Jamie L. Habib

In a highly critical re-analysis of the Women’s Health Initiative (WHI) study of 2002,

 the results of which prompted safety fears about hormone replacement therapy (HRT) significantly increasing the risk of breast cancer, it was concluded that the weight of evidence supports benefits over risks for use of HRT in women with severe symptoms of menopause or other conditions.

The main criticism of the WHI study is how the findings were misrepresented by the media, with little effort made by those affiliated with the study to correct the misinformation. The media focused their reporting on relative risk, citing that women who use HRT have a 26% increased risk of breast cancer developing. The actual risk should have been reported in terms of absolute risk, with a modest increase in risk of 4 additional cases of breast cancer per 1000 women taking HRT over 5 years.

 In addition, of the 16,608 women involved in the WHI study, 11,086 (67%) women were between the ages of 60 and 79 years, generally long past the age at which most women experience menopause. However, the results of the WHI study were generalized to all women. This misreporting changed how many physicians prescribed HRT.

Since 2002, the rates of use of HRT have decreased between 40% and 80%. The effects of this decline in use have not been studied, but the International Menopause Society, as quoted in the re-analysis, believes that the decline in HRT use “has disadvantaged nearly a decade of women who may have unnecessarily suffered severe menopausal symptoms and who may have missed the potential therapeutic window to reduce their future cardiovascular, fracture, and dementia risk.”

A downside of HRT is a modestly increased risk of stroke, venous thromboembolism, and breast cancer. To maximize the benefits of HRT, treatment should be started within a few years of the onset of menopause in women with symptoms. The re-analysis emphasizes that HRT should not be considered safe for most women, but there are cases in which use of HRT is justified. Before prescribing HRT, physicians should consider the severity of a woman’s symptoms and whether there is any history of breast cancer.

-A re-analysis of the Women’s Health Initiative of 2002 has concluded that HRT is associated with the following benefits:

- Improved quality of life in menopausal women
- Reduced risk of coronary heart disease and death (if taken before age 60 years or within 10 years of menopause)
- Reduced risk of colorectal cancer
- Reduced risk of dementia for women beginning HRT early (later use may increase risk)
- Decreased risk of fracture (modest)


1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. 

 2002;288(3):321-333.
2. Special edition on Women’s Health Initiative and HRT. 

Articles

In a highly critical re-analysis of the Women’s Health Initiative (WHI) study of 2002, the results of which prompted safety fears about hormone replacement therapy (HRT) significantly increasing the risk of breast cancer, it was concluded that the weight of evidence supports benefits over risks for use of HRT in women with severe symptoms of menopause or other conditions.

Misreporting and Poorly Presented Results Shrouded Benefits of HRT

In anovulatory women with polycystic ovary syndrome (PCOS), one-time use of progestin to induce withdrawal bleeding before ovulation induction may decrease the odds of conception and live birth, according to a new study conducted by researchers for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIHCD) Cooperative Reproductive Medicine Network (RMN).

Often, one of the first steps in infertility treatment for women with PCOS is a one-time dose of progestin. The hormone causes the uterine lining to thicken, and without progestin maintenance therapy, the uterine lining sloughs off and bleeding begins. The logic behind this common clinical practice is to simulate the bleeding that begins a normal monthly menstrual cycle.

Using data from 626 women with PCOS obtained in a previous study, the researchers performed a secondary analysis to estimate whether using progestin to mimic menstruation before ovulation induction with clomiphene, metformin, or a combination of clomiphene and metformin has any affect on ovulation, conception, and live birth rates.

 Metformin was used in the original study because women with PCOS often have insulin resistance.

 However, the original study showed that women were less likely to become pregnant and give birth than women taking clomiphene alone or clomiphene in combination with metformin.

In this study, ovulation rates were higher after cycles involving spontaneous endometrial shedding than after anovulatory cycles with or without progestin (72% vs 30% vs 27%, respectively).

 However, the rates of conception and live births were higher after anovulatory cycles without the use of progestin. When calculated per cycle, the live birth rates were 2.2% for women who had spontaneous menses, 1.6% for women who had anovulatory cycles with progestin withdrawal, and 5.6% for those who had anovulatory cycles without progestin. Even more significant, the live birth rate per ovulation was 3.0% for the spontaneous menses group, 5.4% for the anovulatory with progestin withdrawal group, and 19.7% for the anovulatory without progestin group.

One study author (Esther Eisenberg, MD) summarized the results as follows: “Our results indicate that a treatment with progestin before ovulation induction is counterproductive in helping women with PCOS achieve pregnancy.”

The common practice of progestin-induced endometrial shedding before ovarian stimulation may adversely effect the rates of conception and live birth in anovulatory women with PCOS.


1. Diamond MP, Kruger M, Santoro N, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. 

 2012;119(5):902-908.
2. U.S. Department of Health and Human Services, National Institutes of Health. 

 Progestin treatment for polycystic ovarian syndrome may reduce pregnancy chances

 Accessed May 28, 2012.
3. Legro RS, Barnhart HX, Schlaff WD, et al, for the Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. 

Progestin May Reduce Conception Rates in Women With PCOS

Whether a woman is overweight or obese before and during pregnancy, and not glucose levels, is the most reliable predictor of a woman’s risk of giving birth to a large-for-gestational-age infant, according to a new study conducted in Canada.

Included in the study were 472 women who did not have gestational diabetes, per the results of an oral glucose tolerance test administered during late pregnancy. Of these 472 women, 104 (22%) had gestational impaired glucose tolerance.1 The researchers measured fasting levels of insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, adiponectin, and C-reactive protein. Obstetric outcomes and the birth weight of the neonate were assessed at delivery.

The mean birth weight was 3481 grams (7 lb 11 oz), and 68 infants were large for gestational age (defined as a newborn weight in the 90th percentile or above on Canadian fetal growth charts, or more than 3992 grams [8 lb 13 oz]).

 After multiple analyses, the study authors found that maternal obesity and leptin levels were more strongly predictive of a woman having an infant who is large for gestational age than glucose intolerance and lipid levels.

Maternal diabetes has long been considered the most common cause of large-for-gestational-age infants. Delivery problems associated with a baby who is large for gestational age are prolonged vaginal delivery, difficult birth, and an increased risk of cesarean section. Infants who are large for gestational age are at greater risk for birth injuries and complications of low blood glucose levels after delivery.

The results of this new study are important because the International Association of Diabetes in Pregnancy Study Groups have proposed new criteria to lower the glucose level cutoff for diagnosing gestational diabetes as a means to better identify which women are at risk for having large infants.

 If this proposed criteria were to become standard clinical practice, the rate of women identified as having gestational diabetes would double. Of concern is that the designation of gestational diabetes alone, irrespective of how well glucose levels are controlled, may lead to increased interventions. The results of this new study suggest that focusing on weight management may be a better strategy to reduce the risk of having large babies.



- Glucose levels are not a significant independent predictor of having a large baby.
- Among women without gestational diabetes, maternal obesity and leptin levels are strong metabolic determinants of having an infant who is large for gestational age.


1. Retnakaran R, Ye C, Hanley AJ, et al. Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birth weight among women without gestational diabetes mellitus. 

 2012;Epub ahead of print.
2. Carlo WA. Large for gestational age infants. In: Kleigman RM, Behrman RE, Jenson HB, Stanton BF, eds. 

 19th ed. Philadelphia: Saunders Elsevier; 2011:chap 91.4.
3. International Association of Diabetes and Pregnancy Study Groups. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. 

Overweight Women Are More Likely to Have Large Babies

The use of the anti-HIV drug tenofovir during pregnancy does  not affect birth weight or birth length, according to new research conducted as  part of the Pediatric HIV/AIDS Cohort Study.

 The impetus for this  study was that previous research in laboratory animals showed that exposure to  tenofovir in the womb was associated with smaller birth size compared with  animals not exposed to the drug.

From 2003  to 2010, the researchers collected data from 2029 children who were exposed in  the womb to anti-HIV drug regimens either with or without tenofovir.

  The association of maternal tenofovir use during pregnancy with size for  gestational age, low birth weight, weight for age, length for age, and head  circumference was then compared. At birth, no significant differences between  infants exposed to combination regimens with tenofovir and infants exposed to  regimens without tenofovir were found. At 1 year of age, however, infants  exposed to combination regimens that included tenofovir were shorter and had  smaller head circumferences compared with infants exposed to regimens that did  not include tenofovir. On average, the infants born to mothers with HIV  infection were smaller than infants born to mothers without HIV infection.

The study  authors consider their findings to be reassuring, especially because use of  tenofovir in pregnant women with HIV infection is becoming more common. In the  study, the percentage of mothers that had been prescribed tenofovir was 14% in  2003, compared with 43% in 2010.

 Before this study, tenofovir had  not been studied specifically for potential effects on infants. The study  authors also note that no serious safety concerns regarding use of tenofovir  during pregnancy were identified.

“Although  further research is needed, on balance, our findings favor the use of tenofovir  in pregnancy to ensure good outcomes in the mother and prevent transmission of  HIV to the infant,” said George Siberry, MD, first author of the study.


   - Tenofovir is safe to use during pregnancy, although the  drug may be associated with a delayed growth effect.
 - Infants exposed to tenofovir in the womb are not smaller  or shorter than infants exposed to other anti-HIV medications in the womb.  However, tenofovir-exposed infants are smaller at their first birthday.


  1. Siberry GK, Williams PL, Nendez H, et al, for the  Pediatric HIVAIDS Cohort Study (PHACS). Safety of tenofovir use during  pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS.  2012;26:1151-1159.
  2. U.S. Department of Health and Human Services, National  Institutes of Health. Anti-HIV drug use during pregnancy does not affect infant  size, birth weight. Available at: 

http://www.nih.gov/news/health/may2012/nichd-01.htm

The use of the anti-HIV drug tenofovir during pregnancy does  not affect birth weight or birth length, according to new research conducted as  part of the Pediatric HIV/AIDS Cohort Study. The impetus for this  study was that previous research in laboratory animals showed that exposure to  tenofovir in the womb was associated with smaller birth size compared with  animals not exposed to the drug.

Jamie L. Habib

Articles

Misreporting and Poorly Presented Results Shrouded Benefits of HRT

Progestin May Reduce Conception Rates in Women With PCOS

Overweight Women Are More Likely to Have Large Babies

Use of Anti-HIV Drug Does Not Effect Birth Size