Thrombocytopenia in Small-for-

Gestational-Age Infants
Robert D. Christensen, MDa,b,c, Vickie L. Baer, RNd, Erick Henry, MPHc, Gregory L. Snow, PhDe, Allison Butler, MSe,
Martha C. Sola-Visner, MDf

BACKGROUND:Thrombocytopenia is common among small-for-gestational-age (SGA) neonates abstract

(birth weight ,10th percentile reference range), but several aspects of this thrombocytopenia
are unclear, including the incidence, typical nadir, duration, association with preeclampsia,
mechanism, and risk of death.
Using 9 years of multihospital records, we studied SGA neonates with $2 platelet
METHODS:
counts ,150 000/mL in their first week.
RESULTS:We found first-week thrombocytopenia in 31% (905 of 2891) of SGA neonates versus
10% of non-SGA matched controls (P , .0001). Of the 905, 102 had a recognized cause of
thrombocytopenia (disseminated intravascular coagulation, early-onset sepsis, or extracorporeal
membrane oxygenation). This group had a 65% mortality rate. The remaining 803 did not have
an obvious cause for their thrombocytopenia, and we called this “thrombocytopenia of SGA.”
They had a mortality rate of 2% (P , .0001) and a mean nadir count on day 4 of 93 000/mL
(SD 51 580/mL, 10th percentile 50 000/mL, 90th percentile 175 000/mL). By day 14, platelet
counts were $150 000/mL in more than half of the patients. Severely SGA neonates (,1st
percentile) had lower counts and longer thrombocytopenia duration (P , .001). High nucleated
red cell counts at birth correlated with low platelets (P , .0001). Platelet transfusions were
given to 23%, and counts typically more than tripled. Thrombocytopenia was more associated
with SGA status than with the diagnosis of maternal preeclampsia.
SGA neonates with clearly recognized varieties of thrombocytopenia have a high
CONCLUSIONS:
mortality rate. In contrast, thrombocytopenia of SGA is a hyporegenerative condition of
moderate severity and 2 weeks’ duration and is associated with evidence of intrauterine
hypoxia and a low mortality rate.

Divisions of aHematology/Oncology, and bNeonatology, Department of Pediatrics, University of Utah School of WHAT’S KNOWN ON THIS SUBJECT: Small-for-
Medicine, Salt Lake City, Utah; cPrimary Children’s Hospital, Salt Lake City, Utah; dWomen and Newborn’s
Clinical Program, Intermountain Healthcare, Salt Lake City, Utah; eStatistical Data Center, LDS Hospital, Salt gestational-age neonates are at risk for
Lake City, Utah; and fDivision of Neonatal Medicine, Children’s Hospital and Harvard Medical School, Boston, thrombocytopenia during the first days and weeks
Massachusetts
after birth. However, the incidence, duration,
Drs Christensen and Sola-Visner and Ms Baer conceptualized and designed the study; Ms Baer severity, responsible mechanism, value of platelet
carried out the initial analyses; Dr Christensen drafted the initial manuscript; Dr Snow and transfusions, and risk of death from this variety of
Ms Butler carried out the statistical analysis; Mr Henry carried out the statistical display; Ms Baer,
Mr Henry, Drs Snow and Sola-Visner, and Ms Butler reviewed and revised the manuscript; and all neonatal thrombocytopenia are unknown.
authors approved the final manuscript as submitted.
WHAT THIS STUDY ADDS: Ten percent of
Accepted for publication May 7, 2015 thrombocytopenic small-for-gestational-age
www.pediatrics.org/cgi/doi/10.1542/peds.2014-4182 neonates have a recognized cause for low
DOI: 10.1542/peds.2014-4182 platelets (aneuploidy, extracorporeal membrane
Address correspondence to Robert D. Christensen, MD, University of Utah Department of Pediatrics, oxygenation, disseminated intravascular
295 Chipeta Way, Salt Lake City, UT 84108. E-mail: [email protected] coagulation); they have a high mortality rate
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). (65%). Ninety percent have a moderate, transient
Copyright © 2015 by the American Academy of Pediatrics (2 weeks), hyporegenerative thrombocytopenia
with a low mortality rate (2%).

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PEDIATRICS Volume 136, number 2, August 2015 ARTICLE
Neonates who are born small for report. Patient records were accessed Neonates were classified as SGA if
gestational age (SGA) (,10th if the neonate had a date of birth from their weight at birth was ,10th
percentile birth weight for a reference January 1, 2004, to December 31, percentile for gestational age, using
population) are at risk for having 2013. The Intermountain Healthcare normative values from our
thrombocytopenia in the first weeks Institutional Review Board approved Intermountain Healthcare
after birth.1–6 Some of these neonates this as a deidentified data–only study population.10 Severity of SGA was
have varieties of thrombocytopenia as not requiring the consent of classified according to 3 categories:
that are readily recognized, such as individual subjects. ,1st percentile (severe), first to fifth
the consumptive thrombocytopenias percentile (moderate), and sixth to
accompanying disseminated Blood Cell Counts and Platelet 10th percentile (mild). Preeclampsia
intravascular coagulation (DIC), Transfusions was identified from case-mix records
extracorporeal membrane Platelet counts and mean platelet using the following definitions from
oxygenation (ECMO), or early-onset volumes (MPVs) were determined in the International Classification of
sepsis or the hyporegenerative all hospitals with the Beckman Diseases, Ninth Revision, Clinical
thrombocytopenias associated with Coulter LH750 Hematology Analyzer Modification (Ingenix Expert, Eden
marrow-failure syndromes. Other SGA (Fullerton, CA) from 2004 to mid- Prairie, MN): 6425, 6426, and 6427.
neonates have a type of 2012. After mid-2012, platelet counts SGA neonates were matched 1:1 with
thrombocytopenia with no obvious and MPVs were determined by using neonates from the same hospitals
explanation, a variety sometimes Sysmex counters (Sysmex America, born during the same period of time
termed by exclusion Lincolnshire, IL). All blood tests were who were not SGA. Matching was
“thrombocytopenia of SGA.”1–6 That performed in accordance with performed on the basis of gestational
variety has been the subject of Intermountain Healthcare Laboratory age (within 1 week) and year/month
previous reports, but many aspects Services standard operating of birth (within 1 month). Early
remain unclear. As a step toward procedures. Nucleated red blood cells thrombocytopenia was defined as $2
enhancing the knowledge base of the were quantified using either platelet counts ,150 000/mL during
thrombocytopenia of SGA, we automated cell counts, performed in the first week after birth. Using chart
conducted an analysis of all SGA accordance with the hematology reviews and electronic reviews of
infants born in our health care system analyzer manufacturer’s instructions, laboratory data, patients whose data
during a 9-year period. The aims were or manual enumeration, performed would otherwise qualify for inclusion
(1) to identify a group of by certified medical technologists on in the SGA and thrombocytopenia
thrombocytopenic SGA neonates in Wright-stained blood smears, group were excluded if they were
whom the thrombocytopenia was not counting a minimum of 100 nucleated recognized to have another variety of
a readily apparent variety; and (2) in cells per test. The reference intervals thrombocytopenia. These specifically
that group (termed thrombocytopenia for complete blood count parameters included early-onset sepsis,
of SGA), to identify the incidence, are those we previously published congenital cytomegalovirus (CMV) or
nadir, severity, and duration of the from Intermountain Healthcare other congenital viral infection, ECMO
thrombocytopenia and whether it was databases.7 treatment, immune-mediated
more closely associated with Guidelines for administering platelet thrombocytopenia, aneuploidy,
preeclampsia versus SGA status, transfusions in the Intermountain varieties of severe congenital
assess the responsible mechanisms, Healthcare NICUs during this period thrombocytopenia, or DIC. DIC was
and describe the outcomes. have been published.8,9 All platelet diagnosed by the combination of
transfusions were type specific or AB hypofibrinogenemia for age,11
(Rh positive or negative) and were schistocytosis,12 prolongation of
METHODS derived from apheresis. They were prothrombin time and activated
not pooled or volume-reduced, but all partial thromboplastin time for age,11
Patient Information were subjected to leukofiltration and and elevated D-dimers.
Data were collected retrospectively as irradiation and administered in
deidentified limited data sets from a volume of 10 to 15 mL/kg body Data Collection and Statistical
archived Intermountain Healthcare weight. Gestational age was Analysis
records. Intermountain Healthcare is determined by obstetrical assignment The program used for data collection
a not-for-profit healthcare system unless changed by the neonatologist was a modified subsystem of Clinical
that owns and operates 19 hospitals on the basis of gestational age Workstation. The 3M Company
with labor and delivery units in Utah assessment (physical examination (Minneapolis, MN) approved the
and Idaho. The information collected and neurologic-neurodevelopmental structure and definitions of all data
was limited to the information in this findings). points for use within the program.

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e362 CHRISTENSEN et al
Data were managed and accessed by Intermountain Healthcare NICU, and Of the 905 thrombocytopenic SGA
authorized data analysts. Means and 3964 of these were SGA (Fig 1). Of the neonates, 102 had a condition
standard deviations were used to SGA infants, 2891 had $2 platelet (besides SGA) that might have caused
express values in groups that were counts measured in the first week, their thrombocytopenia (Fig 1). These
normally distributed, and medians and 905 (31.5%) of these had $2 conditions included treatment with
and ranges to express values in platelet counts ,150 000/mL, ECMO (n = 28), aneuploidy (n = 30,
groups that were not. Differences in thereby qualifying for the definition 3 of whom were also on ECMO),
categorical variables were assessed of early (first-week) early-onset culture-positive bacterial
by using the Fisher exact test or x2. thrombocytopenia. Thus the sepsis (n = 6), congenital CMV (n = 6),
Student nonpaired t test was used to incidence of thrombocytopenia in our congenital marrow failure syndromes
assess continuous variables. SGA neonates was 31.5%, which was (n = 4), alloimmune
Statistical analysis used the higher than the 10.0% incidence of thrombocytopenia (n = 2), DIC (n = 8),
R Foundation package (Statistical early thrombocytopenia among 2891 and various malformation syndromes
Computing, Vienna Austria). The non-SGA control neonates matched (n = 18). These 102 neonates were
mixed-effects model used NIME for gestational age (P , .0001) excluded from further analysis,
software, version 3.1-105, also from (Fig 1). The 2891 non-SGA controls leaving 803 with a condition we
the R package. Statistical significance were well matched with the 2891 termed thrombocytopenia of SGA
was set as P , .05. SGA neonates on the basis of (Table 2).
gestational age (Table 1), but (as Platelet counts in these 803 are
expected) the non-SGA control group shown in Fig 2. The reference interval
RESULTS had a higher birth weight; lower rates for platelet counts of neonates during
of cesarean delivery, maternal their first 3 weeks (5th to 95th
Incidence, Severity, and Duration of eclampsia or preeclampsia, and
Thrombocytopenia percentile limits), which we
mortality; and proportionately more published previously,13 is shown by
During the 9-year period studied, males compared with the SGA the shaded area for comparison. The
24 036 neonates were admitted to an neonates. lowest platelet counts were typically
on day 4, with a mean nadir
of 93 000/mL (SD 51 580/mL,
10th percentile 50 000/mL,
90th percentile 175 000/mL). By day
14 of life, the platelet count had
increased to $150 000/mL in half of
the infants and was $100 000/mL in
70%. By day 21, the count was
$150 000/mL in about two-thirds
(Fig 2). The most severely SGA
neonates (birth weight ,1st percentile
reference range) had lower platelet
counts than those with moderate
(P = .013) or mild (P = .005) SGA
(Fig 3). The severe SGA group also had
a longer duration of thrombocytopenia,
with 50% having platelet counts
,150 000/mL by 28 to 30 days.

SGA and Preeclampsia

Associations of thrombocytopenia
with SGA status versus maternal
preeclampsia were sought by
comparing the lowest platelet count
during the first 4 days of life among
4 groups of NICU patients matched
for gestational age (within 1 week)
FIGURE 1 (Fig 4). Neonates who were SGA but
Study flow diagram to identify neonates with thrombocytopenia of SGA. no maternal preeclampsia was

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PEDIATRICS Volume 136, number 2, August 2015 e363
TABLE 1 SGA Neonates and Non SGA Matched Controls Admitted to a NICU
Group n Gestational Age, wks Birth Weight, g Male Gender Cesarean Delivery Eclampsia or Preeclampsia Mortalitya
SGA 2891 35 6 3 2044 6 634 49.8 53.9 12.8 4.1
Not SGA 2891 35 6 3 2841 6 816 59.8 44.4 1.6 1.6
P .999 ,.0001 ,.0001 ,.0001 ,.0001 ,.0001
SGA neonates (n = 2891) admitted to a NICU who had at least 2 platelet counts obtained in the first week were matched by gestational age and date of birth (within 1 month) with non-SGA
neonates admitted to a NICU with at least 2 platelet counts in the first week, to assess any association between SGA status and early (first-week) thrombocytopenia.
Values are expressed as mean 6 SD or %.
a Deaths in the NICU.

diagnosed (Group 1) had lower platelet an elevated nucleated red blood cell platelet count after transfusion,
counts (mean 153 000/mL) than did count (NRBC, per microliter) at birth calculated by subtracting the
those born to women with correlated with a low platelet count pretransfusion count from the count
preeclampsia but were not SGA (Group in the first week after birth (Fig 5) performed 1 to 24 hours after
2) (197 000mL, P , .0001, 95% (P , .01). MPV measurements transfusion, was 118 990 6 59 736/mL.
confidence interval on the difference 22 accompanying the platelet counts of Figure 7 shows the increase and
to 64). Using linear regression to the 803 thrombocytopenic neonates subsequent decrease in platelet
account for gestational and birth weight, over their first week after birth are counts after platelet transfusion. For
the point estimate of the difference in displayed in Fig 6. Overlying the ease of comparison, all platelet counts
the 2 groups was still significant values in the shaded area is the MPV were normalized to percentage of the
(P = .0189, 95% confidence interval on reference interval (5th to 95th pretransfusion platelet count.
the difference 10 to 61). Among SGA percentile limits) that we published
neonates, the presence or absence of previously.13 Outcomes
preeclampsia made no difference in the Of the 803 neonates with Ten SGA neonates had severe
platelet count. Thus, preeclampsia may thrombocytopenia of SGA, 182 (23%) thrombocytopenia (,50 000/mL)
not be associated with a risk of neonatal received 1 to 33 apheresis platelet that persisted for at least 4 weeks
thrombocytopenia over and above the transfusions. Reviews indicated that (Table 2). Nine of the 10 were
risk associated with SGA status. 98% of the transfusions were given severely SGA (,1st percentile
prophylactically, meaning the patient at birth). Four of these had no
Nucleated Red Blood Cell Count, MPV, did not have active bleeding. Platelet apparent explanation, other than
and Response to Platelet Transfusion counts before the transfusions ranged the SGA status, for persistent
Among the 803 neonates we labeled from 6000 to 110 000/mL; median severe thrombocytopenia. The
as having thrombocytopenia of SGA, count was 49 000/mL. The rise in other 6 had developed late-onset

TABLE 2 Ten SGA Neonates Classified as Having Severe and Persistent Thrombocytopenia of SGA
Birth SGA Gestational Maternal Lowest platelet Lowest platelet Platelet Diagnosis at 4–6 wks Outcome
Weight, g Percentile age at Preeclampsia, count in the first 2 count at 4–6 Transfusions
birth, wk/d Eclampsia, or HELLP wks after birth, /mL weeks, /mL Received, n
350 ,1st 24/0 None 27 000 48 000 21 Necrotizing enterocolitis Died at 6 mo in NICU
with bowel resection
406 ,1st 22/6 HELLP 42 000 30 000 33 a
Died at home at 7 mo
420 ,1st 24/5 HELLP 52 000 23 000 31 Candida sepsis Died at home at 17 mo
470 ,1st 26/5 Eclampsia 46 000 40 000 8 a
Lived
480 ,1st 23/6 Preeclampsia 49 000 38 000 11 a
Lived
510 ,1st 26/4 Preeclampsia 36 000 36 000 8 Klebsiella sepsis Lived
565 ,1st 27/0 HELLP 121 000 47 000 10 Necrotizing enterocolitis Lived
with bowel perforation
and resection
580 ,1st 27/1 None 52 000 10 000 16 Necrotizing enterocolitis Lived
with Enterobacter
cloacae sepsis
663 ,1st 29/2 None 36 000 37 000 4 a
Lived
2100 10th 35/1 None 73 000 12 000 8 Complex congenital heart Died in hospice at 5 y
disease, Klebsiella
sepsis
Ten SGA neonates who were classified as having thrombocytopenia of SGA and, when tabulated 28 to 42 days after birth, were still severely thrombocytopenic (,50 000/µL) and receiving
platelet transfusions. Six of the 10 had “late consumptive thrombocytopenia” and 4 had no explanation for persistent thrombocytopenia, other than thrombocytopenia of SGA.
a No explanation, other than severe SGA, for severe thrombocytopenia continuing at 4 to 6 wks.

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e364 CHRISTENSEN et al
 Mean platelet counts of these
10 during their first 3 weeks (grouped
as the 4 with no explanation for
prolonged thrombocytopenia and the
6 with NEC or late-onset sepsis) are
shown in Fig 2 along with the entire
group of 803 with thrombocytopenia
of SGA (box and whiskers) and the
normal controls (shaded area). This
group of 10 with persistent severe
thrombocytopenia received 4 to
33 platelet transfusions. All of these
were prophylactic, for platelet counts
,50 000 to 60 000/mL, with no signs
of bleeding.
– – – – – –
Of the 1986 SGA neonates in whom
thrombocytopenia was not identified,
FIGURE 2 34 (2%) died. In contrast, of the
Platelet counts of 803 neonates with thrombocytopenia of SGA during their first 30 days. Median
platelet count, first and third interquartile range (box), and 10th and 90th percentile values
905 SGA neonates in whom
(whiskers) are shown. The shaded area shows the normal reference interval for platelet counts of thrombocytopenia was identified,
neonates of $35 weeks’ gestation (modified from Wiedmeier et al13). Also shown are platelet counts 85 (9%) died (P , .0001) (data shown
of 10 of the 803 whose thrombocytopenia persisted when checked in the 28- to 42-day window. Four in Supplementary Table 3). Of the 102
of the 10 (open circles, solid line) had no explanation for prolonged thrombocytopenia besides
thrombocytopenia of SGA, and 6 (closed circles, dashed line) had developed either necrotizing SGA neonates with known varieties of
enterocolitis or late-onset sepsis (see Table 2 for details of these 10). thrombocytopenia (eg, ECMO or DIC),
66 (65%) died. However, of the 803
SGA neonates with thrombocytopenia
thrombocytopenia accompanying gestational age, or platelet counts in
of SGA, 19 (2%) died (P , .0001
necrotizing enterocolitis or sepsis. the first 4 days, we were not able to
vs. SGA neonates with known varieties
Using data from the first days after recognize these 6 as distinct from the
of thrombocytopenia). All
birth, focusing on birth weight, other 2885 in the group of 2891.
thrombocytopenic SGA neonates with
DIC who died had bleeding problems
at the time of death, predominantly
pulmonary hemorrhage. None of those
with trisomy 18 or 13 who died had
bleeding problems (shown in
Supplementary Table 3).
Logistic regression was performed to
identify clinical variables predictive of
severe (,50 000/mL) and prolonged
($2 weeks) thrombocytopenia, which
we judged could be relevant to future
testing of thrombopoietin receptor
agonists such as romiplostim.14 This
medication takes 7 to 10 days to
elevate the platelet count; therefore,
neonates recognized within the first
days as being very likely to remain
severely thrombocytopenic for $2
FIGURE 3 weeks might be candidates for
Platelet counts measured on day 4 of life (the mean nadir of platelet count) of SGA neonates experimental treatment. Three
according to birth weight percentile. Counts are grouped from neonates weighing less than first variables had predictive correlations:
percentile, first to fifth percentile, sixth to 10th percentile, and 11th to 99th percentile for gestational (1) gestational age at birth (shorter
age (the latter group considered controls). In each of the weight categories, the median platelet
count is shown along with the first and third interquartile range (box) and the 10th and gestation was associated with higher
90th percentile values (whiskers). likelihood of severe, persistent

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PEDIATRICS Volume 136, number 2, August 2015 e365
 thrombocytopenia accompanying
bacterial or fungal sepsis or
necrotizing enterocolitis.1,2,5,6 Rare
varieties of hyporegenerative
thrombocytopenia accompany
aneuploidy or syndromes involving
thrombopoietic failure.1–3 A separate
variety of early thrombocytopenia has
been described among neonates who
are SGA. The first report of this entity
was by Meberg et al from Oslo in
1977.19 They studied 23 neonates
weighing ,10th percentile who, with
no other explanation, had $1 platelet
count ,100 000/mL in the first days
after birth. The platelet counts
FIGURE 4 generally increased to .150 000/mL by
Platelet counts during the first 4 days after birth among 4 groups of NICU admissions (each n = 100): day 15 of life, and none had pathologic
(1) SGA but no preeclampsia, (2) preeclampsia but not SGA, (3) both SGA and preeclampsia, and (4) bleeding. The authors speculated that
neither SGA nor preeclampsia.
this thrombocytopenia was the result of
chronic hypoxia in utero induced by
placental insufficiency. In 1983, Shuper
thrombocytopenia); (2) gender predicting severe and prolonged
et al from Israel reported 14 SGA infants
(males were more likely to have thrombocytopenia.
with $1 platelet counts ,100 000/mL
severe, persistent
and no other explanation for the
thrombocytopenia); and (3) lowest
DISCUSSION thrombocytopenia.20 Elevated
platelet count in the first week
NRBCs at birth were common in the
(generally on day 4). However, the Thrombocytopenia is a common
thrombocytopenic neonates; thus
models were insufficiently predictive problem among patients in
they postulated, as had Meberg
for individual patients, and no NICUs.1,2,5,6,14–18 The majority have
et al, that the condition was due to
variable had an odds ratio .1.45 acquired varieties of consumptive
reduced platelet production
associated with chronic intrauterine
hypoxia. Our present study used
a large multihospital dataset to better
define this condition, which has come
to be termed thrombocytopenia of
SGA1–6.
We began by identifying all patients in
the last 9 years admitted to an
Intermountain Healthcare NICU with
a birth weight ,10th percentile.10 We
then determined how many of these
SGA neonates had $2 platelet counts
drawn during their first week, and
how many of those had $2 platelet
counts ,150 000/mL. A low platelet
count in a neonate can be real or
artifactual; the latter typically involves
platelet clumping, either on the wound
when blood is drawn slowly from
a capillary puncture or within the
specimen tube.21 We aimed to reduce
FIGURE 5 the contamination of our dataset with
Among 803 neonates with thrombocytopenia of SGA, NRBC (per microliter) at birth is compared with artifactual thrombocytopenia by
lowest platelet count recorded in the first 3 days after birth. requiring 2 low counts.

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e366 CHRISTENSEN et al
 thrombocytopenia appears to be
primarily hyporegenerative as
opposed to accelerated platelet
consumption or destruction. We
made this judgment on the basis of
normal MPVs and good responses to
platelet transfusions. (2) The low
platelet counts are associated with
intrauterine hypoxemia (elevated
NRBC) and with the pathology that
creates fetal growth restriction, not
the pathology that produces
preeclampsia without fetal growth
restriction. (3) The thrombocytopenia
is typically only moderately severe
(mean nadir count of 93 000/mL) with
a typical nadir on about day 4 and
FIGURE 6 a typical duration (days to a count
MPV (femtoliters). Values are shown from 803 neonates who met a definition of thrombocytopenia of
.150 000/mL) of 2 weeks. However,
SGA. Median values, first and third interquartile range (box), and 10th and 90th percentile values
(whiskers) are shown. The shaded area represents the normal reference interval for MPV (modified those with severe SGA tend to have
from Wiedmeier et al13). lower counts and a longer duration.
Cremer et al also suggested that
After identifying all SGA neonates thrombocytopenia of SGA. We found thrombocytopenia of SGA is the
who had early (first-week) that ∼10% of thrombocytopenic SGA kinetic result of reduced platelet
thrombocytopenia, we sought to cull neonates had a readily identifiable production, by measuring the
those associated with a recognized variety of thrombocytopenia, and that immature platelet fraction.22 They
cause of thrombocytopenia. This was group had a high mortality rate found a trend toward lower
done so that we could tentatively (65%). In contrast, 90% had a low- immature fractions (suggesting
classify the others as having the mortality variety with the following
reduced platelet production) in
exclusionary diagnosis of characteristics. (1) The
thrombocytopenic SGA neonates
compared with thrombocytopenic
neonates who had infection, in whom
the mechanism is likely accelerated
platelet utilization.
Reduced platelet production was
also the mechanism suggested
by the work of Murray et al,
who observed that preterm
infants with thrombocytopenia
had fewer circulating
megakaryocyte progenitors than
nonthrombocytopenic controls.23
Likewise, we reported few
megakaryocytes in the marrow of
3 thrombocytopenic SGA
neonates.24 Both Murray et al23
and Sola et al24 reported low
plasma thrombopoietin concentrations,
FIGURE 7
Platelet counts after apheresis platelet transfusions to 196 neonates. All values are normalized to suggesting inadequate upregulation
percentage of the pretransfusion platelet count (all pretransfusion counts are shown as 100%). of thrombopoietin production.
Median values, first and third interquartile range (box), and 10th and 90th percentile values The hypothesis that the
(whiskers) are shown. The peak and characteristics of the subsequent decrease are used to infer
the kinetic mechanism responsible for the thrombocytopenia (reduced platelet production versus thrombocytopenia of SGA is primarily
accelerated platelet destruction). due to thrombopoietin deficiency

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PEDIATRICS Volume 136, number 2, August 2015 e367
in utero is consistent with these highlighted by Josephson et al, addition, in our studies of
studies but remains to be confirmed. platelet transfusion strategies for associations with preeclampsia, we
The molecular mechanisms resulting neonates lack a strong evidence captured only those women coded as
in thrombocytopenia of SGA may be base.30 There is substantial having HELLP (syndrome of
similar to that causing disagreement on neonatal platelet hemolysis, elevated liver enzymes,
thrombocytopenia of perinatal transfusion thresholds, but it is and low platelets), eclampsia, or
asphyxia.25 We suspect that fetal widely accepted that platelet severe or moderately severe
hypoxia is causally involved in both transfusions should be given to preeclampsia, not those with mild or
varieties, which is consistent with the neonates if their platelet count falls unspecified preeclampsia; thus we
study of McDonald et al,26 in adult below 20 000/mL.1,31,32 Counts that might have ignored associations
mice subjected to hypoxia, and the low should be rare in neonates with between thrombocytopenia and mild
marrow culture studies of thrombocytopenia of SGA. From our preeclampsia. Last, we did not
Saxonhouse et al.27,28 present data, 90% of platelet count identify the molecular mechanisms
among neonates with this diagnosis involved in the association between
If the thrombocytopenia of SGA is SGA status and thrombocytopenia.
determined to be the result of will be .50 000/mL; thus perhaps
Clarifying this mechanism should be
thrombopoietin deficiency, it will 10% will be ,50 000/mL. In our
the topic of future investigations, as it
remain unclear whether present analysis, 182 of the 803
might suggest novel preventive or
thrombopoietin receptor agonists neonates with thrombocytopenia of
treatment approaches.
such as romiplostim or eltrombopag SGA received platelet transfusions. In
will be of value in treating this retrospect, we question how many of Considering the weaknesses and
condition.14,29 Most neonates with those were beneficial. Very few had strengths of our data, we maintain it
the thrombocytopenia of SGA are not a platelet count ,20 000/mL, most is reasonable to conclude that about
severely thrombocytopenic; thus had a pretransfusion platelet count one-third of SGA infants have early
perhaps no treatment is warranted .50 000/mL, and almost all were thrombocytopenia. About 10% of
for most. Moreover, romiplostim and transfused prophylactically with no these have an obvious cause of
eltrombopag require 7 to 10 days bleeding problems prompting the thrombocytopenia such as sepsis,
between commencement of dosing transfusion. aneuploidy, or ECMO treatment, and
and a significant increase in platelet this group has a high mortality rate
We recognize several significant (65% in our dataset). However, 90%
count, and half of the neonates with problems in our retrospective
this variety of thrombocytopenia have of thrombocytopenic SGA neonates
analysis. For instance, surely some have a different variety that could be
platelet counts .150 000/mL by day relevant data were sometimes
14. Because a subset of patients termed thrombocytopenia of SGA.
missing from the charts or electronic Those neonates should have a low
remain severely thrombocytopenic databases, and bias may have been
for .14 days, and some for .28 days, mortality rate, yet some will
unintentionally introduced. Also, probably receive multiple platelet
the efficacy, risks, and benefits of platelet counts after platelet
administering thrombopoietin transfusions.
transfusions were not obtained on
agonists to that group might warrant a standard schedule, and platelet
future study, if they could be transfusions were given to some and
identified in the first week. We found not to others without any clear ABBREVIATIONS
that these are typically males born at explanation. Also, changes in
very early gestational age with very CMV: cytomegalovirus
obstetrical and neonatology practices DIC: disseminated intravascular
low counts initially. However, we occurred during the 9 years of study.
were unable to accurately predict coagulation
The practice changes we recognize ECMO: extracorporeal membrane
during the first week which infants are the overall reduction in NICU
would still have severe, persistent oxygenation
transfusions during this period8 and MPV: mean platelet volume
thrombocytopenia after 2 weeks. the specific reduction in platelet NRBC: nucleated red blood cell
One treatment option for neonates transfusions on the basis of a change count
with thrombocytopenia of SGA is from platelet count–based guidelines SGA: small for gestational age
platelet transfusion, but as to platelet mass–based guidelines.9 In

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This work was partially supported by US National Institutes of Health grant PO1HL046925 (Dr Sola-Visner).

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e368 CHRISTENSEN et al
POTENTIAL CONFLICT OF INTEREST: Dr Sola-Visner presented a webinar on evaluation of neonatal thrombocytopenia and was invited speaker at the Sysmex New
England Users Group Meeting, discussing challenges in the evaluation and management of neonatal anemia and thrombocytopenia. The other authors have
indicated they have no potential conflicts of interest to disclose.

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e370 CHRISTENSEN et al
 Thrombocytopenia in Small-for-Gestational-Age Infants
Robert D. Christensen, Vickie L. Baer, Erick Henry, Gregory L. Snow, Allison Butler
and Martha C. Sola-Visner
Pediatrics 2015;136;e361
DOI: 10.1542/peds.2014-4182 originally published online July 27, 2015;

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 Thrombocytopenia in Small-for-Gestational-Age Infants
Robert D. Christensen, Vickie L. Baer, Erick Henry, Gregory L. Snow, Allison Butler
and Martha C. Sola-Visner
Pediatrics 2015;136;e361
DOI: 10.1542/peds.2014-4182 originally published online July 27, 2015;

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