Browsing by Author "Ambalavanan, Namasivayam"
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Item Advances in Neonatal Acute Kidney Injury(AAP, 2021-11) Starr, Michelle C.; Charlton, Jennifer R.; Guillet, Ronnie; Reidy, Kimberly; Tipple, Trent E.; Jetton, Jennifer G.; Kent, Alison L.; Abitbol, Carolyn L.; Ambalavanan, Namasivayam; Mhanna, Maroun J.; Askenazi, David J.; Selewski, David T.; Harer, Matthew W.; Pediatrics, School of MedicineIn this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in “crosstalk” between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase–associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.Item Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial(AMA, 2017-07) Shankaran, Seetha; Laptook, Abbot R.; Pappas, Athina; McDonald, Scott A.; Das, Abhik; Tyson, Jon E.; Poindexter, Brenda B.; Schibler, Kurt; Bell, Edward F.; Heyne, Roy J.; Pedroza, Claudia; Bara, Rebecca; Van Meurs, Krisa P.; Huitema, Carolyn M. Petrie; Grisby, Cathy; Devaskar, Uday; Ehrenkranz, Richard A.; Harmon, Heidi M.; Chalak, Lina F.; DeMauro, Sara B.; Garg, Meena; Hartley-McAndrew, Michelle E.; Khan, Amir M.; Walsh, Michele C.; Ambalavanan, Namasivayam; Brumbaugh, Jane E.; Watterberg, Kristi L.; Shepherd, Edward G.; Hamrick, Shannon E. G.; Barks, John; Cotten, C. Michael; Kilbride, Howard W.; Higgins, Rosemary D.; Pediatrics, School of MedicineImportance Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). Main Outcomes and Measures The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Conclusions and Relevance Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C.Item Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial(American Medical Association, 2017-10-24) Laptook, Abbot R.; Shankaran, Seetha; Tyson, Jon E.; Munoz, Breda; Bell, Edward F.; Goldberg, Ronald N.; Parikh, Nehal A.; Ambalavanan, Namasivayam; Pedroza, Claudia; Pappas, Athina; Das, Abhik; Chaudhary, Aasma S.; Ehrenkranz, Richard A.; Hensman, Angelita M.; Van Meurs, Krisa P.; Chalak, Lina F.; Hamrick, Shannon E. G.; Sokol, Gregory M.; Walsh, Michele C.; Poindexter, Brenda B.; Faix, Roger G.; Watterberg, Kristi L.; Frantz, Ivan D., III; Guillet, Ronnie; Devaskar, Uday; Truog, William E.; Chock, Valerie Y.; Wyckoff, Myra H.; McGowan, Elisabeth C.; Carlton, David P.; Harmon, Heidi M.; Brumbaugh, Jane E.; Cotten, C. Michael; Sánchez, Pablo J.; Hibbs, Anna Maria; Higgins, Rosemary D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; Pediatrics, School of MedicineImportance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.Item Home Oxygen Use and 1-Year Readmission among Infants Born Preterm with Bronchopulmonary Dysplasia Discharged from Children's Hospital Neonatal Intensive Care Units(Elsevier, 2020-05) Lagatta, Joanne; Murthy, Karna; Zaniletti, Isabella; Bourque, Stephanie; Engle, William; Rose, Rebecca; Ambalavanan, Namasivayam; Brousseau, David; Pediatrics, School of MedicineObjective: To determine associations between home oxygen use and 1-year readmissions for preterm infants with bronchopulmonary dysplasia (BPD) discharged from regional neonatal intensive care units. Study design: We performed a secondary analysis of the Children's Hospitals Neonatal Database, with readmission data via the Pediatric Hospital Information System and demographics using ZIP-code-linked census data. We included infants born <32 weeks of gestation with BPD, excluding those with anomalies and tracheostomies. Our primary outcome was readmission by 1 year corrected age; secondary outcomes included readmission duration, mortality, and readmission diagnosis-related group codes. A staged multivariable logistic regression was adjusted for center, clinical, and social risk factors; at each stage we included variables associated at P < .1 in bivariable analysis with home oxygen use or readmission. Results: Home oxygen was used in 1906 of 3574 infants (53%) in 22 neonatal intensive care units. Readmission occurred in 34%. Earlier gestational age, male sex, gastrostomy tube, surgical necrotizing enterocolitis, lower median income, nonprivate insurance, and shorter hospital-to-home distance were associated with readmission. Home oxygen was not associated with odds of readmission (OR, 1.2; 95% CI, 0.98-1.56), readmission duration, or mortality. Readmissions for infants with home oxygen were more often coded as BPD (16% vs 4%); readmissions for infants on room air were more often gastrointestinal (29% vs 22%; P < .001). Clinical risk factors explained 72% of center variance in readmission. Conclusions: Home oxygen use is not associated with readmission for infants with BPD in regional neonatal intensive care units. Center variation in home oxygen use does not impact readmission risk. Nonrespiratory problems are important contributors to readmission risk for infants with BPD.Item Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia(Massachusetts Medical Society, 2022-03-24) Watterberg, Kristi L.; Walsh, Michele C.; Li, Lei; Chawla, Sanjay; D’Angio, Carl T.; Goldberg, Ronald N.; Hintz, Susan R.; Laughon, Matthew M.; Yoder, Bradley A.; Kennedy, Kathleen A.; McDavid, Georgia E.; Backstrom-Lacy, Conra; Das, Abhik; Crawford, Margaret M.; Keszler, Martin; Sokol, Gregory M.; Poindexter, Brenda B.; Ambalavanan, Namasivayam; Hibbs, Anna Maria; Truog, William E.; Schmidt, Barbara; Wyckoff, Myra H.; Khan, Amir M.; Garg, Meena; Chess, Patricia R.; Reynolds, Anne M.; Moallem, Mohannad; Bell, Edward F.; Meyer, Lauritz R.; Patel, Ravi M.; Van Meurs, Krisa P.; Cotten, C. Michael; McGowan, Elisabeth C.; Hines, Abbey C.; Merhar, Stephanie; Peralta-Carcelen, Myriam; Wilson-Costello, Deanne E.; Kilbride, Howard W.; DeMauro, Sara B.; Heyne, Roy J.; Mosquera, Ricardo A.; Natarajan, Girija; Purdy, Isabell B.; Lowe, Jean R.; Maitre, Nathalie L.; Harmon, Heidi M.; Hogden, Laurie A.; Adams-Chapman, Ira; Winter, Sarah; Malcolm, William F.; Higgins, Rosemary D.; Eunice Kennedy Shriver NICHD Neonatal Research Network; Pediatrics, School of MedicineBACKGROUND Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.)Item Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial(Elsevier, 2021) Laptook, Abbot R.; Shankaran, Seetha; Barnes, Patrick; Rollins, Nancy; Do, Barbara T.; Parikh, Nehal A.; Hamrick, Shannon; Hintz, Susan R.; Tyson, Jon E.; Bell, Edward F.; Ambalavanan, Namasivayam; Goldberg, Ronald N.; Pappas, Athina; Huitema, Carolyn; Pedroza, Claudia; Chaudhary, Aasma S.; Hensman, Angelita M.; Das, Abhik; Wyckoff, Myra; Khan, Amir; Walsh, Michelle C.; Watterberg, Kristi L.; Faix, Roger; Truog, William; Guillet, Ronnie; Sokol, Gregory M.; Poindexter, Brenda B.; Higgins, Rosemary D.; Eunice Kennedy Shriver National Institute of Child Health; Human Development Neonatal Research Network; Pediatrics, School of MedicineObjective: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. Study design: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. Results: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. Conclusions: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia.Item Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants(Wiley, 2021) Salerno, Sara N.; Edginton, Andrea; Gerhart, Jacqueline G.; Laughon, Matthew M.; Ambalavanan, Namasivayam; Sokol, Gregory M.; Hornik, Chi D.; Stewart, Dan; Mills, Mary; Martz, Karen; Gonzalez, Daniel; Pediatrics, School of MedicinePhysiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.Item Predictive Modeling for Perinatal Mortality in Resource-Limited Settings(American Medical Association, 2020-11-02) Shukla, Vivek V.; Eggleston, Barry; Ambalavanan, Namasivayam; McClure, Elizabeth M.; Mwenechanya, Musaku; Chomba, Elwyn; Bose, Carl; Bauserman, Melissa; Tshefu, Antoinette; Goudar, Shivaprasad S.; Derman, Richard J.; Garcés, Ana; Krebs, Nancy F.; Saleem, Sarah; Goldenberg, Robert L.; Patel, Archana; Hibberd, Patricia L.; Esamai, Fabian; Bucher, Sherri; Liechty, Edward A.; Koso-Thomas, Marion; Carlo, Waldemar A.; Pediatrics, School of MedicineImportance: The overwhelming majority of fetal and neonatal deaths occur in low- and middle-income countries. Fetal and neonatal risk assessment tools may be useful to predict the risk of death. Objective: To develop risk prediction models for intrapartum stillbirth and neonatal death. Design, setting, and participants: This cohort study used data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research population-based vital registry, including clinical sites in South Asia (India and Pakistan), Africa (Democratic Republic of Congo, Zambia, and Kenya), and Latin America (Guatemala). A total of 502 648 pregnancies were prospectively enrolled in the registry. Exposures: Risk factors were added sequentially into the data set in 4 scenarios: (1) prenatal, (2) predelivery, (3) delivery and day 1, and (4) postdelivery through day 2. Main outcomes and measures: Data sets were randomly divided into 10 groups of 3 analysis data sets including training (60%), test (20%), and validation (20%). Conventional and advanced machine learning modeling techniques were applied to assess predictive abilities using area under the curve (AUC) for intrapartum stillbirth and neonatal mortality. Results: All prenatal and predelivery models had predictive accuracy for both intrapartum stillbirth and neonatal mortality with AUC values 0.71 or less. Five of 6 models for neonatal mortality based on delivery/day 1 and postdelivery/day 2 had increased predictive accuracy with AUC values greater than 0.80. Birth weight was the most important predictor for neonatal death in both postdelivery scenarios with independent predictive ability with AUC values of 0.78 and 0.76, respectively. The addition of 4 other top predictors increased AUC to 0.83 and 0.87 for the postdelivery scenarios, respectively. Conclusions and relevance: Models based on prenatal or predelivery data had predictive accuracy for intrapartum stillbirths and neonatal mortality of AUC values 0.71 or less. Models that incorporated delivery data had good predictive accuracy for risk of neonatal mortality. Birth weight was the most important predictor for neonatal mortality.Item Safety of sildenafil in extremely premature infants: a phase I trial(Springer Nature, 2022-01) Jackson, Wesley; Gonzalez, Daniel; Smith, P. Brian; Ambalavanan, Namasivayam; Atz, Andrew M.; Sokol, Gregory M.; Hornik, Chi D.; Stewart, Dan; Mundakel, Gratias; Poindexter, Brenda B.; Ahlfeld, Shawn K.; Mills, Mary; Cohen-Wolkowiez, Michael; Martz, Karen; Hornik, Christoph P.; Laughon, Matthew M.; Pediatrics, School of MedicineObjective: To characterize the safety of sildenafil in premature infants. Study design: A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. Results: Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. Conclusion: Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants.Item Treatment for Mild Chronic Hypertension during Pregnancy(Massachusetts Medical Society, 2022) Tita, Alan T.; Szychowski, Jeff M.; Boggess, Kim; Dugoff, Lorraine; Sibai, Baha; Lawrence, Kirsten; Hughes, Brenna L.; Bell, Joseph; Aagaard, Kjersti; Edwards, Rodney K.; Gibson, Kelly; Haas, David M.; Plante, Lauren; Metz, Torri; Casey, Brian; Esplin, Sean; Longo, Sherri; Hoffman, Matthew; Saade, George R.; Hoppe, Kara K.; Foroutan, Janelle; Tuuli, Methodius; Owens, Michelle Y.; Simhan, Hyagriv N.; Frey, Heather; Rosen, Todd; Palatnik, Anna; Baker, Susan; August, Phyllis; Reddy, Uma M.; Kinzler, Wendy; Su, Emily; Krishna, Iris; Nguyen, Nicki; Norton, Mary E.; Skupski, Daniel; El-Sayed, Yasser Y.; Ogunyemi, Dotum; Galis, Zorina S.; Harper, Lorie; Ambalavanan, Namasivayam; Geller, Nancy L.; Oparil, Suzanne; Cutter, Gary R.; Andrews, William W.; Chronic Hypertension and Pregnancy (CHAP) Trial Consortium; Obstetrics and Gynecology, School of MedicineBackground: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. Methods: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. Results: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). Conclusions: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight.