This project was approved by the Institutional Review Board of the University of California San Francisco. Between January 1995 and December 2009, all infants <280/7
weeks gestation, admitted within 15 hours of birth to the William H. Tooley Nursery at University of California San Francisco, were treated according to the following PDA-care oriented protocol. A full description of this approach has been published elsewhere (14
). Infants received either a short 3-dose course of prophylactic indomethacin (0.2, 0.1, 0.1 mg/kg, administered at 24 hr intervals) or an extended 6-dose course (0.2, 0.1, 0.1, 0.1, 0.1, 0.1 mg/kg, at 24 hr intervals) starting within 15 hr of birth. A Doppler examination was performed on the third day after birth, just before the 3rd indomethacin dose. If the ductus was closed on echocardiogram and there was no evidence of ductus patency on the Doppler examination, infants received the third dose (prophylactic indomethacin was stopped after the third dose). If there was any evidence of ductus patency on the exam, infants received the extended 6-dose course. A repeat echocardiogram/Doppler examination was performed on the seventh day after birth (24 hours after the last indomethacin dose) to determine the ductus’ response to prophylactic indomethacin. During the first week after birth platelet counts were measured with an LH750 Beckman Coulter automated platelet counter prior to each prophylactic indomethacin dose and at least every other day thereafter. Platelet counts <100 × 109
/L were routinely repeated for accuracy and all platelet counts <50 × 109
/L were checked manually. Indomethacin dosing was not interrupted for low platelet counts unless the platelet count fell to <50 × 109
/L. If the platelet count fell to <50 × 109
/L, infants were transfused with platelet concentrates and the indomethacin dosing continued. Six of the 497 infants received a platelet transfusion as part of the prophylactic indomethacin protocol.
Following the prophylactic indomethacin treatment, all infants were examined daily for the appearance of clinical symptoms indicative of a PDA (systolic murmur, widened pulse pressure, hyperdynamic precordium). If any of these occurred a repeat echocardiogram/Doppler examination was performed within 24 hours. If the repeat examination found new left-to-right flow through the ductus (and the previous Doppler examination showed that the ductus was closed) the infant was considered to have reopened the PDA and to have failed to achieve permanent ductus closure after indomethacin treatment.
A single neonatologist prospectively evaluated and recorded all of the antenatal and neonatal risk factors during the hospitalization. Gestational age was determined by the date of last menstrual period and early ultrasounds (before 24 weeks gestation). If there were discrepancies, the early ultrasound dating was used. Small for gestational age was defined as birthweight less than the tenth-percentile for gestational age using the growth curves from Alexander et al (15
). Intracranial hemorrhage (ICH) was classified using the four-level grading system (16
). All infants were examined with serial bedside cranial ultrasounds initiated within the first 3 days after birth. These were repeated weekly or biweekly for the first 4 weeks. Infants were excluded from the analysis if they died before the echocardiographic evaluations.
Our intent was to determine if there was a relationship between the lowest platelet count (platelet nadir) during the course of indomethacin treatment and the incidence of persistent ductus patency following treatment. We studied three aspects of persistent ductus patency: (1) ductus patency just prior to the 3rd dose of prophylactic indomethacin (on day 3); (2) ductus patency after the last dose of prophylactic indomethacin (on day 7); and (3) ductus re-opening following initial indomethacin-induced ductus closure. The first two aspects reflect the ability of the ductus to constrict after prophylactic indomethacin treatment. The third aspect reflects the ability of the ductus to undergo anatomic remodeling and permanent closure after indomethacin-induced ductus constriction.
We first examined the distribution of potential antenatal and neonatal risk factors among the groups with an open and closed ductus. Continuous variables were compared using the non-parametric Mann-Whitney rank sum test, and p-values for categorical and binary variables were based on the Chi-square test.
The predictor of primary interest, lowest platelet count (platelet nadir), was characterized in analyses in a variety of ways: as a continuous variable, as a binary variable (to explore a potential plateau effect), and as a categorical variable (in order to account for possible non-linearity), and examined using logistic regression models in order to determine how best to represent it in multivariable models. Univariate logistic regression models were used to obtain odds ratios for the potential predictors of ductus closure.
Adjusted multivariable logistic regression models were built for each of the three aspects of persistent ductus patency to determine if the effects of the platelet nadir were independent of other antenatal/neonatal risk factors. Multivariable logistic regression models were constructed as follows: platelet nadir (variously characterized) were adjusted for variables shown in univariate analysis to be strongly associated with ductus closure (p<0.05), then forward stepwise regression was utilized on the remainder of the variables to obtain a final model. Models including different characterizations of platelet nadir were compared to determine which best fit the data. This process was repeated for each of the three aspects of persistent ductus patency to determine if the effects of the platelet nadir were independent of other antenatal/neonatal risk factors. All analyses were performed using SAS version 9.1.
The final multivariate models included the following variables: 1) a platelet variable (either absolute platelet nadir or distribution of platelet nadirs), plus 2) gestation, plus 3) antenatal betamethasone, plus 4) preeclampsia, plus 5) Respiratory Severity Score (Mean Airway Pressure × FiO2) at 24 hours after birth, plus 6) each of the following perinatal/neonatal risk factors: maternal diabetes, birthweight, small for gestational age, male sex, respiratory distress syndrome, surfactant treatment, intracranial hemorrhage (grades 3 and 4), chorioamnionitis/early neonatal septicemia, and fluid intake.