Many lupus patients experience disease flare in late trimester of pregnancy or puerperium [
Prolactin is a polypeptide hormone secreted by the anterior pituitary gland. It not only regulates the growth and differentiation of the mammary gland and ovary, but also initiates and maintains lactation. Prolactin is considered as well as a cytokine because it is secreted by immune cell and its receptor belongs to the cytokine receptors type 1 family [
95 pregnant SLE patients hospitalized in our hospital between July 2003 and October 2013 were recruited. The study design is presented in Figure
Study design. SLEDAI: systemic lupus erythematosus disease activity index.
Patients were randomly divided into the bromocriptine group and the control group. The bromocriptine group received 14 days of oral bromocriptine 2.5 mg twice a day within 12 hours after delivery and did not breastfeed their infants. The control group was not treated by bromocriptine or any other medicine that might influence patients’ serum prolactin levels.
Demographic data and clinical characteristics were collected 1 to 4 weeks before expected date of childbirth. All patients were followed up every 4 weeks for 12 months. Clinical manifestations and laboratory findings were recorded during every visit to assess the SLE activity. Laboratory investigations included serum levels of antinuclear antibodies, anti-dsDNA antibody, complements, complete blood count, urinalysis, serum albumin, liver function, and creatinine. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to assess the disease activity. SLEDAI was performed two to four weeks before delivery and every six weeks after delivery. To minimize the influence of observation bias on outcome determination, the SLEDAI scores were calculated by two different investigators. One performed the history collection and physical examination and did not know the serologic findings, and the other one performed the serological assessment and the SLEDAI scoring.
The serum prolactin and estradiol levels were measured twice by radioimmunoassay, at the second week and the second month after delivery, respectively.
Increasing of SLEDAI score ≥3 points from antenatal baseline data was defined as the endpoint of this trial—clinical flare. Mild-to-moderate flare was defined if one or more of the following 5 features were fulfilled: (1) an increase of SLEDAI score ≥3 points but <12 points; (2) new/worse discoid, photosensitive, cutaneous vasculitis, bullous lupus, nasopharyngeal ulcers, profundus, pleuritis, pericarditis, arthritis, and fever; (3) an increase in the prednisone dosage but <0.5 mg/kg of body weight per day; (4) initiation of therapy with either hydroxychloroquine or nonsteroidal anti-inflammatory drugs; (5) increase in the physician’s global assessment score but no more than 2.5. Severe flares were defined when one or more of the following 4 features were fulfilled: (1) increasing the SLEDAI score ≥12 points; (2) new or worsening central nervous system (CNS) involvement, vasculitis, glomerulonephritis, myositis, thrombocytopenia (platelet count <60
Survival analysis was used to compare disease aggravation and relapse rate between two groups. Log-rank test was used to assess significant differences between two groups. Parameter data, such as SLEDAI score and sex hormone levels, were recorded as X ± SD and tested by
Ninety-five pregnant lupus patients were screened, 76 of them qualified for the study and were enrolled into the trial. The patients were randomly divided into the treatment group (
Baseline demographic features, clinical findings, and SLEDAI scores in the pregnant SLE patients.
Treatment group ( |
Control group ( |
|
|
---|---|---|---|
Age (years, mean ± SD) | 30.47 ± 4.33 | 30.02 ± 3.95 | 0.57 |
Disease duration (years, mean ± SD) | 3.27 ± 0.91 | 3.45 ± 1.12 | 0.63 |
Inactive SLE (%) | 8 (21.05%) | 8 (21.05%) | 1.00 |
C3 (g/L, mean ± SD) | 0.56 ± 0.29 | 0.58 ± 0.21 | 0.51 |
C4 (g/L, mean ± SD) | 0.13 ± 0.06 | 0.14 ± 0.05 | 0.54 |
SLEDAI score (mean ± SD) | 7.13 ± 1.37 | 6.92 ± 1.98 | 0.43 |
SLEDAI: systemic lupus erythematosus disease activity index.
Twenty pregnant patients experienced 20 flares within 12-month follow-up after delivery. Fifteen cases were mild/moderate flares and five were severe flares. Analysis of flares of any type (mild/moderate or severe) by Kaplan-Meier survival curves found that 6 patients (15.7%) in bromocriptine group and 14 cases (36.8%) in control group experienced at least 1 flare. Log-rank test indicated that there was significant difference on the flare rate between the treatment group and control group (
Kaplan-Meier survival curves for relapse-free Survival between the treatment group and the control group.
The serum prolactin and estradiol levels in the treatment group were significantly lower than the levels in the control group at the second week and the second month after delivery, respectively (shown in Table
Comparison of the serum prolactin/estradiol levels between two groups at the second week and the second month after delivery.
Serum level | Treatment group ( |
Control group ( |
|
---|---|---|---|
Prolactin |
|||
At the second week after delivery | 8.6 ± 5.0 | 72.6 ± 32.6 | <0.001 |
At the second month after delivery | 11.5 ± 7.1 | 25.7 ± 37.6 | <0.05 |
Estradiol |
|||
At the second week after delivery | 78.3 ± 27.3 | 159.5 ± 132.0 | <0.001 |
At the second month after delivery | 77.7 ± 33.6 | 104.7 ± 80.1 | <0.05 |
At the 6th and 12th months after delivery, SLEDAI scores of the treatment group were significantly lower than those of the control group (Table
Change of SLEDAI within 1 years after delivery (mean ± SD).
SLEDAI score | Treatment group ( |
Control group ( |
|
---|---|---|---|
Baseline data, mean ± SD | 7.13 ± 1.37 | 6.92 ± 1.98 | 0.43 |
At the 6th month after delivery, mean ± SD | 4.25 ± 1.28 | 5.85 ± 1.76 | <0.001 |
At the 12th month after delivery, mean ± SD | 3.42 ± 0.95 | 4.53 ± 1.15 | <0.05 |
The cumulative doses of corticosteroid and other immunosuppressive agents after 12-month follow-up were shown in Table
Cumulative doses of corticosteroid and immunosuppressive agents for SLE in 12 months after delivery.
Medicines | Treatment group ( |
Control group ( |
|
---|---|---|---|
Prednisone (g, mean ± SD) | 3.92 ± 1.81 | 8.78 ± 3.84 | <0.001 |
Cyclophosphamide (g, mean ± SD) | 1.57 ± 0.91 | 4.32 ± 2.03 | <0.001 |
Methotrexate (mg, mean ± SD) | 99.28 ± 41.25 | 93.72 ± 42.01 | 0.39 |
Azathioprine (g, mean ± SD) | 3.42 ± 1.90 | 3.27 ± 1.74 | 0.82 |
Three patients had mild vertigo and nausea in the treatment group and all patients could complete the 2 weeks oral bromocriptine therapy. No severe adverse event was found in this study.
For pregnant SLE patients, though many of them can pull through pregnancy and childbirth in the remission stage of disease, some patients still experience relapse or disease flare during the late trimester of pregnancy or puerperium period. Several studies had shown that hyperprolactinemia was associated with lupus activity in pregnancy. Prolactin can stimulate mammary growth and differentiation, and it progressively increases during these periods [
The results in our study showed that the serum prolactin levels in control group were raised obviously at the second week after delivery, about 5 times the upper normal limit of prepregnancy levels. At the second month after delivery, the serum prolactin levels in the control group dropped but still much higher than those in the treatment group. In the control group, SLEDAI scores at the 6th and 12th months after delivery were much higher than those in treatment group. The results of the current study preliminarily indicated that oral bromocriptine for 2 weeks in postpartum patients with SLE may protect them from hyperprolactinemia and hyperestrogenemia and may be beneficial for preventing the patients from disease relapse.
In nonpregnancy SLE patients, some studies had been performed to determine whether there is an association between hyperprolactinemia and lupus activity, but the results were controversial. Orbach et al. [
Bromocriptine is a dopamine receptor agonist that could inhibit prolactin secretion and reduce serum prolactin level. It could also induce humoral and cell-mediated immunosuppression, directly modulate T and B cell function through the dopamine receptor, and reduce IFN production by macrophages [
For postpartum lupus patients, our study showed that oral bromocriptine therapy after delivery could not only reduce serum prolactin level quickly but also be helpful to decrease serum estradiol concentration to pregestation level rapidly. In bromocriptine treatment group, the serum prolactin levels were much lower than the control group at the second week after delivery. The estradiol levels in treatment group were lower than the control group as well. The results of survival analysis in this study confirmed that two weeks of oral bromocriptine therapy could reduce the SLE activity in treatment group even in one year after delivery.
Prolactin could modulate the immune function in SLE obviously but has little influence on the immune system of normal people [
An increasing body of evidences indicated that bromocriptine is a safe drug, even for the patients during pregnancy. In the current study, no severe adverse events were found in patients taking bromocriptine, and vertigo and nausea were the most common complains. Another study [
In conclusion, the current study preliminarily indicates that oral-taking bromocriptine for two weeks in postpartum SLE patients may eliminate the effects of hyperprolactinemia and hyperestrogenemia on disease activity. In addition to the minimal side effects and low cost of treatment, prescribing lupus patients with bromocriptine has potential benefits in preventing postpartum disease relapses in one year after delivery. However, multicenter clinical trials with large sample size should be performed to evaluate the benefit of clinical application of bromocriptine.
Qiu Qian and Liang Liuqin are co-first authors.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the Guangdong Provincial Science and Technology Foundations, China (2011B080701011, 2010B080701099, and 2011B050300009).