Ondansetron in Early Pregnancy Seen Not to Promote Cardiac Birth Defects Overall


A new report provides some reassurance regarding the safety of the antiemetic ondansetron when taken for nausea and vomiting in early pregnancy, researchers say.

In the large retrospective cohort study, use of ondansetron in the first trimester of pregnancy was not associated with an increased risk for cardiac malformations overall.

In a secondary finding, use of the drug was associated with increased risk for oral clefts, although the absolute risk was low.

“These results suggest that ondansetron does not meaningfully increase the risk of congenital malformations, although a small increase in the risk of oral clefts cannot be excluded,” Krista F. Huybrechts, Brigham and Women’s Hospital and Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.

“These results will hopefully provide reassurance to women who experience nausea and vomiting in pregnancy and need to make a risk–benefit trade off regarding treatment,” said Huybrechts, lead author on the study published December 18 in JAMA.

Evidence for the fetal safety of ondansetron, which is often prescribed for nausea and vomiting during pregnancy, is “limited and conflicting,” the researchers note in their article.

They looked at data from the Medicaid Analytic eXtrract (MAX) database of more than 1.8 million pregnancies, including 88,467 (4.9%) with exposure to ondansetron during the first trimester. They focused on cardiac malformations and oral clefts, the main congenital anomalies identified with any consistency in previous studies.

There were 14,577 cardiac abnormalities in 1,727,947 unexposed infants and 835 in 88,467 exposed infants. The adjusted risk difference was −0.8 (95% confidence interval [CI], −7.3 to 5.7 per 10,000 births) and the adjusted relative risk was 0.99 (95% CI, 0.93 to 1.06).

There was a small but statistically significant increased risk for oral clefts with first-trimester exposure to ondansetron (1912 cases in unexposed infants and 124 in exposed infants). The adjusted risk difference was 2.7 (95% CI, 0.2 – 5.2 per 10,000 births) and the adjusted relative risk was 1.24 (95% CI, 1.03 – 1.48).

After multiple adjustments, there was no difference in the risk for cardiac or overall congenital anomalies in infants born to women exposed to ondansetron. The adjusted risk difference was 5.4 (95% CI, −7.3 to 18.2 per 10,000 births) and the adjusted relative risk was 1.01 (95% CI, 0.98 to 1.05).

“The findings were consistent across a broad range of sensitivity analyses,” the authors report.

Although not formally approved for the treatment nausea and vomiting during pregnancy, the drug’s use for this purpose increased from 0.01% in 2000 to 12% in 2013, they point out.

In an accompanying editorial, David M. Haas, MD, Indiana University School of Medicine, Indianapolis, says early and effective safe treatment of nausea and vomiting in pregnancy is “crucial.”

This study provides “important and helpful” information for physicians to use when counseling women about the safety of treatment options, Haas writes.

The study shows clearly that although the adjusted relative risk for oral clefts was “elevated, the absolute risk increase is very low. The multiple adjustments and comparison groups presented, including accounting for the potential baseline risk of nausea and vomiting, demonstrate the robustness of the authors’ conclusions,” he adds.

FDA Clears Test to Analyze Nutrients in Breast Milk


The US Food and Drug Administration (FDA) has cleared for marketing a diagnostic test to measure nutrients in breast milk, including the concentration of fat, carbohydrates, protein, total solids, and energy.

The Miris Human Milk Analyzer

The Miris Human Milk Analyzer (Miris AB) can help with nutritional management of newborns and young infants at risk for growth failure due to prematurity or other medical conditions. Knowing the macronutrient content of the breast milk may help clinicians make informed decisions on how to fortify the breast milk based on the individual needs of the infant, the FDA explained in a news release.

“For the first time, doctors have access to a test to help analyze the nutrients in breast milk. While this test is not for everyone, it has the potential to aid parents and healthcare providers, mainly in a hospital setting, in better assessing the nutrient needs of certain babies who are not growing as expected,” Courtney Lias, PhD, director of the Division of Chemistry and Toxicology Devices in the FDA’s Center for Devices and Radiological Health, said in the release.

The Miris Human Milk Analyzer uses an infrared spectroscopy system to analyze human milk and provide a quantitative measurement of fat, protein, and total carbohydrate content. It can also calculate the total solids and energy content of the milk. It is intended for use by trained personnel in clinical laboratories.

The accuracy of the Miris analyzer was demonstrated in an FDA analysis of 112 samples of human milk tested by the Miris analyzer and by independent methods. Both methods were similarly effective at determining levels of protein, fat, and carbohydrates in the milk.

However, the FDA said certain medications that a nursing mother may be taking could interfere with the test’s ability to accurately measure nutrient levels in breast milk.

The agency advises healthcare providers to carefully evaluate the Miris Human Milk Analyzer test results in conjunction with clinical assessments (such as weight and growth) when creating a nutritional management plan for an infant.

The FDA reviewed the Miris Human Milk Analyzer test through the de novo premarket review pathway, a regulatory pathway for some new types of low- to moderate-risk devices.

Along with this marketing authorization, the FDA is establishing “special controls” that set forth the agency’s expectations in ensuring the accuracy, reliability, and effectiveness of tests intended to measure the nutritional content of human milk to aid in the nutritional management of certain infants.

“These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type,” the agency said.

Longer Breastfeeding Key to Moms’ Slim Waists, Lower CVD Risk


Breastfeeding for 6 months or more was associated with a slimmer waist in mothers years later, compared with shorter or no breastfeeding, new data show.

“Waist circumference…as a measure of central adiposity has been shown to be a superior proxy for assessing long-term risk of coronary artery disease mortality, hypertension, diabetes, dyslipidemia, and the metabolic syndrome, independent of BMI,” Gabrielle G. Snyder, MPH, University of Pittsburgh, Pennsylvania, and colleagues note.

Thus, “breastfeeding duration may be important to consider when studying long-term maternal cardiovascular and metabolic health,” they conclude in their article published online December 11 in the Journal of Women’s Health.

“We consistently detected that a threshold effect may exist,” they report, “for breastfeeding greater than 6 months.” The benefit remained after accounting for demographic, lifestyle, and socioeconomic factors.

Snyder and colleagues analyzed data from 676 women in the Pregnancy Outcomes and Community Health (POUCH) cohort who participated in the POUCHmoms study, 7 to 15 years after delivery. They matched moms with a similar likelihood to breastfeed, and then compared the moms who breastfed for > 6 months versus not at all or less than 6 months.

“This study extends conventional observational study methods,” they write, “to incorporate propensity score approaches that make it possible to…account for systematic differences in women who did and did not breastfeed.”

Central Adiposity

“Metabolically active visceral adipose tissue, a measure of abdominal obesity primarily distributed about the intra-abdominal organs, may increase substantially with a single pregnancy, independent of total body fat,” Snyder and colleagues write.

The World Health Organization recommends exclusive breastfeeding for 6 months for optimal infant health. In addition, breastfeeding consumes nearly 500 calories a day for moms.

Prior studies have reported that women who breastfed their babies had less central obesity years later than women who did not do this, but the studies did not account for different baseline characteristics of the women.

Therefore, Snyder and colleagues compared central obesity after about a decade in women in the POUCHmoms study who were seen in clinics in Michigan communities. Of the women in the cohort, 63% of the mothers were white, 31% were black, and 6% were Asian or Native American.

Prior to pregnancy, about half of the women (49%) had a body mass index (BMI) below 25 kg/m2 (normal weight) and the rest were overweight (21%) or obese (30%).

Overall, 38% of the mothers did not breastfeed their babies, while the others did so for > 0 to 3 months (22%), > 3 to 6 months (13%), or > 6 months (27%).  In unadjusted analyses, women who breastfed for > 6 months were older and more likely to be white and have a higher education level, and less likely to be obese before pregnancy.

At a mean follow-up of 11 years, the mothers had a mean waist circumference of 94 cm if they had breastfed their child for up to 6 months, and 86 cm if they had breastfed longer.

Two types of propensity analyses showed that the mothers who reported breastfeeding their infants for more than 6 months had a mean waist circumferencethat was 3.6 cm smaller and 3.1 cm smaller than other mothers.

“We emphasize [waist circumference] as the outcome of interest,” the researchers write, “given that central adiposity is a better predictor of long-term cardiometabolic and cardiovascular disease risk than BMI alone.”

They acknowledge that study limitations include potential pre-pregnancy differences in diet and exercise, for example, that were not accounted for.

Snyder and colleagues call for more research to investigate the effect of breastfeeding in multiple pregnancies on lifetime risk of cardiovascular disease.

“Our results warrant further analyses of cumulative lifetime duration of breastfeeding,” they write, “to understand the magnitude of the relationship with maternal central adiposity over time.”

Infertility Rates ‘Far Higher’ in Military Women Versus Civilians


Women in the US military describe infertility rates that are approximately three-times higher than the general population, according to a new report.

And they subsequently face challenges gaining access to infertility care, as well as problems following unintended pregnancies and accessing birth control, according to the report, which documents the state of reproductive healthcare among women in the military.

The results are alarming for numerous reasons, says retired Army Col Ellen Haring, CEO of the Service Women’s Action Network (SWAN), which published the report.

“First, over 30% of servicewomen and women veterans suffer from infertility, a far higher rate than their civilian sisters, which leads one to conclude that it may be service connected,” said Haring in a press statement issued by SWAN.

“Second, the military doesn’t appear to be tracking this health risk and when women present with infertility, they receive limited care,” Haring added.

“Women who serve this country should not be jeopardizing their opportunity to have a family,” she stressed.

A Third of Military Women Have Problems Becoming Pregnant

There are over 369,000 servicewomen and more than 2 million women veterans in the United States. Servicewomen comprise more than 17% of the military force and 10% of the veteran population, rates that are predicted to increase exponentially in the coming years.

The comprehensive survey included 799 women in the military in four categories: veterans (not retired), retired military, National Guard and Reserve, and those on active duty.

Across all categories, 33% of women reported problems becoming pregnant who were actively trying to do so, with a rate of 30% of women retirees, 33% of women in the National Guard and Reserve, and as high as 37% of women on active duty.

“This is dramatically higher than the national average,” the authors say, noting that only about 12% of women in the general population — according to data from the Centers for Disease Control and Prevention (CDC) — have “impaired fecundity,” or difficulty becoming pregnant after actively trying for 1 year or being able to carry a pregnancy to live birth.

According to the CDC, age is a key factor for infertility, and the report notes that job commitments cause some women in the military to delay having children.

And access to infertility care is limited. Only five military hospitals offer a full range of infertility treatments, waiting lists for care at those centers are long, and servicewomen often have to pay some of the costs for their own treatment, according to the report.

Infertility care at Veterans Health Administration (VHA) hospitals is only provided if women veterans can show their infertility is related to service.

Women veterans who don’t know the cause of their infertility seem to be treated on a random basis depending on the VHA hospital and provider they see. Some are completely denied care and others receive limited care.

Alternative options for infertility care include using the military Tricare coverage for treatment at civilian providers. However, Tricare only covers limited tests and procedures and does not cover in vitro fertilization, which can cost approximately $15,000 for just one round of treatment.

In addition to barriers to care at hospitals, some women reported being denied infertility treatment because they were unmarried or gay, which directly violates military policy.

“While it is official policy to provide infertility services regardless of sexual orientation or marital status, our research found that reality does not match policy,” the authors say.

Overall, causes of the unusually high rates of infertility in the military and barriers to care need to be better addressed.

In follow-up interviews, women who believe their infertility may be the result of military service, for example, related to exposure to toxins on the job, during deployments and on military installations where they live, or because of wearing ill-fitting equipment, often designed for men, gave further details of how they think this contributed to their inability to have children.

“These data clearly cry out for more research to pinpoint the high levels of infertility…but in the interim military women whose infertility is likely linked to military service should be afforded access to all available infertility diagnosis and treatments at no cost,” the authors emphasize.

Accessing Birth Control a Challenge for Some

In terms of other reproductive issues, a more positive note from the SWAN report was that 95% of women in active duty reported having access to their preferred method of birth control.

Some caveats, however, include the fact that women officers have greater access to care than enlisted women, and when women leave active duty, their access to preferred methods of birth control declines substantially.

Access to birth control is also limited for servicewomen during deployment to remote locations, with causes including prescriptions that simply did not provide enough birth control cover for an entire deployment.

Another barrier is birth control prescriptions are sometimes denied by providers who cite General Orders that prohibit sexual activity during deployment.

But many women who use birth control are not doing so to prevent pregnancy, the authors observe, but rather to control or suppress their menstrual cycles or for other health reasons.

The bottom line is that “providers should not be allowed to deny servicewomen birth control because of General Orders that govern sexual activity,” they say.

Unintended Pregnancies, Access to Abortion Very Limited

Meanwhile, as many as 35% of pregnancies of retired military women were listed as unintended.

Unintended pregnancy rates among women currently serving were significantly lower, however, at 15% among those in the National Guard and Reserve and 13% among those on active duty.

Options for women with unintended pregnancies are severely restricted in the military, as the only choice within the healthcare system is to carry the child to term, unless the pregnancy is the result of rape or incest, or if the mother is at risk.

Among 81 women included the report who indicated they had terminated a pregnancy, four of the 10 women who indicated their unintended pregnancies were the result of rapes had their pregnancies terminated in military treatment facilities (MTF).

The remainder reported terminating their pregnancies through procedures performed at, for example, Planned Parenthood. They reported receiving little or no help from MTF or VHA providers, even after seeking assistance from them.

And many women who did undergo terminations reported a lack of follow-up care. In one case, a servicewoman reported being given only 24 hours of rest after obtaining an abortion and not receiving the care she needed when a bleeding complication arose.

“The attitude was basically ‘You made this choice, you deal with it,'” the woman said in the survey.

“Although military and veteran healthcare providers cannot provide abortions themselves, they could advise military women on where to get them and they should certainly provide follow-up care,” Haring indicated.

“Instead, servicewomen who seek abortions, a constitutionally guaranteed right, are shamed and denied care by military providers, endangering their health and decreasing military readiness,” she added.

Overall, the report sheds important light on the multitude of unique challenges women in the military face in terms of their reproductive health and the need for some improvements, the authors stress.

“Military women deserve access to the full range of reproductive healthcare services to ensure mission-readiness, optimize their own health and well-being and that of their families, enable career advancement, and to decide if, when, and how to start a family,” they conclude.

Giving Birth Tied to Increased CVD, Stroke Risk


Women who have given birth may have a significantly higher risk for cardiovascular disease (CVD) and stroke compared with women who have never had children, and the risk appears to increase with each live birth, new research suggests.

Investigators conducted a meta-analysis of 10 studies involving more than 150,000 cases of CVD among more than 3 million participants and found a 14% higher risk with parity vs nulliparity.

Moreover, when the association was analyzed with respect to the number of births, the investigators found a J-shaped relationship, in which each birth was associated with a 4% higher likelihood of developing CVD, regardless of factors such as body mass index (BMI), diabetes, hypertension, smoking, and income levels.

Each live birth was associated with a 5% higher risk for coronary heart disease (CHD) and a 4% higher risk for stroke.

“We think doctors could play a role in the dissemination [of these findings] for women patients,” study author Dongming Wang, MD, of the Department of Occupational and Environment Health, School of Public Health, Tongii Medical College, Huazhong University of Science and Technology, Hubei, China, told Medscape Medical News.

“The doctors could tell them that ever-parity is related with CVD risk and there is an association between number of pregnancies and risk for CVD,” he said.

The study was published online December 19 in the European Journal of Preventive Cardiology.

Controversial Findings

“Many studies have shown that reproductive factors may affect women’s health in later life, and parity as an important reproductive factor has also been shown to play an important role in the development of CVD,” Wang said.

The association, however, “remains controversial, given the inconsistency of previous findings. Thus, we aimed to conduct a meta-analysis of cohort studies to quantitatively assess the association between parity and CVD risk,” he reported.

To investigate the question, the researchers searched PubMed and Web of Science to identify studies on parity and CVD risk through June 7, 2018. They used the search terms “cardiovascular disease,” “coronary heart disease,” “ischemic heart disease,” and “stroke.”

Studies were required to have a cohort design, with parity number as the exposure of interest. CVD risk, rather than CVD mortality, was the required outcome.

Additionally, studies had to report relative risks (RRs) with 95% confidence intervals (CIs) for ≥3 quantitative categories of parity numbers, or to provide risk estimates per live birth.

To analyze dose and response, the researchers assigned the median or mean parity number in each category to the corresponding RR for each study.

Increased Cardiometabolic Changes

From a total of 4746 citations identified in the initial literature search, the researchers included 10 cohort studies (all published between 1987 and 2018) in the meta-analysis. Of these, nine studies (13 records) analyzed parous vs nulliparous women, and eight studies (11 records) included the dose-response analysis of parity number.

Studies were conducted in Sweden (n = 1), the United States (n = 4), China (n = 2), the United Kingdom (n = 2), and in multiple European countries (n = 1).

Study samples ranged from 867 to 1,332,062 women; the number of CVD cases ranged from 45 to 65,204; and the average duration of follow-up ranged from 6 years to 52 years.

All studies were considered to be of high quality.

For the nine studies that compared parous to nulliparous women (n = 3,014,987 participants and 148,169 CVD cases), the RR of CVD for ever-parity vs nulliparity was 1.14 (95% CI, 1.09 – 1.18), with moderate heterogeneity (I 2 = 62.0%; P = .002).

A sensitivity analysis that excluded one study at a time from the pooled estimate had “little impact” on the overall effect size.

For the eight studies that focused on the relationship between parity number and CVD risk (n = 3,051,107 participants and 144,163 CVD cases), the summary risk estimates for an increase of one live birth was 1.04 (95% CI, 1.02 – 1.05).

The researchers note that “significant heterogeneity” (I 2 = 89.6%) was found in these studies.

Additionally, they observed a J-shaped association in the nonlinear dose-response meta-analysis of parity number and CVD risk when using a cubic spline model.

Similar associations were found between parity number and CHD, ischemic heart disease, and stroke risk.

Egger’s and Begg’s tests showed no publication bias in any of the studies.

The researchers conducted subgroup analyses to “explore the potential source of statistical heterogeneity among the studies and assess the stability of the results.”

These analyses evaluated category of CVD, geographical location, whether there was adjustment for BMI, diabetes mellitus, hypertension, cigarette smoking, income, physical activity, and cholesterol.

They found that the associations of parity number with risk for CVD were similar in subgroup analyses.

“We found a significant association between parity and CVD risk when comparing parity with nulliparous,” Wang summarized.

“In the dose-response analysis, we observed a potential nonlinear J-shaped dose-response relationship between the number of births and CVD risk,” he added.

Wang described the biological mechanisms underlying these associations as “complex.”

He suggested that pregnancy “could lead to the accumulation of abdominal fat, endothelial dysfunction, atherosclerosis, and increased pro-atherogenic lipid levels and systemic inflammation.”

These cardiometabolic changes “may permanently impact the cardiovascular system, leading to a higher risk of CVD in parous women later in life,” he said.

Not Necessarily Applicable to Stroke

Commenting on the study for Medscape Medical News, Cheryl Bushnell, MD, MHS, professor of neurology, vice chair of research, and chief of the stroke division, Wake Forest Baptist Health, Winston Salem, North Carolina, who was not involved with the study, said the analysis contributes to the field through “the assessment of quality of design and outcome capture for each study included in the meta-analysis.”

Moreover, “since population studies on this topic are challenging, it is always useful to combine the results from studies from a variety of countries and geographic regions into one source and perform a meta-analysis,” she continued.

“The primary take-home message is that the results of studies assessing the relationship between parity and CVD is relatively consistent, showing a small but significant increase of CVD with increasing parity,” she said.

However, despite these findings, “there are several issues not addressed in the paper,” she cautioned.

“There is no mention of whether investigators studied the impact of the number of children on fathers, since some studies have suggested that this phenomenon may not be an isolated maternal problem and the same risk for CVD may apply to fathers as the number of children increases.”

She noted that some of the studies “do not include adjustment for socioeconomic status, which could be a significant bias.”

Finally, she added, “the premise was to evaluate CVD, although the majority of studies focused on CHD, and only one included stroke — therefore, the results may not be ideally extrapolated to include stroke.”

The authors state, “Further prospective large-scale studies are warranted to confirm our findings, and to establish causality and to elucidate the underlying mechanism.”

Food and Fertility: What Should Women Consume When Trying to Conceive?


What Should I Eat to Enhance Fertility?

A young fertile couple’s chance of conceiving in the first month they try is 25%-30%.[1] By the end of the first year, about 85% of couples achieve a success; the remaining 15% are diagnosed with infertility.[2]

Infertility has many known causes (eg, ovulatory defect, tubal occlusion, low sperm counts), and many factors lower the chance of pregnancy (eg, older age, lower ovarian reserve, endometriosis). There are modifiable and nonmodifiable risk factors for infertility or reduced fertility. Although some factors can’t be altered (eg, age and ovarian reserve), others, such as body weight and lifestyle habits, are modifiable.

Patients frequently ask providers to offer them guidance on the ideal diet to improve their chances of conceiving and carrying a pregnancy to term. A recent review by Chiu and colleagues[3] summarizes the available epidemiologic literature on the reproductive benefits of diets and dietary supplements.

Nutrition and Fertility: Review Findings

This article reviews the potential benefits of consumption of certain micronutrients, macronutrients, and dietary patterns. The following conclusions are drawn from this review:

Folic acid. Folic acid is important for germ cell production and pregnancy. The recommended daily dose to prevent neural tube defects is 400-800 µg. Women who take folic acid-containing multivitamins are less likely to be anovulatory, and the time to achieve a pregnancy is reduced. Those who consume more than 800 µg of folic acid daily are more likely to conceive with assisted reproductive technology (ART) than those whose daily intake is less than 400 µg.

Vitamin D. Vitamin D may affect fertility through receptors found in the ovaries and endometrium. An extremely low vitamin D level (< 20 ng/mL) is associated with higher risk for spontaneous miscarriage risk. Some reports suggest that women with adequate vitamin D levels (> 30 ng/mL) are more likely to conceive after ART when compared with those whose vitamin D levels are insufficient (20-30 ng/mL), or deficient (< 20 ng/mL). These findings, however, are inconclusive.

Carbohydrates. Dietary carbohydrates affect glucose homeostasis and insulin sensitivity, and by these mechanisms can affect reproduction. The impact is most pronounced among women with polycystic ovary syndrome (PCOS). In women with PCOS, a reduction in glycemic load improves insulin sensitivity as well as ovulatory function. Whole grains have antioxidant effects and also improve insulin sensitivity, thereby positively influencing reproduction.

Omega-3 supplements. Omega-3 polyunsaturated fatty acids lower the risk for endometriosis. Increased levels of omega-3 polyunsaturated fatty acids are associated with higher clinical pregnancy and live birth rates.

Protein and dairy. Some reports suggest that dairy protein intake lowers ovarian reserve. Other reports suggest improved ART outcomes with increased dairy intake. Meat, fish, and dairy products, however, can also serve as vehicles for environmental contamination that may adversely affect the embryo. Fish, on the other hand, has been shown to exert positive effects on fertility.

Dietary approach. In general, a Mediterranean diet is favored (high intake of fruits, vegetables, fish, chicken, and olive oil) among women diagnosed with infertility.

Viewpoint

A well-balanced diet, rich in vegetables and fruits, is preferred for infertile women and should provide the required micro- and macronutrients. It remains common for patients consume a wide variety of vitamin, mineral, and micronutrient supplements daily.[4] Supplements should not replace food sources of vitamins and trace elements because of differences in bioavailability (natural versus synthetic), and inaccuracy of label declarations may result in suboptimal intake of important nutrients.[5,6] Furthermore, naturally occurring vitamins and micronutrients are more efficiently absorbed.

With respect to overall diet, women are advised to follow a caloric intake that won’t contribute to being overweight or obese. Obesity is on the rise among younger people, including children. Obese women have a lower chance of conceiving and are less likely to have an uncomplicated pregnancy.[7] Proper weight can be maintained with an appropriate diet and regular exercise.

Finally, women must abstain from substances that are potentially harmful to pregnancy (eg, smoking, alcohol, recreational drugs, high caffeine intake).

Unfortunately, very few large studies are available to guide us in our recommendations to patients. Most of the available literature is based on retrospective data. Therefore, prospective, randomized studies are urgently needed to study the association between nutrition and fertility, as well as dietary influences on pregnancy outcomes.

FDA Clears Test to Analyze Nutrients in Breast Milk


The US Food and Drug Administration (FDA) has cleared for marketing a diagnostic test to measure nutrients in breast milk, including the concentration of fat, carbohydrates, protein, total solids, and energy.

The Miris Human Milk Analyzer

The Miris Human Milk Analyzer (Miris AB) can help with nutritional management of newborns and young infants at risk for growth failure due to prematurity or other medical conditions. Knowing the macronutrient content of the breast milk may help clinicians make informed decisions on how to fortify the breast milk based on the individual needs of the infant, the FDA explained in a news release.

“For the first time, doctors have access to a test to help analyze the nutrients in breast milk. While this test is not for everyone, it has the potential to aid parents and healthcare providers, mainly in a hospital setting, in better assessing the nutrient needs of certain babies who are not growing as expected,” Courtney Lias, PhD, director of the Division of Chemistry and Toxicology Devices in the FDA’s Center for Devices and Radiological Health, said in the release.

The Miris Human Milk Analyzer uses an infrared spectroscopy system to analyze human milk and provide a quantitative measurement of fat, protein, and total carbohydrate content. It can also calculate the total solids and energy content of the milk. It is intended for use by trained personnel in clinical laboratories.

The accuracy of the Miris analyzer was demonstrated in an FDA analysis of 112 samples of human milk tested by the Miris analyzer and by independent methods. Both methods were similarly effective at determining levels of protein, fat, and carbohydrates in the milk.

However, the FDA said certain medications that a nursing mother may be taking could interfere with the test’s ability to accurately measure nutrient levels in breast milk.

The agency advises healthcare providers to carefully evaluate the Miris Human Milk Analyzer test results in conjunction with clinical assessments (such as weight and growth) when creating a nutritional management plan for an infant.

The FDA reviewed the Miris Human Milk Analyzer test through the de novo premarket review pathway, a regulatory pathway for some new types of low- to moderate-risk devices.

Along with this marketing authorization, the FDA is establishing “special controls” that set forth the agency’s expectations in ensuring the accuracy, reliability, and effectiveness of tests intended to measure the nutritional content of human milk to aid in the nutritional management of certain infants.

“These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type,” the agency said.

Longer Breastfeeding Key to Moms’ Slim Waists, Lower CVD Risk


Breastfeeding for 6 months or more was associated with a slimmer waist in mothers years later, compared with shorter or no breastfeeding, new data show.

“Waist circumference…as a measure of central adiposity has been shown to be a superior proxy for assessing long-term risk of coronary artery disease mortality, hypertension, diabetes, dyslipidemia, and the metabolic syndrome, independent of BMI,” Gabrielle G. Snyder, MPH, University of Pittsburgh, Pennsylvania, and colleagues note.

Thus, “breastfeeding duration may be important to consider when studying long-term maternal cardiovascular and metabolic health,” they conclude in their article published online December 11 in the Journal of Women’s Health.

“We consistently detected that a threshold effect may exist,” they report, “for breastfeeding greater than 6 months.” The benefit remained after accounting for demographic, lifestyle, and socioeconomic factors.

Snyder and colleagues analyzed data from 676 women in the Pregnancy Outcomes and Community Health (POUCH) cohort who participated in the POUCHmoms study, 7 to 15 years after delivery. They matched moms with a similar likelihood to breastfeed, and then compared the moms who breastfed for > 6 months versus not at all or less than 6 months.

“This study extends conventional observational study methods,” they write, “to incorporate propensity score approaches that make it possible to…account for systematic differences in women who did and did not breastfeed.”

Central Adiposity

“Metabolically active visceral adipose tissue, a measure of abdominal obesity primarily distributed about the intra-abdominal organs, may increase substantially with a single pregnancy, independent of total body fat,” Snyder and colleagues write.

The World Health Organization recommends exclusive breastfeeding for 6 months for optimal infant health. In addition, breastfeeding consumes nearly 500 calories a day for moms.

Prior studies have reported that women who breastfed their babies had less central obesity years later than women who did not do this, but the studies did not account for different baseline characteristics of the women.

Therefore, Snyder and colleagues compared central obesity after about a decade in women in the POUCHmoms study who were seen in clinics in Michigan communities. Of the women in the cohort, 63% of the mothers were white, 31% were black, and 6% were Asian or Native American.

Prior to pregnancy, about half of the women (49%) had a body mass index (BMI) below 25 kg/m2 (normal weight) and the rest were overweight (21%) or obese (30%).

Overall, 38% of the mothers did not breastfeed their babies, while the others did so for > 0 to 3 months (22%), > 3 to 6 months (13%), or > 6 months (27%).  In unadjusted analyses, women who breastfed for > 6 months were older and more likely to be white and have a higher education level, and less likely to be obese before pregnancy.

At a mean follow-up of 11 years, the mothers had a mean waist circumference of 94 cm if they had breastfed their child for up to 6 months, and 86 cm if they had breastfed longer.

Two types of propensity analyses showed that the mothers who reported breastfeeding their infants for more than 6 months had a mean waist circumferencethat was 3.6 cm smaller and 3.1 cm smaller than other mothers.

“We emphasize [waist circumference] as the outcome of interest,” the researchers write, “given that central adiposity is a better predictor of long-term cardiometabolic and cardiovascular disease risk than BMI alone.”

They acknowledge that study limitations include potential pre-pregnancy differences in diet and exercise, for example, that were not accounted for.

Snyder and colleagues call for more research to investigate the effect of breastfeeding in multiple pregnancies on lifetime risk of cardiovascular disease.

“Our results warrant further analyses of cumulative lifetime duration of breastfeeding,” they write, “to understand the magnitude of the relationship with maternal central adiposity over time.”

Fetal Exposure to Montelukast and Congenital Anomalies: A Population Based Study in Denmark


Abstract

Background

The objective was to study pregnancy outcomes between groups of Danish women, with pregnancy ending between 1998 and 2009, according to their exposure to montelukast.

Methods

Cross‐sectional observational study in Danish women, selecting live births and stillbirths (Birth Registry) and spontaneous abortions and induced terminations (Patient Registry). Montelukast exposure was obtained from the Prescription Registry (ATC code R03DC03). Exposure period was from 3 months before the last menstrual period until the end of the first trimester. Four groups were studied: (1) women with prescription for montelukast, (2) women with prescription for montelukast and other anti‐asthmatic medications, (3) women with prescription for other anti‐asthmatic medications, (4) women without prescription for any anti‐asthmatic medications.

Results

A total of 754,300 singleton pregnancies (> 12 weeks) were identified: 401 pregnancies in group 1, 426 pregnancies in group 2, 24878 in group 3 and 728,595 in group 4. Risk of preterm birth, maternal preeclampsia and gestational diabetes was increased for pregnancies exposed to montelukast. No significant differences were found for the risk of major congenital anomalies (CA). Adjusted odds ratio for CA was 1.4 (95% CI 0.9–2.3) for the group 1 and 1.0 (95% CI 0.6–1.8) for group 2.

Conclusion

Pregnant women with prescriptions for montelukast had a higher risk of preterm birth and maternal complications. These risks are known to be associated with maternal asthma, no increased risk of CA was found. Further analysis including more exposed pregnancies will be needed to determine the risk of specific CA.

Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy


Nausea and vomiting during pregnancy (sometimes termed morning sickness) are among the most common medical issue to arise during pregnancy. Most pregnant women experience some form of nausea and vomiting, and prevalence rates are as high as 50% to 80%.1 Conservative measures, such as dietary modifications and avoidance of triggers, often do not control symptoms, so medications and other nondrug therapies are tried.2 Nausea and vomiting is one of the most common indications for prescriptions during pregnancy.3 Because this is a condition mainly of the first trimester, pregnant women and clinicians have concerns about the potential effects these therapies might have on the developing fetus.

In this issue of JAMA, Huybrechts and colleagues4 attempt to clarify associations of a commonly used antiemetic, ondansetron, with fetal congenital malformations. Because these malformations are typically rare, establishing cause and effect of a single drug and an anomaly is extremely difficult. Association studies using robust data sets often provide the best available evidence for establishing risk or safety of a drug. The authors describe some of the limitations of prior association studies and detail how the Medicaid Analytic eXtract (MAX) database is ideally suited to overcome some of these prior limitations. Because the authors have used these data for other pregnancy exposure studies, they are well-suited for the current analysis.

In this study, the authors used data from more than 1.8 million pregnancies, allowing for a large number of analyses and adjustments. Focusing on cardiac malformations and oral clefts (the main congenital anomalies identified with any consistency in prior studies), the authors found no significant association between ondansetron and cardiac abnormalities (14 577 abnormalities among 1 727 947 unexposed infants and 835 abnormalities among 88 467 exposed infants; adjusted risk difference, −0.8; 95% CI, −7.3 to 5.7 per 10 000 births; adjusted relative risk, 0.99, 95% CI; 0.93 to 1.06). They also detected a small but statistically significant increased risk of oral clefts with first-trimester exposure to ondansetron (1912 abnormalities among unexposed infants and 124 abnormalities among exposed infants; adjusted risk difference, 2.7; 95% CI, 0.2 to 5.2 per 10 000 births; adjusted RR, 1.24; 95% CI, 1.03 to 1.48). After multiple adjustments, the authors also found no difference in the risk of cardiac or overall congenital anomalies for infants of women exposed to ondansetron.

According to the American College of Obstetricians and Gynecologists (ACOG)–endorsed treatment algorithm, ondansetron, a serotonin receptor antagonist, is not the first-line drug for treatment of nausea and vomiting.1 However, it is one of the most commonly used agents in practice.3,5 This may be because of its different formulations, including an oral dissolving tablet, and its perceived effectiveness. Thus, it is important that clinicians and pregnant women have accurate safety information about its use during pregnancy.

Treatment of nausea and vomiting can be difficult and must be tailored to the individual patient. Often, a single treatment or combination of treatments that work for one woman will be ineffective for another. In the population studied by Huybrecht et al, 139 932 pregnant women (7.7%) also filled a prescription for promethazine, 52 818 (2.9%) filled a prescription for metoclopramide, and 9036 filled a prescription for pyridoxine (vitamin B6, 0.5%)—3 commonly used agents for nausea and vomiting. According to the treatment algorithm proposed by the ACOG Practice Bulletin, pyridoxine, alone or in combination with doxylamine, is listed as the first-line agent. Ondansetron appears as a third-line option in the algorithm.1

Ondansetron is metabolized by cytochrome P450 (CYP) enzymes that are polymorphic, such as CYP 2D6. Understanding how genetic differences among individuals cause varied responses to the same drug may have implications for prescribing.6 Because there are often genetic-based differences in activity of common drug-metabolizing enzymes, transporters, and receptors among individuals, pharmacogenomics can help guide therapeutic choices in several disease states.7 Further research is needed for ondansetron and other drugs for nausea and vomiting to determine if pharmacogenomic or specific phenotype characteristics can help personalize treatment for improved outcomes.8,9

In the evolving era of personalized medicine, rapidly determining the most effective therapy can have tangible benefits. Women with severe nausea and vomiting have decreased work productivity, more time away from personally fulfilling activities, and may have higher rates of adverse pregnancy outcomes.10,11 Additionally, severe nausea and vomiting was cited as a reason for higher rates of pregnancy termination from the Motherisk project in Canada.12 Thus, early and effective safe treatment of nausea and vomiting is crucial.

The article by Huybrechts and colleagues provides important and helpful information for physicians and other clinicians to use when counseling women about the safety of treatment options. The safety of some other options, such as pyridoxine, has been established.13 The current article documents clearly that while the adjusted relative risk of oral clefts was elevated, the absolute risk increase is very low. The multiple adjustments and comparison groups presented, including accounting for the potential baseline risk of nausea and vomiting, demonstrate the robustness of the authors’ conclusions.

In addition, the authors acknowledge the typical limitations of these types of analyses. Because of the low frequency of congenital anomaly outcomes, randomized trials would need to have enormous sample sizes to detect differences between drug exposures. Thus, observational data are best suited for these studies. One additional relevant limitation of the data set is that prescriptions for the current recommended first-line treatment, pryidoxine (with or without doxylamine), may not have been completely captured. The prescription combination of doxylamine and pyridoxine was approved by the US Food and Drug Administration in 2013, the final year the MAX data were queried. Many women may have obtained these components over-the-counter, and thus the true polypharmacy rates for nausea and vomiting treatment are not accounted for in the data set.

Utilizing a large data set, the study by Huybrechts et al provides some reassurance for obstetricians and other clinicians, as well as for pregnant women regarding the safety of a commonly used medication for nausea and vomiting. The potential risk and safety findings must be weighed with the effectiveness of ondansetron in treating nausea and vomiting and avoiding hyperemesis gravidarum. The analysis also provides additional reassurance of no increased risk of cardiac or total congenital malformations. As clinicians and pregnant women engage in informed, shared decision-making surrounding treatment for nausea and vomiting, the current information is important for contextualizing risks in light of the potential benefits.