FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques

  • Review
  • Intervention

Authors

  • Wellington P Martins,

    Corresponding author
    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    • Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, 14048-900, Brazil. wpmartins@gmail.com.

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  • Andrea DD Vieira,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Jaqueline BP Figueiredo,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Carolina O Nastri

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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Abstract

Background

During controlled ovarian hyperstimulation (COH) follicle-stimulating hormone (FSH) is frequently used for several days to achieve follicular development. FSH is a relatively expensive drug, substantially contributing to the total expenses of assisted reproductive techniques (ART). When follicles achieve a diameter greater than 10 mm they start expressing luteinising hormone (LH) receptors. At this point, FSH might be replaced by low-dose human chorionic gonadotropin (hCG), which is less expensive. In addition to cost reduction, replacing FSH by low-dose hCG has a theoretical potential to reduce the incidence of ovarian hyperstimulation syndrome (OHSS).

Objectives

To evaluate the effectiveness and safety of using low-dose hCG to replace FSH during the late follicular phase in women undergoing COH for assisted reproduction, compared to the use of a conventional COH protocol.

Search methods

We searched for randomised controlled trials (RCT) in electronic databases (Menstrual Disorders and Subfertility Group Specialized Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform), conference abstracts (ISI Web of knowledge), and grey literature (OpenGrey); additionally we handsearched the reference list of included studies and similar reviews. The last electronic search was performed in February 2013..

Selection criteria

Only true RCTs comparing the replacement of FSH by low-dose hCG during late follicular phase of COH were considered eligible; quasi or pseudo-randomised trials were not included. Cross-over trials would be included only if data regarding the first treatment of each participant were available; trials that included the same participant more than once would be included only if each participant was always allocated to the same intervention and follow-up periods were the same in both/all arms, or if data regarding the first treatment of each participant were available. We excluded trials that sustained FSH after starting low-dose hCG and those that started FSH and low-dose hCG at the same time.

Data collection and analysis

Study eligibility, data extraction, and assessment of the risk of bias were performed independently by two review authors, and disagreements were solved by consulting a third review author. We corresponded with study investigators in order to solve any query, as required. The overall quality of the evidence was assessed in a GRADE summary of findings table.

Main results

The search retrieved 1585 records; from those five studies were eligible, including 351 women (intervention = 166; control = 185). All studies were judged to be at high risk of bias. All reported per-woman rather than per-cycle data.

When use of low-dose hCG to replace FSH was compared with conventional COH for the outcome of live birth, confidence intervals were very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.56, 95% CI 0.75 to 3.25, 2 studies, 130 women, I² = 0%, very-low-quality evidence). This suggests that for women with a 14% chance of achieving live birth using conventional COH, the chance of achieving live birth using low-dose hCG would be between 10% and 45%.

Similarly confidence intervals were very wide for the outcome of OHSS and findings were compatible with benefit, no effect or harm for the intervention (OR 0.30, 95% CI 0.06 to 1.59, 5 studies, 351 women, I² = 59%, very-low-quality evidence). This suggests that for women with a 3% risk of OHSS using conventional COH, the risk using low-dose hCG would be between 0% and 4%.

The confidence intervals were wide for the outcome of ongoing pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.14, 95% CI 0.81 to 1.60, 3 studies, 252 women, I² = 0%, low-quality evidence). This suggests that for women with a 32% chance of achieving ongoing pregnancy using conventional COH, the chance using low-dose hCG would be between 27% and 53%.

The confidence intervals were wide for the outcome of clinical pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.19, 95% CI 0.92 to 1.55, 5 studies, 351 women, I² = 0%, low-quality evidence). This suggests that for women with a 35% chance of achieving clinical pregnancy using conventional COH, the chance using low-dose hCG would be between 32% and 54%.

The confidence intervals were very wide for the outcome of miscarriage and findings were compatible with benefit, no effect or harm for the intervention (RR 1.08, 95% CI 0.50 to 2.31, 3 studies, 127 pregnant women, I² = 0%, very-low-quality evidence). This suggests that for pregnant women with a 16% risk of miscarriage using conventional COH, the risk using low-dose hCG would be between 8% and 36%.

The findings for the outcome of FSH consumption were compatible with benefit for the intervention (MD -639 IU, 95% CI -893 to -385, 5 studies, 333 women, I² = 88%, moderate-quality evidence).

The findings for the outcome of number of oocytes retrieved were compatible with no effect for the intervention (MD -0.12 oocytes, 95% CI -1.0 to 0.8 oocytes, 5 studies, 351 women, I² = 0%, moderate-quality evidence).

Authors' conclusions

We are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH. More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.

Résumé scientifique

Remplacement de la FSH par l'administration d'hCG à faible dose dans la phase folliculaire tardive comparé à la poursuite de l'administration de la FSH pour les techniques de procréation médicalement assistée

Contexte

Lors de l'hyperstimulation ovarienne contrôlée (HOC), l'hormone folliculo-stimulante (FSH) est fréquemment utilisée pendant plusieurs jours pour susciter le développement folliculaire. La FSH est un médicament relativement onéreux, ce qui contribue considérablement aux dépenses totales des techniques de procréation médicalement assistée (TPMA). Quand les follicules atteignent un diamètre supérieur à 10 mm, ils commencent à exprimer les récepteurs de l'hormone lutéinisante (HL). À ce stade, la FSH pourrait être remplacée par la gonadotrophine chorionique humaine (hCG) à faible dose, qui est moins chère. En plus des réductions de coût, le remplacement de la FSH par l'hCG à faible dose peut théoriquement réduire l'incidence du syndrome d'hyperstimulation ovarienne (SHO).

Objectifs

Évaluer l'efficacité et l'innocuité de l'administration d'hCG à faible dose pour remplacer la FSH pendant la phase folliculaire tardive chez les femmes subissant une hyperstimulation ovarienne contrôlée (HOC) pour une procréation médicalement assistée, comparée à l'utilisation d'un protocole HOC conventionnel.

Stratégie de recherche documentaire

Nous avons recherché des essais contrôlés randomisés (ECR) dans les bases de données électroniques (le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), les registres d'essais (ClinicalTrials.gov, Current Controlled Trials, le système d'enregistrement international des essais cliniques de l'Organisation Mondiale de la Santé), les actes de conférences (ISI Web of knowledge), et la littérature grise (OpenGrey) ; en outre, nous avons effectué des recherches manuelles dans les références bibliographiques des études incluses et les revues similaires. Les dernières recherches électroniques ont été effectuées en février 2013.

Critères de sélection

Seuls les ECR réels comparant le remplacement de la FSH par l'hCG à faible dose pendant la phase folliculaire tardive de l'hyperstimulation ovarienne contrôlée (HOC) ont été considérés comme éligibles ; les essais quasi ou pseudo-randomisés n'ont pas été inclus. Les essais croisés n'ont été inclus que si les données concernant le premier traitement de chaque participante étaient disponibles ; les essais qui ont inclus la même participante plus d'une fois n'ont été inclus que si chaque participante était toujours affectée à la même intervention et si les périodes de suivi étaient les mêmes dans les deux/tous les bras, ou si les données concernant le premier traitement de chaque participante étaient disponibles. Nous avons exclu les essais dans lesquels la FSH a été maintenue après le début de l'administration d'hCG à faible dose et ceux dans lesquels la FSH et l'hCG à faible dose ont été commencées en même temps.

Recueil et analyse des données

L'évaluation de l'éligibilité des études, l'extraction des données, et l'évaluation des risques de biais ont été réalisées indépendamment par deux auteurs de la revue, et les désaccords ont été résolus en faisant intervenir un troisième auteur. Nous avons correspondu avec les chercheurs des études afin d'éliminer le moindre doute, en cas de besoin. La qualité globale des preuves a été évaluée dans un résumé des tables de résultats GRADE.

Résultats principaux

La recherche a permis de trouver 1 585 dossiers ; parmi ces derniers cinq études étaient éligibles, totalisant 351 femmes (intervention = 166 ; témoin = 185). Toutes les études ont été considérées comme présentant des risques élevés de biais. Toutes ont rapporté les données par femme et non pas par cycle.

Lorsque l'administration d'hCG à faible dose pour remplacer la FSH a été comparée à un protocole HOC conventionnel pour le résultat des naissances vivantes, les intervalles de confiance étaient très larges et les observations étaient compatibles avec un bénéfice appréciable, l'absence d'effet ou un danger appréciable pour l'intervention (RR 1,56, IC à 95 % 0,75 à 3,25, 2 études, 130 femmes, I² = 0 %, preuves de très faible qualité). Ceci suggère que pour les femmes ayant 14 % de chances d'obtenir une naissance vivante en utilisant un protocole HOC conventionnel, les chances d'obtenir une naissance vivante avec l'administration d'hCG à faible dose seraient comprises entre 10 % et 45 %.

De même, les intervalles de confiance étaient très larges pour le résultat du syndrome d'hyperstimulation ovarienne (SHO) et les observations étaient compatibles avec un bénéfice, l'absence d'effet ou un danger pour l'intervention (RC 0,30, IC à 95 % 0,06 à 1,59, 5 études, 351 femmes, I² = 59 %, preuves de très faible qualité). Ceci suggère que pour les femmes présentant un risque de 3 % de syndrome d'hyperstimulation ovarienne (SHO) en utilisant un protocole HOC conventionnel, le risque avec l'administration d'hCG à faible dose serait compris entre 0 % et 4 %.

Les intervalles de confiance étaient larges pour le résultat des grossesses en cours et les observations étaient compatibles avec un bénéfice ou l'absence d'effet pour l'intervention (RR 1,14, IC à 95 % 0,81 à 1,60, 3 études, 252 femmes, I² = 0 %, preuves de faible qualité). Ceci suggère que pour les femmes ayant 32 % de chances d'obtenir une grossesse en cours en utilisant un protocole HOC conventionnel, les chances avec l'administration d'hCG à faible dose seraient comprises entre 27 % et 53 %.

Les intervalles de confiance étaient larges pour le résultat des grossesses cliniques et les observations étaient compatibles avec un bénéfice ou l'absence d'effet pour l'intervention (RR 1,19, IC à 95 % 0,92 à 1,55, 5 études, 351 femmes, I² = 0 %, preuves de faible qualité). Ceci suggère que pour les femmes ayant 35 % de chances d'obtenir une grossesse clinique en utilisant un protocole HOC conventionnel, les chances avec l'administration d'hCG à faible dose seraient comprises entre 32 % et 54 %.

Les intervalles de confiance étaient très larges pour le résultat des fausses couches et les observations étaient compatibles avec un bénéfice, l'absence d'effet ou un danger pour l'intervention (RR 1,08, IC à 95 % 0,50 à 2,31, 3 études, 127 femmes enceintes, I² = 0 %, preuves de très faible qualité). Ceci suggère que pour les femmes enceintes présentant un risque de 16 % de fausses couches en utilisant un protocole HOC conventionnel, le risque avec l'administration d'hCG à faible dose serait compris entre 8 % et 36 %.

Les observations pour le résultat de la consommation de FSH étaient compatibles avec un bénéfice pour l'intervention (DM -639 UI, IC à 95 % -893 à -385, 5 études, 333 femmes, I² = 88 %, preuves de qualité modérée).

Les observations pour le résultat du nombre d'ovocytes récupérés étaient compatibles avec l'absence d'effet pour l'intervention (DM -0,12 ovocyte, IC à 95 % -1,0 à 0,8 ovocytes, 5 études, 351 femmes, I² = 0 %, preuves de qualité modérée).

Conclusions des auteurs

Nous n'avons absolument aucune certitude quant à l'effet sur les naissances vivantes, le syndrome d'hyperstimulation ovarienne (SHO) et les fausses couches de l'administration d'hCG à faible dose pour remplacer la FSH pendant la phase folliculaire tardive de l'hyperstimulation ovarienne contrôlée (HOC) chez les femmes bénéficiant d'une technique de procréation médicalement assistée (TPMA), par rapport à l'utilisation d'un protocole HOC conventionnel. Les preuves actuelles suggèrent que cette intervention ne réduit pas les chances de grossesses en cours et cliniques ; et qu'il est probable qu'elle aboutisse à un nombre équivalent d'ovocytes récupérés en utilisant moins de FSH. D'autres études sont nécessaires pour renforcer les preuves concernant l'effet de cette intervention sur d'importants critères de jugement pour la procréation.

Plain language summary

Replacing FSH by hCG to complete follicular growth in women undergoing assisted reproduction

Follicle-stimulating hormone (FSH) - a relatively expensive drug - is commonly used for several days to stimulate the ovaries of women undergoing assisted reproduction. Initial studies have shown that after a few days of using FSH to stimulate the ovaries, it can be replaced by human chorionic gonadotropin (hCG), which is less expensive. In addition to cost reduction, this intervention has a theoretical potential to reduce the risk of ovarian hyperstimulation syndrome (OHSS); though the underlying risk is already very low for most women. We searched the medical literature on in February 2013 for studies that evaluated the effectiveness and safety of using low-dose hCG to replace FSH during the late follicular phase in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction, compared to the use of a conventional COH protocol. Five studies evaluating 351 women were included in this review. These studies were funded by fertility centres, universities, or both. We are very uncertain of the effect of this intervention on live birth, OHSS and miscarriage

When use of low-dose hCG to replace FSH was compared with conventional COH, there was very low quality evidence compatible with appreciable benefit, no effect or appreciable harm for the intervention, suggesting that for women with a 14% chance of achieving live birth using a conventional COH, the chance of achieving live birth using low-dose hCG would be between 10% and 45%. Similarly, there was very low quality evidence suggesting that for women with a 3% risk of OHSS using a conventional COH, the risk using low-dose hCG was also compatible with either benefit or harm, and would be between 0% and 4%.

Additionally we observed that there was low quality evidence suggesting that for women with a 32% chance of achieving ongoing pregnancy using a conventional COH, the chance using low-dose hCG was compatible with either benefit or no effect, and would be between 27% and 53%. There was low quality evidence suggesting that for women with a 35% chance of achieving clinical pregnancy using a conventional COH, the chance using low-dose hCG was compatible with either benefit or no effect, and would be between 32% and 54%. There was very low quality evidence suggesting that for pregnant women with a 16% risk of miscarriage using a conventional COH, the risk using low-dose hCG was compatible with either benefit or harm, and would be between 8% and 36%. We also observed that there is moderate-quality evidence that this intervention reduces the total FSH consumption and is unlikely to materially affect the number of oocytes retrieved

Our conclusions are that we are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH. More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.

Résumé simplifié

Remplacement de la FSH par l'hCG pour achever la croissance folliculaire chez les femmes bénéficiant d'une technique de procréation médicalement assistée

L'hormone folliculo-stimulante (FSH) - un médicament relativement onéreux - est couramment utilisée pendant plusieurs jours pour stimuler les ovaires des femmes bénéficiant d'une technologie de procréation assistée. Des études initiales ont montré que, après quelques jours d'administration de FSH pour stimuler les ovaires, elle peut être remplacée par la gonadotrophine chorionique humaine (hCG), qui est moins chère. En plus des réductions de coût, cette intervention peut théoriquement réduire le risque de syndrome d'hyperstimulation ovarienne (SHO) ; bien que le risque sous-jacent soit déjà très faible pour la plupart des femmes. Nous avons effectué une recherche dans la littérature jusqu'en février 2013 pour identifier des études ayant évalué l'efficacité et l'innocuité de l'administration d'hCG à faible dose pour remplacer la FSH pendant la phase folliculaire tardive chez les femmes subissant une hyperstimulation ovarienne contrôlée (HOC) pour une procréation médicalement assistée, par rapport à l'utilisation d'un protocole HOC conventionnel. Cinq études ayant évalué 351 femmes ont été incluses dans cette revue. Ces études ont été financées par un service de consultation externe de fertilité, une université, ou les deux. Nous n'avons absolument aucune certitude quant à l'effet de cette intervention sur les naissances vivantes, le syndrome d'hyperstimulation ovarienne (SHO) et les fausses couches.

Lorsque l'administration d'hCG à faible dose pour remplacer la FSH a été comparée à un protocole HOC conventionnel, il y avait des preuves de très faible qualité compatibles avec un bénéfice appréciable, l'absence d'effet ou un danger appréciable pour l'intervention, suggérant que pour les femmes ayant 14 % de chances d'obtenir une naissance vivante en utilisant un protocole HOC conventionnel, les chances d'obtenir une naissance vivante avec l'administration d'hCG à faible dose seraient comprises entre 10 % et 45 %. De même, il y avait des preuves de très faible qualité suggérant que pour les femmes présentant un risque de 3 % de syndrome d'hyperstimulation ovarienne (SHO) en utilisant un protocole HOC conventionnel, le risque avec l'administration d'hCG à faible dose était également compatible soit avec un bénéfice soit avec un danger, et serait compris entre 0 % et 4 %.

En outre, nous avons observé qu'il y avait des preuves de faible qualité suggérant que pour les femmes ayant 32 % de chances d'obtenir une grossesse en cours en utilisant un protocole HOC conventionnel, les chances avec l'administration d'hCG à faible dose étaient compatibles soit avec un bénéfice soit avec l'absence d'effet, et seraient comprises entre 27 % et 53 %. Il y avait des preuves de faible qualité suggérant que pour les femmes ayant 35 % de chances d'obtenir une grossesse clinique en utilisant un protocole HOC conventionnel, les chances avec l'administration d'hCG à faible dose étaient compatibles soit avec un bénéfice soit avec l'absence d'effet, et seraient comprises entre 32 % et 54 %. Il y avait des preuves de très faible qualité suggérant que pour les femmes enceintes présentant un risque de 16 % de fausse couche en utilisant un protocole HOC conventionnel, le risque avec l'administration d'hCG à faible dose était compatible soit avec un bénéfice soit avec un danger, et serait compris entre 8 % et 36 %. Nous avons également observé qu'il y avait des preuves de qualité modérée que cette intervention réduit la consommation totale de FSH et qu'il est peu probable qu'elle affecte substantiellement le nombre d'ovocytes récupérés.

Nos conclusions sont que nous n'avons absolument aucune certitude quant à l'effet sur les naissances vivantes, le syndrome d'hyperstimulation ovarienne (SHO) et les fausses couches de l'administration d'hCG à faible dose pour remplacer la FSH pendant la phase folliculaire tardive du protocole HOC chez les femmes bénéficiant d'une technique de procréation médicalement assistée (TPMA), par rapport à l'utilisation d'un protocole HOC conventionnel. Les preuves actuelles suggèrent que cette intervention ne réduit pas les chances de grossesses en cours et cliniques ; et qu'il est probable qu'elle aboutisse à un nombre équivalent d'ovocytes récupérés en utilisant moins de FSH. D'autres études sont nécessaires pour renforcer les preuves concernant l'effet de cette intervention sur d'importants critères de jugement pour la procréation.

Notes de traduction

Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Low-dose hCG compared to FSH throughout the COH for assisted reproductive techniques
  1. 1 The evidence quality was downgraded because of very serious imprecision, and high risk of bias.

    2 The evidence quality was downgraded because of very serious imprecision, inconsistency, and high risk of bias.

    3 The evidence quality was downgraded because of imprecision and high risk of bias.

    4 The evidence quality was downgraded because of imprecision and high risk of bias.

    5 The evidence quality was downgraded because of very serious imprecision, and high risk of bias.

    6 The evidence quality was downgraded because of high risk of bias.

    7 The evidence quality was downgraded because of high risk of bias.

Low-dose hCG compared to FSH throughout the COH for assisted reproductive techniques
Population: women undergoing assisted reproductive techniques
Intervention: low-dose hCG in the late follicular phase
Comparison: FSH throughout the COH
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
FSH throughout the COHLow-dose hCG
Live birth14 per 10022 per 100
(10 to 45)
RR 1.56
(0.75 to 3.25)
130
(2 studies)
⊕⊝⊝⊝
very low 1
OHSS3 per 1001 per 100
(0 to 4)
OR 0.30
(0.06 to 1.59)
351
(5 studies)
⊕⊝⊝⊝
very low 2
Ongoing pregnancy32 per 10038 per 100
(27 to 53)
RR 1.17
(0.83 to 1.64)
252
(3 studies)
⊕⊕⊝⊝
low 3
Clinical pregnancy35 per 10041 per 100
(32 to 54)
RR 1.19
(0.92 to 1.55)
351
(5 studies)
⊕⊕⊝⊝
low 4
Miscarriage16 per 10017 per 100
(8 to 36)
RR 1.08
(0.50 to 2.31)
127
(4 studies)
⊕⊝⊝⊝
very low 5
Total dose of FSHThe average FSH total consumption in control groups was 1390 IUThe average FSH total consumption in intervention groups was 639 IU lower
(893 to 385 IU lower)
 333
(5 studies)
⊕⊕⊕⊝
moderate 6
Oocytes retrievedThe average number of oocytes retrieved in control groups was 9.0Oocytes retrieved in intervention groups was 0.1 lower
(1.0 lower to 0.8 higher)
 333
(5 studies)
⊕⊕⊕⊝
moderate 7
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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).
CI: confidence interval; COH: controlled ovarian hyperstimulation; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Assisted reproductive techniques (ART) are widely used to treat subfertility, which affects approximately 7% to 15% of women of reproductive age (Thoma 2013). ARTs include interventions that require the in vitro handling of both human oocytes and sperm or of embryos with the objective of achieving pregnancy and live birth (Zegers-Hochschild 2009). The most common ARTs are in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). ARTs frequently include the recruitment of multiple follicles through controlled ovarian hyperstimulation (COH). COH is considered an important step in ART: the pregnancy rate per cycle is around 10% when minimal COH is performed (Pelinck 2006), and achieves 33% when standard COH is performed (Gnoth 2011). The most frequently used COH protocols include follicle-stimulating hormone (FSH) (≥ 150 international units (IU)/day) associated with either gonadotropin-releasing hormone (GnRH) agonists or antagonists to avoid premature luteinising hormone (LH) surge (Macklon 2006). Such drugs are relatively expensive (Verberg 2009), further contributing to the total expenses of ART, which is currently unaffordable for the majority of subfertile couples (Aleyamma 2011). In addition, COH poses a risk of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening adverse event (Nastri 2010).

Description of the intervention

To replace FSH by low-dose hCG during late follicular phase of COH in women undergoing ART.

How the intervention might work

After the initial follicular growth induced by FSH, approximately when follicles have a diameter greater than 10 mm, the granulosa cells start expressing LH receptors (Shima 1987; Takao 1997). From this point, FSH is usually continued to complete COH, but LH or hCG could be used as surrogate drugs. Usually hCG is preferred, as both exert the same action, but hCG has a longer half life (Ross 1977) and is less expensive. Initial reports showed that replacing FSH by low-dose hCG during the late follicular phase (after seven days of FSH-induced follicle recruitment) was associated with similar number of large follicles (> 14 mm diameter) and a reduction in the number of smaller ones (Filicori 2002b). These findings suggest that this intervention can potentially reduce the risk of OHSS, without impairing the main reproductive outcomes. Moreover, it could be preferentially used even if both treatments are similar in benefits and harms, as hCG is cheaper than FSH, and such strategy might reduce the total treatment cost (Filicori 2002a).

Why it is important to do this review

COH is an important step for ART. However, the current mainstream protocols for COH are expensive and associated with some risk of developing OHSS. Replacing FSH by low-dose hCG during late ovarian stimulation has a theoretical potential to reduce those problems. However, the effectiveness and safety of this intervention is still not clear; and a systematic review of the best available evidence would be interesting to permit more robust conclusions.

Objectives

To evaluate the effectiveness and safety of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH.

Methods

Criteria for considering studies for this review

Types of studies

Only truly randomised controlled trials (RCTs) were considered eligible; quasi or pseudo-randomised trials were not included. Cross-over trials were included only if data regarding the first treatment of each participant were available.

Types of participants

Women undergoing COH for ART.

Types of interventions

Replacing FSH by low-dose hCG during the late follicular phase - after a fixed number of days of using FSH or when follicles achieved a specific diameter (usually between 12 and 14 mm) - compared with the use of FSH throughout the COH period (conventional COH). We excluded the trials that sustained FSH (same or reduced dose) after starting low-dose hCG; those that started FSH and low-dose hCG at the same time; and those that started low-dose hCG before FSH.

Types of outcome measures

Primary outcomes
Effectiveness

1.1 Live birth per allocated woman.

Adverse events

1.2 OHSS per allocated woman.

Secondary outcomes
Effectiveness

1.3 Ongoing pregnancy per allocated woman.

1.4 Clinical pregnancy per allocated woman.

Adverse events

1.5 Miscarriage per clinical pregnancy.

Additional outcomes

1.6 Total dose of FSH used during ovarian stimulation per allocated woman.

1.7 Oocytes retrieved - mature (MII) (preferentially) or total number - per allocated woman.

Implantation rate (number of gestational sacs observed divided by the number of embryos transferred) was not included in the quantitative meta-analysis because the denominator is not randomised (women, not embryos transferred, were randomised). Implantation rate was included for completeness in the 'Characteristics of included studies' tables.

Search methods for identification of studies

The search strategy was developed in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator.

Electronic searches

The electronic searches were performed in February 2013.

We searched for RCTs in the following electronic databases from their inception: Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 1); Cumulative Index to Nursing and Allied Health Literature (CINAHL) (www.ebscohost.com/cinahl/) (Appendix 2); EMBASE (Appendix 3); this search was combined with trial filters developed by Scottish Intercollegiate Guidelines Network (SIGN; www.sign.ac.uk/methodology/filters.html); Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) (regional.bvsalud.org/php/index.php?lang=en) (Appendix 4); MDSG Specialised Register (Appendix 5); Medical Literature Analysis and Retrieval System Online (MEDLINE) (Appendix 6), this search was combined with the Cochrane highly sensitive search strategy for identifying randomised trials (Higgins 2011); and PsycINFO (Appendix 7).

We searched for study protocols and ongoing trials in the following trials registers (Appendix 8): ClinicalTrials.gov (www.clinicaltrials.gov); Current Controlled Trials (www.controlled-trials.com/isrctn/); and World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.aspx).

We searched for conference abstracts in the ISI Web of Knowledge (isiwebofknowledge.com/) (Appendix 9).

We searched for grey literature in the Open Grey (www.opengrey.eu/) (Appendix 10).

We searched for similar reviews in The Cochrane Library for Database of Abstracts of Reviews of Effects (DARE) (Appendix 11).

Searching other resources

We handsearched the reference list from included trials and similar reviews.

Data collection and analysis

Selection of studies

Titles and abstracts were reviewed independently by two review authors (ADDV and JBPF), checking for duplicates and using the pre-established criteria for inclusion. The same review authors further evaluated the eligibility of potentially eligible records; disagreements were solved by consulting other review author (WPM). Authors tried to correspond with study investigators to clarify study eligibility when required. There was no limitation regarding language, publication date, or publication status.

Data extraction and management

We extracted data from included trials using a data extraction form designed and pilot-tested by the authors. Where trials had multiple publications, the main trial report was used as the reference and additional details were supplemented from secondary papers. We corresponded with study investigators in order to solve any query, as required. Data were extracted independently in a standardised manner by two review authors (ADDV and WPM), disagreements were solved by consulting a third review author (CON).

Assessment of risk of bias in included studies

Two review authors (CON and WPM) independently assessed the risk of selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective outcome reporting) and other potential sources of bias (e.g. difference in the number of embryos transferred, age of participants, co-interventions, early stopping). Disagreements were solved by consensus between these authors. To judge the risk of bias, we followed The Cochrane Collaboration's criteria for judging risk of bias (Higgins 2011): the trials were classified as being of 'low', 'high' or 'unclear' risk of bias.

Measures of treatment effect

The effects of the intervention were summarised as risk ratio (RR) or as Peto odds ratio (OR) for binary outcomes (live birth, OHSS, clinical pregnancy and miscarriage), and as mean difference (MD) for continuous outcomes (total dose of FSH and number of oocytes retrieved). Regarding the binary outcomes, we preferred to use RR because it is easier to use and interpret; however, we planned to use used Peto OR if there was a zero cell count or the prevalence of the event was less than 1% (at least in one group). The precision of the estimates was evaluated by the 95% CI. We considered the clinical relevance of all comparisons taking into account the precision of the estimates; we planned to determine the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) when a significant difference was observed.

Unit of analysis issues

The primary analysis was per woman allocated. If there were any data that did not allow valid analysis (e.g. "per cycle" data), we planned that they would be briefly summarised in an additional table and would not be meta-analysed.  Multiple live births (e.g. twins or triplets) were counted as one live birth event.

Dealing with missing data

We contacted the study authors to obtain missing data. Where they were unobtainable, we planned to assume that clinical pregnancy (and subsequent miscarriage or live birth) did not occur and that no oocyte was retrieved in the women with cycle cancellation. For the total FSH consumption, we used the data for the analysed participants.

Assessment of heterogeneity

Heterogeneity was assessed by the I² statistic. Where substantial heterogeneity was observed (I² > 50%) we planned to address it by: (1) rechecking data; (2) performing the planned subgroup analysis; (3) excluding studies with high risk of bias; and, if it could not be explained, we would either (4) perform a random-effects meta-analysis or (5) not perform the meta-analysis for that outcome.

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were ten or more studies in an analysis, we planned to use a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).

Data synthesis

The data from primary studies were combined using a fixed effect model comparing replacing FSH by low-dose hCG during the late follicular phase versus FSH throughout the COH. An increase in the risk of a particular outcome associated with replacing FSH by low-dose hCG during the late follicular phase, which may be beneficial (e.g. live birth) or detrimental (e.g. miscarriage), was displayed graphically in the meta-analyses to the right of the centre line and a decrease in the risk of an outcome to the left of the centre line.

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses were planned to be performed for the primary outcomes (or, in the absence of live birth data for the outcome of clinical pregnancy) when substantial heterogeneity was observed:

Characteristics of included participants:

  • unselected women or women with predicted normal ovarian response

  • only women with polycystic ovary syndrome (PCOS) or with predicted high response (high risk of OHSS)

  • only women with predicted poor ovarian response

Drug used for avoiding premature LH surge:

  • GnRH agonists

  • GnRH antagonists

Dose of FSH used during early follicular phase:

  • ≤ 150 IU/day

  • > 150 IU/day.

Sensitivity analysis

We planned to perform sensitivity analyses to verify whether the conclusions would differ if eligibility was restricted to studies without high risk of bias.

Overall quality of the body of evidence: Summary of Findings Table

A Summary of Findings Table was generated using GRADEPRO software. This table evaluated the  overall quality of the body of evidence for main review outcomes, using GRADE criteria (study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness and publication bias).

Results

Description of studies

Results of the search

The search performed on 26 July 2012 retrieved 1585 records. Five studies (from seven records) met our inclusion criteria. Fourteen studies (from 16 records) were excluded (Figure 1). See study tables: Characteristics of included studies, Characteristics of excluded studies.

Figure 1.

Study flow diagram.

Included studies

Study design and setting

Five parallel-design RCTs were included in the review: Aflatoonian 2012 (n = 122); Ashrafi 2011 (n = 60); Blockeel 2009 (n = 70); Filicori 2005a (n = 48) and Gomes 2007 (n = 51). We did not identify cross-over trials or studies that permitted the inclusion of the same participant more than once. All studies were single-centred conducted in academic centres from Belgium (Blockeel 2009), Brazil (Gomes 2007), Iran (Aflatoonian 2012; Ashrafi 2011), and Italy (Filicori 2005a).

Regarding the method used for fertilisation: one study used both IVF and ICSI, but did not report the proportion of IVF/ICSI in each arm (Aflatoonian 2012); four studies used only ICSI (Ashrafi 2011; Blockeel 2009; Filicori 2005a; Gomes 2007).

We obtained additional information by corresponding with contact authors of one study (Ashrafi 2011).

Participants

The studies allocated 166 women to the intervention groups (replacing FSH by low-dose hCG) and 185 to the control groups (FSH throughout COH - conventional COH). The sample size evaluated per study ranged from 51 to 122 participants (considering both intervention and control groups): Aflatoonian 2012 = 60/62 (intervention/control group); Ashrafi 2011 = 30/30; Blockeel 2009 = 35/35; Filicori 2005a = 24/24; Gomes 2007 = 17/34.

Regarding the characteristics of the included participants: one study included only women with PCOS (Ashrafi 2011); four studies included unselected women or women with predicted normal ovarian response (Aflatoonian 2012; Blockeel 2009; Filicori 2005a; Gomes 2007); no study included only women with predicted poor ovarian response.

Interventions
  • Five studies compared replacing FSH by 200 IU/day of urinary hCG versus FSH throughout the COH.

Regarding the daily dose of FSH: one study used 150 IU/day (Ashrafi 2011); one study used 150 to 225 IU/day (Aflatoonian 2012); one study used 200 IU/day (Blockeel 2009); one study used 200 to 225 IU/day (Gomes 2007); and one study used 225 to 300 IU/day (Filicori 2005a).

Regarding the criterion used to replace FSH by hCG: three studies used six follicles 12 mm or greater and oestradiol levels greater than 600 pg/mL (Aflatoonian 2012; Blockeel 2009; Filicori 2005a); one study used leading follicle 12 to 13 mm or greater (Gomes 2007); and one study used leading follicle 14 mm or greater (Ashrafi 2011).

Regarding the drug used for avoiding premature LH surge: four studies used GnRH agonists (Aflatoonian 2012; Ashrafi 2011; Filicori 2005a; Gomes 2007); and one study used GnRH antagonists (Blockeel 2009).

Outcomes
  • Two reported live birth.

  • Five reported OHSS.

  • Three reported ongoing pregnancy.

  • Five reported clinical pregnancy.

  • Four reported miscarriage.

  • Five reported total dose of FSH.

  • Five reported oocytes retrieved (three mature oocytes and two total oocytes).

Excluded studies

Fourteen studies were excluded from the review, for the following reasons:

  • five where FSH was not stopped after starting low-dose hCG.

  • three where FSH and low-dose hCG were started simultaneously.

  • two where low-dose hCG was used before starting FSH.

  • two were not RCTs.

  • two where the participants were submitted to intrauterine insemination.

Risk of bias in included studies

The authors' judgements about each risk of bias item for each included study are shown and summarised in Figure 2 and Figure 3.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Four studies were considered to be at low risk of selection bias related to sequence generation, as they used computer randomisation (Aflatoonian 2012; Ashrafi 2011; Blockeel 2009; Gomes 2007); one study was judged to be at unclear risk of bias, as authors only described that participants were "randomly assigned through choice of sealed envelopes" (Filicori 2005a).

Three studies were judged to be at unclear risk as no allocation concealment was reported (Aflatoonian 2012; Filicori 2005a; Gomes 2007); one study was considered to be at high risk of bias because the computer-generated list used for randomisation was concealed from the physician but not from the study nurse (Blockeel 2009); and one study was judged to be at high risk of bias because the allocation was not concealed (Ashrafi 2011).

Blinding

Five studies were considered to be at high risk of performance bias, since they did not blind participants and care providers (Aflatoonian 2012; Ashrafi 2011; Blockeel 2009; Filicori 2005a; Gomes 2007).

Four studies were considered to be at high risk of detection bias since they did not blind outcome assessors (Aflatoonian 2012; Blockeel 2009; Filicori 2005a; Gomes 2007); one study was considered to be at low risk of bias because authors reported that outcome assessors were blinded (Ashrafi 2011).

Incomplete outcome data

Two studies were considered to be at low risk of bias as all allocated women were analysed for the reported outcomes (Aflatoonian 2012; Gomes 2007); one study was considered to be at unclear risk of bias because authors did not report whether all participants were analysed (Filicori 2005a); two studies were considered to be high risk of attrition bias: one was considered at high risk for live birth because authors fail to follow up until birth six of nine ongoing pregnancies in the intervention group and seven of nine ongoing pregnancies in the control group (Ashrafi 2011); the other study was considered at high risk for both ongoing pregnancy and live birth because authors did not wait for the delivery of four ongoing pregnancies (two in each group) and did not report what happened to the one spontaneous clinical pregnancy that occurred in the intervention group (Blockeel 2009); the same two studies were judged to be at low risk of attrition bias for clinical pregnancy and oocytes retrieved because although some women (10-20%) were excluded from analyses due to cycle cancellation (Ashrafi 2011; Blockeel 2009), we assumed that clinical pregnancy did not occur and that no oocyte was retrieved from these participants.

Selective reporting

We considered all five studies to be at low risk of bias. Although four studies did not report live birth and one study did not report miscarriage (Ashrafi 2011; Filicori 2005a), all other evaluated outcomes were reported by the included studies. We considered that live birth and miscarriage were not reported because these outcomes need a longer follow-up to be assessed.

Other potential sources of bias

We did not find any other potential sources of bias in the included studies.

Effects of interventions

See: Summary of findings for the main comparison Low-dose hCG compared to FSH throughout the COH for assisted reproductive techniques

1 FSH replaced by low-dose hCG versus FSH throughout the COH

Primary outcomes
1.1 Live birth (effectiveness)

The CI was very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.56, 95% CI 0.75 to 3.25, P value = 0.24, 2 RCTs, 130 women, I² = 0%, very-low-quality evidence; Analysis 1.1; Figure 4). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 4.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.1 Live birth.

1.2 OHSS (adverse events)

The CI was very wide and findings were compatible with benefit, no effect or harm for the intervention (OR 0.30, 95% CI 0.06 to 1.59, P value = 0.16, 5 RCTs, 351 women, I² = 59%, very-low-quality evidence; Analysis 1.2; Figure 5). Although all five studies planned to report OHSS, only two studies observed cases of OHSS: in one study including only women with PCOS (Ashrafi 2011), and therefore a higher risk of OHSS, the authors observed no events in 30 women allocated to the intervention versus four events in 30 women allocated to the control group (risk difference -13%, 95% CI -27% to 0.0%). In the other study, women with PCOS were not allowed to be included (Gomes 2007), and the authors observed one event in 17 women allocated to the intervention versus one event in 34 women allocated to the control group (risk difference 3%, 95% CI -10% to 15%). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 5.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.2 OHSS.

Secondary outcomes
1.3 Ongoing pregnancy

The CI was wide and findings were compatible with no effect or appreciable benefit for the intervention (RR 1.14, 95% CI 0.81 to 1.60, P value = 0.45, 3 RCTs, 252 women, I² = 0%, low-quality evidence; Analysis 1.3; Figure 6). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 6.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.3 Ongoing pregnancy.

1.4 Clinical pregnancy

The CI was wide and findings were compatible with no effect or appreciable benefit for the intervention (RR 1.19, 95% CI 0.92 to 1.55, P value = 0.19, 5 RCTs, 351 women, I² = 0%, low-quality evidence; Analysis 1.4; Figure 7). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 7.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.4 Clinical pregnancy.

1.5 Miscarriage

The CI was very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.08, 95% CI 0.50 to 2.31, P value = 0.74, 3 RCTs, 127 women, I² = 0%, very-low-quality evidence; Analysis 1.5; Figure 8). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 8.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.5 Miscarriage.

1.6 Total dose of follicle-stimulating hormone

There was a significant benefit associated with the intervention (MD -638.63 IU, 95% CI -892.62 to -384.65 IU, P value < 0.00001, 5 RCTs, 333 women, I² = 88%, moderate-quality evidence; Analysis 1.6; Figure 9). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 9.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.6 Total dose of FSH (IU).

1.7 Oocytes retrieved

Findings were compatible with no relevant effect of the intervention (less than one oocyte) (MD -0.1 oocytes, 95% CI -1.0 to 0.8 oocytes, P value = 0.96, 5 RCTs, 351 women, I² = 0%, moderate-quality evidence; Analysis 1.7; Figure 10). Sensitivity analysis was not performed because all studies were considered to be at a high risk of bias.

Figure 10.

Forest plot of comparison: 1 FSH replaced by low-dose hCG versus FSH throughout the COH, outcome: 1.7 Oocytes retrieved.

Discussion

Summary of main results

We are very uncertain about the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase in women undergoing COH for assisted reproduction. There is low-quality evidence suggesting the non-inferiority of this intervention with respect to ongoing and clinical pregnancy (Summary of findings for the main comparison).There is moderate-quality evidence that this intervention reduces the total FSH consumption and is unlikely to materially affect the number of oocytes retrieved (Summary of findings for the main comparison).

We did not observe important heterogeneity across studies regarding the effect of the intervention on ongoing pregnancy, clinical pregnancy, miscarriage and number of oocytes retrieved. However, substantial heterogeneity was observed for the outcomes of OHSS and total consumption of FSH. Regarding OHSS, one study including only women with PCOS (and therefore a high risk of developing OHSS) observed a significant risk reduction (Ashrafi 2011), while the other four studies either did not observe cases of OHSS (Aflatoonian 2012; Blockeel 2009; Filicori 2005a), or the numbers of cases did not differ significantly between arms (Gomes 2007). Therefore, the pooled results for OHSS should be evaluated with caution: the heterogeneity across studies might not be considered acceptable as the effect of the intervention can be considerably different depending on the subject's characteristics, particularly the diagnosis of PCOS or the risk of developing OHSS, or both. Regarding the total consumption of FSH, all studies observed a significant reduction as expected: It is no surprise that stopping FSH a few days earlier will expend less FSH. We consider that observed heterogeneity is acceptable as regimens for COH are very different worldwide; however, it should be taken into consideration that the exact reduction in FSH consumption will depend on the daily dose of FSH and on the criterion used to replace FSH by low-dose hCG.

Overall completeness and applicability of evidence

The included studies did not answer the main questions of this review. The two included studies that reported live birth were at a very serious risk of attrition bias (Ashrafi 2011; Blockeel 2009), because these studies did not follow-up until birth a substantial proportion of the ongoing pregnancies. Regarding OHSS, a much larger sample of women is needed to have sufficient precision because this event is not common. The overall completeness and applicability of evidence were therefore reduced because of the small number of studies performed so far.

Quality of the evidence

The evidence of the effect of the studied intervention on live birth was considered to be of very low quality: it was downgraded because of serious imprecision (only 23 live births, resulting in very wide 95% CI), and because all included studies were judged to be at high risk of bias, particularly attrition bias.

The evidence of the effect of the studied intervention on OHSS was considered to be of very low quality: it was downgraded because of serious imprecision (only six cases of OHSS, resulting in very wide 95% CI). Additionally, there was an inconsistency between the only two studies that observed cases of OHSS (Ashrafi 2011; Gomes 2007), and all included studies were judged to be at high risk of bias.

The evidence of the effect of the studied intervention on ongoing pregnancy was considered to be of low quality: it was downgraded because of imprecision (only 87 ongoing pregnancies, resulting in wide 95% CI), and because all included studies were judged to be at high risk of bias.

The evidence of the effect of the studied intervention on clinical pregnancy was considered to be of low quality: it was downgraded because of imprecision (only 133 clinical pregnancies, resulting in wide 95% CI), and because all included studies were judged to be at high risk of bias.

The evidence of the effect of the studied intervention on miscarriage was considered to be of very low quality: it was downgraded because of serious imprecision (only 20 miscarriages, resulting in very wide 95% CI), and because all included studies were judged to be at high risk of bias.

The evidence of the effect of the studied intervention on total FSH consumption was considered to be of moderate quality: it was downgraded because all included studies were judged to be at high risk of bias.

The evidence of the effect of the studied intervention on the number of oocytes retrieved was considered to be of moderate quality: it was downgraded because all included studies were judged to be at high risk of bias.

Potential biases in the review process

We did not identify potential biases in the review process.

Agreements and disagreements with other studies or reviews

Two other reviews evaluated the effect of using of low-dose hCG (Checa 2012; Kosmas 2009). One included evidence from RCTs and non-RCTs (Kosmas 2009), and the other only from RCTs (Checa 2012). In contrast to our review, these two other reviews included studies that started low-dose hCG in the early follicular phase and studies that did not stop FSH when low-dose hCG was started. Despite these differences, the authors of these two other reviews also concluded that using low-dose hCG reduces the FSH consumption and provides similar results to conventional COH.

Authors' conclusions

Implications for practice

We are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH.

Implications for research

More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.

Acknowledgements

We acknowledge the important help provided by Helen Nagels - Managing Editor from the Cochrane Menstrual Disorders and Subfertility Group - and by Marian Showell - Trials Search Co-ordinator from the Cochrane Menstrual Disorders and Subfertility Group.

Data and analyses

Download statistical data

Comparison 1. FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Live birth2130Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.75, 3.25]
2 OHSS5351Peto Odds Ratio (Peto, Fixed, 95% CI)0.30 [0.06, 1.59]
3 Ongoing pregnancy3252Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.81, 1.60]
4 Clinical pregnancy5351Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.92, 1.55]
5 Miscarriage4127Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.50, 2.31]
6 Total dose of FSH (IU)5333Mean Difference (IV, Random, 95% CI)-638.63 [-892.62, -384.65]
7 Oocytes retrieved5351Mean Difference (IV, Fixed, 95% CI)-0.12 [1.00, 0.76]
Analysis 1.1.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 1 Live birth.

Analysis 1.2.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 2 OHSS.

Analysis 1.3.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 3 Ongoing pregnancy.

Analysis 1.4.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 4 Clinical pregnancy.

Analysis 1.5.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 5 Miscarriage.

Analysis 1.6.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 6 Total dose of FSH (IU).

Analysis 1.7.

Comparison 1 FSH replaced by low-dose hCG versus FSH throughout the controlled ovarian hyperstimulation, Outcome 7 Oocytes retrieved.

Comparison 2. Analysis grouped by participant characteristics
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 OHSS5 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
1.1 PCOS or predicted high response1 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Unselected or predicted normal response4 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Analysis grouped by participant characteristics, Outcome 1 OHSS.

Comparison 3. Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 OHSS5 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
1.1 GnRH agonist4 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 GnRH antagonist1 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Total dose of FSH5 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 GnRH agonist4272Mean Difference (IV, Fixed, 95% CI)-686.68 [-786.31, -587.05]
2.2 GnRH antagonist161Mean Difference (IV, Fixed, 95% CI)-344.0 [-479.52, -208.48]
Analysis 3.1.

Comparison 3 Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist), Outcome 1 OHSS.

Analysis 3.2.

Comparison 3 Analysis grouped by the drug used to prevent premature LH surge (GnRH agonist or antagonist), Outcome 2 Total dose of FSH.

Comparison 4. Analysis grouped by the daily dose of FSH (≤ 150 IU/day or > 150 IU/day)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 OHSS5 Peto Odds Ratio (Peto, Fixed, 95% CI)Totals not selected
1.1 FSH ≤ 150 IU/day1 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 FSH > 150 IU/day4 Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Analysis grouped by the daily dose of FSH (≤ 150 IU/day or > 150 IU/day), Outcome 1 OHSS.

Appendices

Appendix 1. CENTRAL search strategy

Database: EBM Reviews - Cochrane Central Register of Controlled Trials <July 2012>
Search strategy:
--------------------------------------------------------------------------------
1 exp chorionic gonadotropin/ or exp chorionic gonadotropin, beta subunit, human/ (587)
2 human chorionic gonadotropin.tw. (371)
3 HCG.tw. (981)
4 human chorionic gonadotrophin.tw. (233)
5 pregnyl.tw. (2)
6 or/1-5 (1293)
7 exp ovulation induction/ or superovulation/ (913)
8 superovulation.tw. (118)
9 (ovar$ adj2 stimulat$).tw. (731)
10 (ovulat$ adj2 induc$).tw. (570)
11 (ovar$ adj2 hyperstimulat$).tw. (546)
12 mid follicular.tw. (32)
13 late follicular.tw. (99)
14 mid cycle.tw. (48)
15 folliculogenesis.tw. (58)
16 (ovulat$ adj2 stimulat$).tw. (49)
17 (stimulat$ adj2 follic$).tw. (1163)
18 (oocyte$ adj2 matur$).tw. (264)
19 (ovar$ adj5 steroidogenesis).tw. (27)
20 or/7-19 (2941)
21 6 and 20 (757)
22 (low dos$ or micro dos$ or IU).tw. (18,660)
23 21 and 22 (294)

Search updated 5 February 2013: no new records retrieved.

Appendix 2. CINAHL search strategy

Search strategy for Cumulative Index to Nursing and Allied Health Literature (CINAHL), 27 July 2012:

((ovarian stimulation) or (ovarian hyperstimulation) or (COH) or (ovarian respons$) or ($ovulation$) or (follicular) or (stimulation techniques) or (oocyte development) or (oocyte maturation)) and (($hCG$) or (chorionic gonado$) or (Pregnyl) or (ovidrel)) and ((low dose) or (low-dose) or (micro-dose) or (dose))

9 records.

Search updated 5 February 2013: no further records retrieved.

Appendix 3. EMBASE search strategy

Database: EMBASE <1980 to 2012 week 29>
Search strategy:
--------------------------------------------------------------------------------
1 exp chorionic gonadotropin/ (35,388)
2 human chorionic gonadotropin.tw. (10,821)
3 HCG.tw. (22,343)
4 human chorionic gonadotrophin.tw. (3635)
5 pregnyl.tw. (1395)
6 or/1-5 (44,623)
7 exp ovulation induction/ (10,143)
8 superovulation.tw. (1668)
9 (ovar$ adj2 stimulat$).tw. (6026)
10 (ovulat$ adj2 induc$).tw. (7172)
11 (ovar$ adj2 hyperstimulat$).tw. (4637)
12 mid follicular.tw. (292)
13 late follicular.tw. (820)
14 mid cycle.tw. (591)
15 folliculogenesis.tw. (2187)
16 (ovulat$ adj2 stimulat$).tw. (659)
17 (stimulat$ adj2 follic$).tw. (15,832)
18 (oocyte$ adj2 matur$).tw. (9639)
19 (ovar$ adj5 steroidogenesis).tw. (1130)
20 or/7-19 (46,189)
21 6 and 20 (10,066)
22 Clinical Trial/ (868,729)
23 Randomized Controlled Trial/ (325,499)
24 exp randomization/ (58,867)
25 Single Blind Procedure/ (16,128)
26 Double Blind Procedure/ (109,817)
27 Crossover Procedure/ (34,455)
28 Placebo/ (20,1698)
29 Randomi?ed controlled trial$.tw. (76,732)
30 Rct.tw. (9623)
31 random allocation.tw. (1160)
32 randomly allocated.tw. (17,352)
33 allocated randomly.tw. (1815)
34 (allocated adj2 random).tw. (709)
35 Single blind$.tw. (12,327)
36 Double blind$.tw. (129,024)
37 ((treble or triple) adj blind$).tw. (273)
38 placebo$.tw. (176,710)
39 prospective study/ (208,729)
40 or/22-39 (1,260,300)
41 case study/ (16,255)
42 case report.tw. (227,203)
43 abstract report/ or letter/ (837,841)
44 or/41-43 (1,076,678)
45 40 not 44 (1,225,196)
46 21 and 45 (1862)
47 (2010$ or 2011$ or 2012$).em. (2,701,351)
48 46 and 47 (352)

Search updated 5 February 2013: 127 results retrieved for 2012 and 2013.

Appendix 4. LILACS search strategy

Search strategy for Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), 27 July 2012:

((ovarian stimulation) or (ovarian hyperstimulation) or (COH) or (ovarian respons$) or ($ovulation$) or (follicular) or (stimulation techniques) or (oocyte development) or (oocyte maturation)) and (($hCG$) or (chorionic gonado$) or (Pregnyl) or (ovidrel)) and ((low dose) or (low-dose) or (micro-dose) or (dose))

16 records

Appendix 5. Menstrual Disorders and Subfertility Group (MDSG) search strategy

Search strategy for MDSG database, 27 July 2012:

Keywords CONTAINS "controlled ovarian stimulation"or"controlled ovarian hyperstimulation"or "COH"or"ovarian hyperstimulation"or"ovarian response"or"ovarian responsiveness"or"ovarian stimulation"or"ovulation"or "ovulation induction"or "superovulation"or"superovulation induction"or"late follicular phase"or "follicular maturation"or "follicular growth"or"follicular phase"or "follicular development"or "follicular priming"or"follicular stimulation"or "Stimulation techniques"or "Oocyte Development"or"oocyte maturation" or Title CONTAINS"controlled ovarian stimulation"or"controlled ovarian hyperstimulation"or "COH" or"ovarian hyperstimulation"or"ovarian response"or"ovarian responsiveness"or"ovarian stimulation"or"ovulation"or "ovulation induction"or "superovulation"or"superovulation induction"or"late follicular phase"or "follicular maturation"or "follicular growth"or"follicular phase"or "follicular development"or "follicular priming"or"follicular stimulation"or "Stimulation techniques"or "Oocyte Development"

AND

Keywords CONTAINS "hCG"or "human chorionic gonadotrophin" or "human chorionic gonadotropin" or"chorionic gonadotrophins"or"Pregnyl" or "beta-hCG " or Title CONTAINS "hCG"or "human chorionic gonadotrophin" or "human chorionic gonadotropin" or"chorionic gonadotrophins"or"Pregnyl" or "beta-hCG "

AND

Keywords CONTAINS "low dose"or"low dose gonadotropin"or"low dose hCG"or "ultra low-dose"or"micro-dose HCG"or "dose" or Title CONTAINS "low dose"or"low dose gonadotropin"or"low dose hCG"or "ultra low-dose"or"micro-dose HCG"or "dose"

178 records; search updated 5 February 2013: 9 further records retrieved.

Appendix 6. MEDLINE search strategy

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to present>
Search strategy:
--------------------------------------------------------------------------------
1 exp chorionic gonadotropin/ or exp chorionic gonadotropin, beta subunit, human/ (28,159)
2 human chorionic gonadotropin.tw. (10,717)
3 HCG.tw. (19,967)
4 human chorionic gonadotrophin.tw. (3542)
5 pregnyl.tw. (41)
6 or/1-5 (36,654)
7 exp ovulation induction/ or superovulation/ (9604)
8 superovulation.tw. (1607)
9 (ovar$ adj2 stimulat$).tw. (4480)
10 (ovulat$ adj2 induc$).tw. (6361)
11 (ovar$ adj2 hyperstimulat$).tw. (3478)
12 mid follicular.tw. (260)
13 late follicular.tw. (777)
14 mid cycle.tw. (591)
15 folliculogenesis.tw. (1859)
16 (ovulat$ adj2 stimulat$).tw. (577)
17 (stimulat$ adj2 follic$).tw. (15,802)
18 (oocyte$ adj2 matur$).tw. (8600)
19 (ovar$ adj5 steroidogenesis).tw. (1062)
20 or/7-19 (41,856)
21 6 and 20 (7205)
22 (low dos$ or micro dos$ or IU).tw. (119,003)
23 21 and 22 (1469)
24 randomized controlled trial.pt. (333,009)
25 controlled clinical trial.pt. (84,725)
26 randomized.ab. (248,446)
27 placebo.tw. (142,097)
28 clinical trials as topic.sh. (161,434)
29 randomly.ab. (182,056)
30 trial.ti. (106,887)
31 (crossover or cross-over or cross over).tw. (54,199)
32 or/24-31 (816,408)
33 exp animals/ not humans.sh. (3,759,052)
34 32 not 33 (753,279)
35 23 and 34 (285)

Search updated 5 February 2013: 8 further records retrieved.

Appendix 7. PsycINFO search strategy

Database: PsycINFO <1806 to July week 3 2012>
Search strategy:
--------------------------------------------------------------------------------
1 human chorionic gonadotropin.tw. (65)
2 HCG.tw. (64)
3 human chorionic gonadotrophin.tw. (8)
4 pregnyl.tw. (1)
5 or/1-4 (95)
6 exp Reproductive Technology/ or exp Ovulation/ (1426)
7 (ovar$ adj2 stimulat$).tw. (52)
8 (ovulat$ adj2 induc$).tw. (73)
9 (ovar$ adj2 hyperstimulat$).tw. (9)
10 mid follicular.tw. (30)
11 late follicular.tw. (67)
12 mid cycle.tw. (49)
13 folliculogenesis.tw. (4)
14 (ovulat$ adj2 stimulat$).tw. (14)
15 (stimulat$ adj2 follic$).tw. (446)
16 (oocyte$ adj2 matur$).tw. (23)
17 (ovar$ adj5 steroidogenesis).tw. (8)
18 or/6-17 (2106)
19 5 and 18 (15)
20 random.tw. (35,688)
21 control.tw. (277,569)
22 double-blind.tw. (16,130)
23 clinical trials/ (6181)
24 placebo/ (3239)
25 exp Treatment/ (521,145)
26 or/20-25 (790,334)
27 19 and 26 (5)

Search updated 5 February 2013: one further record retrieved.

Appendix 8. Trials registers search strategy

Search strategy for ClinicalTrials.gov, 27 July 2012:

(hCG OR chorionic gonado$ OR pregnyl OR ovidrel) AND (low dose OR low-dose OR micro-dose OR dose)

234 records

Search strategy for Current Controlled Trials, 27 July 2012:

(hCG OR chorionic gonado$ OR pregnyl OR ovidrel) AND (low dose OR low-dose OR micro-dose OR dose)

45 records

Search strategy for WHO International Clinical Trials Registry Platform, 27 July 2012:

(hCG) AND (low dose)

WHO trials = 10 records

Appendix 9. Web of Knowledge search strategy

Search strategy for Web of Knowledge, 27 July 2012:

((ovarian stimulation) or (ovarian hyperstimulation) or (COH) or (ovarian respons*) or (*ovulation*) or (follicular) or (stimulation techniques) or (oocyte development) or (oocyte maturation)) and ((*hCG*) or (chorionic gonado*) or (Pregnyl) or (ovidrel)) and ((low dose) or (low-dose) or (micro-dose) or (dose))

113 records

Appendix 10. OpenGrey search strategy

Search strategy for OpenGrey, 27 July 2012:

((ovarian stimulation) or (ovarian hyperstimulation) or (COH) or (ovarian respons*) or (*ovulation*) or (follicular) or (stimulation techniques) or (oocyte development) or (oocyte maturation)) and ((*hCG*) or (chorionic gonado*) or (Pregnyl) or (ovidrel)) and ((low dose) or (low-dose) or (micro-dose) or (dose))

0 records

Appendix 11. DARE search strategy

Search strategy for Database of Abstracts of Reviews of Effects (DARE), 27 July 2012:

((ovarian stimulation) or (ovarian hyperstimulation) or (COH) or (ovarian respons$) or ($ovulation$) or (follicular) or (stimulation techniques) or (oocyte development) or (oocyte maturation)) and (($hCG$) or (chorionic gonado$) or (Pregnyl) or (ovidrel)) and ((low dose) or (low-dose) or (micro-dose) or (dose))

44 records

Contributions of authors

Drafting the protocol: Andrea DD Vieira, Jaqueline BP Figueiredo, Carolina O Nastri, Wellington P Martins

Development of search strategy: Carolina O Nastri, Wellington P Martins

Search for trials: Andrea DD Vieira, Jaqueline BP Figueiredo, Wellington P Martins

Obtaining copies of trials: Wellington P Martins

Selection of which trials to include: Andrea DD Vieira, Jaqueline BP Figueiredo, Wellington P Martins

Extraction of data from trials: Andrea DD Vieira, Wellington P Martins

Assessment of risk of bias in included studies: Carolina O Nastri, Wellington P Martins

Entry of data into RevMan: Carolina O Nastri, Wellington P Martins

Drafting the final review: Andrea DD Vieira, Carolina O Nastri, Wellington P Martins

Declarations of interest

The authors declare no conflicts of interest.

Sources of support

Internal sources

  • CAPES, Brazil.

    PhD scholarship

  • FMRP-USP, Brazil.

    Salary

  • CNPq, Brazil.

    Post-doctoral scholarship

External sources

  • No sources of support supplied

Differences between protocol and review

Ongoing pregnancy was added as an outcome of effectiveness because three included studies reported this outcome.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aflatoonian 2012

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Iran) between March 2009 and May 2011
Participants

Inclusion criteria: women aged < 38 years old; regular menstrual cycles (25–35 days); BMI < 30 kg/m²; normal uterus and ovaries in vaginal ultrasound; basal FSH < 10 IU/L; no severe endometriosis, no PCOS, no history of pelvic surgery; no azoospermia; and no more than 2 IVF or ICSI cycle failures

Sample size: 122 women were randomly allocated: 60 to the intervention, and 62 to the control group

Interventions

All participants received a single injection of 3.75 mg of depot triptorelin in mid-luteal phase of a spontaneous menstrual cycle and they menstruated before the initiation of gonadotropin treatment. Gonadotropin stimulation with IM of 150–225 IU hMG per day was started from day 2 of cycle in both groups. Ovarian response was monitored by serial vaginal sonographies and evaluation of serum E2 levels

Intervention: the administration of hMG was discontinued when at least 6 follicles ≥ 12 mm were observed and E2 levels were > 600 pg/mL; hMG was displaced by 200 IU/day of hCG until final follicular maturation. A daily dose of 200 IU of hCG was administrated by diluting one 500 IU ampoule of hCG to 1 mL using normal saline and injection of 0.4 mL of this solution

Control: women received similar doses of hMG based on individual responses until the end of stimulation

In both groups, the ovulation trigger was done by IM injection of 10,000 IU of urinary hCG when at least 3 follicles ≥ 18 mm were observed. Oocyte retrieval was performed 34–36 h after hCG injection and ICSI or conventional IVF was performed appropriately. Luteal phase hormonal support consisted of daily IM injection of 100 mg progesterone in oil

Outcomes

Primary: total doses of gonadotropin and clinical pregnancy rate

Secondary: chemical pregnancy, multiple pregnancy, miscarriage, fertilisation rate, implantation rate, number of oocytes retrieved, ongoing pregnancy

Notes

Did not report live birth

Clinical pregnancy was considered only in the presence of gestational sac with heart activity detected by ultrasonography

None of the 12 reported miscarriages were considered to happen in a clinical pregnancy and were considered as only chemical pregnancy only. In our review miscarriage was considered as the loss of a clinical pregnancy before 20 completed weeks of gestational age

The total number of retrieved oocytes (instead of only MII oocytes) was used for the analysis

This study was funded by Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Implantation rate: intervention (16.67%) vs. control (15.17%); not significant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA computer-generated list was used for randomisation
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Ashrafi 2011

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Iran) between January 2006 to December 2008
Participants

Inclusion criteria: women with diagnosis of PCOS (according to the Rotterdam criteria), with normal uterine cavity and patent tubes (evaluated by hysterosalpingogram, laparoscopy or hysteroscopy), with partner having a normal semen analysis (according to WHO criteria); no previous IVF or ICSI cycles; no use of gonadotropins for ovarian stimulation during the 3 previous months

Sample size: 90 women were randomly allocated: 30 to the intervention 1, 30 to the intervention 2 (not included in this review because FSH was not stopped when low-dose hCG was started), and the other 30 to the control group

Interventions

All the groups received SC GnRH agonist injection for 14 days, after which gonadotropin stimulation was initiated. The goal of ovarian stimulation in all 3 groups was to achieve an average of 2 ovarian follicles with a mean diameter of ≥ 17 mm on the day of hCG administration

Intervention 1: rFSH until the leading follicle reached 14 mm, when it was then discontinued and low-dose hCG (200 IU/day) was initiated

Intervention 2: rFSH until the leading follicle reached 14 mm, when rFSH reduced to 75 IU and low-dose hCG (100 IU/day) was initiated. This intervention was not included in our review, because FSH was not stopped when low-dose hCG was started

Control: received rFSH 150 IU daily. The dose and duration was adjusted by monitoring follicular development and E2 levels. The maximum FSH dose was 225 IU/day

After 2 or 3 follicles reached sizes ≥ 17 mm, 10,000 IU of hCG was administered and oocyte retrieval was performed 34-36 h later

OutcomesHormonal levels (FSH, LH, E2, progesterone and testosterone), stimulation duration days, total rFSH consumption, MII oocytes retrieved, immature oocytes, total # of oocytes retrieved, # of embryos formed, # of embryos transferred, # of embryos cryopreserved, # of medium growing follicles on hCG day, # of large growing follicles on hCG day, endometrial thickness on hCG day, fertilisation rate, implantation rate, clinical pregnancy rate, multiple pregnancy rates, severe OHSS
Notes

Only Intervention 1 was used for comparison with the control group

Authors provided additional information regarding live birth, ongoing pregnancy, miscarriage and allocation concealment by e-mail

Authors failed to follow-up until birth 6/9 ongoing pregnancies in the intervention group and 7/9 ongoing pregnancies in the control group

This study was assumed to be funded by the Royan Institute of Infertility and Reproductive Health, Iran

Implantation rate: intervention 14/53 (26.4%) vs. control: 24/75 (32.0%); not significant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised random number sequence
Allocation concealment (selection bias)High riskThe allocation was not concealed
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors including laboratory technicians and data analysts were blinded to group assignment
Incomplete outcome data (attrition bias)
All outcomes
High risk

Although some participants were excluded from analyses (6 in the intervention group and 3 in the control group), we were able to analyse dichotomous data respecting the ITT principle using the assumption that clinical pregnancy (and subsequent miscarriage or live birth) did not occur and that no oocyte was retrieved in the participants with cycle cancellation

However, the study was judged to be at high risk of attrition bias for live birth, because authors failed to follow-up until birth 6 of 9 ongoing pregnancies in the intervention group and 7 of 9 ongoing pregnancies in the control group

Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Blockeel 2009

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Belgium) between September 2007 and October 2008
Participants

Inclusion criteria: women aged < 36 years; first or second treatment cycle; no request of PGD; no azoospermic partner; no serum FSH level on day 3 of the menstrual cycle > 12 IU/L

Sample size: 70 women were randomly allocated: 35 to the intervention group, and 35 to the control group

Interventions

Intervention: the administration of rFSH was discontinued when at least 6 follicles of 12 mm were observed and E2 levels were higher than 600 ng/L. rFSH was then substituted by 200 IU hCG daily (Pregnyl, Organon), until final oocyte maturation

Control: standard antagonist protocol consisting of daily injections of rFSH, follitropin beta (Puregon, Organon) at a dose of 200 IU/day and maintained for 6 consecutive days. On day 7 of the cycle (day 6 of the stimulation), SC administration of the GnRH antagonist ganirelix (Orgalutran, Organon) was started at a daily dose of 0.25 mg. From day 7 of the cycle onwards, ovarian ultrasound scans to assess follicular growth and blood sampling for E2, progesterone, FSH, LH and hCG levels, were performed on a daily basis

Final oocyte maturation was induced by the administration of 10,000 IU hCG (Pregnyl), when at least 3 follicles of 17 mm diameter were visualised on ultrasonography. Luteal phase support consisted of 600 mg of vaginally administered micronised natural progesterone (Utrogestan, Besins International) per day.

A single embryo transfer policy was applied

Outcomes

Primary: ongoing pregnancy

Secondary: basal hormonal serum values; number of cumulus–oocyte-complexes, number of metaphase II and 2-pronuclei oocytes; duration of stimulation and total cumulative dose of rFSH used; fertilisation and implantation rates in each treatment group

Notes

Authors did not wait for the delivery of 4 ongoing pregnancies (2 for each group) and did not report what happened to 1 spontaneous clinical pregnancy that occurred in the intervention group

The spontaneous clinical pregnancy that occurred in the intervention group was included in our review

The study was assumed to be funded by Univesitair Ziekenhuis Brussel, Brussel

Implantation rate: intervention 16/27 (59.2%) vs. control 14/29 (48.3%); not significant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA computer-generated list was used for randomisation
Allocation concealment (selection bias)High riskThe list used for randomisation was concealed to the physician but not to the study nurse
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
All outcomes
High risk

Although some participants were excluded from analyses (6 in the intervention group and 3 in the control group), we were able to analyse dichotomous data respecting the ITT principle using the assumption that clinical pregnancy (and subsequent miscarriage or live birth) did not occur and that no oocyte was retrieved in the participants with cycle cancellation.

However, the study was judged to be at high risk of attrition bias for live birth and ongoing pregnancy, because authors did not wait for the delivery of 4 ongoing pregnancies (2 for each group) and did not report what happened to 1 spontaneous clinical pregnancy that occurred in the intervention group

Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Filicori 2005a

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Italy) between February and December 2002
Participants

Inclusion criteria: women aged 29–39 years; good general health; regular 26- to 32-day menstrual cycles; BMI of 20–25 kg/m²; pelvic ultrasound showing a uterus and ovaries of normal size and structure (no signs of PCOS); normal baseline biochemical and endocrine determinations; reproductive hormones within the normal range for the early/mid-follicular phase of the cycle; no history or signs of endometriosis; adequate number of motile sperms for ICSI could be obtained from the ejaculate; no more than 2 previous IVF or ICSI cycles; no history of poor response to gonadotropin administration; no hormonal therapy for a period of at least 3 months preceding the study

Sample size: 48 women were randomly allocated: 24 to the intervention group, and 24 to the control group

Interventions

Down-regulation with a single injection of 3.75 mg of depot Triptorelin (Decapeptyl 3.75, IPSEN), 14 days before initiating ovarian stimulation

Intervention: participants received the same amounts of recombinant FSH or hMG until at least 6 follicles > 12 mm in diameter and E2 levels 600 pg/mL were detected; then recombinant FSH/hMG were discontinued and replaced by the daily administration of low-dose hCG (Gonasi HP 250, AMSA). A daily dose of 200 IU of hCG was administered daily by diluting an ampoule of 250 IU of hCG with 1.0 mL of normal saline and then administering SC 0.8 mL of this solution

Control: recombinant FSH (Puregon/Organon, or Gonal-F/Serono) or hMG (Menogon, Ferring) at a dose of 225–300 IU/day based on individual response until the end of COH

Final maturation when 8 follicles > 18 mm and E2 levels 1500 pg/mL with 10,000 IU of hCG (Gonasi HP 5000, 2 ampoules). Oocyte retrieval was performed 35 h later. The luteal phase was supported with 50 mg/day of IM P in oil (Prontogest, AMSA)

Outcomes

Primary: amount of recombinant FSH/hMG

Secondary: FSH, E2, progesterone and testosterone; follicle number and size at ultrasound; number of oocytes retrieved; fertilisation, implantation rate and pregnancy rate

Notes

The study was assumed to be funded by University of Bologna, Italy

Implantation rate: intervention (12%) vs. control (11%); not significant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChoice of sealed envelopes
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAuthors did not report whether participants were excluded or did not undergo oocyte retrieval
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Gomes 2007

  1. a

    BMI: body mass index; COH: controlled ovarian hyperstimulation; E2: oestradiol; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; ICSI: intracytoplasmic sperm injection; IM: intramuscular; ITT: intention to treat; IU: international unit; IVF: in vitro fertilisation; LH: luteinising hormone; PCOS: polycystic ovary syndrome; PGD: preimplantation genetic diagnosis; rFSH: recombinant follicle-stimulating hormone; SC: subcutaneous; WHO: World Health Organization.

MethodsRandomised clinical trial, single-centre, conducted in an academic setting (Brazil)
Participants

Inclusion criteria: women aged 25–35 years; good general health; regular menstrual cycles; BMI of 20–25 kg/m²; FSH ≤ 10 IU/mL; infertility due to tubal factor, moderate or severe male factor, or no apparent cause; no PCOS, no endometriosis; no uterine myomas; no use of injectable hormonal contraceptive up to 6 months before stimulation; no history of previous poor ovarian response to controlled ovarian stimulation; no concomitant uterine alterations; no absence of 1 ovary

Sample size: 51 women were randomly allocated: 17 to the intervention group, and 34 to other 2 groups of 17 participants each. These 2 groups were merged as 1 control group since the only difference between them was regarding the type of FSH (urinary or recombinant)

Interventions

The inhibition of the natural cycle with a low-dose oral contraceptive administered on the first the previous menstruation cycle and discontinued 5 days before the beginning of stimulation. A GnRH agonist, leuprolide acetate (Lupron, Abbott), 0.5 mg/day, was also used for inhibition starting 10 days before the beginning of induction and continued until the day preceding the pre-ovulatory injection of hCG. All the groups received 200 IU SC of rFSH (Puregon, Organon) daily on until the dominant follicles reached 12–13 mm in mean diameter

Intervention: daily IM doses of 200 IU hCG (Profasi, Serono). For hCG administration, 2000 IU were diluted in 10.0 mL 0.9% physiological
saline and 1.0 mL of the solution was injected

Control: participants received either daily IM injections of 225 IU hMG (Menogon; Ferring Gmbh) or daily SC 200 IU rFSH (Puregon, Organon)

Final maturation with 10,000 IU hCG IM (Choragon, Ferring Gmbh) when the presence of follicles 18–19 mm in diameter was detected. Oocyte retrieval was performed 36 h after pre-ovulatory hCG injection. The luteal phase was supplemented with 90 mg progesterone gel (8% Crinone, Fleet)

Outcomes

Primary: amount of gonadotropins needed to achieve comparable levels of folliculogenesis

Secondary: FSH, E2, prostaglandin and testosterone, number of oocytes retrieved, fertilisation, implantation rate, and pregnancy rate and total cost of treatment per embryo transferred

Notes

Did not report live birth

The hMG and rFSH groups were combined into the control group

The total number of retrieved oocytes (instead of only MII oocytes) was used for the analysis

The study was assumed to be funded by University of Sao Paulo, Brazil

Implantation rate: intervention (27.3%) vs. control (16.7%); not significant

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned through computer randomisation
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up
Selective reporting (reporting bias)Low riskNot suspected
Other biasLow riskNone

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; RCT: randomised controlled trial.

Beretsos 2009Low-dose hCG was used before starting FSH
Berkkanoglu 2007FSH and low-dose hCG were started simultaneously
Check 2009FSH was not stopped after starting low-dose hCG
Dehghani-Firouzabady 2006Not IVF/ICSI (only intrauterine insemination)
Drakakis 2009FSH and low-dose hCG were started simultaneously
Filicori 1999FSH and low-dose hCG were started simultaneously
Filicori 2002Not IVF/ICSI (only intrauterine insemination)
Filicori 2005bFSH was not stopped after starting low-dose hCG
Koichi 2006FSH was not stopped after starting low-dose hCG
Lossl 2008Low-dose hCG was used before starting FSH
Mendes 2005Not RCT: not randomised. Additionally, the low-dose hCG group was submitted to another intervention (bromocriptine 2.5 mg) not applied to the control group
Serafini 2006FSH was not stopped after starting low-dose hCG
Thuesen 2012FSH was not stopped after starting low-dose hCG
Van Horne 2007Not RCT: observational retrospective study

Ancillary