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

abstractBACKGROUND: Thrombocytopenia is common among small-for-gestational-age (SGA) neonates(birth weight ,10th percentile reference range), but several aspects of this thrombocytopeniaare unclear, including the incidence, typical nadir, duration, association with preeclampsia,mechanism, and risk of death.

METHODS: Using 9 years of multihospital records, we studied SGA neonates with $2 plateletcounts ,150 000/mL in their first week.

RESULTS: We found first-week thrombocytopenia in 31% (905 of 2891) of SGA neonates versus10% of non-SGA matched controls (P , .0001). Of the 905, 102 had a recognized cause ofthrombocytopenia (disseminated intravascular coagulation, early-onset sepsis, or extracorporealmembrane oxygenation). This group had a 65% mortality rate. The remaining 803 did not havean 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, plateletcounts were $150 000/mL in more than half of the patients. Severely SGA neonates (,1stpercentile) had lower counts and longer thrombocytopenia duration (P , .001). High nucleatedred cell counts at birth correlated with low platelets (P , .0001). Platelet transfusions weregiven to 23%, and counts typically more than tripled. Thrombocytopenia was more associatedwith SGA status than with the diagnosis of maternal preeclampsia.

CONCLUSIONS: SGA neonates with clearly recognized varieties of thrombocytopenia have a highmortality rate. In contrast, thrombocytopenia of SGA is a hyporegenerative condition ofmoderate severity and 2 weeks’ duration and is associated with evidence of intrauterinehypoxia and a low mortality rate.

WHAT’S KNOWN ON THIS SUBJECT: Small-for-gestational-age neonates are at risk forthrombocytopenia during the first days and weeksafter birth. However, the incidence, duration,severity, responsible mechanism, value of platelettransfusions, and risk of death from this variety ofneonatal thrombocytopenia are unknown.

WHAT THIS STUDY ADDS: Ten percent ofthrombocytopenic small-for-gestational-ageneonates have a recognized cause for lowplatelets (aneuploidy, extracorporeal membraneoxygenation, disseminated intravascularcoagulation); they have a high mortality rate(65%). Ninety percent have a moderate, transient(2 weeks), hyporegenerative thrombocytopeniawith a low mortality rate (2%).

Divisions of aHematology/Oncology, and bNeonatology, Department of Pediatrics, University of Utah School ofMedicine, Salt Lake City, Utah; cPrimary Children’s Hospital, Salt Lake City, Utah; dWomen and Newborn’sClinical Program, Intermountain Healthcare, Salt Lake City, Utah; eStatistical Data Center, LDS Hospital, SaltLake City, Utah; and fDivision of Neonatal Medicine, Children’s Hospital and Harvard Medical School, Boston,Massachusetts

Drs Christensen and Sola-Visner and Ms Baer conceptualized and designed the study; Ms Baercarried out the initial analyses; Dr Christensen drafted the initial manuscript; Dr Snow andMs 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 allauthors approved the final manuscript as submitted.

Accepted for publication May 7, 2015

www.pediatrics.org/cgi/doi/10.1542/peds.2014-4182

DOI: 10.1542/peds.2014-4182

Address correspondence to Robert D. Christensen, MD, University of Utah Department of Pediatrics,295 Chipeta Way, Salt Lake City, UT 84108. E-mail: robert.christensen@hsc.utah.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

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Neonates who are born small forgestational age (SGA) (,10thpercentile birth weight for a referencepopulation) are at risk for havingthrombocytopenia in the first weeksafter birth.1–6 Some of these neonateshave varieties of thrombocytopeniathat are readily recognized, such asthe consumptive thrombocytopeniasaccompanying disseminatedintravascular coagulation (DIC),extracorporeal membraneoxygenation (ECMO), or early-onsetsepsis or the hyporegenerativethrombocytopenias associated withmarrow-failure syndromes. Other SGAneonates have a type ofthrombocytopenia with no obviousexplanation, a variety sometimestermed by exclusion“thrombocytopenia of SGA.”1–6 Thatvariety has been the subject ofprevious reports, but many aspectsremain unclear. As a step towardenhancing the knowledge base of thethrombocytopenia of SGA, weconducted an analysis of all SGAinfants born in our health care systemduring a 9-year period. The aims were(1) to identify a group ofthrombocytopenic SGA neonates inwhom the thrombocytopenia was nota readily apparent variety; and (2) inthat group (termed thrombocytopeniaof SGA), to identify the incidence,nadir, severity, and duration of thethrombocytopenia and whether it wasmore closely associated withpreeclampsia versus SGA status,assess the responsible mechanisms,and describe the outcomes.

METHODS

Patient Information

Data were collected retrospectively asdeidentified limited data sets fromarchived Intermountain Healthcarerecords. Intermountain Healthcare isa not-for-profit healthcare systemthat owns and operates 19 hospitalswith labor and delivery units in Utahand Idaho. The information collectedwas limited to the information in this

report. Patient records were accessedif the neonate had a date of birth fromJanuary 1, 2004, to December 31,2013. The Intermountain HealthcareInstitutional Review Board approvedthis as a deidentified data–only studyas not requiring the consent ofindividual subjects.

Blood Cell Counts and PlateletTransfusions

Platelet counts and mean plateletvolumes (MPVs) were determined inall hospitals with the BeckmanCoulter LH750 Hematology Analyzer(Fullerton, CA) from 2004 to mid-2012. After mid-2012, platelet countsand MPVs were determined by usingSysmex counters (Sysmex America,Lincolnshire, IL). All blood tests wereperformed in accordance withIntermountain Healthcare LaboratoryServices standard operatingprocedures. Nucleated red blood cellswere quantified using eitherautomated cell counts, performed inaccordance with the hematologyanalyzer manufacturer’s instructions,or manual enumeration, performedby certified medical technologists onWright-stained blood smears,counting a minimum of 100 nucleatedcells per test. The reference intervalsfor complete blood count parametersare those we previously publishedfrom Intermountain Healthcaredatabases.7

Guidelines for administering platelettransfusions in the IntermountainHealthcare NICUs during this periodhave been published.8,9 All platelettransfusions were type specific or AB(Rh positive or negative) and werederived from apheresis. They werenot pooled or volume-reduced, but allwere subjected to leukofiltration andirradiation and administered ina volume of 10 to 15 mL/kg bodyweight. Gestational age wasdetermined by obstetrical assignmentunless changed by the neonatologiston the basis of gestational ageassessment (physical examinationand neurologic-neurodevelopmentalfindings).

Neonates were classified as SGA iftheir weight at birth was ,10thpercentile for gestational age, usingnormative values from ourIntermountain Healthcarepopulation.10 Severity of SGA wasclassified according to 3 categories:,1st percentile (severe), first to fifthpercentile (moderate), and sixth to10th percentile (mild). Preeclampsiawas identified from case-mix recordsusing the following definitions fromthe International Classification ofDiseases, Ninth Revision, ClinicalModification (Ingenix Expert, EdenPrairie, MN): 6425, 6426, and 6427.

SGA neonates were matched 1:1 withneonates from the same hospitalsborn during the same period of timewho were not SGA. Matching wasperformed on the basis of gestationalage (within 1 week) and year/monthof birth (within 1 month). Earlythrombocytopenia was defined as $2platelet counts ,150 000/mL duringthe first week after birth. Using chartreviews and electronic reviews oflaboratory data, patients whose datawould otherwise qualify for inclusionin the SGA and thrombocytopeniagroup were excluded if they wererecognized to have another variety ofthrombocytopenia. These specificallyincluded early-onset sepsis,congenital cytomegalovirus (CMV) orother congenital viral infection, ECMOtreatment, immune-mediatedthrombocytopenia, aneuploidy,varieties of severe congenitalthrombocytopenia, or DIC. DIC wasdiagnosed by the combination ofhypofibrinogenemia for age,11

schistocytosis,12 prolongation ofprothrombin time and activatedpartial thromboplastin time for age,11

and elevated D-dimers.

Data Collection and StatisticalAnalysis

The program used for data collectionwas a modified subsystem of ClinicalWorkstation. The 3M Company(Minneapolis, MN) approved thestructure and definitions of all datapoints for use within the program.

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Data were managed and accessed byauthorized data analysts. Means andstandard deviations were used toexpress values in groups that werenormally distributed, and mediansand ranges to express values ingroups that were not. Differences incategorical variables were assessedby using the Fisher exact test or x2.Student nonpaired t test was used toassess continuous variables.Statistical analysis used theR Foundation package (StatisticalComputing, Vienna Austria). Themixed-effects model used NIMEsoftware, version 3.1-105, also fromthe R package. Statistical significancewas set as P , .05.

RESULTS

Incidence, Severity, and Duration ofThrombocytopenia

During the 9-year period studied,24 036 neonates were admitted to an

Intermountain Healthcare NICU, and3964 of these were SGA (Fig 1). Of theSGA infants, 2891 had $2 plateletcounts measured in the first week,and 905 (31.5%) of these had $2platelet counts ,150 000/mL,thereby qualifying for the definitionof early (first-week)thrombocytopenia. Thus theincidence of thrombocytopenia in ourSGA neonates was 31.5%, which washigher than the 10.0% incidence ofearly thrombocytopenia among 2891non-SGA control neonates matchedfor gestational age (P , .0001)(Fig 1). The 2891 non-SGA controlswere well matched with the 2891SGA neonates on the basis ofgestational age (Table 1), but (asexpected) the non-SGA control grouphad a higher birth weight; lower ratesof cesarean delivery, maternaleclampsia or preeclampsia, andmortality; and proportionately moremales compared with the SGAneonates.

Of the 905 thrombocytopenic SGAneonates, 102 had a condition(besides SGA) that might have causedtheir thrombocytopenia (Fig 1). Theseconditions included treatment withECMO (n = 28), aneuploidy (n = 30,3 of whom were also on ECMO),early-onset culture-positive bacterialsepsis (n = 6), congenital CMV (n = 6),congenital marrow failure syndromes(n = 4), alloimmunethrombocytopenia (n = 2), DIC (n = 8),and various malformation syndromes(n = 18). These 102 neonates wereexcluded from further analysis,leaving 803 with a condition wetermed thrombocytopenia of SGA(Table 2).

Platelet counts in these 803 areshown in Fig 2. The reference intervalfor platelet counts of neonates duringtheir first 3 weeks (5th to 95thpercentile limits), which wepublished previously,13 is shown bythe shaded area for comparison. Thelowest platelet counts were typicallyon day 4, with a mean nadirof 93 000/mL (SD 51 580/mL,10th percentile 50 000/mL,90th percentile 175 000/mL). By day14 of life, the platelet count hadincreased to $150 000/mL in half ofthe infants and was $100 000/mL in70%. By day 21, the count was$150 000/mL in about two-thirds(Fig 2). The most severely SGAneonates (birth weight ,1st percentilereference range) had lower plateletcounts than those with moderate(P = .013) or mild (P = .005) SGA(Fig 3). The severe SGA group also hada longer duration of thrombocytopenia,with 50% having platelet counts,150 000/mL by 28 to 30 days.

SGA and Preeclampsia

Associations of thrombocytopeniawith SGA status versus maternalpreeclampsia were sought bycomparing the lowest platelet countduring the first 4 days of life among4 groups of NICU patients matchedfor gestational age (within 1 week)(Fig 4). Neonates who were SGA butno maternal preeclampsia was

FIGURE 1Study flow diagram to identify neonates with thrombocytopenia of SGA.

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diagnosed (Group 1) had lower plateletcounts (mean 153 000/mL) than didthose born to women withpreeclampsia but were not SGA (Group2) (197 000mL, P , .0001, 95%confidence interval on the difference 22to 64). Using linear regression toaccount for gestational and birth weight,the point estimate of the difference inthe 2 groups was still significant(P = .0189, 95% confidence interval onthe difference 10 to 61). Among SGAneonates, the presence or absence ofpreeclampsia made no difference in theplatelet count. Thus, preeclampsia maynot be associated with a risk of neonatalthrombocytopenia over and above therisk associated with SGA status.

Nucleated Red Blood Cell Count, MPV,and Response to Platelet Transfusion

Among the 803 neonates we labeledas having thrombocytopenia of SGA,

an elevated nucleated red blood cellcount (NRBC, per microliter) at birthcorrelated with a low platelet countin the first week after birth (Fig 5)(P , .01). MPV measurementsaccompanying the platelet counts ofthe 803 thrombocytopenic neonatesover their first week after birth aredisplayed in Fig 6. Overlying thevalues in the shaded area is the MPVreference interval (5th to 95thpercentile limits) that we publishedpreviously.13

Of the 803 neonates withthrombocytopenia of SGA, 182 (23%)received 1 to 33 apheresis platelettransfusions. Reviews indicated that98% of the transfusions were givenprophylactically, meaning the patientdid not have active bleeding. Plateletcounts before the transfusions rangedfrom 6000 to 110 000/mL; mediancount was 49 000/mL. The rise in

platelet count after transfusion,calculated by subtracting thepretransfusion count from the countperformed 1 to 24 hours aftertransfusion, was 118 9906 59 736/mL.Figure 7 shows the increase andsubsequent decrease in plateletcounts after platelet transfusion. Forease of comparison, all platelet countswere normalized to percentage of thepretransfusion platelet count.

Outcomes

Ten SGA neonates had severethrombocytopenia (,50 000/mL)that persisted for at least 4 weeks(Table 2). Nine of the 10 wereseverely SGA (,1st percentileat birth). Four of these had noapparent explanation, other thanthe SGA status, for persistentsevere thrombocytopenia. Theother 6 had developed late-onset

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 4.1Not SGA 2891 35 6 3 2841 6 816 59.8 44.4 1.6 1.6P .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-SGAneonates 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.

TABLE 2 Ten SGA Neonates Classified as Having Severe and Persistent Thrombocytopenia of SGA

BirthWeight, g

SGAPercentile

Gestationalage at

birth, wk/d

MaternalPreeclampsia,

Eclampsia, or HELLP

Lowest plateletcount in the first 2wks after birth, /mL

Lowest plateletcount at 4–6weeks, /mL

PlateletTransfusionsReceived, n

Diagnosis at 4–6 wks Outcome

350 ,1st 24/0 None 27 000 48 000 21 Necrotizing enterocolitiswith bowel resection

Died at 6 mo in NICU

406 ,1st 22/6 HELLP 42 000 30 000 33 a Died at home at 7 mo420 ,1st 24/5 HELLP 52 000 23 000 31 Candida sepsis Died at home at 17 mo470 ,1st 26/5 Eclampsia 46 000 40 000 8 a Lived480 ,1st 23/6 Preeclampsia 49 000 38 000 11 a Lived510 ,1st 26/4 Preeclampsia 36 000 36 000 8 Klebsiella sepsis Lived565 ,1st 27/0 HELLP 121 000 47 000 10 Necrotizing enterocolitis

with bowel perforationand resection

Lived

580 ,1st 27/1 None 52 000 10 000 16 Necrotizing enterocolitiswith Enterobactercloacae sepsis

Lived

663 ,1st 29/2 None 36 000 37 000 4 a Lived2100 10th 35/1 None 73 000 12 000 8 Complex congenital heart

disease, Klebsiellasepsis

Died in hospice at 5 y

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 receivingplatelet 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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thrombocytopenia accompanyingnecrotizing enterocolitis or sepsis.Using data from the first days afterbirth, focusing on birth weight,

gestational age, or platelet counts inthe first 4 days, we were not able torecognize these 6 as distinct from theother 2885 in the group of 2891.

Mean platelet counts of these10 during their first 3 weeks (groupedas the 4 with no explanation forprolonged thrombocytopenia and the6 with NEC or late-onset sepsis) areshown in Fig 2 along with the entiregroup of 803 with thrombocytopeniaof SGA (box and whiskers) and thenormal controls (shaded area). Thisgroup of 10 with persistent severethrombocytopenia received 4 to33 platelet transfusions. All of thesewere prophylactic, for platelet counts,50 000 to 60 000/mL, with no signsof bleeding.

Of the 1986 SGA neonates in whomthrombocytopenia was not identified,34 (2%) died. In contrast, of the905 SGA neonates in whomthrombocytopenia was identified,85 (9%) died (P, .0001) (data shownin Supplementary Table 3). Of the 102SGA neonates with known varieties ofthrombocytopenia (eg, ECMO or DIC),66 (65%) died. However, of the 803SGA neonates with thrombocytopeniaof SGA, 19 (2%) died (P , .0001vs. SGA neonates with known varietiesof thrombocytopenia). Allthrombocytopenic SGA neonates withDIC who died had bleeding problemsat the time of death, predominantlypulmonary hemorrhage. None of thosewith trisomy 18 or 13 who died hadbleeding problems (shown inSupplementary Table 3).

Logistic regression was performed toidentify clinical variables predictive ofsevere (,50 000/mL) and prolonged($2 weeks) thrombocytopenia, whichwe judged could be relevant to futuretesting of thrombopoietin receptoragonists such as romiplostim.14 Thismedication takes 7 to 10 days toelevate the platelet count; therefore,neonates recognized within the firstdays as being very likely to remainseverely thrombocytopenic for $2weeks might be candidates forexperimental treatment. Threevariables had predictive correlations:(1) gestational age at birth (shortergestation was associated with higherlikelihood of severe, persistent

– – – – – –

FIGURE 2Platelet counts of 803 neonates with thrombocytopenia of SGA during their first 30 days. Medianplatelet count, first and third interquartile range (box), and 10th and 90th percentile values(whiskers) are shown. The shaded area shows the normal reference interval for platelet counts ofneonates of$35 weeks’ gestation (modified from Wiedmeier et al13). Also shown are platelet countsof 10 of the 803 whose thrombocytopenia persisted when checked in the 28- to 42-day window. Fourof the 10 (open circles, solid line) had no explanation for prolonged thrombocytopenia besidesthrombocytopenia of SGA, and 6 (closed circles, dashed line) had developed either necrotizingenterocolitis or late-onset sepsis (see Table 2 for details of these 10).

FIGURE 3Platelet counts measured on day 4 of life (the mean nadir of platelet count) of SGA neonatesaccording to birth weight percentile. Counts are grouped from neonates weighing less than firstpercentile, first to fifth percentile, sixth to 10th percentile, and 11th to 99th percentile for gestationalage (the latter group considered controls). In each of the weight categories, the median plateletcount is shown along with the first and third interquartile range (box) and the 10th and90th percentile values (whiskers).

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thrombocytopenia); (2) gender(males were more likely to havesevere, persistentthrombocytopenia); and (3) lowestplatelet count in the first week(generally on day 4). However, themodels were insufficiently predictivefor individual patients, and novariable had an odds ratio .1.45

predicting severe and prolongedthrombocytopenia.

DISCUSSION

Thrombocytopenia is a commonproblem among patients inNICUs.1,2,5,6,14–18 The majority haveacquired varieties of consumptive

thrombocytopenia accompanyingbacterial or fungal sepsis ornecrotizing enterocolitis.1,2,5,6 Rarevarieties of hyporegenerativethrombocytopenia accompanyaneuploidy or syndromes involvingthrombopoietic failure.1–3 A separatevariety of early thrombocytopenia hasbeen described among neonates whoare SGA. The first report of this entitywas by Meberg et al from Oslo in1977.19 They studied 23 neonatesweighing ,10th percentile who, withno other explanation, had $1 plateletcount ,100 000/mL in the first daysafter birth. The platelet countsgenerally increased to .150 000/mL byday 15 of life, and none had pathologicbleeding. The authors speculated thatthis thrombocytopenia was the result ofchronic hypoxia in utero induced byplacental insufficiency. In 1983, Shuperet al from Israel reported 14 SGA infantswith $1 platelet counts ,100 000/mLand no other explanation for thethrombocytopenia.20 ElevatedNRBCs at birth were common in thethrombocytopenic neonates; thusthey postulated, as had Meberget al, that the condition was due toreduced platelet productionassociated with chronic intrauterinehypoxia. Our present study useda large multihospital dataset to betterdefine this condition, which has cometo be termed thrombocytopenia ofSGA1–6.

We began by identifying all patients inthe last 9 years admitted to anIntermountain Healthcare NICU witha birth weight ,10th percentile.10 Wethen determined how many of theseSGA neonates had $2 platelet countsdrawn during their first week, andhow many of those had $2 plateletcounts ,150 000/mL. A low plateletcount in a neonate can be real orartifactual; the latter typically involvesplatelet clumping, either on the woundwhen blood is drawn slowly froma capillary puncture or within thespecimen tube.21 We aimed to reducethe contamination of our dataset withartifactual thrombocytopenia byrequiring 2 low counts.

FIGURE 4Platelet counts during the first 4 days after birth among 4 groups of NICU admissions (each n = 100):(1) SGA but no preeclampsia, (2) preeclampsia but not SGA, (3) both SGA and preeclampsia, and (4)neither SGA nor preeclampsia.

FIGURE 5Among 803 neonates with thrombocytopenia of SGA, NRBC (per microliter) at birth is compared withlowest platelet count recorded in the first 3 days after birth.

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After identifying all SGA neonateswho had early (first-week)thrombocytopenia, we sought to cullthose associated with a recognizedcause of thrombocytopenia. This wasdone so that we could tentativelyclassify the others as having theexclusionary diagnosis of

thrombocytopenia of SGA. We foundthat ∼10% of thrombocytopenic SGAneonates had a readily identifiablevariety of thrombocytopenia, and thatgroup had a high mortality rate(65%). In contrast, 90% had a low-mortality variety with the followingcharacteristics. (1) The

thrombocytopenia appears to beprimarily hyporegenerative asopposed to accelerated plateletconsumption or destruction. Wemade this judgment on the basis ofnormal MPVs and good responses toplatelet transfusions. (2) The lowplatelet counts are associated withintrauterine hypoxemia (elevatedNRBC) and with the pathology thatcreates fetal growth restriction, notthe pathology that producespreeclampsia without fetal growthrestriction. (3) The thrombocytopeniais typically only moderately severe(mean nadir count of 93 000/mL) witha typical nadir on about day 4 anda typical duration (days to a count.150 000/mL) of 2 weeks. However,those with severe SGA tend to havelower counts and a longer duration.

Cremer et al also suggested thatthrombocytopenia of SGA is thekinetic result of reduced plateletproduction, by measuring theimmature platelet fraction.22 Theyfound a trend toward lowerimmature fractions (suggestingreduced platelet production) inthrombocytopenic SGA neonatescompared with thrombocytopenicneonates who had infection, in whomthe mechanism is likely acceleratedplatelet utilization.

Reduced platelet production wasalso the mechanism suggestedby the work of Murray et al,who observed that preterminfants with thrombocytopeniahad fewer circulatingmegakaryocyte progenitors thannonthrombocytopenic controls.23

Likewise, we reported fewmegakaryocytes in the marrow of3 thrombocytopenic SGAneonates.24 Both Murray et al23

and Sola et al24 reported lowplasma thrombopoietin concentrations,suggesting inadequate upregulationof thrombopoietin production.The hypothesis that thethrombocytopenia of SGA is primarilydue to thrombopoietin deficiency

FIGURE 6MPV (femtoliters). Values are shown from 803 neonates who met a definition of thrombocytopenia ofSGA. 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 (modifiedfrom Wiedmeier et al13).

FIGURE 7Platelet counts after apheresis platelet transfusions to 196 neonates. All values are normalized topercentage of the pretransfusion platelet count (all pretransfusion counts are shown as 100%).Median values, first and third interquartile range (box), and 10th and 90th percentile values(whiskers) are shown. The peak and characteristics of the subsequent decrease are used to inferthe kinetic mechanism responsible for the thrombocytopenia (reduced platelet production versusaccelerated platelet destruction).

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in utero is consistent with thesestudies but remains to be confirmed.

The molecular mechanisms resultingin thrombocytopenia of SGA may besimilar to that causingthrombocytopenia of perinatalasphyxia.25 We suspect that fetalhypoxia is causally involved in bothvarieties, which is consistent with thestudy of McDonald et al,26 in adultmice subjected to hypoxia, and themarrow culture studies ofSaxonhouse et al.27,28

If the thrombocytopenia of SGA isdetermined to be the result ofthrombopoietin deficiency, it willremain unclear whetherthrombopoietin receptor agonistssuch as romiplostim or eltrombopagwill be of value in treating thiscondition.14,29 Most neonates withthe thrombocytopenia of SGA are notseverely thrombocytopenic; thusperhaps no treatment is warrantedfor most. Moreover, romiplostim andeltrombopag require 7 to 10 daysbetween commencement of dosingand a significant increase in plateletcount, and half of the neonates withthis variety of thrombocytopenia haveplatelet counts .150 000/mL by day14. Because a subset of patientsremain severely thrombocytopenicfor.14 days, and some for.28 days,the efficacy, risks, and benefits ofadministering thrombopoietinagonists to that group might warrantfuture study, if they could beidentified in the first week. We foundthat these are typically males born atvery early gestational age with verylow counts initially. However, wewere unable to accurately predictduring the first week which infantswould still have severe, persistentthrombocytopenia after 2 weeks.

One treatment option for neonateswith thrombocytopenia of SGA isplatelet transfusion, but as

highlighted by Josephson et al,platelet transfusion strategies forneonates lack a strong evidencebase.30 There is substantialdisagreement on neonatal platelettransfusion thresholds, but it iswidely accepted that platelettransfusions should be given toneonates if their platelet count fallsbelow 20 000/mL.1,31,32 Counts thatlow should be rare in neonates withthrombocytopenia of SGA. From ourpresent data, 90% of platelet countamong neonates with this diagnosiswill be .50 000/mL; thus perhaps10% will be ,50 000/mL. In ourpresent analysis, 182 of the 803neonates with thrombocytopenia ofSGA received platelet transfusions. Inretrospect, we question how many ofthose were beneficial. Very few hada platelet count ,20 000/mL, mosthad a pretransfusion platelet count.50 000/mL, and almost all weretransfused prophylactically with nobleeding problems prompting thetransfusion.

We recognize several significantproblems in our retrospectiveanalysis. For instance, surely somerelevant data were sometimesmissing from the charts or electronicdatabases, and bias may have beenunintentionally introduced. Also,platelet counts after platelettransfusions were not obtained ona standard schedule, and platelettransfusions were given to some andnot to others without any clearexplanation. Also, changes inobstetrical and neonatology practicesoccurred during the 9 years of study.The practice changes we recognizeare the overall reduction in NICUtransfusions during this period8 andthe specific reduction in platelettransfusions on the basis of a changefrom platelet count–based guidelinesto platelet mass–based guidelines.9 In

addition, in our studies ofassociations with preeclampsia, wecaptured only those women coded ashaving HELLP (syndrome ofhemolysis, elevated liver enzymes,and low platelets), eclampsia, orsevere or moderately severepreeclampsia, not those with mild orunspecified preeclampsia; thus wemight have ignored associationsbetween thrombocytopenia and mildpreeclampsia. Last, we did notidentify the molecular mechanismsinvolved in the association betweenSGA status and thrombocytopenia.Clarifying this mechanism should bethe topic of future investigations, as itmight suggest novel preventive ortreatment approaches.

Considering the weaknesses andstrengths of our data, we maintain itis reasonable to conclude that aboutone-third of SGA infants have earlythrombocytopenia. About 10% ofthese have an obvious cause ofthrombocytopenia such as sepsis,aneuploidy, or ECMO treatment, andthis group has a high mortality rate(65% in our dataset). However, 90%of thrombocytopenic SGA neonateshave a different variety that could betermed thrombocytopenia of SGA.Those neonates should have a lowmortality rate, yet some willprobably receive multiple platelettransfusions.

ABBREVIATIONS

CMV: cytomegalovirusDIC: disseminated intravascular

coagulationECMO: extracorporeal membrane

oxygenationMPV: mean platelet volumeNRBC: nucleated red blood cell

countSGA: small for gestational age

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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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.

REFERENCES

1. Carr R, Kelly AM, Williamson LM.Neonatal thrombocytopenia and platelettransfusion: a UK perspective.Neonatology. 2015;107(1):1–7

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3. Wasiluk A, Mantur M, Kemona H,Szczepa�nski M, Jasi�nska E, Milewski R.Thrombopoiesis in small for gestationalage newborns. Platelets. 2009;20(7):520–524

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7. Christensen RD, Henry E, Jopling J,Wiedmeier SE. The CBC: reference rangesfor neonates. Semin Perinatol. 2009;33(1):3–11

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33. Christensen RD, Yaish HM, Leon EL, Sola-Visner MC, Agrawal PB. A de novo T73Imutation in PTPN11 in a neonate withsevere and prolonged congenitalthrombocytopenia and Noonansyndrome. Neonatology. 2013;104(1):1–5

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DOI: 10.1542/peds.2014-4182 originally published online July 27, 2015; 2015;136;e361Pediatrics 

and Martha C. Sola-VisnerRobert D. Christensen, Vickie L. Baer, Erick Henry, Gregory L. Snow, Allison Butler

Thrombocytopenia in Small-for-Gestational-Age Infants

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