Infertility
Conditions
Keywords
Reproductive Techniques, Embryo Implantation, Endometrium, Ultrasonography
Brief summary
The objective of this study is to evaluate the effect of endometrial injury performed prior ovulation induction for assisted reproductive techniques main outcomes.
Interventions
PROCEDUREEndometrial injury
Evaluate the position and size of the uterus by transabdominal ultrasonography, with the bladder comfortably full. Identify the cervix with a disposable speculum. Open one sealed opaque envelope for allocation. Endometrial injury: * Slide the Pipelle de Cornier® (Laboratoires Prodimed, Neully-En-Thelle, France) gently through the cervix up to the uterine fundus. Transbadominal ultrasound might be used to confirm position. * Draw back the piston to the end of the biopsy cannula until it locks creating a negative pressure. * Sweep the uterine fundus slowly several times up to the internal orifice of the cervix, using regular to-and-fro movements while rotating the sampler to include the whole uterine cavity in the specimen, for 30 seconds or until participant ask for stopping.
PROCEDUREControl group
The investigator will dry the cervix with gauze and forceps for for 30 seconds or until participant ask for stopping.
Sponsors
Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
University of Sao Paulo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 38 Years
Healthy volunteers
No
Inclusion criteria
* Women who will start assisted reproductive techniques with planned fresh embryo transfer. * Age between 18 and 38 years. * Written informed consent.
Exclusion criteria
* None
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live Birth | 1 year | The complete expulsion or extraction from its mother of a product of fertilization, irrespective of the duration of the pregnancy, which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation, or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. Note: All allocated women will be used as denominator when assessing live birth rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ongoing Pregnancy | 6 months | At least one fetus with heart beat after 12 weeks of gestational age. Note: All allocated women will be considered when assessing ongoing pregnancy rate. |
| Miscarriage | 9 months | Loss of a clinical pregnancy before 20 completed weeks of gestational age (18 weeks after fertilization). Note: All allocated women will be considered when assessing miscarriage rate. |
| Implantation Rate | 3 months | The number of gestational sacs observed divided by the number of embryos transferred. |
| Clinical Pregnancy | 3 months | Pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. Multiple gestational sacs are counted as one clinical pregnancy. Note: All allocated women will be considered when assessing clinical pregnancy rate. |
| Endometrial Volume | 1 month | The total volume of endometrial tissue assessed by three-dimensional ultrasonography. This outcome will be assessed when at least one follicle ≥ 17mm is observed. |
| Three-dimensional Doppler Indices From Endometrium (VFI) | 1 month | Vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) assessed from endometrium using three-dimensional Power Doppler ultrasonography. This outcome will be assessed when at least one follicle ≥ 17mm is observed. Only VFI was reported as it is a combination of VI and FI (VFI = VI\*FI/100), and currently there are several concerns about the validity of these indices. Such indices have no scale. |
| Procedure Related Pain | Immediately after procedure | Pain will be assessed using a Visual Analogue Scale (VAS). We will use a 10 cm length horizontal line, anchored by word descriptors at each end: No Pain = 0 cm and Very Severe Pain = 10 cm. This outcome will be assessed in both groups, just after endometrial injury or sham procedure. |
| Endometrial Thickness | 1 month | The maximum distance perpendicular to the inter-endometrial interface from the endometrium-myometrium interface of the anterior to the posterior wall of the uterus assessed in the sagittal plane. This outcome will be assessed when at least one follicle ≥ 17mm is observed. |
Countries
Brazil
Participant flow
Recruitment details
The recruitment occurred from July 2010 to March 2012 in the fertility clinic of an university hospital.
Pre-assignment details
All women that fulfilled eligibility criteria were invited to participate. Those who agreed were included. No women was excluded.
Participants by arm
| Arm | Count |
|---|---|
| Endometrial Injury Group Endometrial biopsy was performed once with a pipelle de Cornier® in the month before initiating controlled ovarian stimulation. The pipelle was introduced gently through the cervix up to the uterine fundus. The piston was then drawn back to the end of the biopsy cannula until it self-locks and creates a negative pressure. Aiming to wound the entire endometrium, the examiner applied regular back-and-forth movements while rotating the sampler covering the whole uterine cavity. This procedure was continued until fragments of uterine mucosa appeared within the sheath, which generally took 30 seconds. | 79 |
| Control Group Introduction of the speculum and wiping of the cervix with gaze for 30 seconds. | 79 |
| Total | 158 |
Baseline characteristics
| Characteristic | Control Group | Endometrial Injury Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 79 Participants | 79 Participants | 158 Participants |
| Age, Continuous | 32.1 years STANDARD_DEVIATION 3.1 | 32.4 years STANDARD_DEVIATION 3.2 | 32.2 years STANDARD_DEVIATION 3.2 |
| Region of Enrollment Brazil | 79 participants | 79 participants | 158 participants |
| Sex: Female, Male Female | 79 Participants | 79 Participants | 158 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 79 | 0 / 79 |
| serious Total, serious adverse events | 0 / 79 | 0 / 79 |
Outcome results
Primary
Live Birth
The complete expulsion or extraction from its mother of a product of fertilization, irrespective of the duration of the pregnancy, which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation, or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. Note: All allocated women will be used as denominator when assessing live birth rate.
Time frame: 1 year
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Injury Group | Live Birth | 33 participants |
| Control Group | Live Birth | 18 participants |
Secondary
Clinical Pregnancy
Pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. Multiple gestational sacs are counted as one clinical pregnancy. Note: All allocated women will be considered when assessing clinical pregnancy rate.
Time frame: 3 months
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Injury Group | Clinical Pregnancy | 39 participants |
| Control Group | Clinical Pregnancy | 23 participants |
Secondary
Endometrial Thickness
The maximum distance perpendicular to the inter-endometrial interface from the endometrium-myometrium interface of the anterior to the posterior wall of the uterus assessed in the sagittal plane. This outcome will be assessed when at least one follicle ≥ 17mm is observed.
Time frame: 1 month
Population: Women that achieved at least one follicle \>17mm during ovarian stimulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Injury Group | Endometrial Thickness | 10.12 mm | Standard Deviation 1.55 |
| Control Group | Endometrial Thickness | 9.98 mm | Standard Deviation 1.62 |
Secondary
Endometrial Volume
The total volume of endometrial tissue assessed by three-dimensional ultrasonography. This outcome will be assessed when at least one follicle ≥ 17mm is observed.
Time frame: 1 month
Population: Women that achieved at least one follicle \>17mm during ovarian stimulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Injury Group | Endometrial Volume | 6.18 cm³ | Standard Deviation 1.63 |
| Control Group | Endometrial Volume | 6.01 cm³ | Standard Deviation 1.48 |
Secondary
Implantation Rate
The number of gestational sacs observed divided by the number of embryos transferred.
Time frame: 3 months
Secondary
Miscarriage
Loss of a clinical pregnancy before 20 completed weeks of gestational age (18 weeks after fertilization). Note: All allocated women will be considered when assessing miscarriage rate.
Time frame: 9 months
Population: The number of clinical pregnancies was used as denominator, since miscarriage is a harm that can only happen in pregnant women.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Injury Group | Miscarriage | 6 Clinical pregnancies |
| Control Group | Miscarriage | 5 Clinical pregnancies |
Secondary
Ongoing Pregnancy
At least one fetus with heart beat after 12 weeks of gestational age. Note: All allocated women will be considered when assessing ongoing pregnancy rate.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Endometrial Injury Group | Ongoing Pregnancy | 33 participants |
| Control Group | Ongoing Pregnancy | 18 participants |
Secondary
Procedure Related Pain
Pain will be assessed using a Visual Analogue Scale (VAS). We will use a 10 cm length horizontal line, anchored by word descriptors at each end: No Pain = 0 cm and Very Severe Pain = 10 cm. This outcome will be assessed in both groups, just after endometrial injury or sham procedure.
Time frame: Immediately after procedure
Population: All women enrolled.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Injury Group | Procedure Related Pain | 6.42 cm | Standard Deviation 2.35 |
| Control Group | Procedure Related Pain | 1.82 cm | Standard Deviation 1.52 |
Secondary
Three-dimensional Doppler Indices From Endometrium (VFI)
Vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) assessed from endometrium using three-dimensional Power Doppler ultrasonography. This outcome will be assessed when at least one follicle ≥ 17mm is observed. Only VFI was reported as it is a combination of VI and FI (VFI = VI\*FI/100), and currently there are several concerns about the validity of these indices. Such indices have no scale.
Time frame: 1 month
Population: Women that achieved at least one follicle \>17mm during ovarian stimulation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Endometrial Injury Group | Three-dimensional Doppler Indices From Endometrium (VFI) | 0.97 index | Standard Deviation 0.51 |
| Control Group | Three-dimensional Doppler Indices From Endometrium (VFI) | 0.76 index | Standard Deviation 0.4 |