MATERIALS AND METHODS

Setting and study patients: A retrospective analysis of ADRs was performed at the Obstetrics and Gynecology Hospital of Fudan University from January, 2010-October, 2015. Informed consent of participants was not required as the retrospective study design did not affect the healthcare of included patients. This study was carried out at the 840-bed academic, tertiary level women’s hospital nationwide. So the source of female patients was stable and the patterns of ADRs were always concerned with multiformity. This study has been approved by the Ethics Committee of Obstetrics and Gynecology Hospital, Fudan University.

Data collection: All data, which have been collected and reported to the national spontaneous ADR reporting system, were recorded by a trained medical team including two experienced pharmacists and ten experienced doctors. The practice training was based on the principle that pharmacists and doctors learned most and made them realistic by practical assignments^16,17. These made sure that once the suspected

Fig. 1:

Procedures of the ADRs’ surveillance

ADRs happened in inpatients or spontaneous reported by outpatients in the gynaecology and obstetrics hospital, pharmacovigilance studies could be started in time. Specialized assessments were performed by well-trained pharmacists and doctors. If there was a discrepancy, a high level of physicians and pharmacists would be consulted to reach a coincidence. We set up drug counselling windows and telephone hotlines to monitor the outpatients’ ADRs that happened in the clinics or communities. As to the hospitalizations, pharmacists reviewed the entire drug treatments when taking pharmacy rounds every day (Fig. 1). Each patient with suspected ADRs has put intimately observed and updated daily until recovery from the ADR, including information on patient characteristics (age, allergic history, physical status, etc.). ADRs were evaluated based on the WHO-Uppsala Monitoring Center criteria¹⁸. Subject markers of ADRs through patient notes (named according to the Adverse Reaction Terminology (ART) of the WHO ADR Monitoring Register in Uppsala (WHO-ART), the latency of ADR’s onset (calculated from the beginning of suspected medication to the immediate occurrence of ADRs), medical interventions and the duration of ADR(counted from the immediate occurrence of ADRs to the point of recovery from ADRs).

Statistical methods: Results are given in terms of the Hazard Ratio (HR) for a particular factor with an accompanying 95% confidence interval (95% CI). Regression analysis via the Cox proportional hazards model was performed to assess independent predictive variables against the latency of ADR as the outcome variable. STATA (version13) statistical software was used for the Cox proportional hazards model analysis. In addition, the Kaplan-Meier survival curve was performed to evaluate patient survival of ADR recovery. A p<0.05 was considered as a statistical significance.

RESULTS

Patient characteristics and ADRs: A total of 357 ADRs were enrolled and 134(37.54%) patients experienced at least one ADR. The subject variables such as age, allergy histories, source of the patients and other presentations are overviewed in Table 1. The younger female patients were more likely to experience ADRs (n = 221, 61.91%). The most frequent ADRs were rash, perineum, vulva or vaginal uncomfortable and nausea, which affected the digestive system (29.1%), skin and appending system (26.37%) and female reproductive system (12.89%) (Table 2). The four classes of drugs followed-up were patent medicines of TCM which were responsible for over one-half of all ADRs (55.74%), antimicrobial agents (20.45%), female reproductive system agents (12.32%) and anti-tumour agents (11.49%) (Table3). Bao Fu Kang suppository (26 ADRs), Xiao Jin pill (21 ADRs) and KunTai capsule (16 ADRs) were chosen for categorizing as patent medicines of TCM because they were reported as the most frequent causative drugs to ADRs.

Latent periods of ADRs: The latency of ADR’s onset in patients ranged from several seconds to a couple of days and0.5-24 hrs was the most frequently (n = 190, 53.22%) in general. In the four groups of medicine categories as indicated, followed up data indicated that the mean latency period in a group of anti-tumour agents with a maximum was 53.06±16.85 hrs and a minimum of 20.89±3.20 hrs was observed in a group of patent medicines of TCM. The Group of antibiotics was 29.34±11.98 hrs and the group of female reproductive system agents was 44.95±13.47 hrs, respectively (Table 4), which offer us the crucial period to attend the ADR of different medicine.

Then we investigated the relationship between ages, source of patients, previous allergy histories, medications (single medication or multi-medications), course of medications and a group of suspected drugs in female patients and the duration period of ADRs. We found that both age and allergy histories were positively correlated with the duration period of ADRs (hazard ratio HR 2.919, 95% CI 1.049-8.124 and HR 4.107, 95% CI 1.478-11.410). In addition, we detected a significantly and inversely association between suspected drugs and increased duration of ADR (HR 0.365, 95% CI 0.159-0.834) (Table 5).

ADRs’ outcome: We also performed two weeks follow-up to assess the relationship between intervention-positive patients and intervention-negative patients after ADRs happened.

Fig. 2:

Kaplan-Meier curve for ADR-free survival in the presence of medical intervention p = 0.018 presence of medical interventions vs. absence of medical interventions

Among all 348 patients, 261 patients have received no treatments except drug withdrawal (non-intervention group), while 87 patients took additional ADR-related treatments (intervention group), such as antihistamines, glucocorticoids, NSAIDs or other medical therapies to recover (Table 6). There was statistical significance in the ADR duration between the non-intervention group and intervention group (Chi-square 5.6, p = 0.018), which indicated that medical treatments for ADRs were effective for earlier recovery compared with no intervention patients (Fig. 2).

DISCUSSION

This study was conducted by doctors and pharmacists’ intensively monitoring to report ADRs to explore the specific characteristics and the duration period of ADRs of side effects of medications that happened in female patients. Previous studies have shown that many factors involved in ADRs, including self-perceived health status, gender, age, sex, as well as drug-related factors^19-21. In our present study, the most frequent ADRs were rash, perineum, vulva or vaginal discomfort, as well as nausea, consistent with previous reports. Ranked from least to most likely of side effects were as follows: anti-tumour agents, female reproductive system agents, antimicrobial agents and patent medicines of TCM, respectively. There are some different aspects: (1) we focused on female due to the different genes, genetics, hormone variations, biological rhythms and other physical conditions between male and female^21,22. Furthermore, the uses of specific medications for female patients, such as oral contraception, the herbal remedy which can conversely influence body endocrine environment²³. In addition, it has been revealed that women were more prone to ADRs than male²⁴. (2) The latency periods of ADR in selected drugs. ADRs were classified as type A and type B according to drugsdose¹⁸. Therapeutic agents and the treatment period were reported to be associated with the latency and acuity of ADRs onset²⁵. However, very little was known about the latency of ADRs’ of different medications. Our results have shown that about 55.74% of patients got ADRs due to the administration of Patent medicines of TCM. Further analyses showed that Patent medicines of TCM also had the shortest mean latency of ADRs. These data indicated that we should take more attention to the ADRs caused by Patent medicines of TCM. Our data also showed that both age and allergy histories were positively correlated with the latent periods of ADRs. (3) We emphasized the outcome of ADRs patients with or without intervention. A previous study suggested that the average length of hospital stay ranged from 8-17 days because of ADRs⁶. So we performed two weeks follow-up since ADRs happened to the end of ADRs with or without interventions.

In the study, the majority of outpatients’ ADRs were typically related to patent medicines of TCM mainly it was difficult to classify, extract and standardise. Pharmacovigilance in TCM safety surveillance is still facing many challenges in China. There are some limitations to our study. Further studies are needed to evaluate the frequency of patients administrated with Patent medicines of TCM.

CONCLUSION

By analysis of 357 female patients’ ADRs, it demonstrates that there is a correlation between suspected ADRs and the class of drugs or an individual’s history of allergy. To the specific patient such as using a drug that is apt to induce ADRs or a patient with prior allergies, it will be valuable for the medical team to draw attention to the entire course of medication. Furthermore, the population in intervention-positive groups is considerable, so we propose that actively medical therapies are necessary for particular ADR-exposed patients, which could have potentially positive consequence, such as cutting down the medical expenses, reducing the injury of body status, etc.

SIGNIFICANCE STATEMENT

This study discovers the characteristics of the ADRs in female patients that can be beneficial for providing an increasing number of female-patient based ADR database and valuable data to study pharmacovigilance. This study will help the researcher to uncover the critical areas of the characteristics of the ADRs in female patients that many researchers were not able to explore. Thus, a new theory on the correlation between suspected ADRs and the class of drugs or an individual’s history of allergy may be arrived at.

ACKNOWLEDGMENT

This work was supported by the Specialized Programs of Shanghai "Rising Stars of Medical Talent" Youth Development Program-Clinical Pharmacist Program [ grant number (2017) No. 5].