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Abstract

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Aim  To examine maternal hypertension, diabetes, and intrapartum fever as potential risk factors for ischemic stroke in infants.

Method  We conducted a retrospective cohort study of 226 117 children born from January 2000 to December 2007 who were enrolled in the South Carolina Medicaid program. We linked maternal and child Medicaid billing records and birth certificate data. Children with ischemic stroke were identified based on the International Classification of Diseases, Ninth Revision (ICD-9), code 434 in the child’s billing data. Independent variables and covariates were identified using ICD-9 codes and birth certificate data. We modeled the odds of ischemic stroke diagnosis in infants, either before 30 days of life or before 365 days.

Results  Forty-three children were diagnosed with ischemic stroke before 30 days and 161 before 365 days. Maternal hypertension (odds ratio 2.31 before 30d) and intrapartum fever (odds ratio 3.36 <30d) were significantly associated with odds of ischemic stroke before 30 days and before 365 days; maternal diabetes was not.

Interpretation  Maternal hypertension and intrapartum fever appear to be risk factors for ischemic stroke in infants. Additional research is needed to determine the mechanism(s) underlying these associations and to develop effective preventive methods for high-risk infants.


What this paper adds

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  •  Maternal hypertension is associated with risk of ischemic stroke during infancy.
  •  Intrapartum fever is associated with risk of ischemic stroke during infancy.
  •  Maternal diabetes mellitus is not a risk factor for ischemic stroke during infancy.

Ischemic stroke is a rare condition in children, occurring most frequently in the neonatal period. Approximately two to four children per 10 000 live births experience ischemic stroke in the first 28 days of life.1 Approximately 60% of infants with neonatal stroke present immediately, most frequently with neonatal seizures.2 In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurological or cognitive development.2 Long-term sequelae of neonatal ischemic stroke include epilepsy, cerebral palsy, intellectual disability, hemiparesis, and other neurological disabilities.3 Risk of perinatal ischemic stroke is higher in infants with conditions that predispose to thrombosis; such conditions are genetic (such as protein S or C deficiency), infectious (such as meningitis or sepsis), and cardiovascular (such as congenital heart defects and cardiac surgery), as well as others.4 Lee et al.5 reported that significant prenatal and perinatal risk factors for perinatal arterial ischemic stroke included a history of infertility, oligohydramnios, pre-eclampsia, prolonged rupture of membranes, umbilical cord abnormality, chorioamnionitis, and primiparity. Cheong and Cowan1 identified five studies that reported pre-eclampsia was a significant risk factor.

Hypertension during pregnancy can be described as chronic/non-gestational, pregnancy-induced or gestational (onset during pregnancy), pre-eclampsia (with proteinuria), or eclampsia (with proteinuria and seizures).6,7 In the USA, pre-pregnancy hypertension is present in approximately 2% of pregnancies, gestational hypertension without pre-eclampsia in 2 to 3%, and pre-eclampsia or eclampsia in approximately 3%.6 Pregnancy-induced hypertension and pre-eclampsia/eclampsia are thought to be initiated by problems with placental development that ultimately lead to an immune response and other physiological changes that produce hypertension and other manifestations of disease.8 Maternal hypertension is a known cause of preterm delivery,9 intrauterine growth restriction,10 and placental abruption.11 We have previously reported associations between maternal pre-eclampsia and intellectual disability, epilepsy, and cerebral palsy.12–14

Between 4% and 14% of pregnant females in the USA experience gestational diabetes mellitus,15 not including females with pre-existing diabetes. Maternal diabetes is a risk factor for preterm labor, maternal hypertension, pregnancy loss, macrosomia, and neonatal hypoglycemia.16 Edmonds et al.17 described a series of neonates with ischemic stroke, and reported that 4 out of 10 had mothers with gestational diabetes; however, we are not aware of adequately powered studies reporting such an association.

We conducted a retrospective cohort study of births reimbursed by the South Carolina Medicaid program, which is a state run health insurance program for low-income individuals and pays for approximately half of all births in South Carolina, to test the hypotheses that maternal hypertension, and diabetes, and intrapartum fever are associated with increased risk of neonatal ischemic stroke. We chose to focus on these maternal characteristics because they are relatively common pregnancy complications, because there is insufficient information about whether they are associated with increased risk, and because identification of risk factors during pregnancy may have the potential to lead to the development of effective preventive interventions for high-risk pregnancies.

Method

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The study protocol was approved by the Institutional Review Board at the University of South Carolina. We obtained linked maternal–child data for all births reimbursed by the South Carolina Medicaid program from January 1, 2000 to December 31, 2007. After excluding the 6581 non-singleton births, 226 117 observations were used in analyses. Independent variables and covariates were identified in both Medicaid billing data and linked birth-certificate data. For example, females with hypertension were identified based on a diagnosis of essential hypertension, secondary hypertension, hypertensive heart or kidney disease, pregnancy-induced hypertension, or pre-eclampsia/eclampsia in the Medicaid data, or identification with pre-pregnancy hypertension, pregnancy induced hypertension, or eclampsia in the birth certificate data. Females with diabetes were identified based on a diagnosis with type 1 or type 2 diabetes, gestational diabetes, or unspecified diabetes complicating pregnancy in the billing data, or with chronic or gestational diabetes on birth certificates. Intrapartum fever and maternal tobacco use were identified using birth certificate data.

The outcome studied was diagnosis with ischemic stroke (‘occlusion of cerebral arteries,’ International Classification of Diseases, Ninth Revision [ICD-9] code 434) in the Medicaid billing data, with initial diagnosis up to 30 days after birth. Though the neonatal period is typically defined as lasting through day 28, we included the additional day because of the possibility that a stroke could occur on day 28 but not be billed until the following day. We also analysed all ischemic stroke diagnosed before 365 days of age, because most of these were probably manifestations of neonatal strokes.2 The complete list of variables is shown in Table I, which includes a description of each variable as well as the data source and ICD-9 codes (if applicable).

Table I. Summary of variables associated with neonatal ischemic stroke
VariableSubcategoriesSource(s)ICD-9 codes
  1. ICD-9, International Classification of Diseases, Ninth Revision; MB, Medicaid billing; BC, birth certificate; NA, not applicable.

Maternal variables
 Any hypertensionChronic/non-gestational hypertensionMB401–405, 642.0–642.2
Gestational hypertension (pregnancy induced hypertension, pre-eclampsia, eclampsia)MB and BC642.3–642.6
Pre-eclampsia/eclampsia superimposed on chronic hypertensionMB642.7
Unspecified timingMB642.9
 Any diabetesChronic diabetes (type 1 or 2)MB and BC248, 250, 648.0
Gestational diabetesMB and BC648.8
 Intrapartum FeverTemperature ≥38°C (2000–2003); temperature >38°C or clinical chorioamnionitis diagnosed during labor (2004–2007)BCNA
 Tobacco useAny use in pregnancyBCNA
 Maternal ageYearsBCNA
 Maternal raceWhite, black, otherBCNA
 Maternal ethnicityHispanic or non-HispanicBCNA
 Placental abruptionAny placental abruptionMB and BC641.2
Child variables
 Gestational ageCompleted weeksBCNA
 Child’s sexMale or femaleBCNA
 Prothrombotic conditionsSickle cell traitMB282.5
Sickle cell diseaseMB282.6
ThalassemiasMB282.4
Primary hypercoagulable stateMB289.8
 MeningitisBacterial, viral, or unspecified meningitisMB320–322, 047–049, 036
 EncephalitisEncephalitis from any causeMB046, 049, 052.0, 055.0, 056.0, 058.2, 062–064, 072.2, 130.0, 139.0, 323
 Congenital infectionsCongenital: rubella pneumonitis, cytomegalic inclusion disease, herpes simplex, listeriosis, malaria, toxoplasmosis, tuberculosisMB771.0–771.2
 Neonatal infectionsSepticemia of newborn, bacteremia of newborn, other infections specific to the perinatal periodMB771.81, 771.83, 771.89
 Birth asphyxiaSevere birth asphyxia, mild or moderate birth asphyxiaMB and BC768.5, 768.6, 768.0
 Birth traumaAny diagnosis of birth trauma, brain or otherMB and BC767
 Neurodevelopmental disabilityHemiplegia/hemiparesisMB342
Late effects of strokeMB438
Intellectual disabilityMB317–319
EpilepsyMB345
Cerebral palsyMB343
 Ischemic strokeOcclusion of cerebral arteries, yes or noMB434

Modeling

We modeled the odds of ischemic stroke using logistic regression. We created separate models for ischemic stroke diagnosed before 30 days, then expanded the period to include all ischemic stroke diagnosed before 365 days. In each model, we excluded children diagnosed with ischemic stroke after the end of the period of interest (≥30d or ≥365d). Because it is possible for the same woman to have multiple births in the study period, there is a potential for lack of independence among observations. One way to deal with clustered observations is to estimate generalized estimating equation models,18 though if the within-cluster dependency is very weak, ordinary logistic regression models (for independent data) are appropriate.18–20 When we fitted the generalized estimating equations models with an exchangeable correlation structure, the working correlation was estimated to be less than 0.01. Given that dependencies among children born to the same mother were very low, we estimated the models using ordinary logistic regression (PROC LOGISTIC in SAS version 9.2; SAS Institute, Cary, NC, USA).

For some variables, we encountered the problem of quasi-complete separation, which can occur when several risk factors nearly perfectly predict the response and results in maximum likelihood estimates that are non-unique and infinite. To address this problem, we used Firth’s method,21 which is considered the best solution to separation in logistic regression.22 Firth’s method estimates the regression coefficients by maximizing a penalized likelihood function. It provides finite parameter estimates for risk factors that cause separation and further reduces bias in the estimation.

To avoid overtaxing the models with unnecessary covariates, we performed variable selection based on Akaike information criterion. For each model, the set of covariates producing the smallest Akaike information criterion value is chosen. Maternal hypertension, diabetes, and fever were retained in all the models, because they are the primary independent variables for the study.

Sensitivity analyses

We used two different case definitions for ischemic stroke for each of the periods for stroke diagnosis. The first definition included all children with at least one diagnosis of ischemic stroke in the period of interest. The second case definition represented ‘confirmed’ cases of ischemic stroke and required at least one diagnosis of ischemic stroke within the period of interest plus at least one of either (1) another diagnosis of ischemic stroke either during the same period or later in childhood, or (2) diagnosis of one of the neurodevelopmental disabilities (hemiplegia/hemiparesis, ‘late effects of stroke,’ cerebral palsy, intellectual disability, or epilepsy) at some time in childhood.

Results

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Forty-three children had at least one diagnosis of ischemic intracerebral stroke before 30 days of age; 37 of these children had confirmed ischemic stroke. An additional 118 children were diagnosed with ischemic stroke after 29 days but before 365 days, 99 of whom had confirmed ischemic stroke. Characteristics of children without ischemic stroke, those with ischemic stroke diagnosed before 30 days, and those diagnosed before 365 days are compared in Table II. Owing to missing values, sums of frequency counts may not equal the corresponding column totals. Maternal hypertension was more common for infants with ischemic stroke before 30 days and before 365 days. Intrapartum fever was significantly more common in mothers of infants with ischemic stroke before 365 days but not before 30 days (though the proportions with maternal fever were very similar). There was not a significant difference in the prevalence of maternal diabetes, for infants with ischemic stroke either before 30 days or before 365 days.

Table II. Cohort characteristics
 Without ischemic stroke (n=225 913)Ischemic stroke before 30d (n=43)Ischemic stroke before 365d (n=161)
Variable n (or mean)a% (or SD) n (or mean)% (or SD) pb n (or mean)% (or SD) p
  1. aFor continuous variables, means (SD) are reported, for categorical variables, frequencies (percentages) are reported. bp values test the equivalence of means (Student’s t-test) for continuous variables and equivalence of proportions (χ2 test) for categorical variables. cNumber of missing values. dOwing to missing values, the total number of frequencies for each categorical variable may not add up to the corresponding column total. eFisher’s exact test. MPT, moderately preterm; VPT, very preterm.

Maternal age (y)23.75.424.45.50.37323.85.40.864
Missingc 13
Gestational age (wks)38.42.235.84.20.00235.35.1<0.001
Missing 565Missing 1
PretermTerm 199 93488.7Term 2558.1<0.001Term 9257.5<0.001
MPT 19 7548.8MPT 1023.3MPT 2716.9
VPT 56602.5VPT 818.6VPT 4125.6
Missing 565Missing 1
Maternal raceWhite 115 547d51.2White 2455.80.607White 7949.10.443
Black 106 28747.1Black 1944.2Black 8150.3
Other 38881.7Other 00.0Other 10.6
Missing 191
Maternal Hispanic ethnicityNo 202 75889.9No 3990.71.000eNo 14690.70.749
Yes 22 71710.1Yes 49.3Yes 159.3
Missing 438
Maternal education ≥12yYes 142 67763.5Yes 2762.80.928Yes 9962.70.836
No 82 17536.6No 1637.2No 5937.3
Missing 1061Missing 3
Child sexMale 115 46951.1Male 2455.80.537Male 9559.00.045
Female 110 44348.9Female 1944.2Female 6641.0
Missing 1
Tobacco use during pregnancyNo 184 00681.5No 3274.40.229No 12879.50.507
Yes 41 67218.5Yes 1125.6Yes 3320.5
Missing 235
Maternal fever at deliveryNo 223 20598.8No 4195.40.094eNo 15395.0<0.001e
Yes 27061.2Yes 24.6Yes 85.0
Missing 2
Maternal diabetesNo 200 85888.9No 4195.40.228eNo 14690.70.474
Yes 25 05511.1Yes 24.7Yes 159.3
Maternal hypertensionNo 194 52586.1No 2967.40.004No 11672.1<0.001
Yes 31 38613.9Yes 1432.6Yes 4527.9
Missing 2
Child birth traumaNo 219 34497.1No 3479.1<0.001eNo 13181.4<0.001e
Yes 65692.9Yes 920.9Yes 3018.6
Child birth asphyxiaNo 225 67899.9No 4093.0<0.001eNo 15294.4<0.001e
Yes 2350.1Yes 37.0Yes 95.6
Child thalassemiaNo 225 68899.9No 43100.01.000eNo 161100.01.000e
Yes 2250.1Yes 00.0Yes 00.0
Child sickle cell diseaseNo 224 83599.5No 4093.00.001eNo 15898.10.043e
Yes 10780.5Yes 37.0Yes 31.9
Child sickle cell traitNo 224 42199.3No 4195.40.033eNo 15998.80.288e
Yes 14920.7Yes 24.6Yes 21.2
Child thrombophiliaNo 225 88399.99No 4093.0<0.001eNo 15696.9<0.001e
Yes 300.01Yes 37.0Yes 53.1
Child congenital infectionNo 225 59399.9No 4297.70.059eNo 15696.9<0.001e
Yes 3200.1Yes 12.3Yes 53.1
Child neonatal infectionNo 220 50897.6No 2762.8<0.001eNo 10867.1<0.001e
Yes 54052.4Yes 1637.2Yes 5332.9
Child meningitisNo 224 49499.4No 3990.7<0.001eNo 14087.0<0.001e
Yes 14190.6Yes 49.3Yes 2113.0
Child encephalitisNo 218 71596.8No 43100.00.648eNo 14690.7<0.001
Yes 71983.2Yes 00.0Yes 159.3
Placental abruptionNo 222 53598.5No 4195.40.135eNo 14791.3<0.001e
Yes 33781.5Yes 24.6Yes 148.7

Infants with ischemic stroke before 30 days had lower gestational ages and were more likely to have experienced birth trauma or birth asphyxia, have sickle disease or sickle cell trait, have thrombophilia, have neonatal infection, and to have meningitis. Expanding the timing of initial diagnosis with ischemic stroke, affected infants were also more likely than unaffected infants to be male and to have congenital infection, encephalitis, and maternal placental abruption, but were not more likely to have sickle cell trait.

We estimated models for any and confirmed ischemic stroke, before 30 days and before 365 days, controlling for covariates. As described previously, variables were selected based on Akaike information criterion, and Firth’s method was used whenever quasi-separation occurred. The results are presented in Tables III and IV. In modeling the outcome of any ischemic stroke before 30 days, maternal ethnicity, child encephalitis, placental abruption, and child thalassemia were not selected. For the model of any ischemic stroke before 365 days, child thalassemia was not selected.

Table III. Adjusted odds ratios (OR) for ischemic stroke before 30 daysa
VariableAny ischemic strokeConfirmed ischemic stroke
OR (95% CI) p OR (95% CI) p
  1. Significant values are shown in bold. aNumber of observations for each model is 223 510 and 223 547 respectively. bBlack vs white. cOther vs white. 95% CI, 95% confidence interval.

Maternal race (0, white; 1, black; 2, other)0.76 (0.41–1.40)b0.378Not in model
0.22 (0.01–6.68)c0.384
Maternal ethnicity (Hispanic vs non-Hispanic)  Not in modelNot in model
Maternal education (<12y vs ≥12y)1.06 (0.58–1.93)0.858Not in model
Maternal age1.03 (0.98–1.08)0.2521.03 (0.97–1.08)0.336
Child sex (female vs male)0.90 (0.51–1.58)0.7140.70 (0.38–1.31)0.269
Tobacco use during pregnancy (yes vs no)1.52 (0.78–2.95)0.2201.61 (0.80–3.24)0.186
Maternal fever at delivery 3.36 (1.01–11.19) 0.048 4.02 (1.18–13.67) 0.026
Maternal diabetes0.35 (0.11–1.16)0.0850.40 (0.12–1.35)0.139
Maternal hypertension 2.31 (1.26–4.24) 0.007 2.75 (1.45–5.24) 0.002
Child birth trauma 7.06 (3.48–14.30) <0.001 8.68 (4.21–17.91) <0.001
Child birth asphyxia 17.15 (5.42–54.23) <0.001 22.22 (6.97–70.88) <0.001
Child sickle cell disease 10.40 (3.07–35.28) 0.002 11.39 (3.29–39.42) 0.001
Child sickle cell trait 6.92 (1.71–28.04) 0.007 6.89 (1.69–28.07) 0.007
Child thrombophilia 367.95 (99.72–1000+) <0.001 413.17 (111.10–1000+) <0.001
Child congenital infection 10.47 (2.17–50.67) 0.004 14.17 (2.83–70.99) 0.001
Child neonatal infection 11.50 (5.64–23.44) <0.001 9.53 (4.39–20.69) <0.001
Child meningitis2.69 (0.49–14.72)0.253Not in model
Child encephalitisNot in modelNot in model
Gestational age (wks) 0.92 (0.86–0.99) 0.029 0.95 (0.87–1.03)0.176
Placental abruptionNot in modelNot in model
Child thalassemiaNot in modelNot in model
Table IV. Adjusted odds ratios (OR) for ischemic stroke before 365 daysa
VariableAny ischemic strokeConfirmed ischemic stroke
OR (95% CI) p OR (95% CI) p
  1. Significant values are shown in bold. aNumber of observations for each model is 223 667 and 223 642 respectively. bBlack vs white. cOther vs white. 95% CI, 95% confidence interval.

Maternal race (0, white; 1, black; 2, other)0.91 (0.64–1.30)b0.6130.92 (0.63–1.35)b0.667
0.39 (0.06–2.49)c0.3180.44 (0.07–2.89)c0.395
Maternal ethnicity (Hispanic vs non-Hispanic)0.96 (0.52–1.78)0.8961.03 (0.54–1.96)0.934
Maternal education (<12y vs ≥12)1.04 (0.73–1.47)0.8441.12 (0.77–1.62)0.564
Maternal age1.00 (0.98–1.04)0.7821.00 (0.97–1.03)0.971
Child sex (female vs male)0.81 (0.59–1.11)0.183 0.68 (0.48–0.96) 0.030
Tobacco use during pregnancy (yes vs no)1.13 (0.75–1.70)0.5701.03 (0.65–1.63)0.891
Maternal fever at delivery 3.16 (1.57–6.37) 0.001 3.04 (1.39–6.65) 0.006
Maternal diabetes0.74 (0.44–1.26)0.2700.91 (0.53–1.55)0.731
Maternal hypertension 1.93 (1.36–2.74) 0.003 1.93 (1.32–2.83) 0.007
Child birth trauma 5.99 (3.95–9.09) <0.001 5.97 (3.82–9.33) <0.001
Child birth asphyxia 11.42 (5.25–24.86) <0.001 11.79 (5.18–26.85) <0.001
Child sickle cell disease 3.58 (1.17–10.98) 0.026 4.04 (1.31–12.47) 0.015
Child sickle cell trait2.45 (0.70–8.65)0.1632.75 (0.78–9.71)0.116
Child thrombophilia 157.99 (54.20–460.56) <0.001 182.64 (62.70–532.05) <0.001
Child congenital infection 5.39 (1.90–15.33) 0.002 3.36 (0.81–13.90)0.095
Child neonatal infection 6.06 (3.93–9.33) <0.001 5.26 (3.26–8.50) <0.001
Child meningitis 6.05 (3.31–11.06) <0.001 6.19 (3.18–12.05) <0.001
Child encephalitis 3.99 (1.67–9.56) 0.002 3.37 (1.19–9.52) 0.022
Gestational age (wks) 0.88 (0.85–0.92) <0.001 0.89 (0.85–0.93) <0.001
Placental abruption1.64 (0.91, 2.97)0.1001.80 (0.95, 3.39)0.071
Child thalassemiaNot in modelNot in model

Maternal hypertension was significantly associated with any ischemic stroke diagnosed before 30 days (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.26–4.24) and before 365 days (OR 1.93, 95% CI 1.36–2.74). Intrapartum fever was also significantly associated with any ischemic stroke both before 30 days (OR 3.36, 95% CI 1.01–11.19) and before 365 days (OR 3.16, 95% CI 1.57–6.37). Maternal diabetes was not significant in either model. Gestational age, birth trauma, birth asphyxia, child thrombophilia, sickle cell disease, congenital infection, and neonatal infection were significantly associated with ischemic stroke in both models. Child sickle-cell trait was a significant risk factor for ischemic stroke before 30 days but not when including strokes up to 364 days. Meningitis was a risk factor for ischemic stroke before 365 days but not before 30 days.

We repeated the model building for confirmed ischemic stroke. Maternal hypertension and intrapartum fever were significantly associated with odds of ischemic stroke in the child, both before 30 days and before 365 days. The odds ratio point estimates were very similar to those for unconfirmed ischemic stroke, but were more strongly significant. Maternal diabetes was not associated with confirmed ischemic stroke in any of the models. The significant covariates for confirmed ischemic stroke were similar to those for any ischemic stroke.

Finally, we created a dichotomous variable (‘otherfactor’) to indicate that an infant was exposed to at least one of the following: birth trauma, birth asphyxia, thalassemia, sickle cell disease or trait, thrombophilia, congenital infection, neonatal infection, meningitis, encephalitis, or placental abruption. We then tested for multiplicative interactions between maternal hypertension and ‘otherfactor,’ and between maternal fever and ‘otherfactor’. Neither interaction term was significant when modeling the odds of ischemic stroke diagnosed before 30 days. When modeling stroke before 365 days, there was a significant interaction between maternal hypertension (but not fever) and the presence of ‘otherfactor’. When we stratified the models by the presence of another risk factor, we found that maternal hypertension was significantly associated with both any ischemic stroke (OR 2.46, 95% CI 1.58–3.84) and confirmed ischemic stroke (OR 2.72, 95% CI 1.66–4.46) before 365 days among children with at least one of the other risk factors. Maternal hypertension was not associated with any ischemic stroke or confirmed ischemic stroke before 365 days among children without any of the risk factors; the OR point estimates were approximately 1.0.

Discussion

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Maternal hypertension and intrapartum fever were both associated with neonatal ischemic stroke, whereas maternal diabetes was not. The findings related to hypertension are consistent with previous evidence that maternal pre-eclampsia is associated with increased risk of neonatal ischemic stroke. We are aware of only one other study23 identifying maternal fever as a significant risk factor for neonatal ischemic stroke. Intrapartum fever can be a marker for chorioamnionitis as well as for other maternal infections and is a risk factor for neonatal encephalopathy and death, cerebral palsy, and other adverse child outcomes.24,25 Intrapartum fever has previously been identified as a risk factor for neonatal death, neonatal encephalopathy, and several other adverse neonatal outcomes.25,26 Fever is associated with a significant systemic inflammatory response,27 and inflammatory cytokines are known to have prothrombotic effects that can precipitate ischemic events such as ischemic stroke.28,29

Although investigating non-maternal risk factors for neonatal ischemic stroke was not the primary goal of this study, it is interesting that we found multiple child characteristics to be associated with increased odds of neonatal/infant ischemic stroke. The significant covariates were generally related to increased propensity for thrombosis, were similar for neonatal ischemic stroke and for stroke up to 364 days after birth, and were consistent with risk factors previously identified for perinatal stroke.4 There appears to be a synergistic relationship between maternal hypertension and the presence of one or more other risk factors in predicting ischemic stroke diagnosed less than 365 days after birth. This synergy is consistent with the multifactorial model of perinatal ischemic stroke, which has been proposed by others.1,30 Taken as a whole, the variables examined in this study are good predictors of the risk of ischemic stroke in infants; among infants with ischemic stroke before 365 days, 65% were identified as having at least one of the risk factors (independent variable or covariate, not including preterm birth), compared with 22% of infants without ischemic stroke.

We also found that gestational age was substantially lower in infants with ischemic stroke. Most studies of perinatal/neonatal ischemic stroke stratify by preterm status and, therefore, cannot comment on the association between preterm birth and risk of ischemic stroke. However, Benders et al.31 report that, in a sample of 73 infants with perinatal arterial ischemic stroke, 42% were preterm (<37wks). We cannot necessarily conclude that preterm birth increases the risk of ischemic stroke. Instead, preterm birth may primarily be a marker of underlying problems in the pregnancy that are associated with increased risk of stroke. In-depth analysis of different causes of preterm birth and how they relate to risk of ischemic stroke in the infant would be needed to answer this question.

It has been postulated that perinatal stroke occurs because of vasculo-placental pathology such as infarctions, which lead to the formation of clots that can embolize to the fetal circulation, pass through the foramen ovale and into the cerebral vasculature.4,30 If this is the case, it stands to reason that maternal conditions that cause or are associated with placental infarction would be associated with increased risk of stroke in the infant. It is well established that placental infarction (and other lesions) are more common in pregnant females with hypertension.32,33 Dueck et al. 34 present a case study of an infant with perinatal stroke attributable to chorioamnionitis. They state, ‘In addition to the recognized inflammatory cascade of in utero infection, umbilical vein thrombosis with subsequent ‘paradoxical’ embolization may represent one mechanism responsible for this association.’ Additional research is needed to investigate likely mechanisms of the associations identified in our analyses.

The most important limitation of this study is its reliance on administrative data for ascertainment of both exposures and neonatal ischemic stroke. It is possible that some females identified as having fever and/or hypertension and some infants diagnosed with ischemic stroke were misclassified; however, given that the maternal diagnoses were made before the occurrence of stroke in the child, there is no reason to believe such misclassification would be differential for those exposures. Such a non-differential misclassification bias would tend to result in underestimation of the strength of the observed associations. It is important to note that, because perinatal ischemic stroke is estimated to occur in two to four infants per 10 000 live births, in our sample of almost 230 000 children, we would anticipate approximately 45 to 90 cases of neonatal ischemic stroke, which is similar to the range of confirmed cases identified in our cohort (37 cases diagnosed < 30d and 99 more between 30–365d).

A second limitation is that the females and children in this study were all enrolled in the South Carolina Medicaid program, which provides health insurance coverage for low-income families. Medicaid pays for approximately 50% of the births in South Carolina. It is possible that the results of this study may not be completely generalizable to middle- and upper-income families in South Carolina, or to females and children outside the southern USA.

A final limitation is that some strokes diagnosed between 30 days and 364 days may not be neonatal, but, rather, may have occurred later in infancy. Others30,35 have pointed out that up to 40 or 50% of neonatal strokes do not present until later in childhood, and that ischemic stroke is much more common in the perinatal period than at any other time in childhood.3 Despite this, it is likely that some of the strokes identified between 30 and 365 days actually did not occur during the neonatal period; we have no way to ascertain this with the information available. However, given that the 28-day cut-off for neonatal stroke is somewhat arbitrary, that strokes occurring later in infancy are also clinically significant, and that the risk factors we identified for stroke before 30 days were very similar to those for all strokes before 365 days, we believe it is appropriate to consider the two periods together as we have done.

The greatest strength of this study is its very large sample size, more than 200 000 births over 8 years, with linked maternal and child Medicaid, and birth certificate data. We had sufficient power to detect statistically significant risk factors for ischemic stroke. We were also able to control for several potential confounders and to perform sensitivity testing on variations in the case definition of neonatal ischemic stroke. Therefore, we believe it is appropriate to be highly confident in the findings of this study.

In summary, maternal hypertension and intrapartum fever appear to be risk factors for neonatal ischemic stroke. Additional research is needed to describe further the links between maternal hypertension and fever, and risk for neonatal stroke, and to investigate the mechanisms that may be involved. If these associations are confirmed, it may be feasible to develop targeted interventions to reduce the risk of ischemic stroke in infants born to females with these risk factors.

Acknowledgements

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This work was funded by the Health Resources Services Administration (HRSA) – Maternal Child Health, grant number R40MC21523. We thank Heather Kirby and other staff at the South Carolina Office of Research and Statistics for providing the linked data used in this study.

References

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References