredited programs also revealed geographic variations in the use of routine screening and the ultrasound approach employed, Dr. Adeeb Khalifeh reported at the annual meeting of the American College of Obstetricians and Gynecologists.

©herjua/Thinkstock

All 78 programs responded to the survey. Fifty-three programs (68%) indicated they had implemented a universal screening program, defined as cervical length screening of women with singleton gestations who had not had a prior spontaneous preterm delivery. Of these, 28 use transabdominal ultrasound (TAU) and 25 use transvaginal ultrasound (TVU) for screening.

While the survey shows that a majority of academic institutions now perform universal cervical length screening, it also reveals that “almost one-third do not,” despite strong evidence of an inverse relationship between cervical length and risk of spontaneous preterm birth, said Dr. Khalifeh, a maternal-fetal medicine fellow at Thomas Jefferson University Hospital in Philadelphia who conducted the survey in 2015 with other physicians there.

Both ACOG and the Society for Maternal-Fetal Medicine recommend transvaginal measurements of cervical length for physicians who decide to implement universal cervical length screening.

ACOG’s 2012 Practice Bulletin on Prediction and Prevention of Preterm Birth, which does not mandate universal screening but supports its consideration, notes that, “if second trimester transabdominal scanning of the lower uterine segment suggests that the cervix may be short or have some other abnormality, it is recommended that a subsequent transvaginal ultrasound examination be performed to better visualize the cervix and establish its length” (Obstet Gynecol. 2012 Oct;120:964-73).

Cervical length assessment performed with TAU is unreliable, and it is less cost effective then assessment using TVU, Dr. Khalifeh said.

Vaginal progesterone as a treatment for short cervix in patients with singleton gestations was assessed and proven to be valuable in studies using TVU, not TAU, he noted.

Institutions in the Midwest had the highest rate of universal screening (94%) and the highest use of TVU (58% of programs with routine screening), while programs in the South had the lowest rate of university screening (58%) and the lowest use of TVU (12.5%).

In the Northeast, universal screening was reported by 60% of institutions, and the use of TVU by 40%. Among institutions in the West, 69% reported performing universal screening, with 40% of these programs using TVU.

Obstetrical volume did not impact the implementation of, or approach to, universal cervical length screening; there were no significant differences between institutions with a higher obstetrical volume (more than 3,000 deliveries annually) and a lower volume.

It’s “hard to extrapolate the practice of academic centers [to the community at large], so the findings might not be representative of what’s happening nationwide,” Dr. Khalifeh said.

He reported that he and his coinvestigators had no relevant financial disclosures.

WASHINGTON – The Centers for Disease Control and Prevention is recommending blood or urine testing for all pregnant women with possible Zika exposure through travel or because they live in an endemic area, regardless of whether they are symptomatic, Dr. Denise J. Jamieson said at the annual meeting of the American College of Obstetricians and Gynecologists.

Couples interested in conceiving who live in or have traveled to areas of active transmission should be alert for any signs of infection, no matter how slight; if they notice any, they should be tested for exposure before attempting conception, Dr. Jamieson, a medical officer with the CDC’s division of reproductive medicine, said in a video interview.

Unfortunately, she said at an update on the Zika situation, labs that process Zika blood and urine samples are backed up, and test results are being “unacceptably delayed.”

During a discussion period, some physicians in the audience complained of waiting up to 6 weeks for results. One said a local health department official told him that the CDC had a backlog of “a million tests.”

“We do not have a 1-million test backup,” Dr. Jamieson said. “But in some places there are still unacceptably long delays. This is not a test you can just check off on a form and send to a lab.”

Many of the tests are being funneled to the CDC’s Division of Vector-Borne Diseases in Ft. Collins, Colo.; that facility is experiencing a long turnaround time. Other samples are being handled in private labs with CDC contracts, but Dr. Jamieson said there’s an urgent need to expand the testing to many more commercial labs. There is no concrete plan for how or when this expansion will happen, however, she added.

Dr. Jamieson also discussed the CDC’s recommendation for managing pregnant women who have a positive serology or urine. These women should have serial ultrasounds every 3-4 weeks to track fetal brain development. Amniocentesis can positively confirm fetal exposure. A maternal-fetal medicine specialist should be on board if the fetus tests positive or if any concerning signs appear on imaging. Newborns can also be tested for exposure, as can placental and cord tissue.

On May 16, the World Health Organization released a comprehensive document describing a management algorithm for pregnant women who live in or travel to Zika-endemic areas.

Women who haven’t experienced signs and symptoms of an infection can proceed with routine care, and, if possible, an ultrasound before 18 weeks’ gestation and another at 28-30 weeks.

Women who have had signs of an infection should be tested for exposure. If negative, routine care with an early ultrasound and one at 28-30 weeks is indicated. If the results are positive, or if an early scan is concerning, patients should have a diagnostic ultrasound and amniocentesis, with referral to specialty care.

In the case of confirmed maternal exposure but normal early ultrasound, serial scans are indicated every month until delivery.

As a federal employee, Dr. Jamieson has no financial disclosures.

[email protected]

WASHINGTON – The Centers for Disease Control and Prevention is recommending blood or urine testing for all pregnant women with possible Zika exposure through travel or because they live in an endemic area, regardless of whether they are symptomatic, Dr. Denise J. Jamieson said at the annual meeting of the American College of Obstetricians and Gynecologists.

Couples interested in conceiving who live in or have traveled to areas of active transmission should be alert for any signs of infection, no matter how slight; if they notice any, they should be tested for exposure before attempting conception, Dr. Jamieson, a medical officer with the CDC’s division of reproductive medicine, said in a video interview.

Unfortunately, she said at an update on the Zika situation, labs that process Zika blood and urine samples are backed up, and test results are being “unacceptably delayed.”

During a discussion period, some physicians in the audience complained of waiting up to 6 weeks for results. One said a local health department official told him that the CDC had a backlog of “a million tests.”

“We do not have a 1-million test backup,” Dr. Jamieson said. “But in some places there are still unacceptably long delays. This is not a test you can just check off on a form and send to a lab.”

Many of the tests are being funneled to the CDC’s Division of Vector-Borne Diseases in Ft. Collins, Colo.; that facility is experiencing a long turnaround time. Other samples are being handled in private labs with CDC contracts, but Dr. Jamieson said there’s an urgent need to expand the testing to many more commercial labs. There is no concrete plan for how or when this expansion will happen, however, she added.

Dr. Jamieson also discussed the CDC’s recommendation for managing pregnant women who have a positive serology or urine. These women should have serial ultrasounds every 3-4 weeks to track fetal brain development. Amniocentesis can positively confirm fetal exposure. A maternal-fetal medicine specialist should be on board if the fetus tests positive or if any concerning signs appear on imaging. Newborns can also be tested for exposure, as can placental and cord tissue.

On May 16, the World Health Organization released a comprehensive document describing a management algorithm for pregnant women who live in or travel to Zika-endemic areas.

Women who haven’t experienced signs and symptoms of an infection can proceed with routine care, and, if possible, an ultrasound before 18 weeks’ gestation and another at 28-30 weeks.

Women who have had signs of an infection should be tested for exposure. If negative, routine care with an early ultrasound and one at 28-30 weeks is indicated. If the results are positive, or if an early scan is concerning, patients should have a diagnostic ultrasound and amniocentesis, with referral to specialty care.

In the case of confirmed maternal exposure but normal early ultrasound, serial scans are indicated every month until delivery.

As a federal employee, Dr. Jamieson has no financial disclosures.

[email protected]

WASHINGTON – The Centers for Disease Control and Prevention is recommending blood or urine testing for all pregnant women with possible Zika exposure through travel or because they live in an endemic area, regardless of whether they are symptomatic, Dr. Denise J. Jamieson said at the annual meeting of the American College of Obstetricians and Gynecologists.

Couples interested in conceiving who live in or have traveled to areas of active transmission should be alert for any signs of infection, no matter how slight; if they notice any, they should be tested for exposure before attempting conception, Dr. Jamieson, a medical officer with the CDC’s division of reproductive medicine, said in a video interview.

Unfortunately, she said at an update on the Zika situation, labs that process Zika blood and urine samples are backed up, and test results are being “unacceptably delayed.”

During a discussion period, some physicians in the audience complained of waiting up to 6 weeks for results. One said a local health department official told him that the CDC had a backlog of “a million tests.”

“We do not have a 1-million test backup,” Dr. Jamieson said. “But in some places there are still unacceptably long delays. This is not a test you can just check off on a form and send to a lab.”

Many of the tests are being funneled to the CDC’s Division of Vector-Borne Diseases in Ft. Collins, Colo.; that facility is experiencing a long turnaround time. Other samples are being handled in private labs with CDC contracts, but Dr. Jamieson said there’s an urgent need to expand the testing to many more commercial labs. There is no concrete plan for how or when this expansion will happen, however, she added.

Dr. Jamieson also discussed the CDC’s recommendation for managing pregnant women who have a positive serology or urine. These women should have serial ultrasounds every 3-4 weeks to track fetal brain development. Amniocentesis can positively confirm fetal exposure. A maternal-fetal medicine specialist should be on board if the fetus tests positive or if any concerning signs appear on imaging. Newborns can also be tested for exposure, as can placental and cord tissue.

On May 16, the World Health Organization released a comprehensive document describing a management algorithm for pregnant women who live in or travel to Zika-endemic areas.

Women who haven’t experienced signs and symptoms of an infection can proceed with routine care, and, if possible, an ultrasound before 18 weeks’ gestation and another at 28-30 weeks.

Women who have had signs of an infection should be tested for exposure. If negative, routine care with an early ultrasound and one at 28-30 weeks is indicated. If the results are positive, or if an early scan is concerning, patients should have a diagnostic ultrasound and amniocentesis, with referral to specialty care.

In the case of confirmed maternal exposure but normal early ultrasound, serial scans are indicated every month until delivery.

As a federal employee, Dr. Jamieson has no financial disclosures.

[email protected]

WASHINGTON – The postpartum readmission rate increased over a recent 8-year period from 1.72% to 2.16%, with readmitted patients more likely to be publicly insured and more likely to have multiple comorbidities, a multistate analysis shows.

The rise in readmissions from 2004 to 2011 “isn’t solely explained by the increasing cesarean rate,” and appears to be significantly influenced “by increasing maternal comorbidities,” said Dr. Mark A. Clapp, who reported preliminary findings at the annual meeting of the American College of Obstetricians and Gynecologists.

©SoberP/thinkstockphotos.com

Dr. Clapp and his coinvestigators analyzed postpartum readmissions occurring in the first 6 weeks after delivery in women in California, Florida, and New York – 3 states whose combined 1 million deliveries a year represent approximately a quarter of all deliveries in the United States. Of approximately 8 million deliveries identified over the study period, 6 million were eligible for analysis.

Medical and surgical readmission rates are used in various specialties as indicators of quality and linked to reimbursement, but “very little is known about readmissions in obstetrics,” he said.

The researchers identified deliveries and postpartum readmissions in state inpatient databases and compared maternal, pregnancy, and delivery characteristics of women who were readmitted with those who weren’t readmitted. This included both “primary” indications for readmissions and “associated diagnoses” listed for these patients.

The most common primary indication for readmission, they found, was wound infection or breakdown (15.5%), followed by hypertensive disease (9.3%), and psychiatric illness (7.7%). The most common associated diagnosis among readmitted patients was psychiatric disease, followed by hypertensive disease.

Women who were readmitted “were more likely to have comorbidities across the board,” said Dr. Clapp, a resident at Brigham and Women’s Hospital, Boston. The readmitted women had higher rates of all “associated diagnoses” listed in the state databases, from asthma and diabetes to obesity and thyroid disease, but the most significant differences were in the rates of hypertensive disease, psychiatric disease, and substance abuse.

Regarding mode of delivery, 37.2% of those who were readmitted had undergone a cesarean delivery versus 32.9% of those not readmitted. Patients who were readmitted also were more likely to have had a multiple gestation, preterm labor, or a placental abnormality.

The majority of readmitted patients in the retrospective cohort study were publicly insured: 54% versus 42%. Readmitted patients also were more likely to be older, with a mean age of 36 years, compared with 28 years in the non-readmitted group. They also were more likely to be black (19% of readmitted patients versus 14% of non-readmitted). Over 50% of readmissions occurred in the first week.

The impact of cesarean delivery on readmission risk needs further investigation, Dr. Clapp said, noting that cesarean delivery was an inconsistent predictor of readmission. In Florida, for instance, patients who had cesarean deliveries in 2011 were actually less likely to be readmitted than those who delivered vaginally.

Psychiatric comorbidities also need to be better understood, as does the “influence of increasing maternal comorbidities, which I suspect is driving the increase in readmissions, rather than the mode of delivery,” Dr. Clapp said.

“Hopefully, we can build a body of evidence to either support or refute the use of readmissions as a measure of quality in our field,” he said.

Dr. Clapp and his coauthors reported no relevant financial disclosures. The study was funded by an ACOG health policy grant.

WASHINGTON – The postpartum readmission rate increased over a recent 8-year period from 1.72% to 2.16%, with readmitted patients more likely to be publicly insured and more likely to have multiple comorbidities, a multistate analysis shows.

The rise in readmissions from 2004 to 2011 “isn’t solely explained by the increasing cesarean rate,” and appears to be significantly influenced “by increasing maternal comorbidities,” said Dr. Mark A. Clapp, who reported preliminary findings at the annual meeting of the American College of Obstetricians and Gynecologists.

©SoberP/thinkstockphotos.com

Dr. Clapp and his coinvestigators analyzed postpartum readmissions occurring in the first 6 weeks after delivery in women in California, Florida, and New York – 3 states whose combined 1 million deliveries a year represent approximately a quarter of all deliveries in the United States. Of approximately 8 million deliveries identified over the study period, 6 million were eligible for analysis.

Medical and surgical readmission rates are used in various specialties as indicators of quality and linked to reimbursement, but “very little is known about readmissions in obstetrics,” he said.

The researchers identified deliveries and postpartum readmissions in state inpatient databases and compared maternal, pregnancy, and delivery characteristics of women who were readmitted with those who weren’t readmitted. This included both “primary” indications for readmissions and “associated diagnoses” listed for these patients.

The most common primary indication for readmission, they found, was wound infection or breakdown (15.5%), followed by hypertensive disease (9.3%), and psychiatric illness (7.7%). The most common associated diagnosis among readmitted patients was psychiatric disease, followed by hypertensive disease.

Women who were readmitted “were more likely to have comorbidities across the board,” said Dr. Clapp, a resident at Brigham and Women’s Hospital, Boston. The readmitted women had higher rates of all “associated diagnoses” listed in the state databases, from asthma and diabetes to obesity and thyroid disease, but the most significant differences were in the rates of hypertensive disease, psychiatric disease, and substance abuse.

Regarding mode of delivery, 37.2% of those who were readmitted had undergone a cesarean delivery versus 32.9% of those not readmitted. Patients who were readmitted also were more likely to have had a multiple gestation, preterm labor, or a placental abnormality.

The majority of readmitted patients in the retrospective cohort study were publicly insured: 54% versus 42%. Readmitted patients also were more likely to be older, with a mean age of 36 years, compared with 28 years in the non-readmitted group. They also were more likely to be black (19% of readmitted patients versus 14% of non-readmitted). Over 50% of readmissions occurred in the first week.

The impact of cesarean delivery on readmission risk needs further investigation, Dr. Clapp said, noting that cesarean delivery was an inconsistent predictor of readmission. In Florida, for instance, patients who had cesarean deliveries in 2011 were actually less likely to be readmitted than those who delivered vaginally.

Psychiatric comorbidities also need to be better understood, as does the “influence of increasing maternal comorbidities, which I suspect is driving the increase in readmissions, rather than the mode of delivery,” Dr. Clapp said.

“Hopefully, we can build a body of evidence to either support or refute the use of readmissions as a measure of quality in our field,” he said.

Dr. Clapp and his coauthors reported no relevant financial disclosures. The study was funded by an ACOG health policy grant.

WASHINGTON – The postpartum readmission rate increased over a recent 8-year period from 1.72% to 2.16%, with readmitted patients more likely to be publicly insured and more likely to have multiple comorbidities, a multistate analysis shows.

The rise in readmissions from 2004 to 2011 “isn’t solely explained by the increasing cesarean rate,” and appears to be significantly influenced “by increasing maternal comorbidities,” said Dr. Mark A. Clapp, who reported preliminary findings at the annual meeting of the American College of Obstetricians and Gynecologists.

©SoberP/thinkstockphotos.com

Dr. Clapp and his coinvestigators analyzed postpartum readmissions occurring in the first 6 weeks after delivery in women in California, Florida, and New York – 3 states whose combined 1 million deliveries a year represent approximately a quarter of all deliveries in the United States. Of approximately 8 million deliveries identified over the study period, 6 million were eligible for analysis.

Medical and surgical readmission rates are used in various specialties as indicators of quality and linked to reimbursement, but “very little is known about readmissions in obstetrics,” he said.

The researchers identified deliveries and postpartum readmissions in state inpatient databases and compared maternal, pregnancy, and delivery characteristics of women who were readmitted with those who weren’t readmitted. This included both “primary” indications for readmissions and “associated diagnoses” listed for these patients.

The most common primary indication for readmission, they found, was wound infection or breakdown (15.5%), followed by hypertensive disease (9.3%), and psychiatric illness (7.7%). The most common associated diagnosis among readmitted patients was psychiatric disease, followed by hypertensive disease.

Women who were readmitted “were more likely to have comorbidities across the board,” said Dr. Clapp, a resident at Brigham and Women’s Hospital, Boston. The readmitted women had higher rates of all “associated diagnoses” listed in the state databases, from asthma and diabetes to obesity and thyroid disease, but the most significant differences were in the rates of hypertensive disease, psychiatric disease, and substance abuse.

Regarding mode of delivery, 37.2% of those who were readmitted had undergone a cesarean delivery versus 32.9% of those not readmitted. Patients who were readmitted also were more likely to have had a multiple gestation, preterm labor, or a placental abnormality.

The majority of readmitted patients in the retrospective cohort study were publicly insured: 54% versus 42%. Readmitted patients also were more likely to be older, with a mean age of 36 years, compared with 28 years in the non-readmitted group. They also were more likely to be black (19% of readmitted patients versus 14% of non-readmitted). Over 50% of readmissions occurred in the first week.

The impact of cesarean delivery on readmission risk needs further investigation, Dr. Clapp said, noting that cesarean delivery was an inconsistent predictor of readmission. In Florida, for instance, patients who had cesarean deliveries in 2011 were actually less likely to be readmitted than those who delivered vaginally.

Psychiatric comorbidities also need to be better understood, as does the “influence of increasing maternal comorbidities, which I suspect is driving the increase in readmissions, rather than the mode of delivery,” Dr. Clapp said.

“Hopefully, we can build a body of evidence to either support or refute the use of readmissions as a measure of quality in our field,” he said.

Dr. Clapp and his coauthors reported no relevant financial disclosures. The study was funded by an ACOG health policy grant.

WASHINGTON – Half of the pregnancy-associated hemorrhage deaths in Michigan were deemed preventable, and most of those occurred in women who received no fresh frozen plasma during their transfusion.

Only 3 women in the 46-case series received the generally accepted one-to-one ratio of fresh frozen plasma to packed red cells, Kathryn De La Rosa said at the annual meeting of the American College of Obstetricians and Gynecologists.

The data, gleaned from state records, were not detailed enough to show with absolute certainty that the failure to follow transfusion protocol was lethal, said Ms. De La Rosa, a medical student at the University of Michigan, Ann Arbor.

“I can’t say in good faith that this is why they died,” she said. “I don’t think we have the ability to say, if these women had gotten fresh frozen plasma, they would be here today. What this does show is that this is an area that needs improvement. It’s something we should be recognizing and dealing with.”

The study plumbed records of all pregnancy-associated deaths examined by the State of Michigan Maternal Mortality review committee from 1998 to 2011. Of these, 46 were due to hemorrhage. As part of the adjudication process, the board reviews each case and determines whether or not it was a preventable death; 23 were deemed preventable.

The most common cause of preventable hemorrhage death was postpartum hemorrhage, occurring in seven cases. Other causes included placental abruption, abortion-related, amniotic fluid embolism, antepartum hemorrhage, uterine rupture, ectopic rupture, preeclampsia, and sepsis.

Most of the women who succumbed to a preventable death were younger than 30 years (13); 7 were aged 30-34 years and the remainder were 35 years or older. There was no relationship between preventable death and race or mode of delivery, Ms. De La Rosa noted.

When she examined details of each patient’s transfusion protocol, it was immediately apparent that the protocol of a one-to-one or higher ratio of fresh frozen plasma to packed red cells was not being applied.

“These women got an average of 10 units of cells but not the proper ratio of fresh frozen plasma. In fact, 17 of our 23 preventable deaths didn’t get any fresh frozen plasma at all,” she said. “Only 3 of the 46 cases conformed to that protocol; of these, one death was considered preventable.”

She conducted a more in-depth analysis of the five postpartum hemorrhage cases that occurred in a hospital (two occurred outside a hospital). These women underwent a large variety of interventions, including uterotonics, oxytocin, bedside interventions like laceration repair, fundal massage and manual extraction of uterine contents, and surgery.

But there were concerns about the adequate application of best transfusion practices, Ms. De La Rosa said. None of the women were at a facility that used a massive transfusion protocol, and none were transfused aggressively with the proper plasma/red cell ratio.

Michigan has recently joined a national project to improve maternal health outcomes, including those related to hemorrhage, she said. The Alliance for Innovation on Maternal Health (AIM) is a partnership of organizations dedicated to reducing severe maternal morbidity by 100,000 events and maternal mortality by 1,000 deaths by 2018. Michigan’s goal is to cut maternal mortality in half by 2017.

In addition to obstetric hemorrhage, the group is developing other bundles on hypertension/preeclampsia, venous thromboembolism, and reduction of primary cesarean section.

Ms. De La Rosa reported having no financial disclosures.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – Half of the pregnancy-associated hemorrhage deaths in Michigan were deemed preventable, and most of those occurred in women who received no fresh frozen plasma during their transfusion.

Only 3 women in the 46-case series received the generally accepted one-to-one ratio of fresh frozen plasma to packed red cells, Kathryn De La Rosa said at the annual meeting of the American College of Obstetricians and Gynecologists.

The data, gleaned from state records, were not detailed enough to show with absolute certainty that the failure to follow transfusion protocol was lethal, said Ms. De La Rosa, a medical student at the University of Michigan, Ann Arbor.

“I can’t say in good faith that this is why they died,” she said. “I don’t think we have the ability to say, if these women had gotten fresh frozen plasma, they would be here today. What this does show is that this is an area that needs improvement. It’s something we should be recognizing and dealing with.”

The study plumbed records of all pregnancy-associated deaths examined by the State of Michigan Maternal Mortality review committee from 1998 to 2011. Of these, 46 were due to hemorrhage. As part of the adjudication process, the board reviews each case and determines whether or not it was a preventable death; 23 were deemed preventable.

The most common cause of preventable hemorrhage death was postpartum hemorrhage, occurring in seven cases. Other causes included placental abruption, abortion-related, amniotic fluid embolism, antepartum hemorrhage, uterine rupture, ectopic rupture, preeclampsia, and sepsis.

Most of the women who succumbed to a preventable death were younger than 30 years (13); 7 were aged 30-34 years and the remainder were 35 years or older. There was no relationship between preventable death and race or mode of delivery, Ms. De La Rosa noted.

When she examined details of each patient’s transfusion protocol, it was immediately apparent that the protocol of a one-to-one or higher ratio of fresh frozen plasma to packed red cells was not being applied.

“These women got an average of 10 units of cells but not the proper ratio of fresh frozen plasma. In fact, 17 of our 23 preventable deaths didn’t get any fresh frozen plasma at all,” she said. “Only 3 of the 46 cases conformed to that protocol; of these, one death was considered preventable.”

She conducted a more in-depth analysis of the five postpartum hemorrhage cases that occurred in a hospital (two occurred outside a hospital). These women underwent a large variety of interventions, including uterotonics, oxytocin, bedside interventions like laceration repair, fundal massage and manual extraction of uterine contents, and surgery.

But there were concerns about the adequate application of best transfusion practices, Ms. De La Rosa said. None of the women were at a facility that used a massive transfusion protocol, and none were transfused aggressively with the proper plasma/red cell ratio.

Michigan has recently joined a national project to improve maternal health outcomes, including those related to hemorrhage, she said. The Alliance for Innovation on Maternal Health (AIM) is a partnership of organizations dedicated to reducing severe maternal morbidity by 100,000 events and maternal mortality by 1,000 deaths by 2018. Michigan’s goal is to cut maternal mortality in half by 2017.

In addition to obstetric hemorrhage, the group is developing other bundles on hypertension/preeclampsia, venous thromboembolism, and reduction of primary cesarean section.

Ms. De La Rosa reported having no financial disclosures.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – Half of the pregnancy-associated hemorrhage deaths in Michigan were deemed preventable, and most of those occurred in women who received no fresh frozen plasma during their transfusion.

Only 3 women in the 46-case series received the generally accepted one-to-one ratio of fresh frozen plasma to packed red cells, Kathryn De La Rosa said at the annual meeting of the American College of Obstetricians and Gynecologists.

The data, gleaned from state records, were not detailed enough to show with absolute certainty that the failure to follow transfusion protocol was lethal, said Ms. De La Rosa, a medical student at the University of Michigan, Ann Arbor.

“I can’t say in good faith that this is why they died,” she said. “I don’t think we have the ability to say, if these women had gotten fresh frozen plasma, they would be here today. What this does show is that this is an area that needs improvement. It’s something we should be recognizing and dealing with.”

The study plumbed records of all pregnancy-associated deaths examined by the State of Michigan Maternal Mortality review committee from 1998 to 2011. Of these, 46 were due to hemorrhage. As part of the adjudication process, the board reviews each case and determines whether or not it was a preventable death; 23 were deemed preventable.

The most common cause of preventable hemorrhage death was postpartum hemorrhage, occurring in seven cases. Other causes included placental abruption, abortion-related, amniotic fluid embolism, antepartum hemorrhage, uterine rupture, ectopic rupture, preeclampsia, and sepsis.

Most of the women who succumbed to a preventable death were younger than 30 years (13); 7 were aged 30-34 years and the remainder were 35 years or older. There was no relationship between preventable death and race or mode of delivery, Ms. De La Rosa noted.

When she examined details of each patient’s transfusion protocol, it was immediately apparent that the protocol of a one-to-one or higher ratio of fresh frozen plasma to packed red cells was not being applied.

“These women got an average of 10 units of cells but not the proper ratio of fresh frozen plasma. In fact, 17 of our 23 preventable deaths didn’t get any fresh frozen plasma at all,” she said. “Only 3 of the 46 cases conformed to that protocol; of these, one death was considered preventable.”

She conducted a more in-depth analysis of the five postpartum hemorrhage cases that occurred in a hospital (two occurred outside a hospital). These women underwent a large variety of interventions, including uterotonics, oxytocin, bedside interventions like laceration repair, fundal massage and manual extraction of uterine contents, and surgery.

But there were concerns about the adequate application of best transfusion practices, Ms. De La Rosa said. None of the women were at a facility that used a massive transfusion protocol, and none were transfused aggressively with the proper plasma/red cell ratio.

Michigan has recently joined a national project to improve maternal health outcomes, including those related to hemorrhage, she said. The Alliance for Innovation on Maternal Health (AIM) is a partnership of organizations dedicated to reducing severe maternal morbidity by 100,000 events and maternal mortality by 1,000 deaths by 2018. Michigan’s goal is to cut maternal mortality in half by 2017.

In addition to obstetric hemorrhage, the group is developing other bundles on hypertension/preeclampsia, venous thromboembolism, and reduction of primary cesarean section.

Ms. De La Rosa reported having no financial disclosures.

[email protected]

On Twitter @Alz_Gal

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

VANCOUVER – Three types of drugs commonly used to treat multiple sclerosis (MS) appear to have a generally good safety profile when administered before and during early pregnancy, suggest a trio of studies reported at the annual meeting of the American Academy of Neurology.

Exposure to interferon-beta during the first trimester did not increase the risks of miscarriage, congenital anomalies, or birth weight. And although use of natalizumab led to higher odds of spontaneous abortion as compared with interferon-beta or no therapy, the absolute rate still fell within that of the general population. Pregnancies occurring weeks to years after treatment with alemtuzumab also had rates of spontaneous abortion, birth defects, and stillbirth on par with population values.

All three drugs fall in a gray area when it comes to use in pregnancy, with a Food and Drug Administration designation of category C, indicating that animal studies have shown adverse effects on the fetus and adequate, quality human data are lacking, but potential benefits may outweigh potential harms in pregnancy. The studies’ findings are therefore likely to be informative to women of reproductive age, a group disproportionately affected by MS.

“It’s very important to collect as much data as possible about potential exposure risks with disease-modifying therapy in pregnancy,” session comoderator Dr. Jennifer Graves, a neurologist at the Multiple Sclerosis Center at University of California–San Francisco Medical Center and UCSF Benioff Children’s Hospital, San Francisco, said in an interview.

“However, all studies have the limitation of sample size,” she added. “The majority of serious adverse effects – teratogenicity, major birth defects – may be less than 1 in 500 [in frequency]. So this is something that puts all of these studies into context because we just don’t have that many pregnancies that have been exposed to some of these agents.” The method whereby miscarriages are ascertained can also influence findings.

Nonetheless, this research is critical for women and their physicians when it comes to making decisions about treatment, Dr. Graves maintained. “Although pregnancy may be protective for many women with MS, many do need treatment during their pregnancy to prevent severe relapses due to various factors. Collecting this type of information is important.”

Interferon-beta safety

In the first study, investigators led by Dr. Sandra Thiel of Ruhr University Bochum and the Heinrich Heine University Düsseldorf, both in Germany, analyzed data from the German Multiple Sclerosis and Pregnancy Registry.

They studied pregnancies among women who had at least 12 months of postpartum follow-up. Exposure to interferon-beta (brand names Rebif, Avonex, Betaseron, and Extavia) was defined as injection of the drug at any time after the last menstrual period.

In all, 251 pregnancies exposed to interferon-beta were compared with 194 pregnancies not exposed to any disease-modifying drugs. The median duration of exposure in the former group was 32 days, indicating that most women stopped the drug soon after discovering they were pregnant, Dr. Thiel noted.

Study results, reported at the meeting and recently published (Mult Scler. 2016 Feb 26. doi: 10.1177/1352458516634872), showed that the rate of miscarriage was 9.96% in the exposed group and 7.73% in the unexposed group, and the rate of congenital anomalies among live births was 3.08% and 5.52%.

In analyses using propensity score adjustment, there were no significant differences between groups in the odds of live birth, spontaneous abortion, congenital anomalies, preterm birth, cesarean section, or small for gestational age, or in mean infant birth weight.

Of note, the women whose pregnancies were not exposed to any disease-modifying therapy had a higher rate of relapse during pregnancy when compared with counterparts whose pregnancies were exposed to interferon-beta (27.3% vs. 14.3%).

“Taken together with the existing literature, our study provides further reassurance that interferon-beta treatment can be safely continued up until the time when women with MS become pregnant,” Dr. Thiel concluded. The safety profile seen “is consistent with the pharmacologically plausible safety of interferon-beta, as interferon-beta is a huge molecule that cannot pass the placental barrier.”

“Since the vast majority of women stopped the interferon-beta treatment during the first trimester of pregnancy, we cannot draw any conclusions about the safety of interferon-beta later in pregnancy,” she cautioned. “Another limitation is the variability in the gestational week of entry into the cohort, as later than first-trimester inclusion can lead to an underestimation of early events, particularly spontaneous abortions.”

Natalizumab safety

In the second study, Dr. Maria Pia Amato, Department of NEUROFARBA, Section of Neurosciences, University of Florence, Italy, and her colleagues with the Italian MS Study Group assessed pregnancy outcomes after exposure to natalizumab (Tysabri). This antibody targets alpha-4 integrins, which play a role in a variety of pregnancy processes and in fetal hematopoiesis and cardiac development, she noted.

They identified women for the study using two sources: the prospective Italian Pregnancy Dataset of consecutive female patients with MS referred to 25 centers and a cohort of women from an Italian interferon-beta study.

In all, they compared 65 pregnancies exposed to natalizumab (any treatment from 8 weeks before the start of the last menstrual period onward), 88 exposed to interferon-beta as a control, and 339 not exposed to either. The mean duration of natalizumab exposure was 1.16 weeks, and the mean duration of interferon-beta exposure was 4.6 weeks.

Results showed that the rate of spontaneous abortion was higher for natalizumab-exposed pregnancies, at 18.5%, than for interferon-beta–exposed pregnancies, at 8%, and for nonexposed pregnancies, at 6.5% (P = .006). But the timing of these abortions was similar, at about 8 weeks of gestation.

In adjusted analyses, natalizumab exposure was still associated with an elevated risk of spontaneous abortion when compared with interferon-beta or no exposure (odds ratio, 3.9). However, the 18.5% rate seen with the antibody fell within the range for the Italian general population of 4.8% to 21.1%.

Infants in the natalizumab group had the lowest birth weight and length, while infants in the interferon-beta group had the youngest gestational age. The groups did not differ significantly with respect to the incidence of birth defects; however, with a single defect seen in each, the study was underpowered to assess differences in this outcome.

Data additionally showed that discontinuation of natalizumab in advance of pregnancy led to an uptick in relapses, with 30% of women having a relapse, according to Dr. Amato. “This increase started during the first trimester of pregnancy and culminated in the second trimester of pregnancy. All the women were retreated soon after delivery with natalizumab, and disease activity returned to the pre-pregnancy period level with resumption of the drug.”

“Patients and clinicians should discuss together and balance the potential risks to the fetus with natalizumab exposure with the potential risks to the mother of disease reactivation during pregnancy,” she recommended, cautioning that the findings were based on first-trimester exposure of short duration. “Decisions should be made case by case on the basis of the disease activity in a specific patient and the availability of alternative treatment, and whether to use a conservative approach, stopping the drug and respecting the washout period, or in a few cases, an active approach, continuing the drug till conception or even discuss continuing the drug during pregnancy.”

Alemtuzumab safety

In the third study, investigators led by Dr. Jiwon Oh of the division of neurology at the University of Toronto analyzed outcomes of pregnancies among women who had been treated with alemtuzumab (Lemtrada), an antibody that targets CD52.

Treatment with alemtuzumab leads to depletion of lymphocytes followed by reconstitution of the immune system with a less inflammatory profile. “This is thought to contribute to the durable efficacy in the absence of continuous treatment with alemtuzumab,” she explained. “This durable efficacy and the fact that you may not need to redose is relevant when you are thinking about pregnancy in patients with MS, just because this is a drug that is given in two different cycles and may not need to be readministered.”

Although the antibody becomes undetectable in serum about 30 days after administration, it is unclear whether the ongoing immune reconstitution has any impact on subsequent pregnancy, Dr. Oh said.

The investigators pooled data from the phase II CAMMS223 trial and the phase III CARE-MS I and CARE-MS II trials of alemtuzumab and their extension phases. Women enrolled in the trials were required to use effective contraception during treatment and for the next 6 months.

Dr. Oh reported interim results based on 200 pregnancies among 137 women. Most pregnancies occurred at least 4 months after the last dose of alemtuzumab; only four occurred within 1 month and another four occurred 1 to 3 months after the last dose.

Among the 181 completed pregnancies with known outcomes, 67.4% resulted in live births. Another 21.5% ended in spontaneous abortion. “Although this is on the higher end of normal, it is still in keeping with what is seen in the general population,” Dr. Oh noted.

The rate of stillbirth was 0.6%, also at the upper end of the range seen for the general population. Finally, 10.5% of the pregnancies ended in elective abortion.

There were no congenital anomalies or birth defects among the live-born infants. One was seen in an electively terminated pregnancy (26 months after the last dose), and another was seen in a stillbirth (4 years after the last dose).

“Two out of 200 is 1%, and this is actually lower than what is normally seen in the general population, approximately 3% to 7%,” Dr. Oh commented.

“To date, there is no indication of an increased risk for congenital anomalies or birth defects in infants,” she summarized. “There has also been no indication of increased rates of spontaneous abortion in women who become pregnant, but obviously, these data are limited because we don’t necessarily have a control group.”

“Based on the pharmacokinetics of alemtuzumab and labeling guidelines, women of childbearing potential should continue to use contraception for 4 months after receiving a course of alemtuzumab,” Dr. Oh concluded. “There is an international Alemtuzumab Pregnancy Exposure Registry that is open and enrolling patients who become pregnant between the first dose of alemtuzumab and 4 months after the last infusion, and hopefully this will give us more information to confirm some of the observations that we see here.”

Dr. Thiel disclosed that she had no relevant conflicts of interest; the German Multiple Sclerosis and Pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Novartis Pharma, Teva Pharma, and Sanofi-Aventis/Genzyme Pharmaceuticals. Dr. Amato disclosed that she has received research grants and honoraria as a speaker from and is a member of advisory boards for Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche; the study did not receive any financial support. Dr. Oh disclosed that she serves on the scientific advisory boards or is a speaker for Biogen Idec, EMD Serono, Genzyme, Novartis, Roche, and Teva; the study was supported by Genzyme and Bayer Healthcare.

BALTIMORE – For a premature infant, breast milk straight from Mom or a donor may not be the ideal meal.

The problem is that breast milk is often unbalanced in its content of protein, fat, and carbohydrates, and for a premature neonate fed by a nasogastric tube, unfortified breast milk can provide too little of one nutrient or too much of another. Conventional fortification of breast milk adds a standardized cocktail of nutrients that doesn’t provide an ideal balance for optimal growth.

Frequent analysis of breast milk’s nutrient content and target fortification to tweak the milk to a more ideal nutrient balance may be a way around this problem, and results from a single-center, randomized trial with 85 premature infants showed that this approach led to significantly better infant weights when measured at 36 weeks postmenstrual age, Dr. Christoph Fusch reported at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Target fortification of breast milk resulted in an average weight at 36 weeks postmenstrual age of 2,510 g among 42 infants in the intervention group, compared with an average weight of 2,280 g among 43 control infants who received breast milk that underwent routine fortification with a commercial product – a statistically significant difference for the study’s primary endpoint, said Dr. Fusch, professor of pediatrics at McMaster University and director of the neonatal intensive care unit at McMaster Children’s Hospital, both in Hamilton, Ont.

Baseline weights in the two groups of premature infants, who were born at an average of 27 weeks’ gestation and began the study at an average age of about 30 weeks’ postmenstrual age, were 970 g in the controls and 960 g in the infants who received target fortification.

The benefit from target fortification was even more dramatic in the 50% of infants fed on breast milk with the lowest protein content. In this subgroup, the 21 infants on target fortification weighed an average of 2,540 g at 36 weeks postmenstrual age, compared with an average weight of 2,170 g among 21 control infants.

“If you use standard fortification you never get [the nutrients] right. Too many nutrients will be outside [the ideal range] and those babies have a high risk of not growing,” Dr. Fusch noted in an interview.

One of the key steps in the study was measuring the protein, fat, and carbohydrate content of the breast milk that each infant received 3 days a week and using those data to guide fortification. Assessment of each breast milk specimen takes about 2 minutes, after which a technician adds the required levels of freshly prepared nutrient supplements to produce a final protein content of 3 g/dL, fat at 4.3 g/dL, and carbohydrate at 8.5 g/dL. The researchers set these levels based on an assumed daily intake of 150 mL/kg of fortified breast milk.

Dr. Fusch and his associates plan additional analyses of the data they collected in this study to look at the impact of target fortification on infant length and head circumference, metabolic responses, body composition, and neurodevelopment out to 18 months of age. They also have launched a larger, multicenter study with a similar design at 10 sites in Europe and 8 sites in North America.

The infants who stand to gain the most from target fortification are those fed donor breast milk, an increasingly popular option when breast milk from the infant’s mother is not available, but also a flawed option because this milk is usually low in protein, said Dr. Fusch, who also holds the Jack Sinclair Chair in Neonatology at the university. Target fortification is not an issue for term infants who feed normally because they usually cry to demand more milk when they lack specific nutrients. Premature infants are much more vulnerable when fed by a nasogastric tube because they will become sated simply by milk volume and then stop eating, even when they ingest an unbalanced nutrient supply.

BALTIMORE – For a premature infant, breast milk straight from Mom or a donor may not be the ideal meal.

The problem is that breast milk is often unbalanced in its content of protein, fat, and carbohydrates, and for a premature neonate fed by a nasogastric tube, unfortified breast milk can provide too little of one nutrient or too much of another. Conventional fortification of breast milk adds a standardized cocktail of nutrients that doesn’t provide an ideal balance for optimal growth.

Frequent analysis of breast milk’s nutrient content and target fortification to tweak the milk to a more ideal nutrient balance may be a way around this problem, and results from a single-center, randomized trial with 85 premature infants showed that this approach led to significantly better infant weights when measured at 36 weeks postmenstrual age, Dr. Christoph Fusch reported at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Target fortification of breast milk resulted in an average weight at 36 weeks postmenstrual age of 2,510 g among 42 infants in the intervention group, compared with an average weight of 2,280 g among 43 control infants who received breast milk that underwent routine fortification with a commercial product – a statistically significant difference for the study’s primary endpoint, said Dr. Fusch, professor of pediatrics at McMaster University and director of the neonatal intensive care unit at McMaster Children’s Hospital, both in Hamilton, Ont.

Baseline weights in the two groups of premature infants, who were born at an average of 27 weeks’ gestation and began the study at an average age of about 30 weeks’ postmenstrual age, were 970 g in the controls and 960 g in the infants who received target fortification.

The benefit from target fortification was even more dramatic in the 50% of infants fed on breast milk with the lowest protein content. In this subgroup, the 21 infants on target fortification weighed an average of 2,540 g at 36 weeks postmenstrual age, compared with an average weight of 2,170 g among 21 control infants.

“If you use standard fortification you never get [the nutrients] right. Too many nutrients will be outside [the ideal range] and those babies have a high risk of not growing,” Dr. Fusch noted in an interview.

One of the key steps in the study was measuring the protein, fat, and carbohydrate content of the breast milk that each infant received 3 days a week and using those data to guide fortification. Assessment of each breast milk specimen takes about 2 minutes, after which a technician adds the required levels of freshly prepared nutrient supplements to produce a final protein content of 3 g/dL, fat at 4.3 g/dL, and carbohydrate at 8.5 g/dL. The researchers set these levels based on an assumed daily intake of 150 mL/kg of fortified breast milk.

Dr. Fusch and his associates plan additional analyses of the data they collected in this study to look at the impact of target fortification on infant length and head circumference, metabolic responses, body composition, and neurodevelopment out to 18 months of age. They also have launched a larger, multicenter study with a similar design at 10 sites in Europe and 8 sites in North America.

The infants who stand to gain the most from target fortification are those fed donor breast milk, an increasingly popular option when breast milk from the infant’s mother is not available, but also a flawed option because this milk is usually low in protein, said Dr. Fusch, who also holds the Jack Sinclair Chair in Neonatology at the university. Target fortification is not an issue for term infants who feed normally because they usually cry to demand more milk when they lack specific nutrients. Premature infants are much more vulnerable when fed by a nasogastric tube because they will become sated simply by milk volume and then stop eating, even when they ingest an unbalanced nutrient supply.

BALTIMORE – For a premature infant, breast milk straight from Mom or a donor may not be the ideal meal.

The problem is that breast milk is often unbalanced in its content of protein, fat, and carbohydrates, and for a premature neonate fed by a nasogastric tube, unfortified breast milk can provide too little of one nutrient or too much of another. Conventional fortification of breast milk adds a standardized cocktail of nutrients that doesn’t provide an ideal balance for optimal growth.

Frequent analysis of breast milk’s nutrient content and target fortification to tweak the milk to a more ideal nutrient balance may be a way around this problem, and results from a single-center, randomized trial with 85 premature infants showed that this approach led to significantly better infant weights when measured at 36 weeks postmenstrual age, Dr. Christoph Fusch reported at the annual meeting of the Pediatric Academic Societies.

Mitchel L. Zoler/Frontline Medical News

Target fortification of breast milk resulted in an average weight at 36 weeks postmenstrual age of 2,510 g among 42 infants in the intervention group, compared with an average weight of 2,280 g among 43 control infants who received breast milk that underwent routine fortification with a commercial product – a statistically significant difference for the study’s primary endpoint, said Dr. Fusch, professor of pediatrics at McMaster University and director of the neonatal intensive care unit at McMaster Children’s Hospital, both in Hamilton, Ont.

Baseline weights in the two groups of premature infants, who were born at an average of 27 weeks’ gestation and began the study at an average age of about 30 weeks’ postmenstrual age, were 970 g in the controls and 960 g in the infants who received target fortification.

The benefit from target fortification was even more dramatic in the 50% of infants fed on breast milk with the lowest protein content. In this subgroup, the 21 infants on target fortification weighed an average of 2,540 g at 36 weeks postmenstrual age, compared with an average weight of 2,170 g among 21 control infants.

“If you use standard fortification you never get [the nutrients] right. Too many nutrients will be outside [the ideal range] and those babies have a high risk of not growing,” Dr. Fusch noted in an interview.

One of the key steps in the study was measuring the protein, fat, and carbohydrate content of the breast milk that each infant received 3 days a week and using those data to guide fortification. Assessment of each breast milk specimen takes about 2 minutes, after which a technician adds the required levels of freshly prepared nutrient supplements to produce a final protein content of 3 g/dL, fat at 4.3 g/dL, and carbohydrate at 8.5 g/dL. The researchers set these levels based on an assumed daily intake of 150 mL/kg of fortified breast milk.

Dr. Fusch and his associates plan additional analyses of the data they collected in this study to look at the impact of target fortification on infant length and head circumference, metabolic responses, body composition, and neurodevelopment out to 18 months of age. They also have launched a larger, multicenter study with a similar design at 10 sites in Europe and 8 sites in North America.

The infants who stand to gain the most from target fortification are those fed donor breast milk, an increasingly popular option when breast milk from the infant’s mother is not available, but also a flawed option because this milk is usually low in protein, said Dr. Fusch, who also holds the Jack Sinclair Chair in Neonatology at the university. Target fortification is not an issue for term infants who feed normally because they usually cry to demand more milk when they lack specific nutrients. Premature infants are much more vulnerable when fed by a nasogastric tube because they will become sated simply by milk volume and then stop eating, even when they ingest an unbalanced nutrient supply.