Study of Pregnancy And Neonatal Health (SPAN)

Study Overview
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Brief Summary
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This study will conduct a randomized trial among women with gestational diabetes (GDM). Study of Pregnancy And Neonatal health (SPAN), TIMing of dElivery (TIME) is a randomized trial that will recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery. Women with GDM who are approached for the trial and are found eligible but do not consent to participating in randomization for delivery will be asked to consent for chart review only (estimated additional n=3,000). The primary objective is to determine the best time to initiate delivery for GDM-complicated deliveries (defined as the time when risk of illness and death for the newborn is the lowest) between 37-39 weeks.

Detailed Description
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This is a randomized clinical trial under an adaptive design nested in a larger observational study, among women who are diagnosed with uncontrolled gestational diabetes mellitus (GDM). Women from multiple clinical sites around the United States will be recruited into the study (n=3,450). Women with GDM who are approached for the trial and are found eligible but do not consent to participating to randomization for delivery will be asked to consent for chart review only (estimated additional n=3,000). The primary objective is to determine the optimal time to initiate delivery for GDM complicated deliveries (defined as the time when neonatal morbidity and perinatal mortality risk is the lowest) between 37-39 weeks (n=3,450 women). Newborn developmental and behavior outcomes, and anthropometric measures will also be assessed as secondary outcomes, as well as an exploratory analysis to investigate whether there are clinical, non-clinical or biochemical factors such as glucose measures that will further assist in refining the interval for optimizing time of GDM complicated deliveries relative to neonatal morbidity and perinatal mortality.

Official Title
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Study of Pregnancy And Neonatal Health (SPAN): TIMing of dElivery (TIME) Trial

Conditions
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Gestational Diabetes Mellitus

Intervention / Treatment
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* Procedure: Childbirth


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Aim 3 (GDM randomized trial, TIME) inclusion criteria: Women inclusion criteria: Age ≥ 18 Years Verified diagnosis of Gestational Diabetes Mellitus (GDM) with abnormal glucose levels*** or meeting other criteria for poor control, specifically any one of the following: Estimated fetal weight ≥90th percentile (LGA), Polyhydramnios, and or Demonstrate noncompliance or nonadherence as defined clinically, including missing visits, not keeping accurate log, etc. ***One or more elevated fasting blood glucoses OR three or more elevated post-prandial blood glucoses after receiving education about appropriate diet and lifestyle modification (e.g. physical activity) Accurate gestational age as verified by ultrasound Singleton gestation English or Spanish speaker Plans to deliver at the study site hospital Ability to provide informed consent to be randomized to initiation of delivery EXCLUSION CRITERIA: Aim 3 (GDM randomized trial, TIME) exclusion criteria: Pre-gestational diabetes* *will be defined as diabetes diagnosis before pregnancy OR before 13 weeks of gestation with a documented fasting plasma glucose ≥ 126 mg/dL, random plasma glucose ≥ 200 mg/dL, 2 hour post glucose ≥ 200 mg/dL during an oral glucose tolerance test (75 g glucose load), or hemoglobin A1c ≥ 6.5%.110. Previous stillbirth defined as fetal demise ≥ 20 weeks of gestation Self-reported history of alcohol dependency disorder and/or other drug/substance dependency in the past year Teratogen exposure (e.g. cyclophosphamide, valproic acid, warfarin) Known infectious diseases associated with neonatal morbidity (e.g. malaria, cytomegalovirus, rubella, toxoplasmosis, syphilis or Zika virus) Genetic disorders, aneuploidy and known major fetal anomalies Fetal demise Pregnancies with concurrent conditions and other indications for earlier delivery will also be excluded. Participation in another interventional study that influences management of labor and delivery or perinatal morbidity or mortality

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm 1<br>Intervention Arm 1 Experimental Initiation of Delivery by induction or planned cesarean at 37 weeks 0-2 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 2<br>Intervention Arm 2 Experimental Initiation of Delivery by induction or planned cesarean at 37 weeks 3-5 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 3<br>Initiation of Delivery by induction or planned cesarean at 37 weeks 6 days to 38 weeks and 1 day. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 4<br>Intervention Arm 4 Experimental Initiation of Delivery by induction or planned cesarean at 38 weeks 2-4 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 5<br>Initiation of Delivery by induction or planned cesarean at 38 weeks 5 days to 39 weeks and 0 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 6<br>Intervention Arm 6 Experimental Initiation of Delivery by induction or planned cesarean at 39 weeks 1-3 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|
| Experimental: Intervention Arm 7<br>Intervention Arm 7 Experimental Initiation of Delivery by induction or planned cesarean at 39 weeks 4-6 days. | Procedure: Childbirth<br>* Induction or planned cesarean<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Neonatal Morbidity and Perinatal Mortality |  | Hospital discharge | 
| Occurrence of Antepartum, intrapartum or neonatal death (Component of primary outcome) |  | Antepartum pregnancy period through Newborn Discharge | 
| Incidence of moderate or higher neonatal respiratory support within 72 hours after birth (Component of primary outcome) | Including any of the following: Nasal cannula >/= 2 LPM (liters per minute), Nasal continuous positive airway pressure (NCPAP), NIPPV; (non-invasive intermittent positive pressure ventilation; Note that NIPPV is more general than Bilevel positive airway pressure (BiPAP) i.e. BiPAP is a form of NIPPV, as is non-invasive NAVA, synchronized NIPPV, non-synchronized NIPPV, some ventilators can do nasal IMV in certain situations, etc.), Mechanical ventilation, High frequency ventilation, and ECMO/ECLS (extracorporeal mechanical support/extracorporeal life support) | Delivery through Newborn Discharge | 
| Occurrence of Pneumonia (Component of primary outcome) | Confirmed by X-ray or positive blood culture | Delivery through Newborn Discharge | 
| Occurrence of Meconium aspiration syndrome (Component of primary outcome) | Respiratory distress in an infant born through meconium-stained amniotic fluid with X-ray findings consistent with meconium aspiration syndrome, and whose symptoms could not be otherwise explained | Delivery through Newborn Discharge | 
| Occurrence of Sepsis (Component of primary outcome) | The diagnosis of sepsis will require the presence of a clinically ill infant in whom systemic infection is suspected with a positive blood, CSF, or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an unequivocal X-ray confirming infection. | Delivery through Newborn Discharge | 
| Occurrence of Neonatal encephalopathy (Component of primary outcome) | Defined by Shankaran et al. 2005 | Delivery through Newborn Discharge | 
| Occurrence of Intracranial hemorrhage (Component of primary outcome) | Intraventricular hemorrhage grades III and IV, subgaleal hematoma, subdural hematoma, or subarachnoid hematoma | Delivery through Newborn Discharge | 
| Occurrence of Seizures (Component of primary outcome) |  | Delivery through Newborn Discharge | 
| Occurrence of Birth trauma (Component of primary outcome) | Bone fractures, brachial plexus palsy, other neurologic injury, retinal hemorrhage, or facial nerve palsy | Delivery through Newborn Discharge | 
| Occurrence of Hypotension requiring pressor support (Component of primary outcome) |  | Delivery through Newborn Discharge | 
| Occurrence of hypertrophic cardiomyopathy (Component of primary outcome) |  | Delivery through Newborn Discharge | 
| Incidence of neonatal intensive care unit (NICU) > 1 day (24 hours) stay | NICU stay > 1 day (24 hours) | Delivery through Newborn Discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of respiratory support less than moderate | Hood oxygen and Nasal cannula <2 LPM (liters per minute); Other than room air (No support) | Delivery through Newborn Discharge | 
| Duration of any respiratory support |  | Delivery through Newborn Discharge | 
| Duration of moderate respiratory support |  | Delivery through Newborn Discharge | 
| Occurrence of Transient tachypnea of the newborn |  | Delivery through Newborn Discharge | 
| Occurrence of Respiratory distress syndrome in Neonates | Both a clinical diagnosis and whether required surfactant | Delivery through Newborn Discharge | 
| Occurrence of Hypoglycemia in neonates | Glucose < 35 mg/dl) and whether required IV therapy | Delivery through Newborn Discharge | 
| Occurrence of Hyperbilirubinemia in Neonates | Requiring phototherapy or exchange transfusion in Neonates | Delivery through Newborn Discharge | 
| Occurrence of Polycythemia in Neonates | Both a clinical diagnosis and whether required partial exchange transfusion | Delivery through Newborn Discharge | 
| Incidence of Therapeutic hypothermia | Head or body cooling | Delivery through Newborn Discharge | 
| Incidence of Transfusion of blood products or blood in neonates |  | Delivery through Newborn Discharge | 
| Occurrence of neonatal intensive care unit (NICU) or intermediate care unit admission |  | Delivery through Newborn Discharge | 
| Duration of Neonatal hospital stay | Measured in days | Delivery through Newborn Discharge | 
| Birthweight |  | Delivery through Newborn Discharge | 
| Incidence of small for gestational age | Defined as < 10th percentile using the Duryea reference | Delivery through Newborn Discharge | 
| Incidence of large for gestational age and macrosomia | LGA defined as > 90th percentile using the Duryea reference and macrosomia defined as birthweight > 4500 g | Delivery through Newborn Discharge | 
| Composite of Maternal Morbidity and Mortality | Maternal death, HELLP syndrome, Eclampsia, Pulmonary edema, placental abruption, blood transfusion | Pregnancy through Discharge | 
| Occurrence of maternal death |  | Pregnancy through Discharge | 
| Occurrence of HELLP syndrome | As defined by American College of Obstetricians and Gynecologists (ACOG) | Pregnancy through Discharge | 
| Occurrence of Eclampsia | As defined by American College of Obstetricians and Gynecologists (ACOG) | Pregnancy through Discharge | 
| Occurrence of Maternal Pulmonary edema | Chest x-ray confirmed | Pregnancy through Discharge | 
| Occurrence of Placental abruption |  | Pregnancy through Delivery | 
| Incidence of Maternal Blood transfusion |  | Pregnancy through Discharge | 
| Incidence of spontaneous labor |  | Pregnancy through Delivery | 
| Incidence of induced labor |  | Pregnancy through Delivery | 
| Incidence of planned cesarean |  | Pregnancy through Delivery | 
| Indication for delivery including cesarean for suspected macrosomia | Defined as estimated fetal weight > 4500 grams | Pregnancy through Delivery | 
| Occurrence of Spontaneous vaginal delivery |  | Pregnancy through Delivery | 
| Occurrence of Operative vaginal delivery | Vacuum or forceps | Pregnancy through Delivery | 
| Occurrence of Cesarean delivery |  | Pregnancy through Delivery | 
| Indications for operative vaginal delivery |  | Pregnancy through Delivery | 
| Indication for cesarean |  | Pregnancy through Delivery | 
| Incidence of Shoulder dystocia |  | Delivery through Newborn Discharge | 
| Occurrence of Maternal lacerations | 1st, 2nd, 3rd or 4th degree perineal; sulcus, vaginal wall; labial, periurethral, clitoral, abrasion, other | Delivery through Discharge | 
| Occurrence of Postpartum hemorrhage | Defined as any of the following: Transfusion, Non-elective hysterectomy, Use of two or more uterotonics other than oxytocin, Other surgical interventions such as uterine compression sutures, uterine artery ligation, embolization, hypogastric ligation, or balloon tamponade, and Curettage | Delivery through Discharge | 
| Occurrence of Maternal ICU Admission |  | Delivery through Discharge | 
| Incidence of Maternal venous thromboembolism | Deep venous thrombosis or pulmonary embolism | Delivery through Discharge | 
| Incidence of Chorioamnionitis | Defined as a clinical diagnosis before delivery | Delivery through Discharge | 
| Maternal postpartum infection | Defined as, Clinical diagnosis of endometritis, Wound reopened for hematoma, seroma, infection or other reasons, Cellulitis requiring antibiotics, Pneumonia, Pyelonephritis, Bacteremia unknown source, and Septic pelvic thrombosis | Delivery through Discharge | 
| Maternal hypertension | Mild and Severe (systolic and diastolic) defined by ACOG | Delivery through Discharge | 
| Incidence of Preeclampsia, with or without severe features | Defined by ACOG | Delivery through Discharge | 
| Use of antihypertensive drugs | Includes oral antihypertensive, intravenous antihypertensive, or intravenous anticonvulsant | Delivery through Discharge | 
| Number of hours in labor and delivery unit |  | Delivery through Discharge | 
| Duration of maternal hospital stay | Measured in Days. | Pregnancy through Newborn Discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gestational Diabetes Mellitus, Delivery Timing