Agulnik, 1
Traveling Scholars Application, Summer 2006
Asya Agulnik, MS I
Faculty Sponsor: Vinod K. Bhutani, MD
Clinical Professor, Neonatal and Developmental Medicine, Dept of Pediatrics
On-site Sponsor: Irina Ryumina, MD
Leading Research Specialist, Moscow Research Institute of Pediatric and Children’s
Surgery; Medical Advisor, healthy Russia 2020 (Bloomberg School of Public Health)
Abstract
Newborn jaundice, usually a benign condition, can be a serious disorder that, if
unmonitored and untreated during the neonatal period, can lead to permanent
neurological injury (kernicterus) and death. While this condition is well managed in the
United States and western Europe by Rh(D) prophylaxis, early and predictive diagnosis
and timely intervention, it poses a significantly greater challenge to newborns and their
physicians in Russia. Neonatal jaundice and severe hyperbilirubinemia is currently the
primary cause of newborn hospital admissions. According to Russian neonatologists,
their inability to effectively predict and prevent cases of severe hyperbilirubinemia often
results in unnecessary morbidity and mortality in newborns. Uncertainty about which
infants need the most extensive care leads to unwarranted and expensive treatment.
Our study seeks to address the disparity between neonatal outcomes in Russia and
countries like the United States and Western Europe by presenting data to identify the
gaps in the healthcare and management of neonatal hyperbilirubinemia in Moscow,
Russia. We will meet these objectives by conducting a chart review and data analysis of
all neonatal admissions to City Hospital No.13, the primary site for neonatal care in
Moscow and its vicinity, in one calendar year. Our study will focus on a root cause
analysis of the demographics, diagnosis and treatment of neonatal jaundice in the
manner used by the American Academy of Pediatrics for similar studies in the United
States. The conclusions of this work will be presented to the Russian medical
community with the intention of aiding them in the creation of updated and more effective
protocols for the management of severe hyperbilirubinemia.
Learning Objectives
In undertaking this project, I hope to gain a valuable experience working
internationally in a clinical setting. While I have done a significant amount of basic
science research for my undergraduate thesis on breast cancer and am currently
involved in a primarily clinical project at Stanford, I have never had the opportunity to
work abroad in the medical setting. Working with Dr. Ryumina will provide me with a
unique experience that I will not likely experience within the United States. As a
prominent Moscow physician working both within the Moscow Neonatal Research
Institute and with Health Russia 2020, a program organized by the Bloomberg School of
Public Health, Dr. Ryumina will be an ideal resource to introduce me both to the clinical
aspects of this project, as well as to its overriding public health implications. The idea for
this work came from Dr. Ryumina’s recognition that infants in Russia were not receiving
the most effective care for the management of neonatal jaundice, and my work with her
will aim at addressing this issue on both of these levels. Along with the practical skills
Agulnik, 2
learned from participating in a comprehensive chart review, I will also be exposed to a
foreign health care and public health system. This experience will allow me to gain a
better understanding about how to approach issues of prevention in countries with less
extensive resources than the United States, an area of particular interest to me. In my
future career, I hope to work extensively in the public health and international fields, and
I see this trip as the first step towards gaining the skills necessary to participate in this
type of work.
I will have a number of resources available to aid me in achieving these learning
objectives. Throughout the summer, I will work closely with both my on-site mentor, Dr.
Ryumina, and, through email, with my Stanford sponsor, Dr. Bhutani. Both physicians
are very enthusiastic about my success in this project and have graciously offered their
time to help me with my work. In Russia, I will meet with Dr. Ryumina on a regular basis
in order to discuss the progress of my work and to ensure that any problems are
addressed as they come up. Because my work will be conducted within the general
scope of the Moscow Neonatal Research Institute, I will also have the aid of its other
research staff as needed. As an expatriate of Russia, I have many personal contacts in
Moscow who will aid me in the non-academic aspects of moving to a foreign country and
adapting to its different culture and society.
Proposal
I. Specific Aims
The long-term goal of this study is to provide contemporaneous information for
clinicians in Moscow, Russia to aid them in the development of a systems-based
approach for the management of neonatal jaundice that is relevant in the context of their
healthcare system. In order to achieve this goal, we will do the following:
I.
Evaluate the magnitude of the problem of hyperbilirubinemia in Moscow
based on a cohort of data collected from infants rehospitalized after
birthing for management of progressive jaundice. For a timed period
between January 1st 2005 and January 1st 2006, we anticipate a chart
review and analysis of about 400 to 500 medical records. Data analysis
will include an estimated incidence of severe hyperbilirubinemia among
live births, the success of early diagnosis, common reasons for jaundice
and outcome of treatment.
II.
Compare the data collected to similar analyses conducted in the United
States and Europe. These data will be evaluated in the context of recent
evidence-based guidelines for management of neonatal
hyperbilirubinemia by the American Academy of Pediatricians (AAP).
III.
Use the evaluations and the comparisons above to identify gaps in the
treatment of hyperbilirubinemia in Moscow, in the context of the Institute
of Medicine’s matrix for “medical failure”. A better understanding of the
root causes for severe hyperbilirubinemia may help identify areas for
improvement in the treatment of neonatal jaundice in the Muscovite and
Russian population.
Agulnik, 3
II. Background and Significance
Neonatal jaundice is the yellowish discoloration of the skin and/or sclerae of
newborn infants caused by tissue deposition of bilirubin. Physiologic jaundice is mild
unconjugated bilirubinemia and is present in approximately 60% of all newborns.
Pathologic jaundice is characterized by abnormally high levels of bilirubin for infant age
after birth (age-in-hours specific TSB levels greater than 95th percentile on Bhutani
nomogram, Figure 1), and occurs in a variety of conditions. Most cases of pathologic
jaundice are caused by exaggeration of the mechanisms that increase bilirubin
production, delay elimination or both. Unmonitored and untreated severe
hyperbilirubinemia can cause neuronal damage that results in acute bilirubin
encephalopathy and may lead to post-icteric brain injury (kernicterus). (1) In the United
States, the prevalence of kernicterus is approximately 1/30,000 (2), while in Europe, and
nations with home-supervised newborn care, such as Denmark, it has been shown to be
1/38,000 or lower (3).
Bilirubin is the product of heme catabolism, the majority of which is produced
during the breakdown of hemoglobin from senescing red blood cells. The conjugation of
bilirubin, from an albumin bound bilirubin to a water soluble compound, is conducted by
the liver and involves the uptake of bilirubin from the circulation, intracellular transport,
conjugation with glucoronic acid, and excretion as bile (4). Neonatal hyperbilirubinemia
results from a disturbance of the production and/or elimination of bilirubin. This can
result from a number of genetic conditions, as well as liver failure, breastfeeding failure,
breast milk jaundice, impaired intestinal motility from obstruction (4). Risk factors
include blood group incompatibility with positive direct antiglobin test, gestational age
<38 wks, known hemolytic disease, sibling history of jaundice, East Asian race, G6PD
deficiency and many others (1).
One of the major causes of neonatal hyperbilirubinemia prior to the institution of
anti-D immune globulin prophylaxis in US and Western Europe was Rh(D) disease. This
disease occurs when an Rh(D)-negative mother becomes alloimmunized to the Rh(D)
antigen and produces antibodies against the red blood cells of her infant (5). In order to
produce Rh(D) in her infant, a woman must first be sensitized to the Rh(D) antigen from
a prior exposure. Risk factors for sensitization include hydatidiform mole, fetomaternal
hemorrhage, fetal death, blunt trauma to abdomen, or external cephalic version (6). In
the US and Western Europe, Rh(D) negative women who are at risk for developing
alloimmunization are universally screened and treated prophylactically with anti-D
immune globulin (Rhogam). This practice, as of 1960s, has significantly reduced the
presence of Rh iso-immunization-induced hyperbilirubinemia in neonates (5).
While the problem of neonatal jaundice has been significantly reduced in the
United States through the use of Rhogam prophylaxis and improved treatment and
diagnosis techniques, this is not the case in many other regions of the world. Even in
relatively developed countries such as Russia, hyperbilirubinemia continues to be a
significant challenge for physicians. Although protocols for using Rh(D)
alloimmunization prophylaxis exist, they are not followed due to lack of resources. Also,
the protocols regarding the diagnosis and treatment of neonatal jaundice are severely
outdated and based on different measuring techniques than those currently employed.
Agulnik, 4
(7)1 These problems with the prevention and treatment of hyperbilirubinemia lead to a
large disparity between the medical care received by neonates in Russia compared to
their counterparts in the United States and Western Europe.
Our study seeks to address this disparity by providing data that can be used by
Russian physicians to develop a better understanding of the management of neonatal
jaundice. We hope that defining the specific and relevant root cause analysis for
occurrence of severe hyperbilirubinemia may help Russian pediatricians develop more
current protocols for the approach of neonatal jaundice. This project has been proposed
by a Russian neonatologist, Dr. Irina Ivanovna Ryumina, who has ties with both an
American School of Public Health (Johns Hopkins—Bloomberg School of Public Health)
and the Моscow Neonatal Research Institute of Pediatrics and Children Surgery. Dr.
Ryumina expressed a strong desire to see a study examining this topic conducted, but
explained that no one in her field was currently working on this issue. Providing Dr.
Ruymina, a leading pediatric researcher in Moscow, with specific evidence-based data
would help address the perceived need of the Russian medical community. As
recommended by Dr. Ryumina and my Stanford mentor, we seek to conduct a
comprehensive chart review of over 400 infants rehospitalized to the Neonatal Intensive
Care Unit of the City Hospital No.13, the major center for neonatal care in Moscow. We
will obtain data regarding demographics, risk factors for newborn jaundice, risk factors
for bilirubin neurotoxicity, detection and outcomes for patients with neonatal jaundice.
The results of this analysis will be compared to similar studies published in the American
literature, and used to identify the specific gaps in newborn healthcare and the
management of hyperbilirubinemia in Moscow. We anticipate that the data collected by
this study can eventually lead to the reduction of the incidence of severe
hyperbilirubinemia and, possibly, kernicterus, as well as to the better management of
neonatal jaundice in Russia.
III. Experimental Design
The aim of our study is to present data to identify the gaps in healthcare and
management of neonatal hyperbilirubinemia in Moscow, Russia. We will meet these
objectives by conducting a chart review and data analysis of all neonatal admissions to
City Hospital No.13 between January 1st 2005 and January 1st 20062. City Hospital No.
13 is the primary neonatal intensive care hospital for all of Moscow and the surrounding
area, and receives the majority of neonatal admissions in this district. This hospital
admits about 1000 patients per year, many of whom are re-hospitalized for management
of severe hyperbilirubinemia. By defining specific eligibility and exclusion criteria, we
expect to identify approximately 400-500 infants for a detailed chart review and analysis.
Our study will focus on infants who are >35 weeks gestational age with a birth weight
>2000 grams and who are <4 weeks of age at admission. We have chosen to set these
parameters because we wish to address the issue of hyperbilirubinemia in term and late
preterm infants (>35 weeks gestation), so that we can compare our data in the context of
the 2004 AAP guidelines.
1
Communicated in Russian by Dr. Irina Ivanovna Ryumina, Neonatal Research Institute of Pediatrics and
Children Surgery. Translated by Asya Agulnik.
2
We have decided to choose a full calendar year in order to eliminate confounding by seasonal variation in
hospital admissions.
Agulnik, 5
From the selected charts, we will collect data in a spreadsheet format about the
demographic information, risk factors, diagnosis, treatment and outcome for the patients
described above. Demographic information will include: gender, gestational age at birth
(wks), birth weight/length/head circumference, age at admission, weight at admission,
admitting diagnosis. Risk factor analysis will include: mode of delivery, breastfeeding,
discharge age, Rh incompatibility. Diagnosis information will include: method used to
test for bilirubin level, method for blood collection, other interventions done. Treatment
information will include: method used for treatment (phototherapy, transfusion, others).
Outcomes information will include: length of treatment, analysis of neural damage
(clinical examination, sensory-neural hearing loss or MRI, if done), kernicterus, and
survival. (Please see Figure 2)
The information collected will be used to conduct a number of analyses. First,
we wish to determine the prevalence of jaundice for our sample population, as well as
the trend in bilirubin levels among these infants. We will also evaluate the effectiveness
of the different measurement and treatment methods used. These results will be
compared to the current protocol for neonatal hyperbilirubinemia released by the
American Academy of Pediatrics (AAP) (8). This comparison will be used to assess
whether the neonatal jaundice in admitted patients was predictable or preventable, as
well as whether the care received was patient centered, timely, effective and safe
(Please see Figure 3 and 4). This analysis will be given as a tool to Russian
neonatologists to aid in the production of a systems-based approach for the
management of neonatal jaundice based on current clinical information and on the
relevant aspects of their medical system.
In approaching this project, we hypothesize that the study will identify a number
of areas in which the current approach to neonatal hyperbilirubinemia is different from
the United States and Europe. We also expect to see different demographical trends
(birthweight, gestational age, etc) associated with different levels of bilirubin than those
observed in America. Both of these criteria will be used by myself and the Russian
physicians to propose changes to the current practices that seek to address the
discrepancies observed between our countries.
It is important to acknowledge that the project proposed is a retrospective
analysis using previously collected patient data rather than a study using true evidencebased medicine. Current AAP suggestions for the management of hyperbilirubinemia
are based on consensus data from a number of such studies. Recent recommendations
proposed by a subcommittee of the AAP on hyperbilirubinemia reviewed retrospective,
admissions based data from a number of international sources to create their proposed
protocol for the managing neonatal jaundice (9). Other sources have supported the use
of this type of retrospective admissions based study to evaluate management of
hyperbilirubinemia and kernicterus for a number of reasons (10,11). It is important to
note that in the analysis conducted by the Subcommittee of the AAP, no data from
Russia was used (9), suggesting a lack of scholarship on this issue within Russia that
we wish to begin to address with our current study.
There are a number of factors that can influence the ultimate success of this
project. A major issue is that this is a retrospective study of a convenience sample.
Thus, it is dependent on the accuracy and thoroughness of clinical information recorded
in the patient charts. It’s possible that several of the criteria we wish to document (ex:
Rh(D) incompatibility, risk factors), may not be recorded either due to omission or lack of
Agulnik, 6
performance. If this is true, however, it is possible to focus on these missing pieces
when we seek identify the gaps and provide a basis for better screening and
documentation policies for specific components of patient history, physical examination
and testing. It is also possible that it will require more time than we expect to evaluate
the proposed number of charts (400-500). If this does occur, we will attempt to use
additional outside resources along with other people’s participation to complete the
project in a timely manner.
In order to conduct the analysis portion of this project, we wish to be careful not
to over-analyze the convenience sample. For basic biostatistical support, we will seek
counsel of Mr. Ron Wong, a bio-scientist at the Stevenson Laboratory. In addition, we
seek bio-statistical consultations from experts at the Моscow Neonatal Research
Institute and the Stanford School of Medicine. To protect patient confidentiality, we will
comply with the US HIPAA and Stanford IRB regulations and de-identify all patient data.
We are currently applying to the Stanford IRB for approval for this study. In addition, Dr.
Ryumina has already obtained approval from the corresponding body in the Моscow
Neonatal Research Institute.
IV. Relevance to Medicine
Newborn jaundice, usually a benign condition, can be a serious disorder that, if
unmonitored and untreated during the neonatal period, can lead to permanent
neurological injury (kernicterus) and death. While this condition is well managed in the
United States and western Europe by Rh(D) prophylaxis, early and predictive diagnosis
and timely intervention, it poses a significantly greater challenge to newborns and their
physicians in Russia. The shortage of Rh(D) prophylaxis, as well as the lack of a
systems-based protocols to address the management of hyperbilirubinemia creates a
wide disparity between the medical care received by neonates born in Russia and their
counterparts in the US. Our project seeks to address this disparity by conducting an
analysis of the current data regarding the demographics, diagnosis and treatment of
neonatal jaundice in Moscow. According to the Russian physicians, information is
severely needed by the medical community in order to improve their care of infants with
hyperbilirubinemia. The data collected will be published in the local medical journals, as
well as be made available to local physicians in order to develop an updated national
protocol for the management of neonatal jaundice.
V. Bibliography
(1) Wong RJ and Stevenson DK. Clinical features and management of unconjugated
hyperbilirubinemia in term or near term infants. UpToDate, August 24th 2005.
(2) Newman TB, Liljestrand P and Escobar GJ. Infants with bilirubin levels of 30 mg/dL
or more in a large managed care organization. Pediatrics 111 (6 Pt 1): 1303-11,
Jun 2003.
(3) Ebbesen F et al. Extreme hyperbilirubinaemia in term and near-term infants in
Denmark. Acta Paediatr 94 (1): 59-64, Jan 2005.
(4) Wong RJ and Stevenson DK. Pathogenesis and etiology of unconjugated
hyperbilirubinemia in the newborn. UpToDate, March 17th 2005.
Agulnik, 7
(5) Moise KJ. Prevention of Rh(D) alloimmunization. UpToDate. January 9th 2006.
(6) Prevention of Rho(D) alloimmunization. American College of Obstetricians and
Gynecologists Practice Bulletin No 4. American College of Obstetricians and
Gynecologists, Washington, DC 1999.
(7) Ryumina II, personal communication. See attachment for Personal
Recommendation Original.
(8) Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of
Gestation. Clinical Practice Guidelines: AAP. Pediatrics 114 (1): 297-316, July
2004.
(9) Ip S et al. An evidence-based review of important issues concerning neonatal
hyperbilirubinemia. Pediatrics 114 (1): e130-53, 2004.
(10) Bhutani VK et al. Kernicterus: epidemiological strategies for its prevention through
systems-based approaches. J. Perinatol 24 (10): 650-62, Oct 2004.
(11) Blackmon LR et al. Research on prevention of bilirubin-induced brain injury and
kernicterus: National Institute of Child Health and Human Development
conference executive summary, 2004. Pediatrics 114(1): 229-33, 2004.
(12) Bhutani VK et al. Risk management of severe neonatal hyperbilirubinemia to
prevent kernicterus. Clin Perinatol 32 (1): 125-39, March 2005.
VI. Appendix
25
20
95th %ile
75th %ile
15
40th %ile
10
S e ru m B iliru b in (m g /d l)
Low-Risk
Jaundice
5
0
0
12
24
36
48
60
72
84
96
108
120
A g e (h o u rs )
Figure 1. Age (hours) specific ranges of Total Serum Bilirubin (TBS) for term or near
term neonates (Bhutani nomogram).
Agulnik, 8
Figure 2. Root Cause Analysis spread sheet (attached)
Root Cause Analysis for Kernicterus
(partial list)












Failure to recognize the clinical significance of jaundice within the first 24 hours after birth.
Failure to recognize the limitations of visual recognition of jaundice.
Failure to recognize clinical jaundice and document its severity by bilirubin measurement
before discharge from the hospital.
Failure to ensure post-discharge follow-up based on the severity of pre-discharge
hyperbilirubinemia.
Failure to account for vulnerability of preterm infants (<37 weeks GA)
Failure to respond to parental concerns of newborn jaundice, poor feeding, lactational
difficulties and change in newborns behavior and activity.
Failure to provide ongoing lactational support in breast-feeding babies to ensure adequacy
of intake.
Failure to recognize the impact of race, ethnicity and family history on severity newborn
jaundice and risk of brain damage.
Failure to diagnose the cause of hyperbilirubinemia.
Failure to institute interventional strategies to prevent severe hyperbilirubinemia when
bilirubin is rising more rapidly than expected.
Failure to aggressively treat severe hyperbilirubinemia with intensive phototherapy or
exchange transfusion for “hazardous” bilirubin levels.
Failure to educate parents and health care providers about the potential irreversible risks
of jaundice during newborn period and infancy.
Figure 3. Root Cause Analysis conclusions from AAP (12)
Patient
Centeredness
Safety
Effective Care
Timeliness
Preventive care
provided
Access
Experience of
services
Diagnosis of
kernicterus
PatientProvider
Partnerships
Treatment
safety
Acute care and
chronic care
effectiveness
Getting the
right care in a
timely
manner
Environment
and facilities
Procedures used
Continuity of
care
Trustworthy
Care
Figure 3. Analysis Criteria (12)
Agulnik, 9
Note about applicant’s relationship to Russia:
My personal interest in this project comes from my family history. I was born in
Moscow and moved to the States in 1991 with my family. I have always been aware that
Russian healthcare has lagged far behind the United States since the fall of communism
shortly after my family left. As a bilingual physician, I wish to address this disparity in
many levels throughout my career. This project also allows me to focus on one of my
own interests in medical care—preventive medicine. Severe hyperbilirubinemia and
kernicterus are seen as never-events (events that should never occur) in the United
States and Europe, and working on this project in Moscow will help make these
conditions similarly rare in Russia. My current research on neonatal morbidities with Dr.
Madan, and my prior experiences have often focused on the topic of prevention, and my
trip to Russia will be a continuation of the kind of work I hope to continue throughout my
career. For these reasons, this project has a personal value to me, and I see this as a
first step in a long collaboration with physicians working to improve patient care in
Russia.
More practically, I am fluent in Russian and can easily navigate the Russian
culture and society based on my own background. This will allow me to begin my
project quickly without much prior introduction to the Russian culture. I will also have a
number of non-academic resources to aid me in the practical aspects of my stay in
Russia. I have many contacts in Moscow who will acculturate me to the new
environment, introduce me to the community and society, and monitor my personal
safety.
Note about Dr. Ryumina’s recommendation:
Dr. Ryumina’s letter of support is a translation by Asya Agulnik of a
recommendation that she wrote in Russian. Dr. Ryumina speaks some English but does
not feel comfortable enough to write a recommendation in English herself. She has
seen many versions of the recommendations, including the final one submitted to the
committee, and made changes where appropriate. I’ve included the most recent version
of the edited recommendation prior to my final translation with her Russian text (please
see attachment Ryumina Letter of Support Original), as proof of our collaboration.