Topiramate in Early Pregnancy Increases Risk of Oral Clefts

Study finds that taking a higher dose of the drug in the first trimester increases risk of cleft lip or cleft palate more than taking a lower dose.

The anti-epileptic drug topiramate has been increasingly prescribed over the last decade not only to prevent seizures, but also to treat bipolar disorder and migraine headaches. In addition, topiramate is a component of a recently FDA-approved drug for weight loss. Past studies have found that women taking topiramate during early pregnancy to prevent epileptic seizures had a two- to five-fold greater chance of giving birth to a baby with an oral cleft, but such studies did not focus on women taking the drug at a lower dose for non-seizure related conditions. A new study by investigators from Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health suggest that using topiramate in early pregnancy, particularly at the high doses used for epilepsy, increases the risk of oral clefts. Their results are published in Neurology.

“Our results suggest that the increased risk of oral clefts is most pronounced in women taking higher doses of topiramate to treat epilepsy. Low doses of topiramate may also increase the risk of oral clefts but to a lesser extent,” said last author Elisabetta Patorno, MD, DrPH, of the BWH Division of Pharmacoepidemiology & Pharmacoeconomics. “We hope that this work gives important information to women and their clinicians as they determine the best course of treatment and options available to individuals.”
The new work leverages nationwide Medicaid data on more than 1 million live births from between 2000 and 2010. The team examined the risk of oral clefts – including cleft palate or cleft lip – among three groups: infants born to women who had taken topiramate in their first trimester; infants born to women who had taken the drug lamotrigine (an unrelated drug used to treat bipolar disorder and epilepsy); and infants who had not been exposed to anti-epileptic medications in utero. They found that the risk of oral clefts was approximately three times higher for the topiramate group than for either the lamotrigine or the unexposed group. Approximately one out of every 1,000 infants are born with an oral cleft, but among infants exposed to low doses of topiramate (median 100-mg daily dose) in the first trimester, that risk was 2.1 out of every 1,000 live births. Among women taking higher dose topiramate (median 200-mg daily dose), the risk was much higher – 12.3 for every 1,000 live births.

“Our results suggest that women with epilepsy on topiramate have the highest relative risk of giving birth to a baby with cleft lip or cleft palate, likely due to the higher doses of topiramate when used for controlling seizures,” said corresponding author Sonia Hernandez-Diaz, MD, DrPH, of the Harvard T.H. Chan School of Public Health. “The best course may be to avoid prescribing high doses of topiramate to women of childbearing age unless the benefits clearly outweigh the risks.”

Funding for this work was provided by an R01 grant (R01 MH100216) from the National Institute of Mental Health, a career development grant (K08HD075831) from the National Institute of Child Health & Human Development and a career development grant (K01MH099141) from the National Institute of Mental Health.

Paper cited: Hernandez-Diaz S et al. “Topiramate use early in pregnancy and the risk of oral clefts” Neurology DOI: 10.1212/WNL.0000000000004857

Testing the Accuracy of FDA-Approved and Lab-Developed Cancer Genetics Tests

Study finds that both laboratory-developed tests and FDA-approved companion diagnostics performed equally well

Cancer molecular testing can drive clinical decision making and help a clinician determine if a patient is a good candidate for a targeted therapeutic drug. Clinical tests for common cancer causing-mutations in the genes BRAF, EGFR and KRAS abound, and include U.S. Food and Drug Administration (FDA)-approved companion diagnostics (FDA-CDs) as well as laboratory-developed tests (LDTs). LDTs are tests that have been designed and implemented in a single laboratory – some are completely homegrown while others are commercial kits, including “off label” uses of FDA-CDs (also known as in vitro diagnostics). Amid the debate about how much these tests should be regulated by the FDA, one question has gone unanswered: how well do LDTs and FDA-CDs perform? A new study published this week in JAMA Oncology, which analyzed data from almost 7,000 tests, finds that the answer is: very well and very comparably.

“We find that both laboratory-developed tests and FDA-approved companion diagnostics demonstrate excellent performance on proficiency testing,” said corresponding author Annette Kim, MD, PhD, of BWH’s Department of Pathology. “And, importantly, more than 60 percent of the laboratories in our study that were using an FDA-CD kit report using it with modifications – rendering those assays LDTs. These modifications appear to be driven by the exigencies of real day-to-day clinical practice that requires altering the assays to meet the needs of a variety of clinical situations that may not be accommodated by the FDA-approved protocol.”

These modifications include, for example, the testing of other tumor types that may carry targetable variants, different types of input specimen preparations available in pathology such as cytology smears or other fresh specimens rather than paraffin blocks and availability of different methods of DNA quantification than those mandated by FDA approval based upon pre-existing technologies in the laboratories.

“In the clinical lab, we are always acutely aware that there is a patient awaiting this result and we validate our assays to ensure that we can provide reliable and accurate results from our laboratory under as many varied clinical situations as possible,” said Kim.

The research team used data from proficiency tests provided by the College of American Pathologists Molecular Oncology Committee which provides external proficiency testing for labs to determine the accuracy of testing. Combing through data from 6,897 proficiency testing responses, the team found that both LDTs and FDA-CDs exceeded 97 percent accuracy combined across the three cancer genes.

The team’s results also indicate that the majority of laboratories purchasing in vitro diagnostics for FDA-CDs are in fact modifying their use – making them into laboratory-developed tests.

“These data question the distinction between FDA-CDs and LDTs from a regulatory standpoint and note the greater clinically relevant applications of LDTs,” the authors write.

Paper cited: Kim, AS et al. “Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing” JAMA Oncology DOI: 10.1001/jamaoncol.2017.4021

Study Explores Whether Use of ADHD Medications During Pregnancy Increases Risk of Birth Defects

Brigham researchers find small increase in the risk of heart defects following first-trimester exposure to methylphenidate but not to amphetamines

Adults, including women of reproductive age, are increasingly being prescribed medications to treat Attention Deficit Hyperactivity Disorder (ADHD) but little evidence has been available about whether exposure to these drugs during early pregnancy may increase the risk of birth defects. A new study conducted by investigators from Brigham and Women’s Hospital (BWH) in collaboration with investigators in the five Nordic countries leverages data from multiple large cohorts to define and quantify what, if any, increased risk may be posed by taking the most commonly used ADHD medications. The team found that one medication, methylphenidate, increased risk of heart defects by a small amount while another medication, amphetamines, did not. Their findings are published this week in JAMA Psychiatry.

“Our findings suggest a small increase in the risk of cardiac malformations associated with first-trimester exposure to methylphenidate, but not to amphetamines,” said corresponding author Krista Huybrechts, PhD, of the BWH Division of Pharmacoepidemiology and Pharmacoeconomics. “This information may be important to patients and their physicians as they weigh the risks and benefits of alternative treatment strategies for attention deficit hyperactivity disorder.”

This study is the first to publish from the International Pregnancy Safety Study (InPreSS) consortium, which seeks to provide the best available human data on the safety of prescription medications during pregnancy by combining large-scale data from several countries using the highest possible methodological standards. Animal studies of very high doses of amphetamines had suggested a potential risk of increased heart defects and other birth defects, but data regarding safety in human offspring had been limited. The new work makes use of data from 1.8 million pregnancies in the U.S. Among the women in this cohort, more than 2,700 filled a prescription for methylphenidate during their first trimester of pregnancy, and more than 5,500 filled one for amphetamines. The team validated their findings by also examining data from a cohort of 2.5 million pregnancies from Nordic registries.

Overall, based on both populations, the team found a 28 percent increased risk of heart malformations after first-trimester exposure to methylphenidate. This increase corresponds to three additional infants born with congenital heart defects for every 1,000 women treated with methylphenidate during the first trimester of pregnancy.  No association was observed for methylphenidate and congenital birth defects overall, or for amphetamines and any congenital or heart defect.

“Our study markedly expands the evidence base regarding the safety of methylphenidate use in pregnancy,” said Huybrechts. “Although the absolute risk is small, it is nevertheless important evidence to consider when treating young women of reproductive age and pregnant women.”

This study was supported by an R01 grant (R01 MH100216) from the National Institute of Mental Health, an R21 grant (R21HD092879) from the Eunice Kennedy Shriver National Institute for Child Health & Human Development, and the Söderström König Foundation.  Huybrechts was supported by a career development grant K01MH099141 from the National Institute of Mental Health.  Co-author Brian Bateman was supported by a career development grant K08HD075831 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Paper cited: Huybrechts K et al. “Use of Methylphenidate and Amphetamines in Pregnancy and Risk of Congenital Malformations: A cohort study from the International Pregnancy Safety Study (InPreSS) Consortium.” JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2017.3644

Weight Loss and Risk of Death: Rheumatoid Arthritis Findings May Have Wider Implications

Researchers call it the obesity paradox: the phenomenon, observed in studies of patients with rheumatoid arthritis (RA) and other chronic conditions, where patients who are obese have a lower risk of death than those who weigh less. But most of these studies focused on patients who have RA for many years, and involved relatively little follow-up prior to death. Researchers from Brigham and Women’s Hospital evaluated the effect of RA diagnosis on weight change and how this subsequently affects mortality risk. They did this by comparing women from the Nurses’ Health Study who had been diagnosed with RA to a similar group of women who had not been diagnosed with RA. Their results suggest that the findings from previous studies regarding lower weight being associated with higher mortality may not be directly related to RA and instead reflect a more generalized phenomenon. Their study is published this week in Arthritis & Rheumatology.

“Our findings are important because they show that weight gain does not offer a mortality benefit for patients with RA,” said Jeffrey Sparks. “Our observations indicate that clinicians can encourage healthy weight loss strategies for RA patients.”

Prior studies testing the relationship between RA and weight loss have typically been performed by including only patients with RA, making it unclear whether the patterns reported were specific to RA or related to general population that was frail and of advanced age. In the current study, the research team narrowed in on the early RA period around the time when women were diagnosed with RA, two to four years after diagnosis or a similar period for women who were comparators. In both RA and the comparator groups, those who had severe weight loss (30 pounds or more) had the highest risk of death decades later. This increased mortality risk for severe weight loss was most likely related to unintentional weight loss, rather than healthy weight loss. Weight gain in this early RA or index period had no effect on mortality risk for either the RA or comparator groups.

“There has been a question among clinicians of whether obesity might offer a mortality benefit for patients with RA, but our data suggest that weight gain was not protective. Instead, we wonder whether people who gain or maintain weight have better observed mortality rates because they aren’t sick, unlike those who unintentionally lose weight,” said Sparks.

The research team accounted for certain factors – such as physical activity and diet – that might contribute to weight loss, but in the future, would like to understand the mechanisms for how weight change may influence risk of death.

This work was supported by the Rheumatology Research Foundation Disease-Targeted Innovative Award, Scientist Development Awards, the National Institutes of Health (grant numbers K24 AR052403, P60 AR047782, L30 AR066953, L30 AR070514, R01 AR049880, UM1 CA186107, K23 AR069688, K01 AR064351, and T32 AR007530). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Paper cited: Sparks JA et al. “Weight change in the early rheumatoid arthritis period and risk for subsequent mortality among women with RA and matched comparators” Arthritis & Rheumatology DOI: 10.1002/art.40346

Removing Cancer Cell Debris Improves Conventional Cancer Treatments

Cancer therapies are designed to kill tumor cells, but produce tumor cell debris in the process. In a study published in The Journal of Experimental Medicine, researchers from Brigham and Women’s Hospital and colleagues show that leftover debris can stimulate inflammation and tumor growth, but that molecules called resolvins can block that unwanted inflammatory response. The findings point towards a new way to enhance the effectiveness of current cancer therapies and potentially prevent tumor recurrence.

When conventional cancer treatments, such as radiation or chemotherapy drugs, break apart tumors, they can also spread and stimulate the production of proinflammatory cytokines. These signaling molecules, known to promote tumor growth, were at the center of the investigation.

“Dead and dying tumor cells are an underappreciated component of the tumor microenvironment that may promote tumor progression,” said Professor Charles Serhan, PhD, DSc, Department of Anesthesiology, Perioperative and Pain Medicine at BWH.

The team administered a variety of therapeutic drugs to lab-cultured cancer cells and collected the resulting debris. When co-injected into mice with a small number of non-growing cancer cells, the debris stimulated tumor formation. A similar test treated mice with the chemotherapy drugs such as cisplatin and vincristine to generate debris in vivo, supporting the conclusion that the debris helped surviving cancer cells form tumors. The researchers concluded that a lipid called phosphatidylserine stimulated immune cells to produce a “cytokine storm” when exposed to the cancerous cells and caused the growth.

The researchers reasoned that if drug-generated debris was promoting tumor growth, clearing the debris might stop it. The team focused on the body’s own resolvins which act as stop signals to end or “resolve” the inflammation. Resolvins counter the debris-stimulated proinflammatory cytokines and stimulate the immune system including white blood cells called macrophages (“the big eaters”) to remove or “mop up” the debris.  Resolvins are biosynthesized by the body from omega-3 essential fatty acids. Resolvins were discovered at the Brigham and Women’s Hospital by Dr. Serhan and his laboratory and are a new approach to turn off inflammation in the human body to prevent a “cytokine storm” rather than blocking a single pro-inflammatory factor

Treating mice with small amounts of resolvins inhibited the subsequent therapy-stimulated tumor growth and prevented cancer cells from spreading. Resolvin treatment enhanced the activity of several cytotoxic therapies against a variety of tumor types resulting in tumor regression. Clinical developments using resolvins as potential therapeutic approaches are already in progress for several inflammatory and neurodegenerative diseases.

“Stimulating the clearance of tumor cell debris via specialized pro-resolving mediators represents a new approach to prevent tumor growth and recurrence,” the authors write.

This work was supported by the National Cancer Institute grants RO1 01CA170549-02 and GM095467; the Stop and Shop Pediatric Brain Tumor Fund; the CJ Buckley Pediatric Brain Tumor Fund; Alex Lemonade Stand; Molly’s Magic Wand for Pediatric Brain Tumors; the Markoff Foundation Art-In-Giving Foundation; the Kamen Foundation; Jared Branfman Sunflowers for Life; and The Wellcome Trust program 086867/Z/08.

Paper Cited: Sulciner, M et al. “Resolvins suppress tumor growth and enhance cancer therapy” The Journal of Experimental Medicine DOI: 10.1084/jem.20170681

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Weight Loss and Risk of Death: Rheumatoid Arthritis Findings May Have Wider Implications

Researchers call it the obesity paradox: the phenomenon, observed in studies of patients with rheumatoid arthritis (RA) and other chronic conditions, where patients who are obese have a lower risk of death than those who weigh less. But most of these studies focused on patients who have RA for many years, and involved relatively little follow-up prior to death. Researchers from Brigham and Women’s Hospital evaluated the effect of RA diagnosis on weight change and how this subsequently affects mortality risk. They did this by comparing women from the Nurses’ Health Study who had been diagnosed with RA to a similar group of women who had not been diagnosed with RA. Their results suggest that the findings from previous studies regarding lower weight being associated with higher mortality may not be directly related to RA and instead reflect a more generalized phenomenon. Their study is published this week in Arthritis & Rheumatology.

“Our findings are important because they show that weight gain does not offer a mortality benefit for patients with RA,” said Jeffrey Sparks. “Our observations indicate that clinicians can encourage healthy weight loss strategies for RA patients.”

Prior studies testing the relationship between RA and weight loss have typically been performed by including only patients with RA, making it unclear whether the patterns reported were specific to RA or related to general population that was frail and of advanced age. In the current study, the research team narrowed in on the early RA period around the time when women were diagnosed with RA, two to four years after diagnosis or a similar period for women who were comparators. In both RA and the comparator groups, those who had severe weight loss (30 pounds or more) had the highest risk of death decades later. This increased mortality risk for severe weight loss was most likely related to unintentional weight loss, rather than healthy weight loss. Weight gain in this early RA or index period had no effect on mortality risk for either the RA or comparator groups.

“There has been a question among clinicians of whether obesity might offer a mortality benefit for patients with RA, but our data suggest that weight gain was not protective. Instead, we wonder whether people who gain or maintain weight have better observed mortality rates because they aren’t sick, unlike those who unintentionally lose weight,” said Sparks.

The research team accounted for certain factors – such as physical activity and diet – that might contribute to weight loss, but in the future, would like to understand the mechanisms for how weight change may influence risk of death.

This work was supported by the Rheumatology Research Foundation Disease-Targeted Innovative Award, Scientist Development Awards, the National Institutes of Health (grant numbers K24 AR052403, P60 AR047782, L30 AR066953, L30 AR070514, R01 AR049880, UM1 CA186107, K23 AR069688, K01 AR064351, and T32 AR007530). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Paper cited: Sparks JA et al. “Weight change in the early rheumatoid arthritis period and risk for subsequent mortality among women with RA and matched comparators” Arthritis & Rheumatology DOI:10.1002/art.40346

Researchers from Brigham and Women’s Hospital led by Ying Bao, MD, ScD, an epidemiologist in BWH’s Channing Division of Network Medicine and Assistant Professor at Harvard Medical School, have found that women with stronger social networks had better survival after colorectal cancer diagnosis and conclude that social network strengthening could be a tool for management of colorectal cancer.

Colorectal cancer is the third most commonly diagnosed and second leading cause of cancer death in the United States. At current rates, approximately 5 percent of individuals will develop a cancer of the colon or rectum within their lifetime. Though social network research has been done in other diseased populations, very few studies have examined the association between social network and survival in varying cancer sites.

The team utilized data from 896 women who participated in the Nurses’ Health Study and had been diagnosed with colorectal cancer between 1992 and 2012. Social integration was assessed every four years during that time using the Berkman-Syme Social Networks Index; the value scale accounts for factors like marital status, social network size, contact frequency and religious or social group participation. This helped organize a patient rating system that identified patients on a range from socially isolated to socially integrated.

The findings indicated that, overall, women with high levels of social integration before a colorectal cancer diagnosis had significantly reduced risk of all-cause and colorectal cancer-specific mortality, particularly among older women. Though the number of extended ties (religious or social group participation) weren’t associated with survival, the presence of more intimate ties (family and friends) was associated with a significantly lower death rate.

“When a patient is diagnosed, health care providers can look to the patient’s social network to see if it provides necessary resources or whether outside help might be something to consider,” said Bao who is also an assistant professor at Harvard Medical School. “That could be assistance from social workers, for example, to ensure access to care. For physicians, portions of a care plan aimed at strengthening a patient’s social network can be valuable tools that haven’t always been considered in the past.”

Due to the complexity of network interactions, there are many pathways through which social networks could cause improved survival among cancer patients. Some prior research indicates that higher levels of social integration are associated with lower levels of inflammation and thus disease progression; other studies indicate it relates to a reduction in psychological stress and poor health behaviors that may contribute to cancer progression. Support from social networks, such as assistance in getting to medical appointments, reminders to take medications, and help with nutrition and mobility, may also explain the observed association. Future investigations are required to understand how these factors are influencing different kinds of patients and their care plans.

The Nurses’ Health Study is supported by NIH grants UM1CA186107 and P01CA87969. Dr. Bao is supported by NIH grants KL2TR001100 and P30DK046200, and by Department of Defense grant CA150357. Dr. Fuchs is supported by NIH grants P30CA016359, R01CA169141, R01CA118553, and by Stand-Up-to-Cancer.

Paper Cited: Sarma, E et al. “Social Integration and Survival after Colorectal Cancer Diagnosis” Cancer DOI: 10.1002/cncr.31117