Obstetrics

SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.

The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.

Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.

The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.

Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).

The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.

Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.

“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.

Dr. Mesinkovska said she has no relevant financial disclosures.

[email protected]

SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.

The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.

Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.

The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.

Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).

The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.

Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.

“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.

Dr. Mesinkovska said she has no relevant financial disclosures.

[email protected]

SAN FRANCISCO – Pregnancy increases the risk of poor outcomes in melanoma, according to a review of melanoma cases at the Cleveland Clinic.

The effect of pregnancy on melanoma has been debated for more than a decade. Some studies have found evidence of worse outcomes, but others have not. That prompted Dr. Natasha Mesinkovska, a dermatologist at the clinic, and her colleagues to review their own melanoma outcomes over the past 20 years. They compared 49 women who were pregnant or within a year of pregnancy at diagnosis, with 418 women of childbearing age who were not pregnant. All the patients had at least 2 years follow-up.

Mortality (20% vs. 10.3%; P = .06); recurrence (12.5% vs. 1.4%; P < .001); metastasis (25% vs. 12.7%; P = .03); and the use of radiation and chemotherapy were all more common in the pregnancy group. On logistic regression, women who were pregnant or recently pregnant at the time of melanoma diagnosis were 5.1 times more likely to die of the disease than those who weren’t (P = .03), Dr. Mesinkovska reported at the annual meeting of the American Academy of Dermatology.

The findings prompted the investigators to compare histologic specimens from 17 pregnant and 14 nonpregnant women to find an explanation.

Pregnancy melanomas had reduced PD-1 [programmed cell death] expression (18.3 vs. 45 cells per high-power field [hpf]); decreased CD-3 [cluster of differentiation 3] (191.7 vs. 265.7 cells/hpf); and increased CD-3/PD-1 ratios (57.4 vs. 8.3).

The findings were statistically significant and may have treatment implications for the use in recently pregnant women of antibodies against PD-1 cell-surface receptors, a class of biologics that include nivolumab and pembrolizumab, both approved in 2014 for advanced melanoma. With reduced expression of PD-1, tumors arising around pregnancy might not be as sensitive to such agents.

Labeling for both biologics, however, note the risk of fetal harm, and advise the use of effective contraception while on the agents and for several months after their discontinuation. Both agents should also be discontinued during breastfeeding.

“Immune ignorance may predominate in melanoma specimens in pregnancy. Most novel melanoma therapies target immune modulation. There’s a need in some pregnant women for neoadjuvant treatment prior to immunotherapy to convert them to an inflamed phenotype,” Dr. Mesinkovska said.

Dr. Mesinkovska said she has no relevant financial disclosures.

[email protected]

Models predicting the likelihood of a successful VBAC are as accurate for women who have undergone two previous cesarean deliveries as they are for women who have had only one previous cesarean, an analysis of registry data shows.

The Maternal–Fetal Medicine Units Network vaginal birth after cesarean delivery (VBAC) prediction model was created for and validated in women with one prior cesarean delivery.

Analysis of data from 369 women with two prior cesarean deliveries undergoing trial of labor after cesarean (TOLAC) delivery showed the area under the receiver operating characteristic curve was 0.74, compared to 0.75 in the original model for women with one prior cesarean delivery (Obstet. Gynecol. 2015;125:948-52).

“When compared with women who had a failed TOLAC, women with a successful TOLAC had a lower mean BMI, were more likely to have a history of vaginal delivery or VBAC, and were less likely to have a history of recurring indication for cesarean delivery or diabetes,” wrote Dr. Torri D. Metz of the University of Colorado, Aurora, and coauthors. Recurring indication for cesarean delivery was defined as arrest of dilation or descent.

The study was supported grants by the Agency for Healthcare Research and Quality and the National Institutes of Health/National Center for Research Resources Colorado. There were no conflicts of interest declared.

Models predicting the likelihood of a successful VBAC are as accurate for women who have undergone two previous cesarean deliveries as they are for women who have had only one previous cesarean, an analysis of registry data shows.

The Maternal–Fetal Medicine Units Network vaginal birth after cesarean delivery (VBAC) prediction model was created for and validated in women with one prior cesarean delivery.

Analysis of data from 369 women with two prior cesarean deliveries undergoing trial of labor after cesarean (TOLAC) delivery showed the area under the receiver operating characteristic curve was 0.74, compared to 0.75 in the original model for women with one prior cesarean delivery (Obstet. Gynecol. 2015;125:948-52).

“When compared with women who had a failed TOLAC, women with a successful TOLAC had a lower mean BMI, were more likely to have a history of vaginal delivery or VBAC, and were less likely to have a history of recurring indication for cesarean delivery or diabetes,” wrote Dr. Torri D. Metz of the University of Colorado, Aurora, and coauthors. Recurring indication for cesarean delivery was defined as arrest of dilation or descent.

The study was supported grants by the Agency for Healthcare Research and Quality and the National Institutes of Health/National Center for Research Resources Colorado. There were no conflicts of interest declared.

Models predicting the likelihood of a successful VBAC are as accurate for women who have undergone two previous cesarean deliveries as they are for women who have had only one previous cesarean, an analysis of registry data shows.

The Maternal–Fetal Medicine Units Network vaginal birth after cesarean delivery (VBAC) prediction model was created for and validated in women with one prior cesarean delivery.

Analysis of data from 369 women with two prior cesarean deliveries undergoing trial of labor after cesarean (TOLAC) delivery showed the area under the receiver operating characteristic curve was 0.74, compared to 0.75 in the original model for women with one prior cesarean delivery (Obstet. Gynecol. 2015;125:948-52).

“When compared with women who had a failed TOLAC, women with a successful TOLAC had a lower mean BMI, were more likely to have a history of vaginal delivery or VBAC, and were less likely to have a history of recurring indication for cesarean delivery or diabetes,” wrote Dr. Torri D. Metz of the University of Colorado, Aurora, and coauthors. Recurring indication for cesarean delivery was defined as arrest of dilation or descent.

The study was supported grants by the Agency for Healthcare Research and Quality and the National Institutes of Health/National Center for Research Resources Colorado. There were no conflicts of interest declared.

Cell-free DNA (cfDNA) testing performed better than did standard screening plus measurement of nuchal translucency and biochemical analytes for detecting trisomy 21 in a large, prospective, multicenter study of women undergoing routine prenatal screening.

In 15,841 women included in the study, known as the Noninvasive Examination of Trisomy (NEXT) study, the area under the curve (AUC) for trisomy 21 was 0.999 for cell-free DNA testing, compared with 0.958 for standard screening – a statistically significant difference. Trisomy 21 was detected in 38 of 38 cases using cfDNA, compared with 30 of 38 cases using standard screening (sensitivity of 100% vs. 78.9%), Dr. Mary E. Norton of the University of California, San Francisco, and her colleagues reported online in the New England Journal of Medicine.

Further, the false positive rate with cfDNA was nearly 100 times lower than that with standard screening (0.06% vs. 5.4%), and the positive predictive value was 80.9% vs. 3.4%, respectively, the investigators said (N. Engl. J. Med. 2015 April 1 [doi:10.1056/NEJMoal407349]).

Although the study was powered to compare only the detection of trisomy 21, cfDNA also appeared to be better for detecting trisomies 18 and 13, and the lower false-positive rate and higher positive predictive value with cfDNA testing support its use in risk assessment for these trisomies, they said.

Participants in the blinded study, which was conducted at 35 centers in six countries in the United States, Canada, and Europe, were pregnant adult women with a mean age of 31 years and a mean gestational age of 12.5 weeks at the time of testing. The women presented for aneuploidy screening between March 2012 and April 2013 and underwent both cfDNA screening and standard screening, which included measurement of serum pregnancy-associated plasma protein A, total or free beta-subunit of human chorionic gonadotropin, and nuchal translucency.

Birth outcome was determined by diagnostic genetic testing in 557 women, and by newborn examination in the remaining subjects.

Cell-free DNA testing was introduced in 2011 and is reported to be highly effective for detecting trisomy 21.

“In practice, the use of this test could result in a significant reduction in diagnostic procedures,” Dr. Norton and her associates wrote.

They noted, however, that while several large proof-of-principle studies have confirmed the high sensitivity and specificity of cfDNA testing for detecting trisomy 21, few direct, well-powered studies have compared cfDNA testing and standard screening in a routine prenatal screening population. Rather, most studies have included only selected populations of high risk women who were sampled prior to invasive testing.

The current findings demonstrating the value of cfDNA in a general screening population are encouraging, but careful consideration of the screening method and costs is necessary before cfDNA testing can be widely implemented for general prenatal aneuploidy screening, Dr. Norton and her associates said.

Expectations regarding prenatal genetic testing also should be considered, they noted.

“For trisomy 21 and other common aneuploidies, cfDNA testing represents a highly accurate screening option … however, maternal serum and nuchal translucency screening can identify risk for a broad array of abnormalities that are not detectable on cfDNA testing,” they said, explaining that cases of trisomy 21 comprised just over 50% of aneuploidy in the study population and that women who desire a comprehensive assessment may prefer to undergo karyotyping or chromosomal microarray analysis.

This study is strengthened by the large sample size in a general prenatal screening population but is limited by the comparison between cfDNA testing and only standard first-trimester screening, the investigators said, explaining that methods such as integrated first- and second-trimester screening with nuchal translucency and biochemical analytes have higher sensitivity and specificity.

Further, the trisomy 21 detection rate of standard screening in this study was 79%, which is lower than the 82%-87% seen in a prior study.

“It is possible that standard screening has worse performance in clinical practice than under the stringent experimental conditions in which previously reported data were collected,” Dr. Norton and her associates noted.

This study was supported by Ariosa Diagnostics and the Perinatal Quality Foundation. Dr. Norton, in addition to most of her coauthors, reported receiving grant or other support from Ariosa. Multiple authors also reported a financial relationship with Natera outside the submitted work. Additionally, Howard Cuckle, Ph.D., is director of Genome Ltd., a provider of prenatal screening services including noninvasive prenatal testing, and Dr. Ronald J. Wapner reported relationships with Illumine and Sequenom, in addition to Ariosa and Natera. The remaining authors had no relevant financial disclosures.

Cell-free DNA (cfDNA) testing performed better than did standard screening plus measurement of nuchal translucency and biochemical analytes for detecting trisomy 21 in a large, prospective, multicenter study of women undergoing routine prenatal screening.

In 15,841 women included in the study, known as the Noninvasive Examination of Trisomy (NEXT) study, the area under the curve (AUC) for trisomy 21 was 0.999 for cell-free DNA testing, compared with 0.958 for standard screening – a statistically significant difference. Trisomy 21 was detected in 38 of 38 cases using cfDNA, compared with 30 of 38 cases using standard screening (sensitivity of 100% vs. 78.9%), Dr. Mary E. Norton of the University of California, San Francisco, and her colleagues reported online in the New England Journal of Medicine.

Further, the false positive rate with cfDNA was nearly 100 times lower than that with standard screening (0.06% vs. 5.4%), and the positive predictive value was 80.9% vs. 3.4%, respectively, the investigators said (N. Engl. J. Med. 2015 April 1 [doi:10.1056/NEJMoal407349]).

Although the study was powered to compare only the detection of trisomy 21, cfDNA also appeared to be better for detecting trisomies 18 and 13, and the lower false-positive rate and higher positive predictive value with cfDNA testing support its use in risk assessment for these trisomies, they said.

Participants in the blinded study, which was conducted at 35 centers in six countries in the United States, Canada, and Europe, were pregnant adult women with a mean age of 31 years and a mean gestational age of 12.5 weeks at the time of testing. The women presented for aneuploidy screening between March 2012 and April 2013 and underwent both cfDNA screening and standard screening, which included measurement of serum pregnancy-associated plasma protein A, total or free beta-subunit of human chorionic gonadotropin, and nuchal translucency.

Birth outcome was determined by diagnostic genetic testing in 557 women, and by newborn examination in the remaining subjects.

Cell-free DNA testing was introduced in 2011 and is reported to be highly effective for detecting trisomy 21.

“In practice, the use of this test could result in a significant reduction in diagnostic procedures,” Dr. Norton and her associates wrote.

They noted, however, that while several large proof-of-principle studies have confirmed the high sensitivity and specificity of cfDNA testing for detecting trisomy 21, few direct, well-powered studies have compared cfDNA testing and standard screening in a routine prenatal screening population. Rather, most studies have included only selected populations of high risk women who were sampled prior to invasive testing.

The current findings demonstrating the value of cfDNA in a general screening population are encouraging, but careful consideration of the screening method and costs is necessary before cfDNA testing can be widely implemented for general prenatal aneuploidy screening, Dr. Norton and her associates said.

Expectations regarding prenatal genetic testing also should be considered, they noted.

“For trisomy 21 and other common aneuploidies, cfDNA testing represents a highly accurate screening option … however, maternal serum and nuchal translucency screening can identify risk for a broad array of abnormalities that are not detectable on cfDNA testing,” they said, explaining that cases of trisomy 21 comprised just over 50% of aneuploidy in the study population and that women who desire a comprehensive assessment may prefer to undergo karyotyping or chromosomal microarray analysis.

This study is strengthened by the large sample size in a general prenatal screening population but is limited by the comparison between cfDNA testing and only standard first-trimester screening, the investigators said, explaining that methods such as integrated first- and second-trimester screening with nuchal translucency and biochemical analytes have higher sensitivity and specificity.

Further, the trisomy 21 detection rate of standard screening in this study was 79%, which is lower than the 82%-87% seen in a prior study.

“It is possible that standard screening has worse performance in clinical practice than under the stringent experimental conditions in which previously reported data were collected,” Dr. Norton and her associates noted.

This study was supported by Ariosa Diagnostics and the Perinatal Quality Foundation. Dr. Norton, in addition to most of her coauthors, reported receiving grant or other support from Ariosa. Multiple authors also reported a financial relationship with Natera outside the submitted work. Additionally, Howard Cuckle, Ph.D., is director of Genome Ltd., a provider of prenatal screening services including noninvasive prenatal testing, and Dr. Ronald J. Wapner reported relationships with Illumine and Sequenom, in addition to Ariosa and Natera. The remaining authors had no relevant financial disclosures.

Cell-free DNA (cfDNA) testing performed better than did standard screening plus measurement of nuchal translucency and biochemical analytes for detecting trisomy 21 in a large, prospective, multicenter study of women undergoing routine prenatal screening.

In 15,841 women included in the study, known as the Noninvasive Examination of Trisomy (NEXT) study, the area under the curve (AUC) for trisomy 21 was 0.999 for cell-free DNA testing, compared with 0.958 for standard screening – a statistically significant difference. Trisomy 21 was detected in 38 of 38 cases using cfDNA, compared with 30 of 38 cases using standard screening (sensitivity of 100% vs. 78.9%), Dr. Mary E. Norton of the University of California, San Francisco, and her colleagues reported online in the New England Journal of Medicine.

Further, the false positive rate with cfDNA was nearly 100 times lower than that with standard screening (0.06% vs. 5.4%), and the positive predictive value was 80.9% vs. 3.4%, respectively, the investigators said (N. Engl. J. Med. 2015 April 1 [doi:10.1056/NEJMoal407349]).

Although the study was powered to compare only the detection of trisomy 21, cfDNA also appeared to be better for detecting trisomies 18 and 13, and the lower false-positive rate and higher positive predictive value with cfDNA testing support its use in risk assessment for these trisomies, they said.

Participants in the blinded study, which was conducted at 35 centers in six countries in the United States, Canada, and Europe, were pregnant adult women with a mean age of 31 years and a mean gestational age of 12.5 weeks at the time of testing. The women presented for aneuploidy screening between March 2012 and April 2013 and underwent both cfDNA screening and standard screening, which included measurement of serum pregnancy-associated plasma protein A, total or free beta-subunit of human chorionic gonadotropin, and nuchal translucency.

Birth outcome was determined by diagnostic genetic testing in 557 women, and by newborn examination in the remaining subjects.

Cell-free DNA testing was introduced in 2011 and is reported to be highly effective for detecting trisomy 21.

“In practice, the use of this test could result in a significant reduction in diagnostic procedures,” Dr. Norton and her associates wrote.

They noted, however, that while several large proof-of-principle studies have confirmed the high sensitivity and specificity of cfDNA testing for detecting trisomy 21, few direct, well-powered studies have compared cfDNA testing and standard screening in a routine prenatal screening population. Rather, most studies have included only selected populations of high risk women who were sampled prior to invasive testing.

The current findings demonstrating the value of cfDNA in a general screening population are encouraging, but careful consideration of the screening method and costs is necessary before cfDNA testing can be widely implemented for general prenatal aneuploidy screening, Dr. Norton and her associates said.

Expectations regarding prenatal genetic testing also should be considered, they noted.

“For trisomy 21 and other common aneuploidies, cfDNA testing represents a highly accurate screening option … however, maternal serum and nuchal translucency screening can identify risk for a broad array of abnormalities that are not detectable on cfDNA testing,” they said, explaining that cases of trisomy 21 comprised just over 50% of aneuploidy in the study population and that women who desire a comprehensive assessment may prefer to undergo karyotyping or chromosomal microarray analysis.

This study is strengthened by the large sample size in a general prenatal screening population but is limited by the comparison between cfDNA testing and only standard first-trimester screening, the investigators said, explaining that methods such as integrated first- and second-trimester screening with nuchal translucency and biochemical analytes have higher sensitivity and specificity.

Further, the trisomy 21 detection rate of standard screening in this study was 79%, which is lower than the 82%-87% seen in a prior study.

“It is possible that standard screening has worse performance in clinical practice than under the stringent experimental conditions in which previously reported data were collected,” Dr. Norton and her associates noted.

This study was supported by Ariosa Diagnostics and the Perinatal Quality Foundation. Dr. Norton, in addition to most of her coauthors, reported receiving grant or other support from Ariosa. Multiple authors also reported a financial relationship with Natera outside the submitted work. Additionally, Howard Cuckle, Ph.D., is director of Genome Ltd., a provider of prenatal screening services including noninvasive prenatal testing, and Dr. Ronald J. Wapner reported relationships with Illumine and Sequenom, in addition to Ariosa and Natera. The remaining authors had no relevant financial disclosures.

Case: Patient asks for transplantation referral
During an annual ObGyn visit, a 28-year-old G0 with congenital absence of the uterus excitedly tells you about the news report of the first birth following uterus transplantation. She always has dreamed of becoming pregnant, and this medical breakthrough has spurred her imagination of what might be. You ask if she would consider adoption or a gestational carrier. Responding that she prefers to carry her own pregnancy, she asks you to refer her to a uterus transplantation program. You promise to look into this option for her. As she opens the door to leave your office, she mentions that her mother has volunteered to be the uterus donor.

Later, you have misgivings about making a referral for uterus transplantation. You wonder: Is this procedure an appropriate use of health care resources? Do its risks outweigh the benefits?

In September 2014, a 36-year-old Swedish woman gave birth following uterus transplantation. A 61-year-old family friend donated the uterus for the procedure.¹ Prior to this breakthrough, women without a uterus had 3 reproductive alternatives: remain childless, adopt a child, or use a gestational carrier to give birth to their child. In many countries and some religions there are prohibitions against the use of a gestational carrier, leaving adoption as the only option to parenthood.

The first successful uterus transplantation did not occur by serendipity; a decade of careful work led to this breakthrough.^2–4 Remarkably, it is now proven that this type of transplantation can result in the successful birth of a baby—but at what cost?

The Brännström Uterus Transplantation Program: A medical breakthrough
Dr. Mats Brännström at the University of Gothenburg, Sweden, is the leader of the courageous and innovative team that developed the world’s first successful uterus transplantation program. The team required a broad range of expertise and skills and included physicians, scientists, and support staff from Sahlgrenska University Hospital and Stockholm IVF in Sweden; University of Valencia, Spain; Griffith University, Australia; and the Cleveland Clinic, Florida. Two recent publications report on the outcomes of the first 9 uterus transplants.^5,6

The successful protocol. The first step in the program is an exhaustive medical and psychosocial evaluation of the prospective uterus donor and recipient. Among the first 9 uterus recipients, 8 women had congenital absence of the uterus and 1 woman had a hysterectomy for cervical cancer. The uterus donors were mothers (in 5 cases), a mother-in-law, a sister, an aunt, and a friend.

After the recipient is approved for uterus transplantation, she undergoes in vitro fertilization (IVF) with cryopreservation of all embryos. IVF is recommended because it may not be possible to include the fallopian tubes in the uterus transplant or the tubes may not function properly following transplantation. The donor organ is harvested, using a modified radical hysterectomy with extended vascular pedicles, and transplanted into the pelvis of the recipient.

Following transplantation, immunosuppressive medications are prescribed daily to reduce the risk of organ rejection. The recipient is followed on a regular basis with physical examination and cervical biopsy to identify histologic markers of organ rejection. Episodes of rejection are treated with glucocorticoids and adjustment in the dose of immunosuppression medications. Fertility treatment with the recipient’s previously cryopreserved embryo begins 1 year following transplantation.

A unique feature of uterus transplantation is that the organ can be removed after childbearing is complete, thereby limiting lifetime exposure to immunosuppressive medications.

Uterus transplantation: Surgical folly?
Transplantation of a uterus involves major surgery. The inescapable reality is that the procedure will cause complications in some donors and recipients.

Specific complications faced. In the Brännström series, 1 uterus donor developed a postoperative ureterovaginal fistula, likely caused by extensive dissection of her ureters. This donor needed an additional operation to repair the fistula. Two of the 9 uterus transplants failed. One uterus was removed from the recipient 3 days after transplantation due to vascular occlusion and 1 uterus was removed 105 days after transplantation due to chronic infection resistant to antibiotic treatment. Seven of the transplants were successful and functioning in situ 12 months after transplantation as evidenced by regular menstrual bleeding. Five of the 7 recipients had rejection episodes, as demonstrated by the histology of cervix biopsies. Two of the recipients had 3 episodes of rejection. The rejection episodes were treated successfully with glucocorticoids and adjustment of immunosuppression medications.

Pregnancy in women with uterus transplantation is high risk because of the complications caused by immunosuppressive drugs and the high blood flow through the vascular grafts.^7–9 In the Brännström series, the agents utilized for immunosuppression included mycophenolate mofetil, azathioprine, tacrolimus, and glucocorticoids. Mycophenolate mofetil is a potent teratogen and routinely is discontinued prior to initiating attempts at pregnancy. Azathioprine is associated with an increased rate of congenital anomalies, but the benefits of this immunosuppressive are believed to outweigh the risks for most pregnant women with an organ transplant. Tacrolimus increases the risk of developing hypertension, preeclampsia, and intrauterine growth restriction during pregnancy.

In the Brännström case report, the woman who became pregnant following uterus transplantation took tacrolimus and azathioprine to prevent organ rejection both before and during her pregnancy. Not unexpectedly, she developed preeclampsia with severe features at 31 weeks and 5 days. After admission to the hospital, a worrisome fetal heart rate pattern developed and a cesarean delivery was performed. The newborn male weighed 1,775 g, and no congenital anomalies were observed. During pregnancy, blood flow to the uterus is in the range of 500 mL/min, the equivalent of 1 unit of whole blood per minute.¹⁰ This torrential pulsating flow may increase the risk of a vascular catastrophe such as the rupture of a major artery at one of the graft anastomoses, potentially causing the death of the fetus or mother. Much more experience will be needed to fully characterize the pattern of pregnancy complications that occurs following uterus transplantation.

The cost issue. Uterus transplantation is an extremely expensive medical procedure. In the United States each transplantation is likely to cost hundreds of thousands of dollars. Health care resources used to support uterus transplantation are not available for other pressing medical needs. Given that it is an experimental procedure, it is unlikely that health insurance will reimburse the costs of the medical care. Transplantation programs will need to seek major donors to support the costs, as was done in the Brännström program, or identify patients capable of paying for the transplant. If programs plan to have most patients pay for the procedure, bioethical concerns of equitable access and fair selection of recipients will need to be addressed.

Ethics. Uterus transplantation raises many bioethical concerns and programs need to engage biomedical ethicists to guide their activities.^11–13 Careful attention to thorough informed consent, risk-benefit analysis, equitable access, and fair selection of participants will be critical to running an ethical program. To reduce the risks of the procedure, programs likely will explore the use of uteri obtained from women who are brain dead or cadavers to spare altruistic living donors from undergoing hysterectomy surgery.

“Group of fools” or Nobel Prize in wait?
On December 23, 1954, the first successful kidney transplant was performed by Dr. Joseph E. ­Murray and his team at the Peter Bent Brigham Hospital, a predecessor to the Brigham and Women’s Hospital.¹⁴ His small group of physicians worked for years to perfect the kidney transplantation technique in the laboratory prior to attempting the case. A key to their success was the decision to perform the transplant with identical twins as the donor and recipient.

In the 1950s there was great controversy about whether kidney transplantation was a medical breakthrough or surgical folly. The lead surgical team was referred to as the “group of fools” by some colleagues. But Dr. Murray and his team succeeded in their efforts and opened the field of solid organ transplant. Recognizing the importance of his accomplishment, the Nobel Prize Committee awarded Dr. Murray the 1990 Nobel Prize in Physiology or Medicine. Dr. E. Donnell Thomas, a co-recipient of the award, was simultaneously recognized for developing bone marrow transplantation as a treatment for leukemia.

A medical breakthrough…
Organ transplantation medicine initially focused on the treatment of life-threatening diseases, including kidney, heart, lung, and liver failure. With recent innovations in composite tissue transplants, including face and limb, transplantation medicine is evolving to expand its focus to the repair of functional deficits that are not life threatening but do significantly impact quality of life. Uterus transplantation is an example of the new era of using transplants to repair functional deficits. The clinicians and patients involved in these innovative programs are courageous pioneers opening new vistas and helping to realize previously impossible dreams. In our time, many stakeholders are likely to conclude that uterus transplantation is a surgical folly. However, I predict that our children will conclude that uterus transplantation represents a medical breakthrough.

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Case: Patient asks for transplantation referral
During an annual ObGyn visit, a 28-year-old G0 with congenital absence of the uterus excitedly tells you about the news report of the first birth following uterus transplantation. She always has dreamed of becoming pregnant, and this medical breakthrough has spurred her imagination of what might be. You ask if she would consider adoption or a gestational carrier. Responding that she prefers to carry her own pregnancy, she asks you to refer her to a uterus transplantation program. You promise to look into this option for her. As she opens the door to leave your office, she mentions that her mother has volunteered to be the uterus donor.

Later, you have misgivings about making a referral for uterus transplantation. You wonder: Is this procedure an appropriate use of health care resources? Do its risks outweigh the benefits?

In September 2014, a 36-year-old Swedish woman gave birth following uterus transplantation. A 61-year-old family friend donated the uterus for the procedure.¹ Prior to this breakthrough, women without a uterus had 3 reproductive alternatives: remain childless, adopt a child, or use a gestational carrier to give birth to their child. In many countries and some religions there are prohibitions against the use of a gestational carrier, leaving adoption as the only option to parenthood.

The first successful uterus transplantation did not occur by serendipity; a decade of careful work led to this breakthrough.^2–4 Remarkably, it is now proven that this type of transplantation can result in the successful birth of a baby—but at what cost?

The Brännström Uterus Transplantation Program: A medical breakthrough
Dr. Mats Brännström at the University of Gothenburg, Sweden, is the leader of the courageous and innovative team that developed the world’s first successful uterus transplantation program. The team required a broad range of expertise and skills and included physicians, scientists, and support staff from Sahlgrenska University Hospital and Stockholm IVF in Sweden; University of Valencia, Spain; Griffith University, Australia; and the Cleveland Clinic, Florida. Two recent publications report on the outcomes of the first 9 uterus transplants.^5,6

The successful protocol. The first step in the program is an exhaustive medical and psychosocial evaluation of the prospective uterus donor and recipient. Among the first 9 uterus recipients, 8 women had congenital absence of the uterus and 1 woman had a hysterectomy for cervical cancer. The uterus donors were mothers (in 5 cases), a mother-in-law, a sister, an aunt, and a friend.

After the recipient is approved for uterus transplantation, she undergoes in vitro fertilization (IVF) with cryopreservation of all embryos. IVF is recommended because it may not be possible to include the fallopian tubes in the uterus transplant or the tubes may not function properly following transplantation. The donor organ is harvested, using a modified radical hysterectomy with extended vascular pedicles, and transplanted into the pelvis of the recipient.

Following transplantation, immunosuppressive medications are prescribed daily to reduce the risk of organ rejection. The recipient is followed on a regular basis with physical examination and cervical biopsy to identify histologic markers of organ rejection. Episodes of rejection are treated with glucocorticoids and adjustment in the dose of immunosuppression medications. Fertility treatment with the recipient’s previously cryopreserved embryo begins 1 year following transplantation.

A unique feature of uterus transplantation is that the organ can be removed after childbearing is complete, thereby limiting lifetime exposure to immunosuppressive medications.

Uterus transplantation: Surgical folly?
Transplantation of a uterus involves major surgery. The inescapable reality is that the procedure will cause complications in some donors and recipients.

Specific complications faced. In the Brännström series, 1 uterus donor developed a postoperative ureterovaginal fistula, likely caused by extensive dissection of her ureters. This donor needed an additional operation to repair the fistula. Two of the 9 uterus transplants failed. One uterus was removed from the recipient 3 days after transplantation due to vascular occlusion and 1 uterus was removed 105 days after transplantation due to chronic infection resistant to antibiotic treatment. Seven of the transplants were successful and functioning in situ 12 months after transplantation as evidenced by regular menstrual bleeding. Five of the 7 recipients had rejection episodes, as demonstrated by the histology of cervix biopsies. Two of the recipients had 3 episodes of rejection. The rejection episodes were treated successfully with glucocorticoids and adjustment of immunosuppression medications.

Pregnancy in women with uterus transplantation is high risk because of the complications caused by immunosuppressive drugs and the high blood flow through the vascular grafts.^7–9 In the Brännström series, the agents utilized for immunosuppression included mycophenolate mofetil, azathioprine, tacrolimus, and glucocorticoids. Mycophenolate mofetil is a potent teratogen and routinely is discontinued prior to initiating attempts at pregnancy. Azathioprine is associated with an increased rate of congenital anomalies, but the benefits of this immunosuppressive are believed to outweigh the risks for most pregnant women with an organ transplant. Tacrolimus increases the risk of developing hypertension, preeclampsia, and intrauterine growth restriction during pregnancy.

In the Brännström case report, the woman who became pregnant following uterus transplantation took tacrolimus and azathioprine to prevent organ rejection both before and during her pregnancy. Not unexpectedly, she developed preeclampsia with severe features at 31 weeks and 5 days. After admission to the hospital, a worrisome fetal heart rate pattern developed and a cesarean delivery was performed. The newborn male weighed 1,775 g, and no congenital anomalies were observed. During pregnancy, blood flow to the uterus is in the range of 500 mL/min, the equivalent of 1 unit of whole blood per minute.¹⁰ This torrential pulsating flow may increase the risk of a vascular catastrophe such as the rupture of a major artery at one of the graft anastomoses, potentially causing the death of the fetus or mother. Much more experience will be needed to fully characterize the pattern of pregnancy complications that occurs following uterus transplantation.

The cost issue. Uterus transplantation is an extremely expensive medical procedure. In the United States each transplantation is likely to cost hundreds of thousands of dollars. Health care resources used to support uterus transplantation are not available for other pressing medical needs. Given that it is an experimental procedure, it is unlikely that health insurance will reimburse the costs of the medical care. Transplantation programs will need to seek major donors to support the costs, as was done in the Brännström program, or identify patients capable of paying for the transplant. If programs plan to have most patients pay for the procedure, bioethical concerns of equitable access and fair selection of recipients will need to be addressed.

Ethics. Uterus transplantation raises many bioethical concerns and programs need to engage biomedical ethicists to guide their activities.^11–13 Careful attention to thorough informed consent, risk-benefit analysis, equitable access, and fair selection of participants will be critical to running an ethical program. To reduce the risks of the procedure, programs likely will explore the use of uteri obtained from women who are brain dead or cadavers to spare altruistic living donors from undergoing hysterectomy surgery.

“Group of fools” or Nobel Prize in wait?
On December 23, 1954, the first successful kidney transplant was performed by Dr. Joseph E. ­Murray and his team at the Peter Bent Brigham Hospital, a predecessor to the Brigham and Women’s Hospital.¹⁴ His small group of physicians worked for years to perfect the kidney transplantation technique in the laboratory prior to attempting the case. A key to their success was the decision to perform the transplant with identical twins as the donor and recipient.

In the 1950s there was great controversy about whether kidney transplantation was a medical breakthrough or surgical folly. The lead surgical team was referred to as the “group of fools” by some colleagues. But Dr. Murray and his team succeeded in their efforts and opened the field of solid organ transplant. Recognizing the importance of his accomplishment, the Nobel Prize Committee awarded Dr. Murray the 1990 Nobel Prize in Physiology or Medicine. Dr. E. Donnell Thomas, a co-recipient of the award, was simultaneously recognized for developing bone marrow transplantation as a treatment for leukemia.

A medical breakthrough…
Organ transplantation medicine initially focused on the treatment of life-threatening diseases, including kidney, heart, lung, and liver failure. With recent innovations in composite tissue transplants, including face and limb, transplantation medicine is evolving to expand its focus to the repair of functional deficits that are not life threatening but do significantly impact quality of life. Uterus transplantation is an example of the new era of using transplants to repair functional deficits. The clinicians and patients involved in these innovative programs are courageous pioneers opening new vistas and helping to realize previously impossible dreams. In our time, many stakeholders are likely to conclude that uterus transplantation is a surgical folly. However, I predict that our children will conclude that uterus transplantation represents a medical breakthrough.

Share your thoughts on this article! Send your Letter to the Editor to  Please include your name and the city and state in which you practice.

Weigh in at the Quick Poll on the homepage. Send your answers to these cases and any comments to [email protected]. Please include your name and the city and state in which you practice.

Case: Patient asks for transplantation referral
During an annual ObGyn visit, a 28-year-old G0 with congenital absence of the uterus excitedly tells you about the news report of the first birth following uterus transplantation. She always has dreamed of becoming pregnant, and this medical breakthrough has spurred her imagination of what might be. You ask if she would consider adoption or a gestational carrier. Responding that she prefers to carry her own pregnancy, she asks you to refer her to a uterus transplantation program. You promise to look into this option for her. As she opens the door to leave your office, she mentions that her mother has volunteered to be the uterus donor.

Later, you have misgivings about making a referral for uterus transplantation. You wonder: Is this procedure an appropriate use of health care resources? Do its risks outweigh the benefits?

In September 2014, a 36-year-old Swedish woman gave birth following uterus transplantation. A 61-year-old family friend donated the uterus for the procedure.¹ Prior to this breakthrough, women without a uterus had 3 reproductive alternatives: remain childless, adopt a child, or use a gestational carrier to give birth to their child. In many countries and some religions there are prohibitions against the use of a gestational carrier, leaving adoption as the only option to parenthood.

The first successful uterus transplantation did not occur by serendipity; a decade of careful work led to this breakthrough.^2–4 Remarkably, it is now proven that this type of transplantation can result in the successful birth of a baby—but at what cost?

The Brännström Uterus Transplantation Program: A medical breakthrough
Dr. Mats Brännström at the University of Gothenburg, Sweden, is the leader of the courageous and innovative team that developed the world’s first successful uterus transplantation program. The team required a broad range of expertise and skills and included physicians, scientists, and support staff from Sahlgrenska University Hospital and Stockholm IVF in Sweden; University of Valencia, Spain; Griffith University, Australia; and the Cleveland Clinic, Florida. Two recent publications report on the outcomes of the first 9 uterus transplants.^5,6

The successful protocol. The first step in the program is an exhaustive medical and psychosocial evaluation of the prospective uterus donor and recipient. Among the first 9 uterus recipients, 8 women had congenital absence of the uterus and 1 woman had a hysterectomy for cervical cancer. The uterus donors were mothers (in 5 cases), a mother-in-law, a sister, an aunt, and a friend.

After the recipient is approved for uterus transplantation, she undergoes in vitro fertilization (IVF) with cryopreservation of all embryos. IVF is recommended because it may not be possible to include the fallopian tubes in the uterus transplant or the tubes may not function properly following transplantation. The donor organ is harvested, using a modified radical hysterectomy with extended vascular pedicles, and transplanted into the pelvis of the recipient.

Following transplantation, immunosuppressive medications are prescribed daily to reduce the risk of organ rejection. The recipient is followed on a regular basis with physical examination and cervical biopsy to identify histologic markers of organ rejection. Episodes of rejection are treated with glucocorticoids and adjustment in the dose of immunosuppression medications. Fertility treatment with the recipient’s previously cryopreserved embryo begins 1 year following transplantation.

A unique feature of uterus transplantation is that the organ can be removed after childbearing is complete, thereby limiting lifetime exposure to immunosuppressive medications.

Uterus transplantation: Surgical folly?
Transplantation of a uterus involves major surgery. The inescapable reality is that the procedure will cause complications in some donors and recipients.

Specific complications faced. In the Brännström series, 1 uterus donor developed a postoperative ureterovaginal fistula, likely caused by extensive dissection of her ureters. This donor needed an additional operation to repair the fistula. Two of the 9 uterus transplants failed. One uterus was removed from the recipient 3 days after transplantation due to vascular occlusion and 1 uterus was removed 105 days after transplantation due to chronic infection resistant to antibiotic treatment. Seven of the transplants were successful and functioning in situ 12 months after transplantation as evidenced by regular menstrual bleeding. Five of the 7 recipients had rejection episodes, as demonstrated by the histology of cervix biopsies. Two of the recipients had 3 episodes of rejection. The rejection episodes were treated successfully with glucocorticoids and adjustment of immunosuppression medications.

Pregnancy in women with uterus transplantation is high risk because of the complications caused by immunosuppressive drugs and the high blood flow through the vascular grafts.^7–9 In the Brännström series, the agents utilized for immunosuppression included mycophenolate mofetil, azathioprine, tacrolimus, and glucocorticoids. Mycophenolate mofetil is a potent teratogen and routinely is discontinued prior to initiating attempts at pregnancy. Azathioprine is associated with an increased rate of congenital anomalies, but the benefits of this immunosuppressive are believed to outweigh the risks for most pregnant women with an organ transplant. Tacrolimus increases the risk of developing hypertension, preeclampsia, and intrauterine growth restriction during pregnancy.

In the Brännström case report, the woman who became pregnant following uterus transplantation took tacrolimus and azathioprine to prevent organ rejection both before and during her pregnancy. Not unexpectedly, she developed preeclampsia with severe features at 31 weeks and 5 days. After admission to the hospital, a worrisome fetal heart rate pattern developed and a cesarean delivery was performed. The newborn male weighed 1,775 g, and no congenital anomalies were observed. During pregnancy, blood flow to the uterus is in the range of 500 mL/min, the equivalent of 1 unit of whole blood per minute.¹⁰ This torrential pulsating flow may increase the risk of a vascular catastrophe such as the rupture of a major artery at one of the graft anastomoses, potentially causing the death of the fetus or mother. Much more experience will be needed to fully characterize the pattern of pregnancy complications that occurs following uterus transplantation.

The cost issue. Uterus transplantation is an extremely expensive medical procedure. In the United States each transplantation is likely to cost hundreds of thousands of dollars. Health care resources used to support uterus transplantation are not available for other pressing medical needs. Given that it is an experimental procedure, it is unlikely that health insurance will reimburse the costs of the medical care. Transplantation programs will need to seek major donors to support the costs, as was done in the Brännström program, or identify patients capable of paying for the transplant. If programs plan to have most patients pay for the procedure, bioethical concerns of equitable access and fair selection of recipients will need to be addressed.

Ethics. Uterus transplantation raises many bioethical concerns and programs need to engage biomedical ethicists to guide their activities.^11–13 Careful attention to thorough informed consent, risk-benefit analysis, equitable access, and fair selection of participants will be critical to running an ethical program. To reduce the risks of the procedure, programs likely will explore the use of uteri obtained from women who are brain dead or cadavers to spare altruistic living donors from undergoing hysterectomy surgery.

“Group of fools” or Nobel Prize in wait?
On December 23, 1954, the first successful kidney transplant was performed by Dr. Joseph E. ­Murray and his team at the Peter Bent Brigham Hospital, a predecessor to the Brigham and Women’s Hospital.¹⁴ His small group of physicians worked for years to perfect the kidney transplantation technique in the laboratory prior to attempting the case. A key to their success was the decision to perform the transplant with identical twins as the donor and recipient.

In the 1950s there was great controversy about whether kidney transplantation was a medical breakthrough or surgical folly. The lead surgical team was referred to as the “group of fools” by some colleagues. But Dr. Murray and his team succeeded in their efforts and opened the field of solid organ transplant. Recognizing the importance of his accomplishment, the Nobel Prize Committee awarded Dr. Murray the 1990 Nobel Prize in Physiology or Medicine. Dr. E. Donnell Thomas, a co-recipient of the award, was simultaneously recognized for developing bone marrow transplantation as a treatment for leukemia.

A medical breakthrough…
Organ transplantation medicine initially focused on the treatment of life-threatening diseases, including kidney, heart, lung, and liver failure. With recent innovations in composite tissue transplants, including face and limb, transplantation medicine is evolving to expand its focus to the repair of functional deficits that are not life threatening but do significantly impact quality of life. Uterus transplantation is an example of the new era of using transplants to repair functional deficits. The clinicians and patients involved in these innovative programs are courageous pioneers opening new vistas and helping to realize previously impossible dreams. In our time, many stakeholders are likely to conclude that uterus transplantation is a surgical folly. However, I predict that our children will conclude that uterus transplantation represents a medical breakthrough.

Share your thoughts on this article! Send your Letter to the Editor to  Please include your name and the city and state in which you practice.

Weigh in at the Quick Poll on the homepage. Send your answers to these cases and any comments to [email protected]. Please include your name and the city and state in which you practice.

Newborns of women who have gestational diabetes treated with glyburide appear to be at increased risk for admission to the neonatal intensive care unit, respiratory distress, hypoglycemia, birth injury, and large for gestational age status, compared with newborns of women treated with insulin, according to a report published March 30 in JAMA Pediatrics.

In recent years, off-label use of glyburide for gestational diabetes has risen dramatically in the United States. A few small clinical trials and observational studies have suggested that the agent is associated with poorer neonatal outcomes than insulin. Currently, insulin is the only pharmacologic treatment approved for the treatment of gestational diabetes mellitus by the Food and Drug Administration and endorsed by the American Diabetes Association.

To examine the issue in a study population large enough to detect small, but clinically important, differences between the two treatments, researchers performed a retrospective cohort study involving 9,173 mother/infant pairs enrolled in a health plan database that covered approximately 30 million patients per year across the United States.

Compared with insulin, glyburide was associated with an increased risk in the newborns of NICU admission (adjusted relative risk, 1.41), respiratory distress (aRR, 1.63), neonatal hypoglycemia (aRR, 1.40), birth injury (aRR, 1.35), and large for gestation age status (aRR, 1.43).

Glyburide was not associated with an increased risk of neonatal jaundice, obstetric trauma, or preterm birth, the investigators wrote (JAMA Pediatr. 2015 March 30 [doi:10.1001/jamapediatrics.2015.74]).

The study population included women (average age, 33.5 years) who delivered singleton live-born infants in 2000-2011 and who filed pharmacy claims for either glyburide (4,982 patients) or insulin (4,191 patients) during the 150 days preceding delivery.

The mean duration of treatment was 50.4 days with glyburide and 54.1 days with insulin.

The proportion of women treated with glyburide rose from 8.5% at the beginning of the study period to 64.4% at the end, wrote Wendy Camelo Castillo, Ph.D., of the department of pharmaceutical health services research, University of Maryland, Baltimore, and her associates.

Glyburide’s link to adverse outcomes “demands further attention” and suggests that women treated with the drug are not achieving adequate glucose control, the researchers wrote.

The Agency for Healthcare Research and Quality and the University of North Carolina at Chapel Hill supported the study. Dr. Camelo Castillo reported having no financial disclosures; her associates reported financial ties to varous pharmaceutical companies.

Newborns of women who have gestational diabetes treated with glyburide appear to be at increased risk for admission to the neonatal intensive care unit, respiratory distress, hypoglycemia, birth injury, and large for gestational age status, compared with newborns of women treated with insulin, according to a report published March 30 in JAMA Pediatrics.

In recent years, off-label use of glyburide for gestational diabetes has risen dramatically in the United States. A few small clinical trials and observational studies have suggested that the agent is associated with poorer neonatal outcomes than insulin. Currently, insulin is the only pharmacologic treatment approved for the treatment of gestational diabetes mellitus by the Food and Drug Administration and endorsed by the American Diabetes Association.

To examine the issue in a study population large enough to detect small, but clinically important, differences between the two treatments, researchers performed a retrospective cohort study involving 9,173 mother/infant pairs enrolled in a health plan database that covered approximately 30 million patients per year across the United States.

Compared with insulin, glyburide was associated with an increased risk in the newborns of NICU admission (adjusted relative risk, 1.41), respiratory distress (aRR, 1.63), neonatal hypoglycemia (aRR, 1.40), birth injury (aRR, 1.35), and large for gestation age status (aRR, 1.43).

Glyburide was not associated with an increased risk of neonatal jaundice, obstetric trauma, or preterm birth, the investigators wrote (JAMA Pediatr. 2015 March 30 [doi:10.1001/jamapediatrics.2015.74]).

The study population included women (average age, 33.5 years) who delivered singleton live-born infants in 2000-2011 and who filed pharmacy claims for either glyburide (4,982 patients) or insulin (4,191 patients) during the 150 days preceding delivery.

The mean duration of treatment was 50.4 days with glyburide and 54.1 days with insulin.

The proportion of women treated with glyburide rose from 8.5% at the beginning of the study period to 64.4% at the end, wrote Wendy Camelo Castillo, Ph.D., of the department of pharmaceutical health services research, University of Maryland, Baltimore, and her associates.

Glyburide’s link to adverse outcomes “demands further attention” and suggests that women treated with the drug are not achieving adequate glucose control, the researchers wrote.

The Agency for Healthcare Research and Quality and the University of North Carolina at Chapel Hill supported the study. Dr. Camelo Castillo reported having no financial disclosures; her associates reported financial ties to varous pharmaceutical companies.

Newborns of women who have gestational diabetes treated with glyburide appear to be at increased risk for admission to the neonatal intensive care unit, respiratory distress, hypoglycemia, birth injury, and large for gestational age status, compared with newborns of women treated with insulin, according to a report published March 30 in JAMA Pediatrics.

In recent years, off-label use of glyburide for gestational diabetes has risen dramatically in the United States. A few small clinical trials and observational studies have suggested that the agent is associated with poorer neonatal outcomes than insulin. Currently, insulin is the only pharmacologic treatment approved for the treatment of gestational diabetes mellitus by the Food and Drug Administration and endorsed by the American Diabetes Association.

To examine the issue in a study population large enough to detect small, but clinically important, differences between the two treatments, researchers performed a retrospective cohort study involving 9,173 mother/infant pairs enrolled in a health plan database that covered approximately 30 million patients per year across the United States.

Compared with insulin, glyburide was associated with an increased risk in the newborns of NICU admission (adjusted relative risk, 1.41), respiratory distress (aRR, 1.63), neonatal hypoglycemia (aRR, 1.40), birth injury (aRR, 1.35), and large for gestation age status (aRR, 1.43).

Glyburide was not associated with an increased risk of neonatal jaundice, obstetric trauma, or preterm birth, the investigators wrote (JAMA Pediatr. 2015 March 30 [doi:10.1001/jamapediatrics.2015.74]).

The study population included women (average age, 33.5 years) who delivered singleton live-born infants in 2000-2011 and who filed pharmacy claims for either glyburide (4,982 patients) or insulin (4,191 patients) during the 150 days preceding delivery.

The mean duration of treatment was 50.4 days with glyburide and 54.1 days with insulin.

The proportion of women treated with glyburide rose from 8.5% at the beginning of the study period to 64.4% at the end, wrote Wendy Camelo Castillo, Ph.D., of the department of pharmaceutical health services research, University of Maryland, Baltimore, and her associates.

Glyburide’s link to adverse outcomes “demands further attention” and suggests that women treated with the drug are not achieving adequate glucose control, the researchers wrote.

The Agency for Healthcare Research and Quality and the University of North Carolina at Chapel Hill supported the study. Dr. Camelo Castillo reported having no financial disclosures; her associates reported financial ties to varous pharmaceutical companies.

The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).

This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.

Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.

Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).

In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”

©Juanmonino/iStockphoto

Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.

The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.

Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).

It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.

Courtesy of the National Cancer Institute (NCI)

Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.

A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at [email protected].

The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).

This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.

Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.

Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).

In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”

©Juanmonino/iStockphoto

Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.

The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.

Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).

It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.

Courtesy of the National Cancer Institute (NCI)

Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.

A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at [email protected].

The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).

This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.

Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.

Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).

In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”

©Juanmonino/iStockphoto

Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.

The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.

Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).

It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.

Courtesy of the National Cancer Institute (NCI)

Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.

A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.

Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at [email protected].

Women who had gestational diabetes mellitus and gained weight after pregnancy were significantly more likely to progress to type 2 diabetes, according to a study.

Among the 1,695 women in the Diabetes & Women’s Health study with a history of gestational diabetes mellitus (GDM), researchers documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. Each 1 kg/m² increase in baseline body mass index was associated with a 16% higher risk of type 2 diabetes (hazard ratio, 1.16).

Each 5 kg of weight gain after the development of GDM was associated with a 27% higher risk of type 2 diabetes (HR, 1.27).

“Our findings provide evidence to support the recent call from the [National Diabetes Education Program] and highlight the importance of achieving and maintaining a healthy weight in these high-risk women to prevent future development of type 2 diabetes,” the researchers wrote.

The study was supported by the National Institute of Child Health and Human Development, part of the National Institutes of Health.

Read the full study in Diabetologia (doi: 10.1007/s00125-015-3537-4).

Women who had gestational diabetes mellitus and gained weight after pregnancy were significantly more likely to progress to type 2 diabetes, according to a study.

Among the 1,695 women in the Diabetes & Women’s Health study with a history of gestational diabetes mellitus (GDM), researchers documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. Each 1 kg/m² increase in baseline body mass index was associated with a 16% higher risk of type 2 diabetes (hazard ratio, 1.16).

Each 5 kg of weight gain after the development of GDM was associated with a 27% higher risk of type 2 diabetes (HR, 1.27).

“Our findings provide evidence to support the recent call from the [National Diabetes Education Program] and highlight the importance of achieving and maintaining a healthy weight in these high-risk women to prevent future development of type 2 diabetes,” the researchers wrote.

The study was supported by the National Institute of Child Health and Human Development, part of the National Institutes of Health.

Read the full study in Diabetologia (doi: 10.1007/s00125-015-3537-4).

Women who had gestational diabetes mellitus and gained weight after pregnancy were significantly more likely to progress to type 2 diabetes, according to a study.

Among the 1,695 women in the Diabetes & Women’s Health study with a history of gestational diabetes mellitus (GDM), researchers documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. Each 1 kg/m² increase in baseline body mass index was associated with a 16% higher risk of type 2 diabetes (hazard ratio, 1.16).

Each 5 kg of weight gain after the development of GDM was associated with a 27% higher risk of type 2 diabetes (HR, 1.27).

“Our findings provide evidence to support the recent call from the [National Diabetes Education Program] and highlight the importance of achieving and maintaining a healthy weight in these high-risk women to prevent future development of type 2 diabetes,” the researchers wrote.

The study was supported by the National Institute of Child Health and Human Development, part of the National Institutes of Health.

Read the full study in Diabetologia (doi: 10.1007/s00125-015-3537-4).

Extending breastfeeding time increased IQ scores, years of education, and income later in life, according to a population-based birth cohort study of nearly 3,500 people.

The prospective study included nearly 6,000 infants born in Pelotas, Brazil, in 1982. The researchers recorded information on breastfeeding in early childhood and followed up 30 years later with a Wechsler Adult Intelligence Scale IQ test. They also collected information on education and income. The final analysis included 3,493 people.

©Lev Olkha/iStockphoto.com

Individuals who had received 12 months or more of breastfeeding had an average IQ score that was 3.8 points higher than those who had been breastfed for less than 1 month. Those with a year or more of breastfeeding also had 0.91 more years of education on average, and earned 341 Brazilian reals per month more than those with the shortest breastfeeding time.

“The likely mechanism underlying the beneficial effects of breast milk on intelligence is the presence of long-chain saturated fatty acids (DHAs) found in breast milk, which are essential for brain development,” Bernardo Lessa Horta, Ph.D., of the Federal University of Pelotas in Brazil and lead author of the study, said in a statement. “Our finding that predominant breastfeeding is positively related to IQ in adulthood also suggests that the amount of milk consumed plays a role.”

The study was funded by the Wellcome Trust, International development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health.

Find the full study in the Lancet Global Health (2015;3:e199-205).

Extending breastfeeding time increased IQ scores, years of education, and income later in life, according to a population-based birth cohort study of nearly 3,500 people.

The prospective study included nearly 6,000 infants born in Pelotas, Brazil, in 1982. The researchers recorded information on breastfeeding in early childhood and followed up 30 years later with a Wechsler Adult Intelligence Scale IQ test. They also collected information on education and income. The final analysis included 3,493 people.

©Lev Olkha/iStockphoto.com

Individuals who had received 12 months or more of breastfeeding had an average IQ score that was 3.8 points higher than those who had been breastfed for less than 1 month. Those with a year or more of breastfeeding also had 0.91 more years of education on average, and earned 341 Brazilian reals per month more than those with the shortest breastfeeding time.

“The likely mechanism underlying the beneficial effects of breast milk on intelligence is the presence of long-chain saturated fatty acids (DHAs) found in breast milk, which are essential for brain development,” Bernardo Lessa Horta, Ph.D., of the Federal University of Pelotas in Brazil and lead author of the study, said in a statement. “Our finding that predominant breastfeeding is positively related to IQ in adulthood also suggests that the amount of milk consumed plays a role.”

The study was funded by the Wellcome Trust, International development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health.

Find the full study in the Lancet Global Health (2015;3:e199-205).

Extending breastfeeding time increased IQ scores, years of education, and income later in life, according to a population-based birth cohort study of nearly 3,500 people.

The prospective study included nearly 6,000 infants born in Pelotas, Brazil, in 1982. The researchers recorded information on breastfeeding in early childhood and followed up 30 years later with a Wechsler Adult Intelligence Scale IQ test. They also collected information on education and income. The final analysis included 3,493 people.

©Lev Olkha/iStockphoto.com

Individuals who had received 12 months or more of breastfeeding had an average IQ score that was 3.8 points higher than those who had been breastfed for less than 1 month. Those with a year or more of breastfeeding also had 0.91 more years of education on average, and earned 341 Brazilian reals per month more than those with the shortest breastfeeding time.

“The likely mechanism underlying the beneficial effects of breast milk on intelligence is the presence of long-chain saturated fatty acids (DHAs) found in breast milk, which are essential for brain development,” Bernardo Lessa Horta, Ph.D., of the Federal University of Pelotas in Brazil and lead author of the study, said in a statement. “Our finding that predominant breastfeeding is positively related to IQ in adulthood also suggests that the amount of milk consumed plays a role.”

The study was funded by the Wellcome Trust, International development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health.

Find the full study in the Lancet Global Health (2015;3:e199-205).