Formation of a National Perinatal Nitrous Oxide Data Registry: The Intrapartum Nitrous Oxide Workgroup I-NOW

Background: There are a variety of labor analgesic options for parturients, such as intravenous opioids, neuraxial interventions, hydrotherapy, hypnosis, as well as inhaled nitrous oxide (N 2 O). Inhaled N 2 O has been utilized outside of the United States (U.S.) for decades but has only recently gained popularity in the U.S. as a labor analgesic. There are no current multi-center data registries evaluating N 2 O use as a labor analgesic regarding conversion rates, side effects, and delivery outcomes. Methods: We created the first multi-center N 2 O data registry to gather maternal and newborn outcome data from several institutions across the U.S. All centers were required to sign a Memorandum of Understanding (MOU) which stated that at least 80% of all parturients utilizing N 2 O for labor would be included in the database. We hypothesized that the data would assist in counseling and consenting parturients regarding incidence of side effects, conversion rates and etiologies, as well as neonatal outcomes. This manuscript demonstrates the steps taken to create the data registry, including institutional enrollment, development of a data collection tool, selection of the data management system and administrator, organization of multiple institutional review boards, delineation of responsibilities and challenges encountered with implementation. Conclusion: The development of a multi-center data registry was successfully created as we saw a need for a safe data-sharing system to answer mutually determined research questions, and to collect strong data information in order to provide evidenced based data to patients and providers.


INTRODUCTION
Close to four million women in the US give birth each year and for most of them pain control during labor is a major concern [1]. Easy access to effective and safe pain management options is essential to provide care for the parturient. Inhaled nitrous oxide (N 2 O) has a long history of use in European countries and Australia and is becoming more mainstream in the U.S. [2].
The limited use of N 2 O for labor analgesia in the U.S. is likely due to both an increase in popularity of neuraxial analgesia [3] and concerns for the safe delivery of N 2 O to the parturient and the staff caring for her. In 2007 utilization of N 2 O in the U.S., for labor analgesia, was as low as 1% [4], however, a supporting position statement from the American College of Nurse-Midwives was published in 2010 and the FDA approved a safe delivery system in 2012 that both increased use in the U.S. [5]. While there is anecdotal evidence regarding the safety of N 2 O for both mother and baby, as well as its efficacy in reducing pain during labor, there is a paucity of scientific data and no large multi-center N 2 O database to further evaluate the evidence. The available data suggests that although N 2 O provides minimal analgesia to laboring women, it does help them cope with labor pain [6] and they are just as satisfied with N 2 O as they are with neuraxial analgesia [7].   Table 1. MOU required each institution to include at least 80% of all laboring parturients utilizing N 2 O for labor analgesia.
The data collection tool was developed and housed at CU following input from all participating institutions and included 147 data points per patient (See questionnaire attached: addendum). There were many reiterations of this tool over a 10-month period. A statistician reviewed the data collection tool and it was pre-tested at CU. Data collection was audited every 6 months for data completeness and each institution only had access to their own data. A data administrator, housed at CU, was responsible for all data management and available to assist all institutions with data entry and access issues. The goal was to obtain data on 8000 mother/neonate dyads to evaluate after 3 years.

STEPS FOR THE FORMATION OF A MULTI-INSTITUTIONAL DATA REGISTRY
After completion of all institutional MOUs and approval of each institutional IRB, each institution obtained access and training for the REDCap® database. I-NOW chose the REDCap® Data Management System as the data repository for the project due to programming expertise, data management, branching logic and extensive formatting options. A system within REDCap® allows for practice data entry prior to full implementation; this helps with discovering missed items or missed data point. REDCap® provides automated export procedures for unified data downloads to Excel and common statistical packages (SPSS; SAS; Stata, R). The I-NOW reviewed and approved all research requests and released only de-identified data to the requesting institution. This novel database was titled the National Perinatal Nitrous Oxide Data Registry.
Industry support was identified and secured from Porter Instruments, a division of Parker Industries and U.S. supplier of the Nitronox © machine used to administer perinatal N 2 O at CU. A Sponsorship Agreement was vetted through CU's legal team and $5000 was secured as support for the data administrator. Porter Instruments has no rights to involvement in the dissemination of any research related to the data registry. Originally, participating institutions had no funding for research assistants, however, four institutions have secured funding for data collection and entry.

RESULTS
The database collected almost 2000 parturients over 3 years. Unfortunately, two institutions (New Mexico and Brigham) withdrew due to inability to meet MOU requirements regarding data entry. Several publications have already resulted from this novel data registry and include a data analysis of the Satisfaction, Adverse Effects, and Predictors of Conversion to Neuraxial Analgesia [8] and nitrous oxide use for labor analgesia at high and low-altitude institutions [9]. This I-Now group creation was presented at a few national meetings [10][11][12].
These publications and presentations have contributed uniquely to field of N 2 O use in labor with this large database, especially in areas that had not been well studied in the past such as maternal side effects and satisfaction, baby safety, and impact of high altitude on N 2 O usage.

CONCLUSION
Clinicians from six academic institutions throughout the U.S. formed the National Perinatal Nitrous Oxide Data Registry to gather clinical data to better understand the best-use, benefits, risks, and side effects of perinatal N 2 O use for labor analgesia.
Today's technical advancements, including conference calls, emails, meeting schedulers and electronic data management systems, have made it possible for clinicians to create a large data sharing system while being located throughout the country.
The process of development of a multicenter data registry is feasible for clinical experts who see the use of a systematic, safe data-sharing system to answer research questions not otherwise answerable without a large, more diverse data set, but who have minimal research funding. These projects take a great deal of time, dedication and commitment on the part of the participants to initiate and maintain, but allow for a tremendous amount of data collection and information that might be used to better counsel and care for our patients.

ADDITIONAL FILE
The additional file for this article can be found as follows: