Dopamine agonists for preventing future miscarriage in women with high prolactin levels and a history of recurrent miscarriage

What is the issue

Hyperprolactinemia is the presence of high circulating serum levels of prolactin, a hormone that is best known for its role in lactation. Idopathic hyperprolactinemia is the term used when no cause of prolactin hypersecretion can be identified and it is associated with miscarriage in pregnant women, especially women who have experienced several unexplained pregnancy losses. Occult hyperprolactinemia where prolactin levels are normal in the morning but rise during the day is one special type of hyperprolactinemia that is also associated with miscarriage. A dopamine agonist is a type of drug that is highly effective in lowering prolactin levels. One such drug is bromocriptine. It restores important functions of the ovaries that could allow women to maintain pregnancy.

Why is this important

We were most interested to know if dopamine agonists could lower rates of miscarriage and improve women's chances of having a live birth. We reviewed the evidence about the effectiveness and safety of dopamine agonists for preventing future miscarriage in women with a history of recurrent miscarriage.

What evidence did we find

We searched for evidence on 30 June 2016 and identified one trial with a small number of women - 48 women were recruited but 46 women (42 pregnancies - 4/46 women did not conceive during the study period) are included in the analysis). The trial took place in Japan and was judged to have a high risk of bias. The trial included women (aged 24 to 40 years) with idiopathic hyperprolactinemia and a history of two to four spontaneous miscarriages; 24 had occult hyperprolactinemia with equal numbers in each group. Women were followed during the study (until the end of the ninth week of pregnancy) and then observed for one year afterwards. In the study, one group of women received a dopamine agonist, bromocriptine (2.5 to 5.0 mg/day until the end of the ninth week of gestation), and the other group of women did not receive any treatment (control group).

Evidence from this study showed that the dopamine agonist bromocriptine was effective in preventing future miscarriage (low-quality evidence). However, live birth and conception rates remained similar between women who received bromocriptine and the women who did not receive treatment (very low-quality evidence). The study only reported on serum prolactin levels in the women who were pregnant. The study did not report on any adverse effects that dopamine agonists might possibly have for the women (e.g. nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) or her baby (e.g. birth defects, low birthweight, and developmental disabilities).

What does this mean

We rated the evidence for the review outcomes of miscarriage as low quality and live birth and conception as very low quality due to questions we had about the study design, the small number of women in the study, and because only one randomized controlled study was identified. Currently, there is not enough evidence (from one small trial) to evaluate the effectiveness and safety of dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history. There is a need for further, high-quality research in this area. Future studies (involving large numbers of women) are needed to expand on the findings of this review. Further studies should examine various dopamine agonists (including bromocriptine, cabergoline and quinagolide) and consider important outcomes (including adverse effects for both the mother and her baby).

Authors' conclusions: 

Currently, there is insufficient evidence (from a single randomized trial with a small sample size, and judged to be at high risk of bias) to evaluate the effectiveness of dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. We assessed outcomes using GRADE methodology. Miscarriage was assessed as low quality due to risk of bias concerns in the one trial contributing data (no description of allocation concealment, lack of blinding and possible reporting bias) and to imprecision (effect estimates were based on small sample size and few events). Live births and conception were assessed as of very low quality due to the same risk of bias concerns in study design and to imprecision (with a wide 95% CI consistent with either benefit or harm), and a small sample size. There were no data relating to adverse effects of the intervention for either the mother or her baby.

Futher high-quality research in this area is warranted. There is a need for well-designed, larger RCTs to confirm and extend the findings of the trial reviewed here. Many questions remain unanswered. Some important considerations for future research include, the need for well-designed RCTs with large sample sizes, and for those studies to consider important outcomes (including adverse effects for both the mother and her baby). Future studies should examine the effectiveness and safety of various dopamine agonists including bromocriptine, cabergoline and quinagolide.

Read the full abstract...
Background: 

Hyperprolactinemia is the presence of abnormally high circulating levels of prolactin. Idopathic hyperprolactinemia is the term used when no cause of prolactin hypersecretion can be identified and it is causally related to the development of miscarriage in pregnant women, especially women who have a history of recurrent miscarriage. A possible mechanism is that high levels of prolactin affect the function of the ovaries, resulting in a luteal phase defect and miscarriage. A dopamine agonist is a compound with high efficacy in lowering prolactin levels and restoring gonadal function.

Objectives: 

To assess the effectiveness and safety of different types of dopamine agonists in preventing future miscarriage given to women with idiopathic hyperprolactinemia and a history of recurrent miscarriage.

Search strategy: 

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2016) and reference lists of retrieved studies.

Selection criteria: 

Randomized controlled trials (RCTs) in all languages examining the effect of dopamine agonists on preventing future miscarriage. Women who had idiopathic hyperprolactinemia with a history of recurrent miscarriages were eligible for inclusion in this review. Comparisons planned included: dopamine agonists alone versus placebo/no treatment; and dopamine agonists combined with other therapy versus other therapy alone.

Data collection and analysis: 

Two review authors independently assessed a single trial for inclusion, evaluated trial quality and extracted data. Data were checked for accuracy.

Main results: 

One study (recruiting 48 women with idiopathic hyperprolactinemia) met our inclusion criteria; 46 women (42 pregnancies - 4/46 women did not conceive during the study period) were included in the analysis. The study compared the use of a dopamine agonist (bromocriptine, 2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus a no-treatment control. The study was judged as being at a high risk of bias. It was not possible to carry out meta-analysis due to insufficient data.

The study reported both of this review's primary outcomes of miscarriage and live birth. Results from this single study suggest that, compared to no treatment, oral bromocriptine was effective in preventing future miscarriage (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.09 to 0.87, 46 participants (low-quality evidence)) in women with idiopathic hyperprolactinemia. There was no clear difference with regard to the other primary outcome of live births (RR 1.50, 95% CI 0.93 to 2.42, 46 participants (very low-quality evidence)).

There was no difference with regard to this review's secondary outcome of conception (RR 0.92, 95% CI 0.77 to 1.09, 46 participants (very low-quality evidence)) between the group of women who received dopamine (21 out of 24 women conceived) and women in the no-treatment group (21 out of 22 women conceived). The included study only reported the serum prolactin levels in pregnant women and therefore the data could not be analyzed in this review. No other secondary outcomes relevant to this review were reported; adverse effects for women (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) and infants (birth defects, low birthweight, and developmental disabilities) were not reported.

We downgraded the quality of the evidence for risk of bias in the one trial contributing outcome data (no description of allocation concealment, lack of blinding and possible reporting bias) and for imprecision (all effect estimates were based on small sample size, miscarriage was based on few events, and the 95% CIs of live birth and conception cross the line of no effect).

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