Morning Sickness: Antihistamines Linked to Poor Outcomes

Steven Fox

Jun 14, 2013

 

Pregnant women who take antihistamines to help alleviate symptoms of hyperemesis gravidarum are significantly more likely to experience adverse outcomes, according to results from a new case-control study published online May 28 in theEuropean Journal of Obstetrics & Gynecology.

"Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, accounts for over 285,000 hospital discharges in the US annually," write Marlena S. Fejzo, PhD, assistant professor of research in obstetrics and gynecology, University of California, Los Angeles, and colleagues.

Previous studies have shown a link between HG and adverse outcomes, and Dr. Fejzo and colleagues decided to investigate what the causes might be. They compared 2 cohorts of women: 254 women who experienced HG during their pregnancies and were treated with intravenous fluids and 308 women who had had normal pregnancies.

The researchers asked the women which of 35 different medications and other treatments they had used during pregnancy.

They found that women in the HG group were 4 times more likely to experience adverse outcomes, including preterm birth and lower birth weight, than women with normal pregnancies (P < .0001). They also found that both gestational hypertension and early-onset of HG symptoms were linked to poor outcomes.

Moreover, methylprednisolone and promethazine were both linked to adverse outcomes (P < .0217 andP < .0386, respectively). Other antihistamines, including diphenhy-dramine, dimenhydrinate, doxylamine, hydroxyzine, doxylamine, and pyridoxine, were also associated with adverse outcomes (P< 0.0151), regardless of efficacy.

The researchers say antihistamines also tended to be prescribed regardless of the severity of the symptoms. Nearly half of the women with HG who experienced adverse outcomes reported having taken antihistamines, yet the drugs were effective in less than 20% of cases.

In contrast, they report that women who were treated as outpatients and/or who made use of alternative treatments such as acupuncture, acupressure, and Bowen massage were more likely to have better outcomes.

The authors note that their findings are surprising, given the large body of evidence on the safety of antihistamine use during pregnancy.

"Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy," the authors conclude.

This study was funded by the Hyperemesis Education and Research Foundation. The authors have disclosed no relevant financial relationships.

Eur J Obstet Gynecol. Published online May 28, 2013. Abstract

Postpartum Depression Underidentified, Undertreated

One in 7 Women Positive for Recurrent Episodes of Major Depression

Deborah Brauser

Mar 21, 2013

Postpartum depression is increasingly common, new research suggests.

In a study of 10,000 women who had recently given birth, 14% — or roughly 1 in 7 — screened positive for recurrent episodes of major depression. And of these, more than 19% reported having considered harming themselves.

"The rate of postpartum depression was not surprising and [was] consistent with other estimates that have been developed from smaller samples of patients," lead author Katherine L. Wisner, MD, professor of psychiatry and behavioral sciences and of obstetrics and gynecology, and director of the Asher Center for the Study and Treatment of Depressive Disorders at Northwestern University Feinberg School of Medicine in Chicago, Illinois, told Medscape Medical News.

The largest-scale depression screening of postpartum women, the study marks the first time a full psychiatric assessment was done in this patient population.

"Although this is a bit of a controversial subject, we were able to show that women will accept these types of screenings. But where we need a lot more work is how to get those who screen positive to treatment," added Dr. Wisner.

The study was published online March 13 in JAMA Psychiatry.

Dr. Katherine Wisner

A second study also conducted by Dr. Wisner and colleagues and published online March 20 in the American Journal of Psychiatry showed that infant growth during the first 12 months is unaffected by prenatal exposure to antidepressants or by maternal depression.

Although the 2 studies are very different, Dr. Wisner noted that they both highlight the importance of screening women both before and after giving birth and to discuss treatment options.

"I've been doing this for about 30 years, and I'm still really troubled by the number of women who are pregnant or postpartum and depressed and not identified. And I just want them to know that they don't have to feel like that. Don't suffer, get some help!"

Huge Public Health Problem

In the study on postpartum depression, the investigators aimed to screen for the disorder, determine the timing of episode onset, and evaluate the possibility of thoughts of self-harm.

"In the US, the vast majority of postpartum women with depression are not identified or treated even though they are at higher risk for psychiatric disorders," said Dr. Wisner in a release.

"It's a huge public health problem. A woman's mental health has a profound effect on fetal development as well as her child's physical and emotional development."

The researchers evaluated 10,000 women older than 18 years who underwent screenings 4 to 6 weeks after delivery at Magee-Womens Hospital in Pittsburgh, Pennsylvania.

Results showed that 1396 of the women screened positive for depression, as shown by a score of 10 or higher on the Edinburgh Postnatal Depression Scale (EPDS), and 19.3% of these women reported having thoughts of self-harm.

Seven percent of the positive-screening women had a score of 13 or higher on the EPDS, and of these, 30% reported self-harm ideation.

Of the 1396 women, 826 (59.2%) received full psychiatric assessments during at-home visits, and 147 (10.5%) underwent a diagnostic interview by telephone.

"Most of these women would not have been screened and therefore would not have been identified as seriously at risk," said Dr. Wisner.

High Rate of Bipolar Disorder

In addition, 26.5% of the women who screened positive and had an in-home assessment reported having depression prior to their pregnancy, 33.4% had first-episode onset during pregnancy, and 40.1% had first onset postpartum. More than two thirds reported a comorbid anxiety disorder.

"Clinicians need to know that the most common clinical presentation in the postbirth period is more complex than a single episode of depression," said Dr. Wisner. "The depression is recurrent and superimposed on an anxiety disorder."

Interestingly, 68.5% of the women had unipolar depressive disorders, and 22.6% had bipolar disorder.

"That's a very high rate of bipolar disorder that has never been reported in a population screened for postpartum depression before. It is significant because antidepressant drug treatment alone can worsen the course of [this] disorder," added Dr. Wisner.

Overall, she noted that screenings are very important for this patient population. In fact, she reported that screenings for perinatal mental health disorders are now mandatory in the state of Illinois.

However, "if we identify patients, we must have treatment to offer them. If you try to refer them from an obstetrical setting to a mental health setting, because of stigma and other barriers, that's very difficult," said Dr. Wisner.

"So the newer models are treatment in the obstetrical or primary practice settings — so it's like 1-stop shopping. We need to integrate our system more. If we identify these women, then we have the responsibility to provide accessible treatment. And we aren't doing so good at that right now as a society."

Infant Growth Unaffected

For the second study, the investigators evaluated 3 groups of pregnant women between the ages of 15 and 44 years: those who did not use selective serotonin reuptake inhibitors (SSRIs) and did not have depression (n = 97), those who did not use SSRIs but did have major depression (n = 31), and those who used SSRIs and had major depression (n = 46).

All were assessed at 20, 30, and 36 weeks' gestation. In addition, pairs of mothers and infants were evaluated at 2, 12, 26, and 52 weeks postpartum.

Results showed that neither maternal major depression or SSRI exposure was significantly associated with infant weight, length, or head circumference. This nonsignificance continued even after evaluating prepregnancy body mass index.

In addition, the observed infant values were comparable with population statistics from the Centers for Disease Control and Prevention.

"Use of SSRIs is widespread, and women who stop taking them near the time of conception have a high relapse rate," said Dr. Wisner. "Given that depression has its own negative consequences, it's important to know the effects of both treatment and the lack of treatment."

The investigators note that larger studies are now needed.

"The effect of SSRI dose or, more directly, maternal serum drug level...is also needed to drive the process of risk-benefit decision making to a new level of sophistication," they write.

Gold Standard Research

In an accompanying editorial, Barbara L. Parry, MD, from the Department of Psychiatry at the University of California, San Diego, agrees that clinicians who manage major depression during pregnancy and lactation must weigh both the risks and benefits of prescribing antidepressants.

Although previous studies have suggested that prenatal depression is associated with increased risk for preterm birth and low birth weight and that use of antidepressants during pregnancy is linked to several adverse outcomes, Dr. Parry noted that much of that research was limited because of the exclusion of specific participants — and by not assessing longer-term outcomes.

She notes that "the distinguishing feature of the current study" is its examination of the 3 distinct groups of pregnant women.

"Other strengths of the study include its prospective design, thorough participant (mother and child) assessments of clinical history, and physical examinations by raters blind to the condition," said Dr. Parry.

"Thus, this study sets the gold standard as to how to conduct sound methodological investigations in this field so that clinicians and patients have the necessary information to make informed decisions about reproductive choices."

Both studies were supported by grants from the National Institute of Mental Health. The study authors have reported several relevant financial relationships, which are fully listed in the original articles. Dr. Parry has reported no such financial relationships.

JAMA Psychiatry. Published online March 13, 2013. Abstract

Am J Psychiatry. Published online March 20, 2013. Abstract, Editorial

Overdiagnosis on Screening Mammography 'Unavoidable'

Medscape Medical News > Oncology

Pam Harrison

Mar 19, 2013

 

VIENNA, Austria — The risk for overdiagnosis on screening mammography is unavoidable, and healthcare providers need to inform patients of this risk prior to screening, investigators say.

For women screened every 2 years from the age of 50 to the age of 70, about 1% "will have a breast cancer detected and treated that otherwise would not have surfaced clinically during their lifetime," Ulrich Bick, MD, from Charité Medical University in Berlin, Germany, told Medscape Medical News.

"This is highly significant and it's something we have to talk about," Dr. Bick said here at European Congress of Radiology 2013.

When he and his colleagues tracked the 30-year trend in breast cancer incidence, they found a 20% to 25% increase in the incidence of ductal carcinoma in situ (DCIS).

If the excess risk was solely related to the overdiagnosis of DCIS, the issue could be easily resolved. "Unfortunately, it is not that simple," Dr. Bick said.

Over the same 30-year interval, the investigators found an increase in the incidence of invasive breast cancer. Some, but not all, of this was likely influenced by the widespread use of hormone replacement therapy during that timeframe, Dr. Bick explained.

 

This is highly significant and it's something we have to talk about.

 

In fact, when a team of Norwegian investigators calculated the combined incidence of overdiagnosis of DCIS and invasive breast cancer in women who participated in the Norwegian Breast Cancer Screening Programme, they found an estimated incidence of 17% to 20%.

In the same dataset, the overdiagnosis of invasive breast cancer alone was 11% to 13%, "suggesting that about two thirds of overdiagnosis actually represents invasive cancer that's detected during screening," Dr. Bick said.

Low- and even intermediate-grade DCIS lesions can have an excellent prognosis, even in the absence of treatment, but some DCIS lesions are actually high-grade in situ cancers.

"These cancers are highly relevant for mortality and they need to be diagnosed in a timely way," Dr. Bick said.

As for low-grade DCIS, data on the natural history of these breast cancers are sparse.

The numbers suggest that roughly 50% of DCIS patients will eventually develop an invasive breast cancer, but that can take several decades.

"The main problem is whether or not you consider low-grade DCIS a cancer," Dr. Bick said. Guidelines currently dictate that once detected, DCIS should be treated and, if it is treated, it needs to be excised completely.

"These lesions are often large," Dr. Bick explained, "and a large proportion of women with low-grade DCIS undergo mastectomy." In contrast, the excision of invasive breast cancer often requires that only a small amount of tissue be removed, so surgery is often minimal, he noted.

Clinical trials have not yet identified the subset of patients who can be spared radiotherapy because of the low malignant potential of their in situ carcinoma. In the absence of these data, patients could receive radiotherapy they don't need.

In fact, no clinical trial of low-grade DCIS has found an effect of any kind of adjuvant therapy on metastatic disease or long-term survival.

Radiologists can take steps to lower the likelihood of unavoidable overdiagnosis on screening mammography.

"We all know that digital mammography increases both in situ detection of lesions, independent of grade, and invasive cancer, so it's important to use digital mammography in screening to better diagnose relevant disease," Dr. Bick said.

Screening Asymptomatic Patients

Adequate pursuit of microcalcifications on breast imaging is "highly relevant" for the detection of small invasive cancers because many of the high-grade cancers have microinvasions that are important to detect, he explained.

"I believe biopsy of a microcalcification is necessary to define the nature of the underlying abnormality," Dr. Bick said. When choosing not to treat a low-grade DCIS and proceeding with a wait and see approach, "I feel much better if I have a magnetic resonance imaging [MRI] result first. Sometimes microcalcifications are only the tip of the iceberg, and you need an MRI to exclude relevant high-grade or invasive disease in other locations, distant from the area of biopsy."

These patients should be followed-up within 6 months, he noted.

"If we diagnose low-grade DCIS, it's crucial for us as radiologists to tell patients that if they do have cancer at all, it's not the invasive breast cancer they read about, that this is not a dangerous disease. And we need to encourage physicians to reduce overtreatment," Dr. Bick said.

Session cochair Harry de Koning, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands, agrees there will always be overdiagnosis when asymptomatic patients are screened.

"However, the amount of overdiagnosis is limited to perhaps 10% to 20% of all cancers detected on mammography screening. Given the benefits of mammography, it's a reasonable balance," Dr. de Koning told Medscape Medical News.

He explained that it is reasonable to question whether certain subtypes of breast cancer, most notably low-grade DCIS, can be treated less aggressively, or perhaps not at all.

In the United Kingdom, plans are currently underway for a randomized controlled trial to evaluate whether the prognosis of low-grade DCIS is equivalent in those who receive treatment and those who do not.

Dr. Bick reports receiving equipment support from Hologic and Toshiba, holding a patent with Hologic, and speaking on behalf of the General Electric Company and Carestream Health. Dr. de Koning has disclosed no relevant financial relationships.

European Congress of Radiology (ECR) 2013: Abstracts A63. Presented March 8, 2013.

Low-calorie Sweeteners and the Risk of Preterm Delivery

Results From Two Studies and a Meta-analysis

Carlo La Vecchi

J Fam Plann Reprod Health Care. 2013;39(1):12-13. 

 

• Print
• Email

• Background
• Norwegian Cohort Data
• Danish Cohort Data
• Meta-analysis

• References

Background

The possible relation between low-calorie sweeteners (as well as sugar-sweetened beverages) and unfavourable pregnancy outcomes, in particular preterm delivery and low birth weight, has recently become of considerable interest, given the widespread use of low-calorie sweeteners, and the high frequency of preterm deliveries in high-income countries.

Meta-analysis

We pooled the main findings of the two studies described above using standard meta-analytic techniques.^[8] The Danish data were introduced in two separate strata of carbonated and non-carbonated beverages, since any possible association was apparently stronger for carbonated beverages, both sugar-sweetened and low-calorie ones.

The results of the meta-analysis are given in Table 1. The pooled RRs in all levels of consumption were close to unity both for sugar-sweetened and for low-calorie beverages and, most important, there was no difference in the risk estimates of sugar and low-calorie beverages, since all the CIs largely overlap.

There is therefore no evidence that low-calorie beverages, which are US Food and Drug Administration approved for consumption during pregnancy, have an impact on preterm delivery at any variance from that of sugar-sweetened beverages.

Contraception: What's Most Effective?

From Medscape Ob/Gyn > Viewpoints

Posted: 07/03/2012Peter Kovacs, MD, PhD

Effectiveness of Long-Acting Reversible Contraception

Winner B, Peipert JF, Zhao Q, et al
N Engl J Med. 2012;366:1998-2007

Contraceptive Methods

Contraception is used for 2 reasons. First for birth control, but also because most methods offer noncontraceptive benefits. For example, oral contraceptives can be used to manage hirsutism, dysmenorrhea, and menorrhagia; a progesterone intrauterine device (IUD) is also highly effective in treating menorrhagia.

The efficacy of different contraceptive methods in preventing pregnancy varies and is influenced by whether the method is used "perfectly" or "typically." The efficacy of a few methods of contraception (tubal ligation, subdermal implants) is independent of the user, but most methods are dependent on the level of compliance. Compliance is generally not perfect; therefore, in a small proportion of users, the contraceptive method will fail and pregnancy can ensue. Contraceptive failure is the most common reason for undesired pregnancy. About half of all pregnancies are unplanned, and about half of these are terminated. This puts the patient at risk and is associated with psychological consequences and significant healthcare expenses

Women can select from numerous contraceptive options. Patients with different backgrounds (eg, age, socioeconomic status, education, parity) typically choose different methods, but the healthcare provider plays an equally important role in decision-making. Contraception is expensive; therefore, insurance coverage also influences the decision.

The study by Winner and colleagues compared the efficacy of long-acting, reversible methods of contraception (subdermal implant, IUD) in a large group of women at risk for pregnancy with that of depot medroxyprogesterone acetate injection (DMPA; Depo-Provera®; Pfizer, New York, New York) and other shorter-acting hormone preparations (pill, patch, vaginal ring).

Study Summary

A total of 7486 women participated in the study. All contraceptive methods were free for 2-3 years. The patient was allowed to select the method (and to switch methods if needed) after appropriate counseling. Conception that occurred while using the method was considered a contraceptive failure.

Women who chose the pill, patch, or ring were more likely to be nulliparous and to have private insurance. These women also had fewer previous unintended pregnancies. DMPA users were more likely to be black and to have less education and lower socioeconomic status. Women who selected IUDs or implants were more likely to be older and to be parous.

During the study period, the participants had a total of 156 unintended pregnancies. These women were younger, had lower socioeconomic status, were more likely to be black, and were more likely to have previous undesired pregnancies. Women who used IUDs or implants had a level of risk for unintended pregnancy similar to that of DMPA users. Risk for unintended pregnancy was significantly higher in pill, patch,and ring users (hazard ratio. 21; 95% confidence interval, 13.67-34.88). Younger (under 21 years of age) pill users had a 2-fold increased risk for unintended pregnancy than older pill users. Winner and colleagues concluded that the effectiveness of long-acting reversible contraception is superior to that of the contraceptive pill, patch, or ring and is not altered in adolescents and young women.

Viewpoint

No contraceptive method provides 100% efficacy, but with perfect use, hormonal contraception, long-acting implants, IUDs, and tubal ligation are associated with failure rates of less than 1%. Most methods are associated with higher failure rates with ordinary (typical) use.

The choice of contraception depends on several factors. Reversibility and interference with everyday life are important considerations for some women, whereas other women need a method that also protects them from sexually transmitted infections. Multiparous women typically choose longer-acting methods or may decide on tubal ligation. Parous women also more often select IUDs. Younger women are more likely to choose short-acting hormonal or barrier contraception. They are also more likely to be noncompliant and thus at higher risk for unintended pregnancy. Multiparous women tend to be more compliant, and because pregnancy rates also decline with age, the risk for undesired pregnancy diminishes over time.

Unintended pregnancies should be prevented in all age groups, and especially among nulliparous women who tend to have more psychological consequences. Longer-acting methods that are less user-dependent may be the best options for these women. In well-screened cases, IUDs or subdermal implants may be good choices. DMPA is another option, but the patient needs to be educated about the potential side effects to improve long-term compliance. All women who select long-acting methods should be educated about the prevention of sexually transmitted infections because these options do not protect against these diseases.

Finally, the method must be affordable to the patient. Inability to pay might be a reason for lack of contraception or noncompliance. The costs of contraception should be balanced against the expenses associated with pregnancy termination. This study shows the huge difference in unintended pregnancy rates with short- and long-acting contraceptive methods in favor of the long-acting methods. Counseling should include a discussion of the benefits of long-acting reversible contraception when patients seek medical advice with regard to their contraceptive options
.

Cervical Cancer Screening guidelines

From Medscape Ob/Gyn > Kaunitz on Women's Health

Updated Guidelines for Cervical Cancer Screening: Less Is More

Andrew Kaunitz, MD

Posted: 04/05/2012

Hello. I'm Andrew Kaunitz, Professor and Associate Chair of the Department of Obstetrics and Gynecology at the University of Florida College of Medicine in Jacksonville, Florida. Today, I'd like to discuss Updated Guidelines for Cervical Cancer Screening: Less Is More.

The profound impact that annual pap smears have made in reducing the incidence of and mortality from cervical cancer represents a triumph of preventive medicine. Over time, we have learned that beginning screening at age 21 years and performing cytology less often than annually will not compromise outcomes. We also have come to appreciate the role human papillomavirus (HPV) plays in causing cervical neoplasia.

Over the last decade, cotesting, which employs cytology along with testing for 12 or 13 oncogenic HPV types, has been found to be superior to cytology alone in identifying preinvasive lesions in women older than 30 years of age, while allowing women with negative cytology and HPV results to be safely screened less often.

The American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) have now published new, evidence-based guidelines that will change how we screen for cervical cancer.^[2] To summarize:

• Screening should begin at age 21 years. Cytology alone is recommended every 3 years for women 21-29 years of age.
• For women 30-65 years of age, cotesting every 5 years is recommended. If HPV testing is not available, cytology alone should be continued every 3 years.
• Cytologic findings of atypical squamous cells of undetermined significance (ASCUS) accompanied by HPV-negative results should be managed the same as with a normal screening result.

I anticipate the greatest confusion will surround the management of women who are cytology negative but HPV-positive:

• Option #1 in this setting is to repeat cotesting in 1 year. At that time, women who retest HPV-positive or have low-grade squamous intraepithelial lesion changes on cytology should undergo colposcopy. Women with normal or ASCUS cytology and who are HPV-negative at 1 year should return to routine screening.
• Option #2 is immediate testing for HPV types 16 and 18. Women who test positive for either of these viral types should undergo colposcopy. Women who test negative for both of these viral types should be cotested in 12 months, with management of results as outlined in Option #1.

Women with all other abnormalities should be managed as per existing guidance from ASCCP^]

Most women can discontinue screening after age 65 years or after hysterectomy. Once discontinued, screening should not resume even if a woman reports having a new sexual partner.

Following spontaneous regression or appropriate treatment, women with a history of CIN2 (cervical intraepithelial neoplasia grade 2) or a more severe lesion should continue screening for at least 20 years, even if this extends beyond age 65 years.

New recommendations issued by the US Preventive Services Task Force^[4] are now similar to the updated guidance from ACS/ASCCP/ASCP that is summarized here.

As we implement these new guidelines in our practices, our challenge as women's health clinicians will include educating our patients not only that cervical cancer screening can be performed less frequently without placing them at risk, but also that well-woman visits and pelvic examinations provide health benefits above and beyond early detection of cervical cancer.

Breast Cancer n Underarm Products

From Medscape Medical News > Oncology

Link Between Parabens and Breast Cancer?

Roxanne Nelson

January 26, 2012 — Can the use of antiperspirants and deodorants increase the risk for breast cancer?

Data from a study published online January 12 in the Journal of Applied Toxicology could relieve some of the fears about using underarm products, but could also raise questions and concerns.

The issue centers on exposure to alkyl esters of p-hydroxybenzoic acid (parabens), which are widely used as antimicrobial preservatives in pharmaceuticals, foods, and cosmetics. About 10 years ago, note the researchers, studies began to reveal that parabens had estrogenic properties, and estrogen plays a central role in the development, growth, and progression of breast cancer.

In this new study, researchers in the United Kingdom examined 160 breast-tissue samples obtained from 40 patients who had undergone a mastectomy for primary breast cancer. They found that 99% of samples had traces of at least 1 paraben, and that 60% had traces of 5 different parabens.

Importantly, 7 of the women reported never having used underarm products. This suggests that the parabens originated from another source, note the authors.

The source of the parabens measured in this and in previous studies cannot be identified; it is also not clear if the paraben traces come from long-term accumulation, current exposure, or a combination of both.

Parabens are only one part of a much bigger picture.

"I do think that the parabens are only one part of a much bigger picture," said lead author Philippa D. Darbre, PhD, a reader in oncology at the University of Reading, United Kingdom.

"That is not to say that they do not contribute, but the issue is bigger," she told Medscape Medical News. "Parabens are only one component...of personal care products. What is needed now is...a map of what chemicals there are in a human breast in the modern world and how they distribute across the breast, especially in relation to the site of the tumor."

Adding to the Evidence

In their study, Dr. Darbre and colleagues found a disproportionate incidence of breast cancer in the upper outer quadrant of the breast. In all 40 women, levels of n-propylparaben were higher in the axilla region than in the mid or medial regions (Wilcoxon matched pairs test, P = .004 and P = .021, respectively).

This finding is not unusual; a number of studies over the past several decades have reported that a disproportionately high number of breast tumors in women originate in the upper outer quadrant of the breast, "for which a definitive explanation remains lacking," the authors write. This disproportionality has been increasing in the United Kingdom, and now exceeds 50% of breast cancers.

"The detection of intact esters is more suggestive of a dermal route of exposure," said Philip W. Harvey PhD, a registered toxicologist at Covance Laboratories Ltd, North Yorkshire, United Kingdom, who was not involved in the study. "Oral exposure results in the rapid conversion of the esters to the common metabolite p-hydroxybenzoic acid in both gut and liver. The skin has a much lower esterase capacity, which may explain the fact that 5 different intact paraben esters were found."

Dr. Harvey told Medscape Medical News that the gradient or differential concentrations between zones with the highest levels in the axilla are consistent with a dermal route of exposure. "If the residues derive from dermal sources, the highest concentrations are likely to be at the site of exposure," said Dr. Harvey, who is editor-in-chief of the Journal of Toxicology. "That the axilla shows the highest concentrations is consistent with local application and implicates any products applied there."

He emphasized that Dr. Darbre and colleagues did not investigate causal mechanisms of breast cancer, and did not claim that either parabens or underarm products actually caused the cancer in the patients studied. "However, it does add to the dataset that these weakly estrogenic chemicals are found in significant quantities in estrogen-sensitive tissue," he noted. "Not all women will be sensitive to this, but...there will be a proportion of women who are sensitive."

Causal Relationship Undetermined

Personal care products have been used since the days of Cleopatra, but unprecedented quantities are being used nowadays, and are ultimately being released into the environment, explained Dr. Darbre. Investigations have shown that there is widespread aquatic environmental pollution stemming from use, and therefore little doubt that these chemicals are entering human tissues. The human breast has "become a sink for lipophilic compounds due to its high adipose tissue content," she said.

However, in a previous paper, Dr. Darbre and colleagues pointed out that it remains to be determined whether there is any causal relation between individual or combinations of chemicals and the development of breast cancer (CML Breast Cancer. 2010;22:113-122). The real environmental impact of estrogenic chemicals needs to comprise the entire chemical load in the breast.

An increasing number of environmental chemicals with estrogenic properties have been measured in human breast tissues, the authors of that paper write, which shows that the human breast is exposed to many estrogenic compounds in low doses and over a long period of time. These chemicals could act synergistically to "produce an estrogenic stimulus even at concentrations at which each alone would be ineffective."

There is a gap in our understanding of the combined effect of different chemicals in a single human breast, the authors note, because reports of measurements to date have generally evaluated only single groups of chemicals in any one study group.

"In the meantime, I remain rather ambivalent about hounding just one chemical," said Dr. Darbre. "My advice remains as always — to cut down on, or cut out as much as possible, overall use of personal care products, especially those left on the skin around the breast area."

"When even the water systems are now having to remove personal care product compounds from them, we must be simply using too much in the modern world — too much for our own bodies and too much even for the environment," she added. "The only way forward at the moment is for us all to cut down."

Higher Levels Seen

In this study, Dr. Darbre and her team measured the concentrations of 5 parabens at 4 serial locations in the human breast, from the axilla to the sternum, using tissue samples collected in from 2005 to 2008.

The authors found that at least 1 paraben ester was quantifiable in 158 of 160 specimens (99%), and that all 5 esters were quantifiable in 96 of 160 specimens (60%).

The overall median value for total parabens in the breast tissue was 85.5 ng/g (range, 0.0 to 5134.5 ng/g). This level is 4 times higher than the 20.6 ng/g seen in a smaller previous study, which was also led Dr. Darbre (J Appl Toxicol. 2004;24:5-13).

The highest values were observed for n-propylparaben, at 16.8 ng/g (range, 0.0 to 2052.7), and methylparaben, at 16.6 ng/g (range, 0.0 to 5102.9). They were much lower for n-butylparaben, at 5.8 ng/g (range, 0.0 to 95.4), ethylparaben, at 3.4 ng/g (range, 0.0 to 499.7), and isobutylparaben, at 2.1 ng/g (range, 0.0 to 802.9).

More Research Needed

Dr. Harvey noted that the dataset is sparse and there is a need for further research. "The rising incidence of breast cancer in recent decades points to environmental or lifestyle factors, and chemical exposure — of which the cosmetics scenario is one of the most obvious for direct dermal exposure — is just one implicated factor, together with all the other known factors for breast cancer," he said.

In addition, the regulatory toxicology dataset on parabens as a whole needs to be updated, he added, noting that European regulators are slowly taking steps on information that is coming to light, specifically reducing permitted concentrations of some paraben esters.

"The wisdom of putting estrogenic chemicals in any dermal product must be questioned, particularly compounds with an old regulatory toxicology dataset that probably does not achieve adequate modern standards, and particularly where current-use patterns already indicate that there is insufficient margins of safety in some groups, such as children," Dr. Harvey said.

It is easy to say that there is no evidence of parabens or cosmetics being associated with a health effect if the research has not been done.

"The whole area is poorly researched, but it's now time to coordinate funding and support into a few key areas of environmental endocrine disruption and human health, and the cosmetics scenario is one of the most promising to study in a controlled way," he emphasized. "It is easy to say that there is no evidence of parabens or cosmetics being associated with a health effect if the research has not been done; indeed, the statement is misleading to the public."

Michael J. Thun, MD, vice president emeritus of epidemiology and surveillance research at the American Cancer Society, cautioned that this analysis not be misinterpreted. "The purpose was not to study whether parabens in general or underarm deodorants affect breast cancer risk," he said. "Rather, it examined the levels and anatomic distribution of various paraben compounds in the excised breasts of 40 women with breast cancer."

However, he agrees that more research is needed. "Questions have been raised about their safety because parabens are absorbed through the skin and trace amounts can be detected in tissues, including breast tissue," he explained. "Parabens weakly mimic the effects of estrogen, a hormone known to play a role in breast cancer. No study has yet shown that the concentration of parabens in breast tissue taken from women with breast cancer are higher than that in breast tissue of women without breast cancer. A well-designed study of this issue would be useful."

The Genesis Breast Cancer Prevention Appeal funded the salary of a clinical research fellow and the cost of the liquid chromatography–tandem mass spectrometry analysis. The authors have disclosed no relevant financial relationships.

J Appl Toxicol. Published online January 12, 2012. Abstract