AHA/ASA Scientific Statement Guidelines for the Early Management of Patients With Ischemic Stroke 2005 Guidelines Update A Scientific Statement From the Stroke Council of the American Heart Association/American Stroke Association
Harold Adams, MD, FAHA; Robert Adams, MS, MD, FAHA;
Gregory Del Zoppo, MD, MS, FAHA; Larry B. Goldstein, MD, FAHA
This article serves as an update of "Guidelines for the demonstrated relevant abnormalities in 21% of cases.3
Early Management of Patients With Ischemic Stroke,"
Changes in Ϸ44% of cases are detected by T2-weighted or
published in Stroke in 2003 (http://stroke.ahajournals.org/cgi/
fluid attenuation inversion recovery MRI studies.
content/full/34/4/1056). This update is intended to reflect
A scientific statement authored by a panel of the American
advances in the field since the publication of the full
Heart Association focused on perfusion imaging in the setting
guidelines. See Tables 1 and 2, reprinted in this article from
of acute ischemic stroke was published simultaneously with
the 2003 document, for explanations of grade (strength of
the original 2003 ischemic stroke guidelines.4 Information
about the advantages and disadvantages of each imagingtechnique is included in the statement. The panel concluded
that more comparison testing of the different techniques is
CT remains the most widely used neuroimaging technique for
needed to determine their relative abilities to differentiate
the evaluation of patients with suspected acute ischemic
tissues having normal perfusion and reversible or irreversible
stroke. Quantitative CT-based scoring systems (eg, the Al-
ischemic injury. Clinical trials must determine whether per-
berta Stroke Program Early CT Score [ASPECTS]) are useful
fusion data help forecast outcomes after stroke and the ability
for identifying patients who are unlikely to recover fully
to triage patients to specific interventions.
despite thrombolytic therapy.1 Substantial agreement between
The 2003 ischemic stroke guidelines indicated that addi-
the ASPECTS rating performed in real time and the score
tional research was needed to determine the utility of MRI as
obtained later by an expert can be achieved when used by an
a substitute for CT among patients with suspected acute
experienced reader, but correlations are not perfect (weighted
stroke because detection of acute intracerebral hemorrhage
0.69, 95% CI 0.59 to 0.79).2 This scoring system has not
via MRI had not been fully validated. A study addressing this
been assessed in general clinical practice and is limited to use
need has been reported. In comparison with CT, MRI
in patients with infarctions suspected to be in the distribution
detected intracranial bleeding with 100% sensitivity and
of the middle cerebral artery. In addition, advances in CT
100% accuracy, as identified by 3 experienced readers. Three
technology, including the development of CT angiography
medical students also interpreted the studies with a sensitivity
and perfusion studies, may affect future recommendations
of 95%. Additional studies have produced similar results.5,6
about the use of CT in the evaluation of patients with
These results suggest that MRI may replace CT in the initial
screening for hemorrhage among patients with suspected
MRI techniques also are used widely in the assessment of
stroke. Additional experience for detection in the acute
patients with suspected stroke or transient ischemic attack
setting in real time and outside specialized academic centers
(TIA). For example, a retrospective analysis of patients
in the United States is needed. Besides its utility in the
having diffusion-weighted MRI studies within 3 days of TIA
diagnosis of acute brain ischemia, MRI also may help in
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside
relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are requiredto complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 19, 2005. A single reprint
is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX75231-4596. Ask for reprint No. 71-0317. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000or more copies, call 410-528-4121, fax 410-528-4264, or e-mail email@example.com. To make photocopies for personal or educational use, call theCopyright Clearance Center, 978-750-8400.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development,
visit http://www.americanheart.org/presenter.jhtml?identifierϭ3023366. (Stroke. 2005;36:916-921.) 2005 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000163257.66207.2d 916 Adams et al Guidelines for the Early Management of Patients With Ischemic Stroke 917 Levels of Evidence
that MRI is superior to CT for selecting patients who could betreated with intravenous recombinant tissue plasminogen activa-
tor (rtPA). The use of MRI outside the setting of clinical research
studies should not delay treatment of a patient who is otherwise
false-positive and low false-negative errors
eligible for treatment with intravenous rtPA (grade B, no change
false-positive or high false-negative errors
Treatment of Arterial Hypertension
The treatment of arterial hypertension immediately after
stroke is problematic, as stated in the 2003 guidelines. Since
then, a placebo-controlled phase II safety trial tested the
utility of candesartan administered from day 1 to hyperten-
sive patients with acute ischemic stroke.10 At 12 months,
patients treated with candesartan had improved survival and
few subsequent vascular events. No differences in blood
Supported by level III, IV, or V evidence
pressure values were noted, however, and the effects on theoutcome of the stroke are not described. This preliminary
identifying patients with previous microhemorrhages that
observation must be confirmed by a larger clinical trial.
could be associated with an increased risk of bleedingsecondary to thrombolysis.7,8
Pharmacological (Intravenous or
MRI with susceptibility-weighted imaging may be useful
in detecting areas of hemorrhage after intraarterial
Symptomatic hemorrhagic transformation of the infarction
thrombolysis in situations in which CT findings could be
remains the primary concern with the administration of
equivocal because of residual contrast staining.9 The impor-
intravenous rtPA in the treatment of acute ischemic stroke.11
tance of this finding needs clarification. Prospective studies
A recent pooled analysis of several trials of rtPA confirms
are needed to determine whether the findings of
that symptomatic hemorrhagic transformation is the primary
susceptibility-weighted MRI affect either prognosis or
complication of acute treatment with rtPA.12 A meta-analysis
of the postmarketing open-label studies demonstrates that the
Brain imaging is required to guide the selection of acute
risk of hemorrhage is Ϸ5.2%.13 A subsequent report by the
interventions to treat patients with stroke (grade A, no change
same group demonstrated a marked decline in major bleeding
from 2003). For most cases and at most institutions, CT remains
complications when the guidelines were followed.14 Schmull-
the most important brain imaging test; however, new studies
ing et al15 found that previous use of aspirin does not increase
suggest that MRI also may be used to detect acute intracerebral
the risk of symptomatic intracranial bleeding after the admin-
hemorrhage and that it could be an alternative to CT. Additional
istration of rtPA. The studies show that rtPA can be given
studies are under way. There is general agreement that perfusion
with an acceptable margin of safety in a community setting
and diffusion-weighted MRI may be helpful in diagnosing and
when the guidelines for selection and treatment of patients are
treating patients with acute stroke under some circumstances, but
logistical issues, including the availability of the equipment and
Hill et al16 reported orolingual angioedema in 9 of 176
the presence of physicians with expertise in interpreting the tests,
patients treated with intravenous rtPA. In most cases, the
limit the use of MRI. At present, no data are available to show
findings were mild, transient, and contralateral to the in-
Quality of Evidence Ratings for Radiological Diagnostic Tests
Evidence provided by a prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for casedefinition, where test is applied in a blinded evaluation, and enabling the assessment of the appropriate tests of diagnostic accuracy.
Evidence provided by a prospective study of a narrow spectrum of persons with a suspected condition, or a well-designed retrospectivestudy of a broad spectrum of persons with an established condition (by the "gold standard") is compared to a broad spectrum of controls,where test is applied evaluation and enabling the assessment of appropriate tests of diagnostic accuracy.
Evidence supplied by a retrospective study where either persons with an established condition or controls are of a narrow spectrum, andwhere test is applied in a blinded evaluation.
Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series(without controls).
Established as useful/predictive or not useful/predictive for the given condition in the specified population.
Probably useful/predictive or not useful/predictive for the given condition in the specified population.
Possibly useful/predictive or not useful/predictive for the given condition in the specified population.
Data are inadequate or conflicting. Given current knowledge, the test/predictor is unproven. 918 Stroke April 2005
volved cerebral hemisphere. They noted that the likelihood
tional data are needed to support a recommendation for
was increased among patients who were taking angiotensin-
converting enzyme inhibitors and among those who had
Using transcranial Doppler ultrasonography, Alexandrov
evidence of ischemia in the frontal cortex and insula on CT.
and Grotta32 found that approximately one third of patients
Other cases of more severe edema of the throat and mouth
develop reocclusion of the artery after intravenous
also have been described.17-19 Although the previous use of
thrombolysis. Patients with partial recanalization were the
angiotensin-converting enzyme inhibitors is not a contraindi-
most likely to experience reocclusion and poorer neurological
cation for the administration of rtPA, physicians should be
outcomes. These results are stimulating research on adjunctive
aware of this potential complication. Presumably, medica-
antithrombotic therapies that help maintain arterial patency.
tions used to treat angioedema would be indicated to treat a
Among the interventions are anticoagulants and rapidly acting
parenterally administered antiplatelet agents.15,33-36 Although
A recent report offered a pooled analysis of data from
preliminary results are promising, experience is limited. Addi-
several clinical trials of rtPA.12 The data from each of these
tional data are needed before changing the current recommen-
trials have been reported independently. Although the trials
dations to withhold adjunctive antithrombotic therapy for the
used different definitions of outcomes, the combined analysis
first 24 hours after administration of rtPA.
applied definitions used in the National Institute of Neuro-
Because of the current time requirements for the adminis-
logical Disorders and Stroke trials (eg, no or minimal disabil-
tration of rtPA, all aspects of the healthcare system must
ity at 3 months as measured by modified Rankin Scale, the
respond with a sense of urgency. Community-wide stroke
Barthel Index, and the National Institutes of Health [NIH]
programs are increasing the number of patients that can be
Stroke Scale) plus a global statistical test. The lower 95%
treated.37-39 Delays within the hospital emergency department
confidence limit for the adjusted odds ratio for a favorable
also need to be addressed.39 Telemedicine and emergency air
outcome crossed unity at 4.5 hours from symptom onset. This
transportation are among the ways to speed the treatment of
finding suggests that some patients may benefit from treat-
ment beyond the current 3-hour window; however, additional
Novel thrombolytic agents such as desmotoplase, rete-
information is necessary to move the maximal time window
plase, and tenecteplase are being evaluated, but prospective
to 4.5 hours in the guidelines. Ongoing studies are evaluating
data comparing these drugs with intravenous rtPA are few.
the potential utility of rtPA given Ͼ3 hours after the onset of
Although experience is limited, thrombolytic agents have
been given successfully to children with acute ischemic
Hsia et al20 found that the subtypes of ischemic stroke do
not influence responses to treatment with rtPA. This findingimplies that the determination of the subtype of stroke (eg,
cardioembolism, large artery atherosclerosis, or small artery
The recommendation for the intravenous administration of
occlusion) is not a prerequisite for the administration of rtPA.
rtPA within 3 hours of onset of stroke in carefully selected
Intraarterial administration of thrombolytic agents has
patients should not be changed (grade A, no change from
considerable appeal.21 A review of the available data shows
2003). The evidence is strong that all delays in treating
that intraarterial thrombolysis is associated with a reduction
patients should be avoided (grade A, new recommendation).
in mortality and an improvement in favorable outcomes after
Although intraarterial thrombolysis alone or in combination
a stroke, but it is also associated with an increased risk of
with intravenous thrombolysis holds great promise, the use of
hemorrhagic complications.22 Additional studies have been
these approaches is preferable in the setting of randomized
published since the development of the 2003 guidelines. In
clinical trials. A correction is needed in Table 7 of the 2003
general, the results are similar to those published previous-
Guidelines. Patients with an INR level of 1.7 or below can be
ly.23-26 Studies testing the utility of intraarterial thrombolysis
are ongoing. Recommendations for the design and organiza-tion of such trials were published recently.27 At present, no
evidence is available to show that intraarterial thrombolysis is
Current data do not provide evidence in support of the
superior to intravenous treatment. Therapy should not be
efficacy of early anticoagulation in improving outcomes after
withheld from patients who are eligible for treatment with
acute ischemic stroke.43 The recommendations of the 2003
intravenous thrombolysis so that medications can be admin-
guidelines are in agreement with other statements indicating
istered intraarterially, except in the setting of a comparative
that most stroke patients do not need emergency administra-
tion of anticoagulants.44-46 Despite the lack of supporting
The combination of administering intravenous therapy and
data, anticoagulants are still given frequently.47
then intraarterial therapy is being tested. This strategy could
A preliminary clinical study of argatroban has been com-
allow for early treatment of stroke with intravenous medica-
pleted and the agent was deemed to be safe.48 Burak et al49
tion while the resources to deliver intraarterial therapy are
administered enoxaparin to 8 children with stroke and con-
organized.21,28,29 Additional reports that have become avail-
cluded that the low-molecular-weight heparin was a safe and
able since the 2003 guidelines reflect mixed results.30,31
effective alternative to heparin for children. Anticoagulants
Clinical trials testing the utility of the combination of intra-
also are being explored as an adjunct to thrombolytic thera-
venous and intraarterial therapy are in progress, and addi-
py.15 Although the preponderance of past acute anticoagula-
Adams et al Guidelines for the Early Management of Patients With Ischemic Stroke 919 Characteristics of Patients With Ischemic Stroke
form and are apparently promising but have not been
Who Could Be Treated With rtPA
Diagnosis of ischemic stroke causing measurable neurological deficit
The neurological signs should not be clearing spontaneously
Recommendations Although the new data do not change the recommendation
The neurological signs should not be minor and isolated
that most patients should receive aspirin within 48 hours of
Caution should be exercised in treating a patient with major deficits
stroke, the data also support the conclusion that the effects of
The symptoms of stroke should not be suggestive of subarachnoid
aspirin are modest (grade A, no change from 2003). Aspirin
should not be considered as an alternative to intravenous
Onset of symptoms Ͻ3 hours before beginning treatment
thrombolysis or acute therapies aimed at improving outcomes
No head trauma or prior stroke in previous 3 months
after stroke. Additional research on abciximab or other
No myocardial infarction in the previous 3 months
rapidly acting antiplatelet agents is needed before any rec-
No gastrointestinal or urinary tract hemorrhage in previous 21 days
ommendation about their use can be made.
No arterial puncture at a noncompressible site in the previous 7 days
Volume Expansion and
No history of previous intracranial hemorrhage
Blood pressure not elevated (systolic Ͻ185 mm Hg and diastolic
Medical measures to improve cerebral blood flow are being
evaluated. In addition to its ability to improve flow to the
No evidence of active bleeding or acute trauma (fracture) on examination
ischemic region, albumin may have neuroprotective effects
Not taking an oral anticoagulant or if anticoagulant being taken, INR Յ1.7
and is being tested. In a pilot study, Hillis et al52 found that
If receiving heparin in previous 48 hours, aPTT must be in normal range
drug-induced hypertension can improve blood flow and
lessen the neurological consequences of stroke. This regimenhas been used to treat patients with vasospasm after subarach-
Blood glucose concentration Ն50 mg/dL (2.7 mmol/L)
noid hemorrhage. Although drug-induced hypertension holds
No seizure with postictal residual neurological impairments
promise, this therapy may be associated with an increased
CT does not show a multilobar infarction (hypodensity Ͼ1⁄3 cerebral
risk of brain edema, hypertensive encephalopathy, or hemor-
rhagic transformation of the infarction. Additional
The patient or family understand the potential risks and benefits from
vasopressor-related complications may include cardiac ische-
mia or arrhythmias. The intervention also may require admis-sion to an intensive care unit and close monitoring. Further
tion trials has failed to show a benefit, newer clinical trials
testing of drug-induced hypertension is in progress.
testing heparin and other anticoagulants continue. Recommendations Recommendations
At present, drug-induced hypertension cannot be recom-
No data are available to support changing the recommenda-
mended for the treatment of most patients with ischemic
tions about the use of anticoagulants in the urgent treatment
stroke (grade A, new recommendation).
of patients with acute ischemic stroke. Surgical and Endovascular Procedures Antiplatelet Aggregating Agents
Gay et al53 successfully performed carotid endarterectomy
Since the publication of the 2003 guidelines, Roden-Jullig et
in 21 patients with acute ischemic symptoms. In another
al50 have reported the results of a placebo-controlled trial of
study of 67 patients, emergency carotid endarterectomy
aspirin (325 mg/day) for the treatment of patients with stroke.
achieved recanalization in all but 5 cases.54 The patients
The trial enrolled 441 patients (220 took aspirin) within 48
who were selected for surgery had normal preoperative
hours of the onset of stroke. Patients were treated for 5 days;
flow in the middle cerebral artery. The aim was to avoid
no significant reduction in the rate of neurological worsening
performing surgery on the internal carotid artery if an
was noted. No differences in outcomes were noted at 3
ipsilateral embolic occlusion of the middle cerebral artery
months. This study was underpowered to detect the mild
had already occurred. Another study found that the pres-
beneficial effects of aspirin identified in earlier megatrials. A
ence of a diffusion/perfusion mismatch could be used to
small study found that the combination of aspirin and a
low-molecular-weight heparin did not improve outcomes
Endovascular and adjunctive mechanical thrombolytic
methods include lasers, intraarterial suction devices,
Other rapidly acting antiplatelet agents are being evaluated
snares, angioplasty, and clot-retrieval devices.56,57 In some
for their usefulness in treating patients with stroke. These
cases, these devices have been used in conjunction with
agents are being administered as a monotherapy or in com-
pharmacological thrombolysis.58 In addition, therapeutic
bination with thrombolysis.33-36 In a placebo-controlled
ultrasonography has been used to help break fibrin mono-
study, abciximab was administered within 6 hours of the
mers, dissolve thrombi, and improve recanalization.59,60
onset of stroke. The results have been presented in abstract
Although these preliminary reports suggest that mechani-
920 Stroke April 2005
cal thrombolysis has great potential for the treatment of
nesium and patients given placebo when the medication was
patients with acute ischemic stroke, these procedures have
administered within 12 hours of the onset of stroke; however,
not been tested sufficiently to make any recommendation
only 3% of the patients were enrolled within 3 hours of the onset
of symptoms. Another trial of magnesium is under way62; in thistrial, the medication is initiated while the patient is being
At present, none of the methods of mechanical thrombolysis
Citicoline is another putative neuroprotective agent that
has been adequately tested to draw conclusions about effi-
has been studied extensively. Although no significant
cacy. These interventions cannot be recommended outside the
benefit was associated with use of citicoline based on the
setting of clinical trials (grade A, no change from 2003).
primary, predetermined end points of any of the stroketrials, Davalos et al performed a meta-analysis of individ-ual patient data.63 The analysis tested the hypothesis of
whether 6 weeks of treatment with oral citicoline would
The last full guideline statement reviewed the results of several
improve outcomes at 3 months. Data from patients receiv-
clinical trials that tested putative neuroprotective agents. No
ing various doses of citicoline or placebo who were
agent had demonstrated clinical benefit. Since the publication of
enrolled in 4 clinical trials were analyzed. Only patients
the guidelines, the results of the IMAGES (Intravenous Magne-
with compatible neuroimaging results, a moderate-to-
sium Efficacy in Stroke) study have been reported.61 No overall
severe neurological deficit (NIH Stroke Scale score Ն8),
difference in outcomes was noted between patients given mag-
and a prestroke modified Rankin Scale score of 0 or 1 were
Approach to Elevated Blood Pressure in Acute Ischemic Stroke
Observe unless other end-organ involvement (eg, aortic dissection, acute myocardialinfarction, pulmonary edema, hypertensive encephalopathy)
Treat other symptoms of stroke (eg, headache, pain, agitation, nausea, vomiting)
Treat other acute complications of stroke, including hypoxia, increased intracranial pressure,seizures, or hypoglycemia
May repeat or double every 10 min (max dose 300 mg)
Nicardipine 5 mg/h IV infusion as initial dose; titrate to desired effect by increasing 2.5 mg/hevery 5 min to max of 15 mg/h
Aim for a 10%-15% reduction in blood pressure
Nitroprusside 0.5 g.kgϪ1.minϪ1 IV infusion as initial dose with continuous blood pressuremonitoring
Aim for a 10%-15% reduction in blood pressure
Check blood pressure every 15 min for 2 h, then every 30 min for 6 h, and finally every hourfor 16 h
Sodium nitroprusside 0.5 g.kgϪ1.minϪ1 IV infusion as initial dose and titrate to desired bloodpressure
May repeat or double labetalol every 10 min to maximum dose of 300 mg, or give initiallabetalol dose, then start labetalol drip at 2-8 mg/min
Nicarpidine 5 mg/h IV infusion as initial dose and titrate to desired effect by increasing 2.5mg/h every 5 min to maximum of 15 mg/h; if blood pressure is not controlled by labetalol,consider sodium nitroprusside
4. Systolic 180-230 OR diastolic 105-120
May repeat or double labetalol every 10-20 min to maximum dose of 300 mg or give initiallabetalol dose, then start labetalol drip at 2-8 mg/min
Adams et al Guidelines for the Early Management of Patients With Ischemic Stroke 921
included. Recovery was assessed on the basis of a global
increased risk of infections including pneumonia, gastroin-
estimate of effect on the modified Rankin Scale, NIH
testinal bleeding, and pressure sores. Data about the effec-
Stroke Scale, and the Barthel Index. Recovery at 3 months
tiveness of specific therapies aimed at improving nutrition are
was found in 25.2% of citicoline-treated patients versus
not yet available. Still, these data provide a strong rationale
20.2% of placebo-treated patients (Pϭ0.0034). The data
for assessment of the patient's nutritional status at the time of
for this exploratory, post hoc analysis were obtained from
admission. In addition, measures should be implemented to
a highly selected group of patients. Of particular concern
maintain or improve the nutritional status of all patients with
is that none of the individual clinical trials, which were the
source of the data, was able to find a benefit fromtreatment with citicoline. Thus, additional research is
needed to substantiate these results.
Assessment of the patient's baseline nutritional status and institutionof measures to correct any major nutritional problems are recom-
mended (grade C, new recommendation).
At present, no agent with putative neuroprotective effects canbe recommended for the treatment of patients with acute
ischemic stroke (grade A, no change from 2003).
Small preliminary clinical studies suggest that hypothermiamay be feasible and beneficial for treatment of acute
Nutrition and Hydration
stroke.65-68 Two important articles in the New England
In a randomized trial, the FOOD (Feed Or Ordinary Diet)
Journal of Medicine showed significant benefits for hypo-
Trial Collaboration is testing the utility of several feeding
thermia in cardiac arrest survivors.69,70 Hypothermia for acute
strategies including oral supplementation, early versus de-
stroke is a promising area for development, but data are
layed nasogastric tube feeding, and nasogastric versus per-
cutaneous endoscopic gastrostomy feeding. A preliminaryreport based on 3012 patients indicates that poor baseline
nutritional status is associated with worse outcomes at 6
Table 6 of the 2003 Guidelines has been updated with the
months.64 Although weakened, this relationship persists after
table on page 920. The 2003 Guidelines online now show this
adjustment for other factors including the patient's age,
update, and the table is being printed here for reference. Disclosure
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all members of the writing group are required to complete and submit.
prestroke functional level, living conditions, and severity ofstroke. A poor nutritional status was associated with an
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KEY WORDS: AHA/ASA Scientific Statements Ⅲ stroke Ⅲ thrombolytic
suction thrombectomy in acute stroke. Am J Neuroradiol. 2002;23:783-786.
therapy Ⅲ anticoagulation Ⅲ evaluation
SECTION A: HISTORY 8. Does exposure to perfumes, insecticides,fabric shop odors and other chemicals provoke. For each “yes” answer in Section A, circle Optimum Function: the point score for that question . Total Dysbiosis Questionnaire your score and record it in the box at theend of the section. Then move to sections9. Are your symptoms worse on damp, muggyThis questionnair
Definition and diagnosis of sexuality in the XXI century Camil Castelo-Branco, Milagro León Huezo, José Luís Ballescá Lagarda Hospital Clínic, Institut Clínic de Ginecologia, Obstetrícia i Neonatologia, Faculty of Medicine, University of Barcelona, Spain. Correspondence Address: Camil Castelo-Branco Institut Clinic of Gynecology, Obstetrics and Neonatology Hospital Clinic