Clinical and Laboratory Predictors of COVID-19 Progression and Maternal and Perinatal Outcomes in Infected Pregnant and Postpartum Women in Six Reference Centers in the Northeast of Brazil

Brief Summary

Detailed Description

General Objective: To determine the frequency of COVID-19 in pregnant and postpartum women admitted with flu syndrome, to evaluate the clinical and laboratory predictors of COVID-19 progression and to identify the factors associated with adverse maternal and perinatal / neonatal outcomes in six reference centers in the Northeast of Brazil. Specific objectives In pregnant and postpartum women admitted to the four institutions involved with flu-like symptoms or SARS: 1. To describe the biological characteristics (maternal age and pre-pregnancy maternal weight, maternal height, pre-gestational body mass index - BMI and pre-gestational nutritional classification), sociodemographic characteristics (color, number of people living in the household, per capita family income, education, occupation, occupation, marital status, origin and religion), habits (smoking, drinking and use of illicit drugs), obstetric characteristics (number of pregnancies, parity, previous vaginal delivery and previous cesarean, previous abortions, number live children, entry into the study and number of prenatal consultations) and the service of origin (IMIP, HDM, ISEA or MFD); 2. To describe the clinical characteristics (gestational age or postpartum days at the beginning of signs and symptoms, duration of symptoms, isolation, social distance and quarantine before signs and symptoms, need for hospitalization due to infection and / or complications, day of hospitalization due to flu-like syndrome and / or complications, length of hospital stay due to flu-like syndrome and / or complications and the main related signs and symptoms and days of onset - dry or productive cough, runny nose, sore throat, body pain, abdominal pain , chest pain, headache, smell and taste changes, dyspnoea, subfebrile state and fever, diarrhea, asthenia, saturation level, axillary temperature and mild / moderate signs and symptoms); 3. To determine the frequency of COVID-19 infection according to the results of diagnostic tests (rapid test, RT-PCR and serology) applied during hospitalization; 4. To describe the maternal laboratory parameters at the time of the diagnosis of influenza syndrome and the worst laboratory tests (result of RT-PCR for COVID-19, result of viral panel and type of virus, serology for COVID-19 - IgM, IgA and serial IgG, inflammatory cytokines - interleukins - IL-1ra, IL-6, IL-2, IL-5, IL-10, IL-12, IL-13, IL17A, IL-4, IL-1β, IL-9, IL-15, Interferon - IFN-γ, tumor necrosis factor - TNF-α, blood count, coagulogram, urea, creatinine, transaminases - ALT, AST, erythrocyte sedimentation rate - VSH, C reactive protein - CRP), D-dimer, lactic dehydrogenase - LDH, alkaline phosphatase, bilirubins, ferritin, troponin, blood culture, urine culture, blood gas analysis and day of all tests); 5. To describe the radiological findings (chest X-rays, computed tomography), the pulmonal ultrasonography and day of exam alteration and normalization; 6. To describe the therapeutic modalities performed (oxygen therapy - nasal catheter or Venturi with its maximum flows, use of prone in spontaneous ventilation and / or mechanical ventilation, use of mechanical ventilation, use of neuromuscular blocker, use of extracorporeal membrane oxygenation - ECMO, use of: antibiotics, azithromycin, hydroxychloroquine / chloroquine, antiparasitic drugs such as ivermectin, anticoagulant and / or antiretroviral, pulse therapy, convalescent plasma, need for renal replacement therapy, blood products and others, start day and duration of all therapeutic modalities performed); 7. To describe the characteristics of obstetric ultrasound (tachycardia, frequency of diagnosis of fetal growth restriction, fetus small for gestational age - SGA, changes in amniotic fluid and fetal morphological changes) performed during the course of infection and post-infection follow-up; 8. To describe the doppler velocimetric parameters of the uterine and fetal circulation (pulsatility index of the middle uterine arteries, the middle fetal cerebral artery - MCA, the umbilical artery, the venous duct, the frequency of changes in the doppler velocimetry of all the vessels studied and the speed of the systolic peak in MCA) during infection and in the post-infection follow-up; 9. To describe invasive intrauterine diagnostic procedures (amniocentesis), gestational age at which amniocentesis was performed, indications, results of the RT-PCR test for COVID-19, results of the TORCHS survey, results of the karyotype and results of the inflammatory cytokines - interleukins - IL-1ra, IL-6, IL-2, IL-5, IL-10, IL-12, IL-13, IL17A, IL-4, IL-1β, IL-9, IL-15, Interferon - IFN- γ, tumor necrosis factor - TNF-α; 10. To determine comorbidities / complications associated with pregnancy or the puerperium (need for hospitalization due to obstetric causes, length of hospital stay, obesity, multiple pregnancy, hypertensive syndromes, diabetes - clinical or gestational, heart disease, chronic obstructive pulmonary disease, bronchial asthma, cerebrovascular disease, renal failure, immunosuppression, severe acute respiratory syndrome - SARS, premature rupture of membranes, premature labor, placenta praevia, urinary tract infection, pneumonia, sepsis, septic shock, abortion, abruptio placenta, postpartum hemorrhage, infection of surgical site, endometritis, peritonitis, thromboembolic events, need for postpartum hysterectomy, need for other surgeries after delivery and tubal ligation, maternal near miss criteria); 11. To describe the delivery outcomes (type of delivery - vaginal, spontaneous or operative, or cesarean section, indication for cesarean section, indication for labor induction, method of labor induction, duration of induction, gestational age at delivery, use of labor analgesia, type of anesthesia for cesarean section); 12. To describe prenatal interventions (antenatal corticosteroid therapy - number of doses, use of magnesium sulfate and prophylactic antibiotic therapy); 13. To describe the final maternal outcome (discharge of the pregnant woman, discharge of the postpartum woman, death of the pregnant woman and death of the postpartum woman); 14. To describe perinatal and neonatal outcomes (fetal death, perinatal death, birth weight, birth weight adequacy - SGA, AGA, LGA, Apgar scores in the first and fifth minutes, need for neonatal resuscitation, ICU admission, need for assisted mechanical ventilation, oxygen therapy, oxygen therapy modalities, hypothermia, hypoglycemia, polycythemia, anemia, neonatal infection, chorioamnionitis, type of respiratory distress, breastfeeding, neonatal congenital infections (TORCHS), congenital malformation, other neonatal morbidities, neonatal near miss, neonatal death, days of life of neonatal death and length of hospital stay and in neonatal ICU); 15. To determine the procedures in neonatal care in the delivery room (cord clamping - early or opportune, skin-to-skin contact, breastfeeding in the delivery room) and, subsequently, rooming-in or admission to a neonatal ICU / nursing unit; 16. To describe the neonatal laboratory parameters of the suspected diagnosis or confirmation of COVID-19 and the worst test results (days of life of the newborn's suspected diagnosis, result of rapid neonate test, RT-PCR for COVID-19 in nasopharyngeal swab , result of viral panel and virus type, serology for COVID-19 - IgM, IgA and IgG serial, inflammatory cytokines - interleukins - IL-1ra, IL-6, IL-2, IL-5, IL-10, IL -12, IL-13, IL17A, IL-4, IL-1β, IL-9, IL-15, Interferon - IFN-γ, tumor necrosis factor - TNF-α, blood count, coagulogram, urea, creatinine, transaminases - ALT, AST, erythrocyte sedimentation rate - VSH, C-reactive protein - CRP), D-dimer, lactic dehydrogenase - LDH, alkaline phosphatase, bilirubins, ferritin, troponin, blood culture, urine culture, blood gas analysis and day of all tests); 17. To describe the laboratory parameters in the placenta (result of RT-PCR / viral panel by swab and anatomopathological study) and in cord blood (RT-PCR); 18. To determine the frequency of vertical transmission and the factors associated with a higher risk of its occurrence (gestational age at infection, severity of infection, laboratory markers, type of delivery, labor, cord clamping practice, placental findings, maternal interleukins); 19. To describe the laboratory parameters in breast milk (result of RT-PCR / viral panel); 20. To describe the neonatal imaging exams (chest X-rays, computed tomography and day of exam changes and normalization); 21. To determine the association of biological, sociodemographic, obstetric variables, habits, clinical, maternal laboratory parameters in the diagnosis and the worst result, radiological findings, therapeutic modalities, ultrasound and doppler velocimetric characteristics, invasive procedures, comorbidities / complications and characteristics of childbirth with adverse maternal outcome (maternal near miss and maternal death). 22. To determine the association of biological, sociodemographic, obstetric variables, habits, clinical, maternal laboratory parameters in the diagnosis and the worst result, radiological findings, therapeutic modalities, ultrasound and doppler velocimetric characteristics, invasive procedures, comorbidities / complications, delivery results, prenatal interventions, final pregnancy outcome, delivery room procedures, neonatal care and neonatal laboratory parameters, placenta, amniotic fluid and breast milk with adverse perinatal / neonatal outcome (neonatal near miss and fetal / neonatal death); 23. To analyze maternal and perinatal mortality according to gestational age at the onset of symptoms (Kaplan-Meier survival curve); 24. To compare data from two states in Northeast Brazil with official general data in the country according to the Ministry of Health for the pregnancy-puerperal cycle. 25. In a subset of women routinely assessed on admission through the rapid test (ISEA and Unimed-João Pessoa), to determine the frequency of positive rapid test, positive RT-PCR, associated symptoms, asymptomatic carriers and to compare maternal and perinatal outcomes according to test results. 26. To carry out long-term monitoring of women and babies included in the cohort in 2020, to detect recurrence of symptoms, frequency of reinfection, evolution of laboratory parameters (repetition of RT-PCR and serology) and monitoring of growth and development in the cohort of children aged six months, 12 and 24 months. Methods: A prospective and retrospective cohort study will be conducted including pregnant and postpartum women with clinical or laboratorial diagnosis of COVID-19, admitted in six healthcare centers in the Northeast of Brazil. All pregnant and postpartum women with clinical and/or diagnosis of COVID-19, attended in prenatal care, in emergency (maternity triage), high-risk pregnancy ward, obstetric intensive care unit and rooming-in ward will be included. The data will be collected in specific forms. The exams will be carried out by trained professionals within each institution. A database will be created on the RedCap platform. For the association of dependent variables (maternal mortality / near miss and unfavorable perinatal outcomes) with independent variables (biological, sociodemographic characteristics, history, clinical characteristics, ultrasound modifications, doppler velocimetric and laboratory tests, chi-square tests will be used and Fisher's exact, when pertinent, with a significance level of 5%. The relative risk and its 95% confidence interval will also be calculated to determine the strength of association between the variables. outcomes, Student t or Mann-Whitney tests will be adopted. A multivariate analysis will be performed to determine the variables that will actually remain associated, in addition, a Kaplan-Meier survival curve will be constructed.

Primary Outcomes

Secondary Outcomes

• Maternal occupation with financial income(1 hour)
• Maternal age(1 hour)
• Maternal pre-pregnancy weight(1 hour)
• Maternal height(1 hour)
• Pre-gestational nutritional classification(1 hour)
• Pre-gestational body mass index (BMI)(1 hour)
• Maternal color(1 hour)
• Number of people living in the household(1 hour)
• Family income per capita(1 hour)
• Maternal education(1 hour)
• Maternal occupation(1 hour)
• Maternal marital status(1 hour)
• Maternal origin(1 hour)
• Maternal religion(1 hour)
• Maternal smoking(1 hour)
• Maternal alcoholism(1 hour)
• Maternal use of illicit drugs(1 hour)
• Number of pregnancies(1 hour)
• Parity(1 hour)
• Number of previous cesarean sections(1 hour)
• Number of previous vaginal births(1 hour)
• Gestational age of the onset of flu-like signs and symptoms(1 hour)
• Number of puerperium days of onset of flu-like signs and symptoms(14 days)
• Need for hospitalization due to flu-like syndrome and/or complications(1 hour)
• Number of previous abortions(1 hour)
• Social isolation during the signs and symptoms of flu-like syndrome(14 days)
• Social distance before the signs and symptoms of flu-like syndrome(1 hour)
• Result of polymerase chain reaction - real time (RT-PCR) for maternal COVID19 in diagnosis, at 6 months, 12 months and 24 months(24 months)
• Number of children alive(1 hour)
• Quarantine(14 days)
• Result of polymerase chain reaction - real time (RT-PCR) for the differential diagnosis of maternal respiratory syndrome (viral panel)(10 days)
• Serial maternal serology day(6 months, 12 months and 24 months)
• Day of the first blood count from the beginning of the flu syndrome or COVID-19(14 days)
• Hemoglobin of maternal diagnosis(14 days)
• Day of the first urea from the beginning of the flu syndrome or COVID-19(14 days)
• Urea from maternal diagnosis(14 days)
• CRP of maternal diagnosis(14 days)
• Number of prenatal consultations(1 hour)
• Duration of maternal symptoms(1 hour)
• Length of hospital stay due to flu-like syndrome and/or complications(14 days)
• Maternal signs and symptoms of flu-like syndrome at diagnosis, at 6 months, 12 months and 24 months(24 months)
• Typical lymphocytes of maternal diagnosis(14 days)
• Maternal diagnosis clotting time (CT)(14 days)
• Creatinine of maternal diagnosis(14 days)
• Day of hospitalization due to flu syndrome and/or complications(1 hour)
• Serial maternal IgM COVID-19(6 months, 12 months and 24 months)
• Maternal reinfection(14 days)
• Day of the first cytokine dosage from the beginning of the flu syndrome or COVID-19(14 days)
• Maternal diagnosis bleeding time (TB)(14 days)
• Maternal viral panel in the diagnosis, at 6 months, 12 months and 24 months(24 months)
• Rapid test for maternal COVID-19 at diagnosis, at 6 months, 12 months and 24 months(24 months)
• Serial maternal IgA COVID-19(6 months, 12 months and 24 months)
• Serial maternal IgG COVID-19(6 months, 12 months and 24 months)
• Cytokines in maternal diagnosis(14 days)
• Leukocytes from maternal diagnosis(14 days)
• Maternal prothrombin time of diagnosis (TD)(14 days)
• International normalized ratio (INR)(14 days)
• Day of the first erythrocyte sedimentation rate (VSH) of maternal diagnosis from the beginning of the flu syndrome or COVID-19:(14 days)
• VSH of maternal diagnosis(14 days)
• Deviation to the left of the maternal diagnosis(14 days)
• Platelets of maternal diagnosis(14 days)
• Atypical lymphocytes of maternal diagnosis(14 days)
• Day of the first coagulogram from the beginning of the flu syndrome or COVID-19(14 days)
• Maternal active partial thromboplastin time of diagnosis (APTT)(14 days)
• Day of the first creatinine from the beginning of the flu syndrome or COVID-19(14 days)
• Transaminases in maternal diagnosis(14 days)
• D-dimer of maternal diagnosis(14 days)
• DHL of maternal diagnosis(14 days)
• Day of the first alkaline phosphatase from the beginning of the flu syndrome or COVID-19(14 days)
• Alkaline phosphatase in maternal diagnosis(14 days)
• Day of the first C-reactive protein (CRP) from the beginning of the flu syndrome or COVID-19(14 days)
• Day of the first troponin from the beginning of the flu syndrome or COVID-19(14 days)
• Day of the first D-dimer from the beginning of the flu syndrome or COVID-19(14 days)
• Day of the first lactic dehydrogenase (DHL) from the beginning of the flu syndrome or COVID-19(14 days)
• Troponin in maternal diagnosis(14 days)
• Day of the first blood culture from the beginning of the flu syndrome or COVID-19(14 days)
• Day of the first ferritin from the beginning of the flu syndrome or COVID-19(14 days)
• Ferritin in maternal diagnosis(14 days)
• Blood culture of maternal diagnosis(14 days)
• Blood culture microorganism in maternal diagnosis(14 days)
• Uroculture microorganism in maternal diagnosis(14 days)
• Day of the worst urea result from the beginning of the flu syndrome or COVID-19(14 days)
• Bilirubins in maternal diagnosis(14 days)
• Day of the first uroculture from the beginning of the flu syndrome or COVID-19(14 days)
• Uroculture of maternal diagnosis(14 days)
• IgM COVID-19 worst maternal result(5 days)
• IgA COVID-19 worst maternal result(5 days)
• Maternal IgG COVID-19 - worst serial result(14 days)
• Creatinine worst maternal result(14 days)
• Day of the worst result of the erythrocyte sedimentation rate of maternal diagnosis (VSH) from the beginning of the flu syndrome or COVID-19(14 days)
• Cytokines worst maternal outcome(14 days)
• Urea worst maternal result(14 days)
• Day of the worst creatinine result from the beginning of the flu syndrome or COVID-19(14 days)
• VSH worst maternal result(14 days)
• CRP worst maternal result(14 days)
• Ferritin worst maternal result(14 days)
• Bilirubins worst maternal result(14 days)
• Result of maternal chest radiography(14 days)
• Transaminases worst maternal outcome(14 days)
• DHL worst maternal result(14 days)
• Alkaline phosphatase worst maternal result(14 days)
• Day of the worst C-reactive protein (CRP) result from the onset of the flu syndrome or COVID-19(14 days)
• Day of the worst D-dimer result from the onset of the flu syndrome or COVID-19(14 days)
• Day of the worst result of lactic dehydrogenase (DHL) from the beginning of the flu syndrome or COVID-19(14 days)
• D-dimer worst maternal result(14 days)
• Blood culture worst maternal result(14 days)
• Blood culture microorganism worst maternal result(14 days)
• Uroculture worse maternal result(14 days)
• Presence of changes in the mother's chest tomography(14 days)
• Day of normalization of the alteration of the tomography of the maternal chest(14 days)
• Result of maternal chest tomography(14 days)
• Use of maternal nasal catheter(1 month)
• Use of maternal Venturi Mask(1 month)
• Prone maternal position on spontaneous ventilation(1 month)
• Use of therapeutic antibiotics(14 days)
• Troponin worst maternal result(14 days)
• Uroculture microorganism worst maternal result(14 days)
• Presence of changes in maternal chest radiography(14 days)
• Use of azithromycin(14 days)
• Use of maternal hydroxychloroquine/chloroquine(14 days)
• Use of antiparasitic drugs(14 days)
• Use of anticoagulant(14 days)
• Use of antiretroviral(14 days)
• Use of pulse therapy(14 days)
• Use of convalescent plasma(14 days)
• Assisted Mechanical Ventilation (AMV)(1 month)
• Use of neuromuscular blocker(14 days)
• Use of Extracorporeal Circulation (ECMO)(1 month)
• Renal replacement therapy (dialysis)(1 month)
• Blood products(1 month)
• Other therapeutic modalities(1 month)
• Amniotic fluid in the last ultrasound examination(14 days)
• Fetal growth restriction(14 days)
• Small fetus for gestational age (SGA)(14 days)
• Presence of fetal morphological changes(1 month)
• Fetal morphological changes(1 month)
• Frequency of fetal tachycardia (FFT)(1 month)
• Doppler velocimetry parameters in the last ultrasound examination(1 month)
• Gestational age of amniocentesis(1 month)
• Amniocentesis indications(1 month)
• Result of amniocentesis for COVID19(1 month)
• Amniocentesis cytokines(1 month)
• Need for hospitalization due to obstetric causes(1 month)
• Maternal hospital stay(1 month)
• Obesity(1 month)
• Chronic arterial hypertension (CAH)(1 month)
• Superimposed preeclampsia(1 month)
• Gestational hypertension(1 month)
• Pre-eclampsia(1 month)
• Eclampsia(1 month)
• HELLP syndrome(1 month)
• Clinical diabetes(1 month)
• Gestational diabetes(1 month)
• Premature rupture of membranes(1 month)
• Premature labor(1 month)
• Placenta previa(1 month)
• Abortion(1 month)
• Normally inserted placental abruption(1 month)
• Maternal urinary tract infection(1 month)
• Maternal heart disease(1 month)
• Bronchial asthma(1 month)
• Chronic obstructive pulmonary disease (COPD)(1 month)
• Cerebrovascular disease(1 month)
• Chronic kidney injury(1 month)
• Immunosuppression(1 month)
• Maternal pneumonia(1 month)
• Maternal sepsis(1 month)
• Septic shock(1 month)
• Severe acute respiratory syndrome (SARS)(1 month)
• Postpartum hemorrhage(14 days)
• Infection of the operative site(14 days)
• Endometritis(14 days)
• Peritonitis(14 days)
• Need for postpartum hysterectomy(1 month)
• Type of delivery(1 hour)
• Indication of cesarean section(1 hour)
• Gestational age at birth(1 hour)
• Use of labor analgesia(4 hours)
• Type of anesthesia for cesarean section(1 hour)
• Antenatal corticosteroid therapy (pulmonary maturity)(14 days)
• Use of maternal magnesium sulphate (prophylaxis of the newborn and / or prevention of eclampsia)(32 weeks)
• Maternal prophylactic antibiotic therapy (prophylaxis of neonatal sepsis)(14 days)
• Hospital discharge when pregnant(1 month)
• Hospital discharge when puerperal(1 month)
• Maternal death when pregnant(1 month)
• Maternal death when puerperal(45 days)
• Fetal death(10 hours)
• Perinatal death(27 days)
• Birth weight(1 hour)
• Adequacy of birth weight(1 hour)
• Apgar scores in the first minute(1 minute)
• Apgar scores in the fifth minute(5 minutes)
• Neonatal ICU admission(1 hour)
• Need for neonatal resuscitation(27 days)
• Need for neonatal mechanical ventilation(27 days)
• Neonatal nasal catheter(27 days)
• Neonatal Continuous Positive Airway Pressure (CPAP) mask(27 days)
• Chorioamnionitis(27 days)
• Skin-to-skin contact(1 hour)
• Breastfeeding in the delivery room(1 hour)
• Days of life of the newborn's diagnostic suspicion(1 month)
• Result of the Polymerase Chain Reaction - Real Time (RT-PCR) for neonatal COVID-19 in diagnosis, at 6 months, 12 months and 24 months(6 months, 12 months and 24 months)
• Result of Polymerase Chain Reaction - Real Time (RT-PCR) for the differential diagnosis of neonatal respiratory syndrome (viral panel)(6 months, 12 months and 24 months)
• Neonatal reinfection(14 days)
• Neonatal hypothermia(27 days)
• Congenital malformation(1 month)
• Neonatal hypoglycemia(27 days)
• Breastfeeding(1 month)
• Neonatal IgM COVID-19(5 days)
• Diagnostic neonatal clotting time (CT)(1 month)
• Neonatal IgG COVID-19 - worst serial result(14 days)
• Result of RT-PCR of the placenta(1 month)
• Parameters for monitoring the growth of the newborn at 6, 12 and 24 months - Weight(6, 12 and 24 months)
• Development of the newborn up to 6 months(6 months)
• Development of the newborn up to 24 months(24 months)
• Neonatal infection(27 days)
• Neonatal respiratory distress modality(1 month)
• Neonatal congenital infection (TORCHS)(1 month)
• Cord ligation(10 minutes)
• Neonatal viral panel in the diagnosis, at 6 months, 12 months and 24 months(6 months, 12 months and 24 months)
• Neonatal cytokines(6 months, 12 months and 24 months)
• Serial neonatal IgG COVID-19(14 days)
• Uroculture of neonatal diagnosis(1 month)
• Gasometry - worst neonatal result(1 hour)
• Presence of alteration of the neonatal chest tomography(1 day)
• IgA COVID-19 neonatal serial(5 days)
• Hemoglobin from neonatal diagnosis(14 days)
• Diagnostic neonatal bleeding time (BT)(1 month)
• Creatinine from neonatal diagnosis(1 month)
• Day of the worst blood count result from the beginning of the suspected diagnosis by COVID-19(1 month)
• Bleeding time - worst neonatal result (BT)(1 month)
• Urea - worst neonatal result(1 month)
• Blood culture - worst neonatal result(1 month)
• Placental viral panel(1 month)
• Histopathological of the placenta(1 month)
• Presence of alteration of the neonatal chest radiography(1 day)
• Urea from neonatal diagnosis(1 month)
• Cytokines - worst neonatal result(14 days)
• Day of the worst value of the neonatal coagulogram from the suspicion of the diagnosis by COVID-19(1 month)
• Transaminases - worst neonatal result(1 month)
• Result of RT-PCR in breast milk at diagnosis, at birth and with and at hospital discharge(1 month)
• Viral panel in breast milk(1 month)
• Result of neonatal chest radiography(1 day)
• Result of neonatal chest tomography(1 day)
• Parameters for monitoring the growth of the newborn at 6, 12 and 24 months - Head circumference(6, 12 and 24 months)
• Transaminases of the neonatal diagnosis(1 month)
• Blood culture of the neonatal diagnosis(1 month)
• IgM COVID-19 - worst neonatal result(5 days)
• Creatinine - worst neonatal result(1 month)
• Uroculture - worst neonatal result(1 month)
• Parameters for monitoring the growth of the newborn at 6, 12 and 24 months - Height(6, 12 and 24 months)
• Development of the newborn up to 12 months(12 months)