多巴胺激动剂预防特发性高催乳素血症和复发性流产史女性的未来流产
摘要
研究背景
高催乳素血症是指循环中催乳素水平异常高。特发性高催乳素血症是指无法确定催乳素高分泌的原因，并且与妊娠妇女（尤其是有复发性流产史的妇女）发生流产有因果关系的术语。一种可能的机制是高水平的催乳素影响卵巢的功能，导致黄体期缺陷和流产。多巴胺激动剂是一种能高效降低催乳素水平和恢复性腺功能的化合物。
研究目的
评估不同类型的多巴胺激动剂预防患有特发性高催乳素血症和有复发性流产史的女性未来流产的有效性和安全性。
检索策略
我们检索了Cochrane妊娠和分娩组试验注册库（Cochrane Pregnancy and Childbirth Group's Trials Register）（2016年6月30日）以及相关研究的参考文献列表。
纳入排除标准
评价多巴胺受体激动剂预防未来自然流产效果的所有语言随机对照试验（randomized controlled trials, RCTs）。患有特发性高催乳素血症并有反复流产病史的妇女符合本综述研究的纳入标准。计划的比较包括：单独使用多巴胺激动剂与使用安慰剂或不进行治疗；以及多巴胺激动剂联合其他疗法与单独使用其他疗法。
资料收集与分析
两位综述作者独立评估一项试验是否纳入，评价试验质量并提取资料。我们对数据准确性进行了检查。
主要结果
一项研究（招募48名患有特发性高催乳素血症的女性）符合我们的纳入标准；46名女性（42名孕妇——4/46名女性在研究期间未怀孕）被纳入分析。该研究比较了使用多巴胺激动剂（溴隐亭，2.5毫克至5.0毫克/天，直至妊娠第九周结束）与不治疗控制的情况。该研究被判定为具有较高的偏倚风险。由于数据不足，无法进行meta分析。
该研究报告了本综述的两个主要结局：流产和活产。这项单一研究的结果表明，对于患有特发性高催乳素血症的女性，与不治疗相比，口服溴隐亭可有效预防未来 流产 （风险比（risk ratio, RR）=0.28，95% 置信区间（confidence interval, CI）[0.09, 0.87]，46名受试者（ 低质量证据 ））。在 活产 这一其他主要结局方面，两组无明显差异（RR=1.50，95%CI [0.93, 2.42]，46名受试者（ 极低质量证据 ））。
在本综述的次要结局即 受孕 方面，接受多巴胺治疗的女性组（24名女性中有21名受孕）与未接受治疗的女性组（22名女性中有21名受孕）之间没有差异（RR=0.92，95% CI [0.77, 1.09]，46名受试者（ 极低质量证据 ））。纳入的研究仅报告了孕妇 血清催乳素水平 ，因此本综述无法分析其数据。没有报告与本综述相关的其他次要结果；没有报告对女性（恶心、呕吐、头痛、眩晕、疲劳、低血压、心律失常和精神病症状）和婴儿（出生缺陷、低出生体重和发育障碍）的不良影响。
由于一项提供结局数据的试验具有偏倚风险（没有描述分配方案隐藏，缺乏盲法和可能的报告偏倚）和不精确性（所有效果估计都基于小样本量，流产基于少数事件，活产和受孕的95%可信区间越过了无效线），我们降低了证据质量。
作者结论
目前，没有足够的证据（来自样本量较小的单个随机试验，并被判定为具有高偏倚风险）来评估多巴胺激动剂对预防特发性高催乳素血症和有复发性流产史的女性未来流产的有效性。我们使用GRADE方法评估结果。由于一项试验提供的数据存在偏倚风险（没有描述分配方案隐藏、缺乏盲法和可能的报告偏倚）以及不精确（效果估计基于小样本量和少数事件），流产被评估为低质量。由于研究设计中存在同样的偏倚风险，且不精确（95%置信区间较宽，与获益或伤害相一致），以及样本量较小，活产和受孕被评估为质量极低。没有关于干预对母亲或婴儿产生不利影响的数据。
有必要在该领域开展进一步的高质量研究。需要精心设计、更大规模的RCT来确认和扩展本综述的试验结果。许多问题仍未得到解答。未来研究的一些重要考虑因素包括：需要设计良好、样本量大的RCT，以及这些研究需要考虑重要结局（包括对母亲及其婴儿的不良影响）。未来的研究应该评价各种多巴胺激动剂的有效性和安全性，包括溴隐亭、卡麦角林和喹那戈利特。
PICOs
简语概要
多巴胺激动剂可用于预防催乳素水平高且有反复流产史的女性未来流产
研究问题
高催乳素血症是指血清中催乳素水平过高，催乳素是一种因其在泌乳中的作用而最为人所知的激素。特发性高催乳素血症是指无法确定催乳素分泌过多的原因，并且与孕妇（尤其是经历过几次不明原因流产的妇女）流产有关的术语。隐匿性高催乳素血症是指早晨催乳素水平正常，但在白天升高，这是一种特殊类型的高催乳素血症，也与流产有关。多巴胺激动剂是一种能高效降低催乳素水平的药物。其中一种药物就是溴隐亭。它可以恢复卵巢的重要功能，使女性能够维持怀孕。
研究的重要性
我们最关注的是知道多巴胺激动剂是否可以降低流产率并提高女性活产的机会。我们研究了多巴胺激动剂预防有复发性流产史的女性未来流产有效性和安全性的有关证据。
我们发现了哪些证据？
我们于2016年6月30日检索证据，发现一项女性人数较少的试验——招募了48名女性，但有46名女性（42名女性怀孕——4/46名女性在研究期间没有怀孕）被纳入分析。该试验在日本进行，被认为具有很高的偏倚风险。试验纳入了患有特发性高催乳素血症且有2至4次自然流产史的女性（年龄24至40岁）；其中24人患有隐匿性高催乳素血症，每组人数相等。研究期间对女性进行随访（直到怀孕第九周结束），随后观察一年。在研究中，一组女性接受多巴胺激动剂溴隐亭（2.5至5.0毫克/天，直至妊娠第九周结束），另一组女性未接受任何治疗（对照组）。
这项研究的证据表明，多巴胺激动剂溴隐亭可有效预防未来流产（ 低质量证据 ）。然而，接受溴隐亭治疗的女性和未接受治疗的女性在活产率和受孕率方面仍然相似（ 极低质量证据 ）。该研究仅报告了怀孕妇女的血清催乳素水平。该研究没有报告多巴胺激动剂可能对女性（例如恶心、呕吐、头痛、眩晕、疲劳、低血压、心律失常和精神病症状）或其婴儿（例如出生缺陷、低出生体重和发育障碍）产生的任何不良影响。
这意味着什么？
由于我们对研究设计存在疑问、研究中的女性数量很少，并且只发现一项随机对照研究，我们将流产综述结局的证据评定为低质量，将活产和受孕综述结局的证据评定为极低质量。目前，还没有足够的证据（来自一项小型试验）来评估多巴胺激动剂对预防特发性高催乳素血症和复发性流产史的女性未来流产的有效性和安全性。该领域需要进一步开展高质量的研究。需要未来的研究（涉及大量女性）来扩展本综述的结果。进一步的研究应该评价各种多巴胺激动剂（包括溴隐亭、卡麦角林和喹那戈利特），并考虑重要的结局（包括对母亲和婴儿的不利影响）。
Authors' conclusions
Summary of findings
| Bromocriptine treatment versus no treatment for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history | ||||||
| Patient or population: women with idiopathic hyperprolactinemia and recurrent miscarriage history Comparison: no treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo/no treatment | Risk with Dopamine agonists alone | |||||
| Miscarriages | Study population | RR 0.28 | 46 | ⊕⊕⊝⊝ | ||
| 455 per 1000 | 127 per 1000 | |||||
| Moderate | ||||||
| 455 per 1000 | 127 per 1000 | |||||
| Live births | Study population | RR 1.50 | 46 | ⊕⊝⊝⊝ | ||
| 500 per 1000 | 750 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 750 per 1000 | |||||
| Conception | Study population | RR 0.92 | 46 | ⊕⊝⊝⊝ | ||
| 955 per 1000 | 878 per 1000 | |||||
| Moderate | ||||||
| 955 per 1000 | 878 per 1000 | |||||
| Proportion reduction in serum prolactin levels | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Serum prolactin normalization | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Adverse maternal effects | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Adverse fetal outcomes | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 One trial with design limitations, including no description of allocation concealment, lack of blinding and possible outcome reporting bias (‐1). | ||||||
Background
Description of the condition
Recurrent miscarriage
Recurrent miscarriage is defined as three or more consecutive spontaneous abortions at a stage where the embryo or fetus is incapable of surviving, generally within the first 20 weeks of gestation (Dlugi 1998; Katharina 2008). With the declining birth trend, more and more researchers tend to define recurrent miscarriage to be at least two spontaneous abortions (Toth 2010). Ten per cent to 15% of all clinically recognized pregnancies end in a miscarriage (Regan 1989), and recurrent miscarriage affects 1% to 3% of all women (Stirrat 1990; Toth 2010). The most common symptoms of a miscarriage are vaginal bleeding and lower abdominal pain (Yip 2003).
Recurrent miscarriage is a heterogeneous condition, of which the etiology is not completely understood. Known risk factors include chromosomal abnormalities, endocrine disorders (luteal phase deficiency, thyroid disorders, diabetes mellitus, high androgen levels, hyperprolactinemia, polycystic ovary syndrome, antiphospholipid syndrome, et al), anatomic abnormalities (uterine synechiae, cervical incompetence, intrauterine adhesion, uterine malformation such as uterine septum, uterine fibroids, scar tissue, et al), immunologic factors (humoral response abnormalities, cellular response abnormalities, et al), infections and endometriosis (Dlugi 1998; García‐Enguídanos 2002; Daya 2004; Toth 2010). Increased age, smoking, caffeine or alcohol intake, and administration of certain drugs may also increase the incidence of miscarriage (García‐Enguídanos 2002). However, nearly 50% of recurrent miscarriages are unexplained (Toth 2010).
Hyperprolactinemia
Biological action of prolactin
Prolactin was first confirmed in humans in 1970 (Friesen 1970). It is a 23 kDa polypeptide hormone (198 amino acid) with a structure similar to that of growth hormone and placental lactogen (Mancini 2008; Majumdar 2013). It is mainly produced by the lactotrope cells in the anterior pituitary gland with a diurnal secretion pattern, peaking during rapid eye movement in the early morning, and decreasing thereafter. In normal conditions, its secretion is regulated by the prolactin inhibitory factors (PIF) and prolactin‐releasing factors (PRF) from the pituitary. Dopamine, the main PIF, acts on surface membrane dopamine D2 receptors on lactotroph cells to decrease prolactin. Physical factors (stress, food ingestion, pregnancy, trauma, et al) or pathological factors (some drugs, pituitary tumors, systemic and endocrine diseases, et al) could affect serum prolactin levels (Majumdar 2013). The actual serum prolactin level is the result of a balance between various internal and external, positive and negative factors. With commonly used assays, normal serum prolactin levels vary from 5 μg/L to 25 μg/L in women (Melmed 2008).
Prolactin is best known for its role in inducing and maintaining lactation; in addition, it exerts metabolic effects, regulates functions of lymphocytes and stimulates immune responsiveness, takes part in reproductive mammary development, participates in osmoregulation, provides the body with sexual gratification after sex, and contributes to surfactant synthesis of the fetal lungs (Tyson 1973; Majumdar 2013).
Definition and etiology
Hyperprolactinemia is the presence of abnormally high circulating levels of prolactin, which is usually defined to be above 25 μg/L (530 mIU/L (milli‐international units per liter)) in women (Chahal 2008; Melmed 2011). Known reasons include physiological hypersecretion (pregnancy, breastfeeding, stress, et al), drug‐induced hypersecretion (dopamine receptor blockers, dopamine synthesis inhibitors, calcium channel blockers, et al), pituitary hypersecretion (prolactinomas, et al), systemic and endocrine diseases (renal failure, hepatic failure, primary hypothyroidism, polycystic ovary syndrome (PCOS), et al) (Stirrat 1990; Chahal 2008; Glezer 2014).
When no cause of hyperprolactinemia can be identified, the condition is termed idiopathic hyperprolactinemia (Majumdar 2013). Long‐term follow‐up found that microadenomas show up in approximately 10% of those patients that were too small to be detected originally (Chahal 2008). Occult hyperprolactinemia (or latent hyperprolactinemia) is one special type of idiopathic hyperprolactinemia in which the serum prolactin levels are normal in the morning, but become excessive during the day, or under stimulation (Schenker 1992; Kostál 1997). This condition could be detected by thyrotropin‐releasing hormone (TRH) test or metoclopramide test (MCT) (Aisaka 1993; Kostál 1997). Some researchers have defined occult hyperprolactinemia as a prolactin level above 70 μg/L at 30 minutes after TRH injection (Aisaka 1993). Others have defined it as prolactin level above 150 ng/mL at 30 minutes after metoclopramide administration (Schenker 1992; Kostál 1997). However, the criteria for hyperprolactinemia, including occult hyperprolactinemia, may vary among different laboratories and different groups of people.
Prevalence
Hyperprolactinemia is a common endocrine disorder in women. The prevalence was found to be 0.4% in an unselected population, 5% in a family planning clinic, 9% in women with adult onset amenorrhea, 17% among women with PCOS (Majumdar 2013), and 36% among recurrent miscarriage patients (Hirahara 1996; Bussen 1999). Idiopathic hyperprolactinemia accounts for 40% of hyperprolactinemia (Huang 2007). Occlut hyperprolactinemia was claimed to cause 43% to 70% of luteal phase disorders (Mühlenstedt 1977; Aisaka 1993), and was observed at night in 80% of patients with normal prolactin levels who had galactorrhea (Aisaka 1993).
Clinical manifestations
A high serum prolactin level does not just inhibit the secretion of follicle‐stimulating hormone (FSH) and gonadotropin‐releasing hormone (GnRH), but it directly inhibits the secretion of estradiol and progesterone, leading to hypogonadism and hypoestrogenemia. Clinical manifestations of hyperprolactinemia include galactorrhea, menses changes (menstrual flow changes, irregular menses, amenorrhea, et al), reproductive dysfunction (anovulation, luteal insufficiency, miscarriage, et al), a long‐term risk of osteopenia, and loss of interest in sex (Ben‐David 1983; Yamaguchi 1991; Asukai 1993; Hirahara 1998; Majumdar 2013; Molitch 2015).
Clinical observations have found prolactin concentrations were significantly higher in women experiencing recurrent miscarriage, suggesting that hyperprolactinemia was causally related to the development of miscarriage, especially in women with recurrent miscarriage in whom no other cause for their repeated pregnancy loss was apparent (Ando 1992; Hirahara 1996; Hirahara 1998; Bussen 1999). Hirahara identified this situation as hyperprolactinemic recurrent miscarriage (Hirahara 1998). A possible mechanism is that high levels of prolactin affect the function of the ovaries, resulting in a luteal phase defect and miscarriage.
Diagnosis
A serum prolactin above normal (usually 25 μg/L) confirms the diagnosis of hyperprolactinemia (Chahal 2008; Melmed 2011). It should be measured in the morning at least two hours after waking up to ensure the measurement is accurate. Other factors affecting the result include non‐fasting sample, excessive exercise and history of drug intake (Majumdar 2013). The diagnosis should be cautious when the prolactin level is slightly elevated and the examination should be repeated later. A falsely‐high measurement may occur due to the presence of the biologically‐inactive macroprolactin in the serum. This can show up as high prolactin in some types of tests, but is asymptomatic. The TRH stimulation test is used as a provocative pituitary test, which is helpful to detect patients with normal baseline serum prolactin levels and a greater capacity for prolactin secretion after TRH administration (Dlugi 1998).
Medical history is collected to exclude possible etiology. Patients should be evaluated for symptoms including amenorrhea or oligomenorrhea, infertility, fractures, vision changes, and galactorrhea et al. Magnetic resonance imaging (MRI) is the most sensitive test for detecting pituitary tumors and computed tomography (CT) is the second choice.
Description of the intervention
A dopamine agonist is a compound that activates signaling pathways through the dopamine receptor in the brain. Its high efficacy has been well‐demonstrated in lowering prolactin levels, reducing prolactinoma size, and restoring gonadal function (Webster 1999; Gillam 2006; Melmed 2011). A systematic review found the proportions of patients with hyperprolactinemia with improved outcomes under dopamine agonists are: normalization of prolactin level (68%; 40% to 100%), reduction in tumor size (mean 62%; range 20% to 100%), resolution of amenorrhea (78%; 40% to 100%), resolution of infertility (53%; 10% to 100%), resolution of galactorrhea (86%; 33% to 100%), and improvement of sexual function (67%; 6% to 100%) (Wang 2012). Ovulation rates achieved by dopamine agonist treatment only are approximately 80% to 90% if hyperprolactinemia is the only cause for anovulation (Majumdar 2013). Sixty per cent of patients with galactorrhea and 47% of patients with luteal insufficiency with occult hyperprolactinemia recovered after bromocriptine treatment (Aisaka 1993). Side effects mainly include nausea, vomiting, headache, hypotension, arrhythmia, and psychotic symptoms. The most commonly used dopamine agonists for hyperprolactinemia are bromocriptine, cabergoline and quinagolide. Others include lisuride, pergolide, quinagolide, terguride, and metergoline et al. Although it is generally recommended to withdraw dopamine agonist therapy during pregnancy in patients with prolactinomas, there is evidence about the safety of some kind of dopamine agonists (mainly bromocriptine, cabergoline and quinagolide) use during pregnancy.
Bromocriptine is the first option for hyperprolactinemia. It is a lysergic acid derivative with a bromine substitute at position 2 (Vance 1984), and acts as a strong dopamine agonist. It decreases DNA synthesis, prolactin synthesis, and cell multiplication. Bromocriptine is initiated at 1.25 mg to 2.5 mg in divided doses administered twice a day. The majority of patients with hyperprolactinemia respond to bromocriptine in doses of 7.5 mg/day (Morange 1996). Some patients are intolerant of bromocriptine. The intolerance is likely to occur with initiation of treatment or when the dose is increased. Administration via the vaginal route may reduce the incidence of side effects and avoid first‐pass metabolism by the liver (Kletzky 1989; Ginsburg 1992). This route of administration has no effect on sperm activity (Carranza‐Lira 1999). Bromocriptine is also available in a long‐acting form for intramuscular injection. The safety of bromocriptine on ovulation, pregnancy and fetal development is well‐documented in humans (Turkalj 1982; Krupp 1987; Majumdar 2013; Hurault‐Delarue 2014). Approximately 25% of patients are resistant to bromocriptine (Verhelst 1999).
Cabergoline is an ergot‐derived dopamine agonist, which has low affinity for D1 dopamine receptors and high affinity for D2 receptors (Del Dotto 2003). Cabergoline is better tolerated than bromocriptine with approximately 10% of patients resistant, and 80% of patients who are resistant to bromocriptine may achieve prolactin normalization on cabergoline (Colao 1997; Verhelst 1999). Rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells. Cabergoline is a long‐acting dopamine agonist with less side effects and better patient compliance. It is frequently used as a second‐line agent in the management of hyperprolactinemia when bromocriptine is ineffective. A dose of 0.25 mg twice per week is usually adequate for hyperprolactinemia. Beltrame 1996 proved that cabergoline was not teratogenic or embryotoxic in mice and rabbits and did not affect the latter phase of gestation or parturition in the rat. The safety of cabergoline on embryo‐fetal development was been proved in humans (Robert 1996; Auriemma 2013; Hurault‐Delarue 2014).
Quinagolide is a non ergot‐derived dopamine agonist with a chemical structure similar to apomorphine. It acts specifically and with high affinity on D2 dopamine receptors and has little affinity for D1 dopamine receptors (Closse 1988). Both the specificity and the non‐ergot nature of quinagolide reduce the risk of side effects. Patients are typically initiated at a dose of 0.025 mg/day and increased to a dose of 0.075 mg/day. If necessary, the quinagolide dose can be increased up to a maximum dose of 0.3 to 0.6 mg/day (Barlier 2006). No teratogenic effects of quinagolide during early pregnancy in humans have been reported in a relatively small number of pregnancies (Homburg 1990; Morange 1996; Schultz 2000).
Terguride is the C9‐10 dihydrogenated derivative of lisuride. It has mixed dopaminergic‐antidopaminergic activity with fewer side effects. Lisuride is a dopamine agonist with a high affinity for the dopamine D2. Pergolide is an ergoline‐based dopamine receptor agonist. Quinagolide is also a selective, D2 receptor agonist.
How the intervention might work
The possible mechanisms of dopamine agonist on preventing recurrent miscarriage are as follows (Seppälä 1976; Lecomte 1997).
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It acts on ovaries directly to promote synthesis of steroid hormones.
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It acts on pituitary to promote synthesis of steroid hormones.
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It acts on hypothalamus to promote secretion of luteinizing hormone‐releasing hormone (LHRH).
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It inhibits secretion of prolactin.
Why it is important to do this review
Although recurrent miscarriage affects only 1% to 3% of women, it influences the well‐being and psychosocial status of patients. Hirahara and Bussen reported hyperprolactinemia was found in around 36% of recurrent miscarriage patients (Hirahara 1996; Bussen 1999). Due to the fact that prolactin levels are important in maintaining early pregnancy and hyperprolactinemia is relatively common in women who miscarry, hyperprolactinemia may be linked to recurrent miscarriage (Ando 1992; Hirahara 1996; Hirahara 1998; Bussen 1999). In clinics, doctors tend to examine the patients' serum prolactin levels when no cause of recurrent miscarriages has been found, and treatment is given when hyperprolactinemia is found. However, the pathophysiologic mechanisms and effects of treatments on a future pregnancy are still incompletely understood. Accordingly, we set out to determine the benefits and harms from dopamine agonists in preventing a future miscarriage given to women who had idiopathic hyperprolactinemia (including occult hyperprolactinemia) with a history of recurrent miscarriages.
Objectives
To assess the effectiveness and safety of different types of dopamine agonists in preventing future miscarriage given to women diagnosed with idiopathic hyperprolactinemia, with a history of recurrent miscarriage.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) examining the effect of dopamine agonists on preventing future miscarriage, given to women who were diagnosed with idiopathic hyperprolactinemia (including occult hyperprolactinemia), with a history of recurrent miscarriages, were eligible for inclusion in this review. There were no restrictions on language and publication status. RCTs using a cluster‐randomized were eligible for inclusion in this review, but none were identified.
Quasi‐RCTs, RCTs using a cross‐over design and studies published in abstract form only (where insufficient information was available) were not eligible for inclusion in this review.
Types of participants
Women who were diagnosed with idiopathic hyperprolactinemia (including occult hyperprolactinemia) with a history of recurrent miscarriages.
Types of interventions
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Dopamine agonists alone versus placebo/no treatment.
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Dopamine agonists combined with other therapy versus other therapy alone.
Types of outcome measures
Primary outcomes
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Rate of miscarriage (before 20 weeks of gestation).
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Rate of live birth (term delivery or premature delivery rate).
Secondary outcomes
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Rate of conception.
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Proportion of reduction in serum prolactin levels.
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Rate of serum prolactin normalization.
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Rates of adverse maternal effects: nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms.
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Rates of adverse fetal outcomes: birth defects, low birthweight, and developmental disabilities.
Search methods for identification of studies
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting their Information Specialist (30 June 2016)
The Register is a database containing over 22,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate the Pregnancy and Childbirth Group’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth Group in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.
Briefly, the Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by their Information Specialist and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth Group review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set which has been fully accounted for in the relevant review sections (Included studies).
Searching other resources
We searched the citation lists of retrieved studies. We did not apply any language or date restrictions.
Data collection and analysis
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Selection of studies
Two review authors (Chen and Fu) independently examined titles and abstracts from the initial search in order to identify studies that met the inclusion criteria. The full text of those studies thought to fulfil the inclusion criteria were retrieved. We resolved any disagreement through discussion.
Data extraction and management
We designed a format extract data. For the eligible study, two review authors (Chen and Fu) extracted data using the agreed form. We resolved discrepancies through discussion. We entered data into Review Manager software (RevMan 2014) and checked for accuracy. When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors (Chen and Fu) independently assessed risk of bias for the included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion. We did not require consultation with a third party, but will use this strategy if required when conducting future updates of the review.
(1) Random sequence generation (checking for possible selection bias)
We described for the one included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described the method used to conceal the allocation sequence and determined whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
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low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We had determined that studies would be considered at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods used to blind outcome assessment as:
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low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We described for the included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re‐include missing data in the analyses which we undertook.
We assessed the methods as:
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low risk of bias (where less than 20% of the randomized population was excluded);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomization);
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unclear risk of bias.
(5) Selective reporting bias
We described how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other sources of bias
We described any important concerns we had about other possible sources of bias.
We assessed whether the included study was free of other problems that could put it at risk of bias:
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low risk of other bias;
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high risk of other bias;
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unclear whether there is risk of other bias.
(7) Overall risk of bias
We made explicit judgements about whether the included study was at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. In future updates, if more studies are included, we will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Assessment of the quality of the evidence using the GRADE approach
The quality of the evidence was assessed using the GRADE approach as outlined in the GRADE handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparisons.
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Rate of miscarriage.
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Rate of live birth.
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Rate of conception.
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Proportion reduction in serum prolactin levels.
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Rate of serum prolactin normalization.
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Rates of adverse maternal effects: nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms.
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Rates of adverse fetal outcomes: birth defects, low birthweight, and developmental disabilities.
We used the GRADEpro Guideline Development Tool to import data from Review Manager 5.3 (RevMan 2014) in order to create a ’Summary of findings’ table. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Measures of treatment effect
For binary data, we presented results as risk ratio with 95% confidence intervals. If appropriate, in future updates of this review, for continuous date, we will use the mean difference to combine trials if outcomes are measured in the same way between trials. We will use the standardized mean difference to combine trials that measure the same outcome but use different methods.
Unit of analysis issues
Cluster‐randomized trials
No cluster‐randomized trials were identified. However, in future updates of the review, if identified, we will include cluster‐randomized trials in the analyses along with individually‐randomized trials.We will adjust their sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomized trials and individually‐randomized trials, we plan to synthesis the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomization unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomization unit and perform a sensitivity analysis to investigate the effects of the randomization unit through undertaking sensitivity analyses ‐ see Sensitivity analysis.
Cross‐over trials
Cross‐over trials are not eligible for inclusion as this particular design is inappropriate for our review question.
Other unit of analysis issues
In future updates, if we include trials with more than two treatment groups, we will assess the most appropriate way to include the data (such as combining groups to create a pair‐wise comparison or selecting the most appropriate pair of interventions and excluding the others).
Dealing with missing data
For the included study, we noted levels of attrition. In future updates, we will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomized to each group in the analyses, and all participants were analyzed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomized minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
In future updates, we will assess statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
In future updates of this review, if there are 10 or more studies, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If we detect asymmetry by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
As only one study was included, we did not combine data in a meta‐analysis. In future updates, we will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials' populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. We will treat the random‐effects summary as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing among trials. If the average treatment effect is not clinically meaningful, we will not combine trials.
If we use random‐effects analyses, we will present the results as the average treatment effect with its 95% confidence interval, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
We did not carry out subgroup analyses because that there was only one included study and insufficient information. If appropriate in future updates of this review, we will investigate heterogeneity using subgroup analyses and sensitivity analyses. We will carry out the following subgroup analyses if required.
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Different types of dopamine agonists (e.g. comparisons between bromocriptine, cabergoline, and quinagolide).
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Routes of supplementation (e.g. oral versus vaginal).
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Dosage of supplementation (e.g. for bromocriptine, < 7.5 mg/day versus > 7.5 mg/day).
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Level of serum prolactin on admission (e.g. prolactin > 100 mg/mL versus < 100 mg/mL).
We will use the following outcomes in subgroup analysis: rates of live births (term delivery or premature delivery); rates of miscarriage.
We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it.
We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We will report the results of subgroup analyses quoting the Chi2 statistic and P value, and the interaction test I² value.
Sensitivity analysis
We only identified a single study for inclusion in this review. In future updates of this review, we will conduct sensitivity analyses to investigate the following effects.
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Inclusion/exclusion of trials with "no intervention" as the control group.
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Inclusion/exclusion of trials at high risk of bias, as determined the risk of allocation concealment.
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Inclusion/exclusion of trials with high levels of missing data.
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Fixed‐effect/random‐effects analyses for outcomes with statistical heterogeneity.
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To examine the effect of the randomization unit (where we combine cluster‐RCTs along with the individually‐randomized trials).
Outcomes in the sensitivity analysis will include rates of miscarriage and rates of live births (term delivery or premature delivery).
Results
Description of studies
Results of the search
See: Figure 1.
Study flow diagram.
The search retrieved just two reports, one was screened out at the title stage and one was included (Hirahara 1998).
Included studies
Study design and setting
We included one parallel‐design randomized controlled trial (Hirahara 1998) in this review. Hirahara 1998 was a single‐centre study, conducted at the recurrent spontaneous abortion clinic at Yokohama City University Hospital in Japan.
Participants
Forty‐eight women were enrolled after assessment for eligibility (24 in the intervention group and 24 in the no treatment control group). The women (aged 24 to 40 years) were diagnosed with idiopathic hyperprolactinemia and had a history of two to four spontaneous miscarriages. Twenty‐four women had occult hyperprolactinemia (12 in the intervention group and 12 in the non treatment control group).
Interventions
Hirahara 1998 compared the use of bromocriptine (2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus no treatment (control).
Outcomes
Outcomes were divided into primary and secondary, as listed above. Primary outcomes were reported, including rates of miscarriage and live birth. Live birth was not specified as term delivery or preterm delivery in this study. For secondary outcomes, conception and serum prolactin levels were assessed, while adverse effects on mother (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) and adverse fetal outcomes (birth defects, low birthweight, and developmental disabilities) were not reported.
Follow‐up
Women were followed during the treatment period and a subsequent 12‐month observation period.
Excluded studies
There are no excluded studies.
Risk of bias in included studies
The included study was judged as being at a high risk of bias overall. See: Figure 2 for 'Risk of bias' assessment in our included study. For detailed descriptions of each risk of bias, see Characteristics of included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Hirahara 1998 used a computer‐generated randomization process (low risk of bias), but it did not mention whether allocation concealment was used (unclear risk of bias).
Blinding
Hirahara 1998 did not use placebo and was thus deemed to be at high risk of performance bias. The blinding of outcome assessment was not mentioned and we therefore rated the study as being at unclear risk of detection bias. We did not consider that blinding was likely to influence findings for the primary review outcome (miscarriage and live birth). However for some subjective secondary outcomes (maternal adverse effects such as nausea, headache, et al.), blinding status could potentially affect findings.
Incomplete outcome data
In Hirahara 1998, two women in the control group dropped out of the study after randomization. The reasons for dropouts were not explained in the trial report. The remaining 46 women were followed up and included in the analysis. The low rate of missing data (4.2%) was considered to represent a low risk of attrition bias.
Selective reporting
We intended to compare the protocols with published trials to assess reporting bias, however no protocol was available for the included study. So we compared the methods and results sections of the trial. Each outcome discussed in the methods sections was reported by Hirahara 1998 except that serum prolactin levels were only reported for pregnant women. The trial failed to report adverse events as an outcome, only mentioning that women in the trial who became pregnant did not require further medications or hospitalization. Hence we assessed this included study as of unclear risk for selective reporting bias.
Other potential sources of bias
There were no significant differences between the groups with regard to the baseline of included women (Hirahara 1998). We found no potential sources of within‐study bias in this study.
Effects of interventions
Only one trial (Hirahara 1998) compared bromocriptine versus no treatment. There were no randomized controlled trials focusing on other types of dopamine agonists such as cabergoline and quinagolide. Meta‐analysis was not possible and we did not carry out subgroup analyses as there is only one included study.
Dopamine agonist (bromocriptine) alone versus no treatment (control) ‐ comparison 1
The Hirahara 1998 trial (46 women were analyzed) compared bromocriptine (2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus no treatment.
Primary outcomes
1.1 Miscarriage
Compared to no treatment control, oral bromocriptine was associated with a reduction in 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 (Analysis 1.1). See summary of findings Table for the main comparison.
1.2 Live birth
There was no clear difference with regard to live births among women in the bromocriptine group compared to the rate of live births in the no treatment control group (RR 1.50, 95% CI 0.93 to 2.42, 46 participants, very low‐quality evidence) (Analysis 1.2). See summary of findings Table for the main comparison.
Secondary outcomes
1.3 Conception
There was no difference with regard to the rate of conception (RR 0.92, 95% CI 0.77 to 1.09, 46 participants, very low‐quality evidence) between the bromocriptine and no treatment groups. See Analysis 1.3 and summary of findings Table for the main comparison.
1.4 Proportion reduction in serum prolactin levels and rate of serum prolactin normalization
The included study only reported the serum prolactin levels in pregnant women and could not be analyzed further in this review.
1.5 Adverse maternal effects
None of our prespecified maternal adverse effects (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) were reported in the included study.
1.6 Adverse fetal outcomes
None of our pre‐specified fetal adverse effects (birth defects, low birthweight, and developmental disabilities) were reported in included study. The trial authors only mention that no women who became pregnant required further medications or hospitalizations.
Discussion
Summary of main results
This review assessed the effects of dopamine agonists preventing future miscarriage in women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. However, only one randomized controlled trial (RCT) recruiting 48 patients met our inclusion criteria. The included study was judged as being at a high risk of bias. Low‐quality evidence from this study showed bromocriptine was effective in preventing future miscarriage. However, very low‐quality evidence also showed that live birth and conception rates were similar between the bromocriptine group and the no treatment group. The included study did not report adverse effects (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms; fetal outcomes: birth defects, low birthweight, and developmental disabilities). The trial authors do mention that there were no further medications or hospitalizations required for women in the trial who became pregnant.
We did not identify any randomized controlled trials focusing on other types of dopamine agonists such as cabergoline and quinagolide.
Overall completeness and applicability of evidence
To the best of our knowledge, this is the only systematic review on dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history. Very little on this topic was identified, with only one trial meeting our inclusion criteria. This study was conducted in 1998 in Japan. The definition of hyperprolactinemia in this trial (above 10 ng/mL; n = 48) was different from the most widely accepted definition nowadays (above 25 ng/mL). Trial authors justified their inclusion criteria by stating that their definition was based on data from 96 healthy menstruating women and 367 infertile women. This included study did not report on adverse effects of the intervention for the mother and her baby.
Quality of the evidence
There are multiple sources of potential bias in the included study and we rated the evidence for the review outcomes of miscarriage as low quality and live birth and conception as very low quality (see summary of findings Table for the main comparison).
Limitations can largely be attributed to the small number of studies and participants. There was only one trial that met our inclusion criteria. This trial recruited small numbers of women. Details of allocation concealment and blinding of assessment were not given. Lack of blinding would be less important for objective outcomes such as miscarriage, live birth, and conception. A number of this review's secondary outcomes regarding safety were not reported in the included trial (maternal outcomes: nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms; fetal outcomes: birth defects, low birthweight, and developmental disabilities). Consequently, no definitive conclusions could be made from this review about the efficacy and safety of dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and a history of recurrent miscarriage.
We assessed outcomes with the GRADE methodology. Miscarriage was assessed as of 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 same risk of bias concerns in study design and to imprecision (with a wide 95% confidence interval consistent with either benefit or harm), and a small sample size.
Potential biases in the review process
In the process for conducting a systematic review, biases could include publication bias, selective outcome reporting bias, selective analysis bias and fabrication bias (Higgins 2011). We prepared this review using Cochrane methodology, and were guided by both the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and the standard methods of the Cochrane Pregnancy and Childbirth Group. Two review authors independently performed study selection, data extraction and assessment of risk of bias. We used standardized data extraction forms.
Agreements and disagreements with other studies or reviews
The evidence in this review is consistent with the findings of a non‐randomized study by Rossi 1995, which reported 103 pregnancies in 64 women (49 with bromocriptine treatment and 15 with no treatment). In that study, the rate of miscarriage was 18% in bromocriptine group and 16% in no treatment group, while term delivery was 72% and 48%, respectively.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Dopamine agonists alone versus no treatment, Outcome 1 Miscarriages.
Comparison 1 Dopamine agonists alone versus no treatment, Outcome 2 Live births.
Comparison 1 Dopamine agonists alone versus no treatment, Outcome 3 Conception.
| Bromocriptine treatment versus no treatment for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history | ||||||
| Patient or population: women with idiopathic hyperprolactinemia and recurrent miscarriage history Comparison: no treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Risk with placebo/no treatment | Risk with Dopamine agonists alone | |||||
| Miscarriages | Study population | RR 0.28 | 46 | ⊕⊕⊝⊝ | ||
| 455 per 1000 | 127 per 1000 | |||||
| Moderate | ||||||
| 455 per 1000 | 127 per 1000 | |||||
| Live births | Study population | RR 1.50 | 46 | ⊕⊝⊝⊝ | ||
| 500 per 1000 | 750 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 750 per 1000 | |||||
| Conception | Study population | RR 0.92 | 46 | ⊕⊝⊝⊝ | ||
| 955 per 1000 | 878 per 1000 | |||||
| Moderate | ||||||
| 955 per 1000 | 878 per 1000 | |||||
| Proportion reduction in serum prolactin levels | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Serum prolactin normalization | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Adverse maternal effects | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| Adverse fetal outcomes | Study population | Not estimable | 0 | See comment | No data in included study | |
| See comment | See comment | |||||
| Moderate | ||||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 One trial with design limitations, including no description of allocation concealment, lack of blinding and possible outcome reporting bias (‐1). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Miscarriages Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.09, 0.87] |
| 2 Live births Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.93, 2.42] |
| 3 Conception Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.77, 1.09] |
