Neonatal Intra-Ventricular-Hemorrhage prevention in premature at < 30 weeks gestational Age

Introduction : Intraventricular Hemorrhage (IVH) is a devastating condition mostly in preterm infants at < 30 weeks GA with large morbidities and mortality usually in the first 72 hours after birth. Prevention seems to be the only way to completely deal with this problem. Material and method: We design a before and after observational study and measured the incidence of IVH when a minimum manipulation protocol was implemented at the Clínica del Country (CDC) unit. We also compare these findings to those of other units in the EpicLatino network. All patients born <30 weeks GA with less than 2 days of age, who survived at least 3 days, and had a neuroimaging taken were included. Results: We collected data from 46 cases before, 40 after implementation, and 203 cases from the EpicLatino registry. Demographic characteristics were very similar in the post-intervention with few statistically significant differences in antenatal steroid use, prolonged rupture of implemented with only 5 (7.5%) cases post-intervention compared to 19 (29.4%) case before, and when compared to the 81 (39.1%) cases in the registry, p< 0.001. Most of the cases that occurred in the post-intervention occurred before admission to the unit due to obstetric trauma. Discussion: If a well-controlled delivery minimizing obstetric trauma is achieved, a minimal manipulation protocol appears to significantly decrease the incidence of HIV. Controlled, multicenter studies are still required to confirm these findings.


Introduction
Intra-Ventricular-Hemorrhage (IVH) is a devastating condition mostly in preterm infants < 30 weeks gestational age (GA) at birth, with large morbidities and mortality. [1][2][3] The timing of the IVH appears to occur in the first 6 hours of life 4,5 but it can continue to develop and most cases are found in the first 72 hours after birth. 6 Hemorrhage at delivery due to obstetric complications probably accounts for many of these cases.
Observational studies show that elective cesarean section reduces the risk of IVH in preterm infants <30 weeks GA when they present with preterm labor. 7 Other risk factors such as germinal matrix immaturity and fluctuations in the cerebral blood flow are described. 8,9 Clinically, low birth weight or low gestational age, lack of antenatal corticosteroids, maternal chorioamnionitis, low Apgar score (<5) at 5 min, respiratory distress syndrome, early onset sepsis, hypercapnia or PCO2 fluctuations, inotropes or boluses, metabolic disorders, opioids infusions, and bicarbonate therapy are also associated with IVH. 6,7,10 Prevention seems to be the only way to reduce this phenomenon. The prevention of IVH in this age group is focuses on strategies such as prenatal corticosteroids, 11 cesarean delivery, 7 careful extraction and other nurse practices, 12 but it still has an unacceptably high incidence in this population.
A new strategy for neuroprotection was develop years ago under the name "Drive to Zero IVH Prevention Project" 13 and was presented in one of the EpicLatino conferences. Our unit decided to adapt this project as a quality improvement practice. In this study we measured the results of this project by comparing cases before and after the intervention and we also used the EpicLatino registry as a concurrent cohort.

Study design
Observational nonconcurrent cohort study querying a prospectively collected registry (EpicLatino).

Setting
Epiclatino is a registry of neonatal intensive care units in Latin America, based on the CNN (Canadian Neonatal Network) collection instrument for quality improvement. 14 Clínica del Country (CDC) is a third level private general hospital located in Bogota, Colombia with a third level neonatal unit with a high incidence of high-risk deliveries. In October 2017, we designed and adapt a strategy for minimum manipulation to the existing prevention strategies in place. At the end we came up with this approach (Table 1).

Subjects
All patients <30 weeks of GA less than 2 days old were included in the new strategy at CDC, for this study we included patients who survived at least 3 days and had a neuroimaging taken (November 2017 to discharge by August 31 2021). For comparison, other cases from the other EpicLatino units from 2018 and 2019 and cases at the CDC from previous years (January 2016-October 2017) also born with <30 weeks GA and surviving 3 days and had a neuroimage were selected for analysis.

Variables
We define IVH grade 1 and 2 as hemorrhage in the germinal matrix and/or ventricles, without intraventricular dilation or periventricular hemorrhage. Grades 3 and 4 were defined as bleeding with ventricular dilatation or bleeding outside the ventricles. We also capture birthweight, gestational age (GA), sex, inborn/outborn, temperature at admission, prenatal corticosteroids, prolonged (>24h) rupture of membranes (ROM), delivery (vaginal or cesarian), suspected chorioamnionitis, Apgar score at 5 minutes, deaths after day 3 and treated patent ductus arteriosus (PDA).

Analysis
We gathered all available cases in a convenience sample with no sample size calculation. All the parameters were compared within the two time periods and the EpicLatino registry using Chi-square test by Fischer's exact method or Kruskal-Wallis rank test, depending on the type of variable. A p value less that 0.05 was considered significant.

Ethics
EpicLatino registry is an approved registry by the local institutional review board at each center with a waiver of informed consent as it gathers non identifiable data for research and quality improvement programs. This manuscript has been also approved by an ethic comity as a minimal risk and wavered the inform consent.

Results
We collected a total of 46 cases at CDC before and 40 post-implementations, and we gather 203 cases Regarding IVH, distribution was statistically significant among the groups (Figure 1). There were one grade 1-2 hemorrhage and 2 grade 3-4 during the post-intervention period. Both grade 3-4 happened during very traumatic deliveries with multiples hematomas around the head, body, and extremities.

Discussion
We found a statistically significant reduction in the incidence of IVH in the post-intervention group when compere to the historical cohort (before) and the EpiLatino registry, and both severe cases were related to delivery trauma. The hemorrhage during delivery is well described 15 and must be prevented by the obstetric team.
We found some factors that could explain some of the difference in the intraventricular hemorrhagic results. Temperature at admission as a marker of moderate/severe acute transitional hypothermia has been associated with increased risk of intraventricular hemorrhage (from 6.8% in normal temperature to 13% with moderate/severe hypothermia), 16 but not in all studies. 17 Prolonged ROM has been associated with increased risk of IVH 18 but it is difficult to separate it from the risk of prematurity, so it is not easy to evaluate how much ROM > 24 hours can increase the risk of IVH. Lack of prenatal corticosteroids increases the risk of IVH, 11 and can explain in part the increased risk of IVH in the EpicLatino group. On the other hand, suspected chorioamnionitis also increases de risk of IVH 11 in the EpicLatino group but decreases the risk in the historical cohort since it is lower than the post-intervention group. The relation between vaginal delivery and C-section may also favor the post-intervention group, especially compared to EpicLatino 7 but more PDA treatment in both control groups could favor IVH prevention since in the post-intervention group only 10% were treated even if some studies question its significance. 19 We believe that this large difference in IVH incidence is not explain by the difference in these factors described above but in the protocol applied.
Our study has limitations as is not a randomized control study, the variables affecting the incidence of IVH could not be properly control and this could explain at least part of the results.
Large randomized clinical trials are needed to confirm our findings.

Conclusion
We believe that the gentle handling described with minimal manipulation and unnecessary laboratories and therapies is linked to reducing the incidence of HIV in this population.
Modification of a single parameter, as observed in randomized control studies, will probably not change the incidence of IVH significantly, but a set of modifications in many as observed in this quality improvement protocol may decrease the incidence of IVH. Large multicenter clinical trials are needed to confirm these findings.