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American Scientist

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Macroscope

The Blue Baby Syndromes


Roger P. Smith

cience can be a powerful tool


for discovery and problem solving, but it can also be a messy, nonlinear
process that does not provide all the answers. In such cases, people are forced
to make the best decisions possible
based on the available information, often erring on the side of cautionespecially where public health is concerned.
Whether or not those decisions are too
conservative will often be the topic of
long debate. One such example, involving drinking water standards and the
health of newborns, has continued for
more than half a century.
In 1987, the Journal of the American
Medical Association reprinted, as part
of its Landmark series, a case study
originally published in 1945, accompanied by a commentary and a report of
a new and fatal instance. The author of
the original paper, Hunter Comly, was
a pediatric resident in Iowa City when
he described two examples of a previously unrecognized blood condition in
infants. Called infantile methemoglobinemia, the affliction had as its main
symptom cyanosis, or turning blue
(thus the condition was also sometimes
called blue baby syndrome). Cyanosis
can also be a symptom of a congenital
heart disease, so Comly felt that the
two conditions might be confused.
In the congenital condition, called
tetralogy of Fallot, a complicated
structural defect allows blood returning from the body to the heart to be
pumped out again without going to
Roger P. Smith is the Irene Heinz Given Professor of Pharmacology and Toxicology, Emeritus, at
Dartmouth College and former chair of the department. He also served on the Associate Consulting
Staff of Mary Hitchcock Memorial Hospital in Lebanon, New Hampshire, and as a consultant to the VA
Hospital Medical Center in White River Junction,
Vermont. He received his Ph.D. from Purdue University. Address: Department of Pharmacology and
Toxicology, Dartmouth Medical School, Hanover,
NH 03755. Internet: roger.p.smith@dartmouth.edu
94

American Scientist, Volume 97

Did environment
or infection cause
a blood disorder in
newborns?
the lungs to be resupplied with oxygen. The hemoglobin in red blood cells
turns red when iron in the molecule
binds to oxygen; it turns bluish-purple
when the oxygen is unloaded, which is
why veins are bluish. With too much
deoxygenated blood in the arteries, the
skin turns from pink to blue (cyanosis
comes from the Greek kyanos, meaning
dark blue).
Alternatively, some chemicals can
oxidize the iron in hemoglobin. The
altered form, called methemoglobin,
loses the ability to bind oxygen, and
the pigment now changes to greenish brown or almost black. The human body contains enzymes to reverse
methemoglobinemia, but only up to
certain levels. After blood levels reach
15 percent, adults become visibly cyanotic. If more than half of the hemoglobin is converted, oxygen transport,
particularly to the brain, is severely
hampered, respiratory distress is likely,
and death is possible.
In congenital heart disease the cyanosis is apt to improve if treated with
oxygen, and if a sample of shed blood
is shaken in air, it often becomes lighter and redder in color. Since methemoglobin does not bind oxygen, infants with that condition do not pink
up on oxygen, and samples of shed
blood exposed to air undergo little or
no change in color.
The two conditions also look a little
different. During the influenza epidemic of 1918, the word heliotrope
was used to describe the color of the

cyanosis of hypoxia, whereas the cyan


osis of methemoglobinemia is often
described as slate-gray. Simple laboratory tests are available to identify
and quantify methemoglobin in blood,
and infants with high levels of it respond rapidly to intravenous methylene bluethis blue dye turns the blue
baby pink. When cyanosis develops
post-partum, it is usually noticed first
in the lips, spreading gradually to the
nail beds of the fingers and toes, the
face and then the whole body. Both
congenital heart disease and methemoglobinemia tend to result in hypoxia and peripheral vasodilation, which
may intensify the cyanosis.
Dont Drink the Water

In the condition first described by


Comly (now known as well-water methemoglobinemia), affected infants appeared healthy at birth and remained
so through discharge. The cyanosis
arose only after days, weeks or months
in the home environment. What made
Comlys paper so noteworthy was the
full explanation offered for the etiology of the diseaseone that has been
largely undisputed for 60 years.
He recognized that the only significant change in the infants environment from hospital to farm home was
in the water that was used to prepare
the formula. But what was the nature of the difference between hospital
and home water? After the third episode of admission and treatment with
methylene blue for one child, her father demanded to know exactly what
poison in his well was responsible.
Analyses of the water showed high
levels of nitrate.
Inquiries to other physicians in the
area about unpublished, similar cases
turned up 17 more, with one fatality, suggesting that the condition was
more common than suspected. As the
number of physicians who reported
seeing unexplained cyanosis in in-

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fants who had been fed powdered formula prepared with well water grew,
measurements of the nitrate content
of Iowa wells showed that more than
half of the 91 wells initially sampled
contained nitrate nitrogen in excess of
10 parts per million, and 20 contained
more than 65 parts per million.
Those wells that tested high for nitrates were clearly undesirable from a
public health standpoint. Most of them
were old, shallow and dug rather than
drilled, and they often had inadequate
casings. Many were poorly covered so
that surface runoff containing nitrate fertilizers or animal excreta rich in nitrates
could enter freely. They were often found
near barnyards, feedlots or pit privies, and some were contaminated with
coliform bacteria. Although the wells
served as the drinking water source for
the entire family, only formula-fed infants were affected, and most were less
than three months of age.
Subsequent independent surveys in
midwestern states confirmed the initial results in Iowa. The most complete
survey of all 48 states, plus what were
then the territories of Alaska and Hawaii, was compiled in 1951 and identified 278 cases with 39 deaths. No cases
were found in which wells contained
10 parts per million nitrate nitrogen or
less, and only 2.3 percent of the cases
involved wells with between 10 and
20 parts per million. Above 20 parts
per million, the severity of the symptoms seemed to parallel the amount of
nitrate present. Breastfed infants were
never involved; neither were families
who used municipal water supplies.
No reports of cases prior to World War
II were found. However, physician
reporting was not mandatory for the
condition, and the true number may
have been much higher.
But by the time that report was
published, the worst seemed to have
passed, and the number of cases fell
off steadily through the early 1950s.
Today the disease has all but disappeared, with reports appearing only
sporadically in the literature. Only
two cases have been reported since the
mid-1960s and none since 2000. Within
10 years the epidemic had waned as
suddenly as it had appeared, without
any preventive action having knowingly been taken. Whether it was because of public awareness, a massive
improvement in rural drinking water
quality, a trend toward breastfeeding
or other factors may never be known.

From the mid-1940s through the early 1950s, a number of midwestern farm babies developed
a potentially fatal blood disorder that leads to cyanosis, or blue baby syndrome. The infants
were all healthy at birth, but upon returning home, they were all fed with formula prepared
with well water. The miniepidemic had 278 cases and 39 deaths, but physician reporting was
not mandatory for the condition, so the true number may have been higher.

Nitrates to Nitrites

Comly realized that he needed to explain the sensitivity of newborns to


nitrates in order to complete the picture. He also needed an explanation
for how biologically inert nitrate was
responsible for oxidizing hemoglobin
to methemoglobin. The most plausible
candidate for the oxidizing agent was
nitrite, which was known to be a potent generator of methemoglobin. To
find it, he needed to look no further
than the diverse normal microflora of
the infant gut. Many common organisms found in the bowel were known
to convert nitrate to nitrite; the nitrite
could then be readily absorbed into the
blood to do its damage.
In adults, however, ingested nitratesmore than 97 percent of which
come from vegetables and other foods,
not waternever come in contact with
intestinal microflora, which are found
largely in the colon. Nitrates are absorbed rapidly in the duodenum and
excreted promptly in the urine. That
led to a consideration of the secondmost common finding in affected infants, namely evidence of gastrointestinal upset in the form of vomiting or
diarrhea, things so usual as to excite
little attention. A few infants who were
tested were found to have high gastric

pH in relation to adult values. Presumably the acidic milieu of the stomach


and duodenum discourages microflora
from invading the small intestine of
adults. But if the pH were high enough
in newborns, perhaps nitrate-reducing
organisms could survive in the small
intestine and come in contact with unabsorbed nitrate. This problem should
be self-solving as infants mature, because acid production in their stomachs increases to adult levels by about
six months of age. That coupled with a
relative deficiency in the enzyme that
reverses methemoglobin production in
infant red blood cells could be enough
to explain their sensitivity to nitrates.
As Comlys explanation stands, it is
both complete and plausible, but a
long way from scientifically proven.
Largely because of Comlys recommendation, 10 parts per million of
nitrate nitrogen quickly became the
standard for potable water supplies in
the U.S., and that maximum was reaffirmed in 1995 in the most recent review by the National Research Council. Unfortunately, nitrate removal from
raw drinking water involves considerable expense. Conventional treatment
processes are ineffective. A much more
expensive process of ion exchange is
the only one currently used. But those

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2009 MarchApril

95

St. Bartholomews Hospital, London/Photo Researchers

Cyanosis, caused by blood insufficiently supplied with oxygen, turns areas of an infants
skin visibly blue. The condition can be a
symptom of a heart defect, as is the case for this
infant. But it can also indicate exposure to a
chemical that alters hemoglobin in the blood.

at riskinfants under three months


of ageare one of the most vulnerable and emotionally charged groups
in our population, one that all agree
we would most like to protect.
A New Syndrome?

In the 1980s a new phenomenon


seemed to appear, namely, a form of
infantile methemoglobinemia associated with inflammatory bowel disease
(including diarrhea, acidosis, infection and gastroenteritis), where exposure to excessive nitrates could not be
clearly established. The first of these
reports appeared around 1982. Over
the course of a year the authors had
seen 11 infants with the triad of met
hemoglobinemia, diarrhea and acidosis. All were under three months of
age, and all lived in homes with municipal water supplies. Although infection was suspected in at least some of
these cases, no common fecal pathogens were isolated.
In the same year, a report from Israel described a study of 58 infants,
age one week to one and a half years,
admitted to the hospital for acute
diarrhea. Over 100 admitted infants
without gastrointestinal disturbances
served as controls. All were fed the
same milk, food and water, which had
been analyzed for nitrates and nitrites.
The study excluded infants with con96

American Scientist, Volume 97

founding factors such as genetic defects or exposure to drugs or chemicals


that generate methemoglobin. None
of the affected infants was said to be
cyanotic, and only 12 of the 58 had
methemoglobin levels above 8 percent.
However, infants with the more severe
diarrhea seemed to have higher methemoglobin levels. The nitrate concentration of the drinking water was well
under the U.S. standard, and the diet
was unusually low in nitrates. There
was no clear correlation of the degree
of acidosis and methemoglobin levels.
The most seminal observation was
that the affected infants had high
blood levels of nitrate, and those levels
did appear to parallel the degree of
methemoglobinemia. Affected infants
excreted several times more nitrate
in their urine than they consumed in
their diet. In the control group the urinary excretion of nitrate was about the
same as the daily intake or only slightly higher. Previously, scientists at the
Massachusetts Institute of Technology
had demonstrated nitrate production
within the body in germ-free rats.
As is often the case, these two reports opened the floodgates. Between
1983 and 1996 reports of more than
90 cases came out in the medical literature, and then, maddeningly, the
reports stopped appearing, just as they
had with well-water methemoglobinemia 50 years before.
In 1999, Alex Avery of the Center for
Global Food Issues at the Hudson Institute and his colleagues offered an ingenious explanation of the etiology after
an analysis of some seemingly unrelated
literature on inflammatory bowel disease. Noting that the earlier Israeli study
strongly suggested that nitrites produced in the body were responsible for
the methemoglobinemia and that their
end product, nitrates, were elevated in
urine and blood, they suggested the involvement of endogenous production
of nitric oxide from arginine. The importance of nitric oxide as a normal biological mediator in a number of physiological processes has only recently been
recognized. In solution, nitric oxide exists in equilibrium with nitrite. There is
some published evidence to suggest that
certain viral or bacterial infections of the
bowel cause an increase in nitric oxide
levels in human colonic epithelial cells.
Although these studies were focused on
explaining the pathologic changes in the
bowel, they offer a possible explanation
for the methemoglobinemia. That expla-

nation, however, does not yet suggest


why infants may be more susceptible.
At a Standstill

Few pursuits are more frustrating to the


biomedical scientist than attempts to investigate diseases of very low incidence.
It is a mixed blessing that both episodes
of infantile methemoglobinemia ended
spontaneously, because at this juncture
no further elucidation of either is in
sight. Try as we might, we face formidable obstacles in studying diseases that no
longer exist and for which there are no
satisfactory animal models. Nor is there
any incentive to carry out such studies.
The hypothesis that Avery has offered for the etiology of the endogenous disease is, of course, incompatible
with the exogenous well-water nitrate
hypothesis. If Comly was wrong, exogenous nitrates were a red herring, and
the drinking water standard for nitrate
has been set at an unnecessarily low
level. Communities may have incurred
needless expense in pursuing nitrate
removal. However, the evidence for
the involvement of well-water nitrate
in the first miniepidemic is at least as
strong, if not stronger, than the evidence for the involvement of gastrointestinal infections in the second. The
clear dose-response relationship between the well-water nitrate content
and the severity of the methemoglobinemia, and the logical explanation
for the sensitivity of infants to nitrate,
support the etiology proposed for the
first episode, but their equivalents are
lacking for the second.
Science is simply not always able to
provide neat and clean answers, and
in order to protect the public, expensive policy decisions must sometimes
be made based on whatever facts are
known. We seem to be forced to the
conclusion that an exceedingly rare
toxic condition, methemoglobinemia
in infants, is linked to two episodes of
exposure to endogenous nitrite, but
generated by two entirely different
mechanisms. More improbable still is
that both episodes suddenly appeared
and then spontaneously resolved over
the space of a dozen years, each in the
second half of the 20th century. As
Sherlock Holmes famously remarked
to Dr. Watson, When you have eliminated the impossible, whatever remains, however improbable, must be
the truth. It also may be, in a way,
a vindication of the now 50-year-old
drinking water standard for nitrate.

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