Women with HIV have increased risk of missed menstrual periods

Women living with HIV have a significantly higher risk of the menstrual disorder amenorrhea (missing three of more consecutive periods), according to a meta-analysis published in the online edition of AIDS. Infection with HIV was associated with a 70% increase in the risk of amenorrhea, and low body mass index (BMI) emerged as a possible risk factor.

“Overall, we found a positive association between HIV and amenorrhea,” comment the authors. “These finding suggest that premenopausal women living with HIV have a higher risk of developing amenorrhea, a finding that is corroborated by several observational studies in the literature. The clinical relevance of this finding may be increasing as women with HIV are living longer, healthier lives with childbearing potential.”

Although the meta-analysis clearly shows the need for clinicians to screen HIV-positive women for amenorrhea, it should be noted that most of the data were collected before modern HIV therapy became available.

Amenorrhea was first recognised in women with HIV in 1988 when it was noted in over a quarter of women newly diagnosed with HIV in Uganda. Since then the condition has been described in pre-menopausal HIV-positive women in a variety of settings. It is unclear if amenorrhea is a complication of HIV infection itself or due to other risk factors that are more common in women with HIV, such as low body weight and immune suppression. The high prevalence of opioid use in women with HIV in some settings could also be a cause.

The complications of amenorrhea may include infertility, impaired bone metabolism, raised cardiovascular risk, depression, anxiety and sexual dissatisfaction.

To establish a clearer understanding of the relationship between amenorrhea and HIV, a team of Canadian investigators conducted a meta-analysis of observational studies involving pre-menopausal women that reported on amenorrhea.

Only observational studies that matched pre-menopausal women with HIV-negative controls were eligible for inclusion. Studies were excluded if they examined amenorrhea in the context of menopause, contraception, pregnancy, breast feeding or as secondary to antiretroviral therapy (ART).

Six studies published between 1996 and 2010 met the authors’ inclusion criteria. Five were conducted in the US, three of which used data from the Women’s Interagency Health Study (WIHS). The sixth study was conducted in Nigeria. The total number of study participants – women living with HIV and controls – was 8925 individuals.

Different definitions were used for amenorrhea, ranging from absence of periods for three months through to more stringent diagnostic criteria such as not menstruating for one year with follicle stimulating hormone levels below 25 milli-IU-ml.

The overall prevalence of amenorrhea among women with HIV was 5%.

Two studies showed a significant association between HIV and amenorrhea. The first was conducted in Nigeria between 2005 and 2007, with 50% of HIV-positive women taking ART. HIV was associated with a more than twofold increase in the risk of amenorrhea (OR = 2.11; 95% CI, 1.25-3.55, p = 0.005).

The other study was conducted in the US, with recruitment between 1994 and 1995.  It showed that HIV was associated with a more than threefold increase in the odds of amenorrhea (OR = 3.41; 95% CI, 1.36-8.57, p = 0.009). Just under half (47%) had ever taken ART, though the date of the study means this is likely to have been with dual therapy and other suboptimal regimens.

No significant association was present in the other four studies.

Across the six studies, the median age of the study participants ranged between 33 and 37 years. The combined prevalence of illicit drug use was 27% with rates comparable between women with HIV and the controls. In four of the studies, BMI was significantly lower among women with HIV compared to the HIV-negative women. A fifth study also showed higher rates of weight loss in the women with HIV. Approximately a quarter of the women with HIV had a CD4 cell count below 200 cells/mm³.

The meta-analysis showed a significant association between HIV and amenorrhea (OR = 1.68; 95% CI, 1.29-2.20, p = 0.001). This association remained largely unchanged when only one of the WIHS studies was included.

“Our study suggests a possible link between amenorrhea and HIV-associated low BMI, the mechanism of which may relate to immune dysregulation,” note the investigators. The five US studies all controlled for opioid use when calculating whether HIV was associated with an increased risk of amenorrhea.

Much of the study data came from the era before combination antiretroviral therapy (cART) was introduced in the late 1990s, but the authors argue that overall cART coverage in the studies – 15% to 50% – is similar to that seen in the current population of all HIV-positive women in the United States (24% to 37%), including undiagnosed individuals. However, further research involving women taking modern antiretroviral regimens is clearly needed.

“This meta-analysis establishes an association between amenorrhea and HIV,” write the researchers. “We suspect that health implications within this population are widespread and may include established clinical links that are commonly found in other populations of women with amenorrhea such as infertility, impact on bone mineral density and cardiovascular risk.”

The authors suggest that all women with HIV should be screened for amenorrhea, concluding: “Care providers should be aware of health issues that may accompany amenorrhea and routinely include reproductive history such as last menstrual period and birth control methods in every health visit to allow for early diagnostic evaluation and treatment.”

King EM et al. HIV and amenorrhea: a meta-analysis. AIDS, online edition, DOI: 10.1097/QAD.0000000000002084, 2018.