Premenstrual Disorders Among Perinatally HIV-Infected Adolescents

To the Editors: INTRODUCTION With antiretroviral therapy (ART), many children born with HIV survive and grow into adolescence. In some countries, over 30% of HIV-positive perinatally infected children are now above the age of 121,21,2 and about half of them are females.1 Girls with severe HIV disease can experience delayed onset of puberty.3,43,4 With earlier treatment, maturation timing seems to be normalized.4 Comparably, ART use and higher CD4 counts have been linked to lower rates of persistent menstrual problems in behaviorally HIV-infected women.5 However, the presence of a regular menstrual cycle has been related to premenstrual syndrome (PMS) in women in the general population, with onset in the adolescent years.6 PMS is a group of physical, emotional, and behavioral symptoms in the luteal phase of the menstrual cycle, which interferes with the daily functioning of women.7 Premenstrual dysphoric disorder (PMDD), the most severe form of PMS, is included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).6,8,96,8,96,8,9 Here, we report the prevalence of PMS and PMDD in a cohort of perinatally HIV-infected Thai adolescents compared with that of healthy controls. In addition, we evaluated factors associated with the prevalence of PMS in HIV-positive adolescents. To the best of our knowledge, this is the first report on PMS prevalence in perinatally HIV-infected adolescents. METHODS We conducted a cross-sectional assessment of PMS in perinatally HIV-infected adolescents in 5 sites throughout Thailand: The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok; Faculty of Medicine, Khon Kaen; Phra Chomklao Hospital, Phetchaburi; Phrapokklao Hospital, Chanthaburi; and Chiangrai Prachanukroh Hospital, Chiangrai. To participate in the assessment, HIV-positive adolescents had to be between 12 and 24 years, perinatally infected, self-aware of HIV status, postmenarche, and not pregnant; all participants in the HIV-positive group were sexually active. Healthy controls, with no history of HIV infection, were enrolled from first-year university students in Bangkok. All participants (and their caregivers if younger than 18 years) gave consent. The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, and by the respective institutional review boards at each site. For evaluation of PMS/PMDD, with the permission of the university, we used a premenstrual symptom screening tool (PSST), developed, validated, and adapted for use in adolescents by McMaster University, Canada.10 The PSST consists of 19 items, 14 premenstrual symptoms (13 mood-related symptoms + 1 physical symptom such as breast tenderness/headache/joint or muscle pain/bloating/weight gain) and 5 functional items (impact of PMS symptoms on daily activities), which could be self-graded as “not at all,” “mild,” “moderate,” or “severe.” As the study was designed before the implementation of DSM-5, we applied the DSM-IV criteria for PMS as follows: (1) at least 1 of 4 “core PMS symptoms as follows: anger/anxiety/sensitivity to rejection or depression,” rated either moderate or severe, (2) at least 4 additional PMS symptoms rated either moderate or severe, and (3) at least 1 of 5 “functional” items rated either moderate or severe. In case, the core PMS symptom and the functional item are graded “severe,” the condition is defined as PMDD. Reproductive history of HIV-positive participants and laboratory data from their medical records within 6 months of enrollment were collected as well. Data were analyzed by calculating median and interquartile range for quantitative characteristics and number and percentage for categorical characteristics using Stata version 11.2 (StataCorp LP, College Station, TX). Factors related to PMS/PMDD were assessed by univariate and multivariate logistic regression. Wilcoxon rank sum (Mann–Whitney) test was used to compare variables between study groups. RESULTS Between June 2013 and August 2014, 73 perinatally HIV-infected girls (median = 19 years) and 87 healthy controls (median = 21 years) completed the PSST assessment. Baseline characteristics of the 2 groups are presented in Table 1. Most (95%) HIV-positive girls were on antiretrovirals, the median CD4 was 508 cells per cubic millimeter, and 73% had viral load (VL) <1000 copies per milliliter. The differences between the groups in age, length of menstrual period, and education status were statistically significant.TABLE 1: Baseline Demographic, Medical, and Social CharacteristicsAll PMS symptoms, assessed with the PSST, in the HIV-positive group were self-graded more often as not at all/mild; in the control group, all symptoms were reported more often in moderate/severe grade. The impact of these symptoms on daily activities was milder in the HIV-positive group and more severe in the control group. Nevertheless, there was no statistically significant difference in the prevalence of PMS between the 2 groups (Table 1); 25 (34%) of HIV-positive adolescents met the criteria for PMS vs. 42 (48%) in the control group, P = 0.074. Eleven percent of the adolescents in each group met the PMDD criteria, P = 0.915. In the HIV-positive group, PMS prevalence was positively associated in a univariate analysis with CD4 <200 cells per cubic millimeter, VL >1000 copies per milliliter, history of physical abuse by caregiver or partner, and a longer duration of the menstrual period. However, neither of these relations was confirmed in the multivariate model, with an exception of a trend in case of a longer menstrual period (odds ratio = 1.3; 95% confidence interval: 0.95 to 1.88; P = 0.079). HIV-positive adolescents with a longer menstrual period were also more likely to have PMDD (odds ratio = 1.4; 95% confidence interval: 0.99 to 1.96; P = 0.044). No association was observed in the control group. DISCUSSION We observed similar prevalence rates of PMS and PMDD in perinatally HIV-infected and healthy adolescents. About one-third of adolescents reported PMS, and one-tenth reported PMDD. These rates are within the wide range reported in the literature, from <5% for severe forms up to 80% for all severity of PMS symptoms.11–1611–1611–1611–1611–1611–16 There is a tendency for higher prevalence of PMS and PMDD in younger women, with considerable variations at an individual level.17 Earlier reports from Thailand in Thai nurses found about 25% prevalence for self-reported PMS, including PMDD, with higher rates in those below 30 years of age.18 PMS symptoms appear after ovulation and are related to the production of progesterone by the ovary7 and its interaction with the gamma-aminobutyric acid (GABAergic), the main inhibitor in the brain, and serotoninergic systems. In a similar way, PMS symptoms might be triggered by progestin components in hormonal contraceptives or hormone replacement therapy. The role of genetic influence is under study as well.19 Literature is conflicting whether HIV-positive women are less prone to PMS because of lower ovarian function. Shorter menstrual cycles, including amenorrhea, and lower rates of premenstrual symptoms such as breast tenderness and dysmenorrhea have been reported with severe HIV disease.5,205,20 Others have not found direct effects of HIV or immunosuppression on menstrual function.21–2321–2321–23 We observed a trend towards lower PMS prevalence in the HIV-positive group, but this did not reach statistical significance. Our patient population was relatively healthy with high CD4 counts and possibly had preserved ovarian function as illustrated by the onset of menarche at a similar age as those without HIV, followed by regular menstrual cycles. Most of the symptoms defining PMS are related to mood disorders. HIV-positive adolescents are generally at higher risk of mental health problems in comparison with HIV-negative controls.24,2524,25 Studies report on possible overlap between PMS and mental health disorders26–2826–2826–28 as well as the premenstrual state exacerbating mental health conditions.29–3129–3129–31 Here, we found a trend of higher PMS prevalence in HIV-positive adolescents with low CD4 and high VL, which could indicate poor adherence to ART, as well as in those with history of physical abuse by caregiver/partner. The latest relationship is explained by increased sensitivity to pain.32,3332,33 The trend of lower PMS prevalence in the HIV-positive group may also be interpreted by a somewhat higher “resilience” in the positive group to natural “challenges.” HIV-positive adolescents with all their medical and social problems might not be unhappy to experience something, which symbolizes a normal physiological function, such as the menstrual cycle. In contrast, monthly menstrual cycle can be perceived as a much more disagreeable health/social condition by healthy first-year university students. Negative attitudes toward menstruation were associated with premenstrual symptoms and a desire for less frequent menstruation in several studies.19,34–3719,34–3719,34–3719,34–3719,34–37 Our study is limited by the small sample size and absence of complete match for age and social and educational status between the 2 groups. Nevertheless, the study provides a report on PMS prevalence in perinatally HIV-infected adolescents, using validated tools. The study also draws attention to important knowledge gaps in this field, such as a lack of a comprehensive characterization of ovarian function, as well as the lack of analysis of the complex relations between PMS and psychiatric mood disorders in perinatally HIV-infected female adolescents. In conclusion, with ART, perinatally HIV-infected children can survive, grow up, and have a development more comparable with that of the general population. Conditions, such as PMS, become common as well. The study highlights the importance of comprehensive care including clinical, reproductive health, and psychosocial support for this target population.37 ACKNOWLEDGMENTS The authors are grateful to all the study participants, as well as to the research and clinical staff and clients at the 5 sites of the study for their contribution to this assessment; more specifically, HIV-NAT: Amornrat Srimuan, Supalak Klungkang, Oratai Butterworth, Prapatsara Larpmahawong, Kanitta Pussadee, Ganon Yosphan, and Bencharat Thongpunchang; Khon Kaen: Chanasda Sopharak and Somjai Rattanamanee; Phetchaburi: Manee Yentang and Paweena Kaewdang; Chantaburi: Wanna Jamjumrus, Naulta Selawattanakul, and Chuleewan Siromkul; Chiangrai: Aree Sophradit, Benjamas Jongrungrotsakul, and Kannikar Saisawat.

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