Risk Factors for Neonatal Seizures: A Population-based Study, Harris County, Texas, 1992–1994

Rima M. Saliba1, F. John Annegers1,, D. Kim Waller1, Jon E. Tyson1,2 and Eli M. Mizrahi3

1 The University of Texas School of Public Health, Houston, TX.
2 Department of Pediatrics, The University of Texas School of Medicine, Houston, TX.
3 Section of Neurophysiology, Department of Neurology, The Methodist Hospital, Baylor College of Medicine, Houston, TX.
{dagger} Deceased.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Risk factors for neonatal seizures were evaluated in 116,048 infants born between 1992 and 1994 to residents of Harris County, Texas; 207 of these infants were diagnosed with clinical neonatal seizures. Information was obtained from the infant's birth certificate to assess the relation between seizures and birth weight, gender, ethnicity, place of birth, mother's age, method of delivery, parity, and multiple births. These factors were evaluated by univariate and multivariate analysis using logistic regression. For preterm infants, a birth weight of <1,500 g was the strongest risk factor (relative risk (RR) = 9.1, 95% confidence interval (CI): 4.7, 17.5), followed by birth in a private/university hospital (RR = 2.8, 95% CI: 1.5, 5.0) and male gender (RR = 1.8, 95% CI: 1.0, 3.4). For term infants, significant risk factors included birth by cesarean section (RR = 2.2, 95% CI: 1.5, 3.2), small birth weight for gestational age (RR = 1.9, 95% CI: 1.2, 2.9), birth in a private/university hospital (RR = 1.8, 95% CI: 1.1, 3.0), and maternal age of 18–24 compared with 25–29 years (RR = 1.6, 95% CI: 1.1, 2.3). Birth by assisted vaginal delivery and primiparity were marginally significant for term infants. Birth weight is a significant risk factor for neonatal seizures. The role of perinatal complications warrants further evaluation.

birth weight; newborn; perinatology; risk factors; seizures

Abbreviations: CI, confidence interval; LMP, last menstrual period; RR, relative risk.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent population-based estimates of the incidence of neonatal seizures range from 1.0 to 3.5 per 1,000 livebirths ((1GoGo–3Go); A. Hauser, Mayo Clinic, personal communication, 1996). Information is limited on risk factors for neonatal seizures in light of advancements in obstetric and neonatal care over the last decade. Most of the published studies are restricted to referral series, term infants, seizures occurring within the first 3 days of life, or specific seizure etiologies (4GoGoGoGo–8Go). The only two known published case-control studies on risk factors for neonatal seizures indicate a role for antepartum and intrapartum factors (5Go, 7Go). In a population-based study, Minchom et al. (7Go) reported the following factors to be significant for seizures occurring in term infants within the first 48 hours of birth: nulliparity, hydramnios, post-term pregnancy, oxytocin augmentation of labor, fetal distress, prolonged second stage of labor, emergency cesarean section, assisted vaginal delivery, low Apgar score, resuscitation at delivery, and subsequent ventilatory support. These factors were not evaluated in multivariate analysis. Similarly, in a hospital-based case-control study, Patterson et al. (5Go) reported that, on multivariate analysis, antepartum anemia, antepartum bleeding, asthma, meconium-stained amniotic fluid, presentation other than occiput anterior, fetal distress, and shoulder dystocia were significant for seizures in term infants within the first 72 hours of birth.

We conducted this study to evaluate risk factors for clinical neonatal seizures ascertained within a large and ethnically diverse, geographically defined population. Because the risk of neonatal seizures varies significantly for term and preterm infants (1Go, 9Go), risk factors were assessed separately for each group.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The design and methods of this investigation have been described previously (1Go). In brief, incident cases of neonatal seizures were ascertained in infants born between September 1992 and August 1994 to residents of Harris County, Texas. Cases were identified from discharge diagnoses at birthing hospitals in Harris and adjacent counties, from birth certificates, from death certificates, and from a clinical study of neonatal seizures conducted concurrent with this study at Texas Children's Hospital, a large tertiary care center in Houston, Texas. The medical records of all potential cases were reviewed by one of the authors (R. S.). Infants were included in the study if the transcribed description of the clinical seizure event in the medical record (reviewed by E. M.) was consistent with the various types of clinical seizures proposed by Volpe (9Go) and by Mizrahi and Kellaway (10Go). To ascertain seizures at equivalent conceptional ages for preterm and term infants, the neonatal period was defined as the first 28 days of life for term infants and up to 44 completed weeks of conceptional age for preterm infants. A total of 207 cases of clinical seizures were thus ascertained in 116,048 livebirths, resulting in an incidence of 1.8 per 1,000 livebirths (1Go).

All 207 ascertained cases were linked to their birth certificate records to compare birth certificate information for infants with and without seizures. The linkage was done by using a computer program and was verified manually. Information used in this analysis included birth weight (grams), gestational age at birth based on the date of the mother's last menstrual period (LMP), mother's ethnicity, mother's age, parity, method of delivery, multiple births, hospital of birth, and place of birth (home vs. hospital). For seven cases, the LMP estimate of gestational age was missing from the birth certificate. For six of these infants, the clinical estimate of gestational age was available on the birth certificate and was substituted for the LMP estimate.

Infants coded on their birth certificates as born before 20 or after 44 completed weeks of gestation (1.9 percent of all births, including 7/207 cases) were excluded from the analysis because of the inaccuracies associated with LMP estimates of gestational age outside this range (11Go). In addition, infants whose birth weight was unknown (1.4 percent of all births, including 6/207 cases), whose gestational age was unknown (7.1 percent of all births, including 1/207 cases), or whose birth weight was implausible for gestational age (0.5 percent of all births, including 4/207 cases) were excluded from the analyses involving both birth weight and gestational age. Ranges of plausible birth weight for gestational age were adopted from Alexander et al. (12Go). These ranges were based on distributions of gestational age for birth weights grouped into 125-g intervals for 3,808,689 singleton livebirths in the United States in 1991. After all exclusions, the analysis was performed on 89 percent of all livebirths, including 91.3 percent (189/207) of the cases of neonatal seizures. The findings were similar when the analysis was conducted by using all available data, irrespective of the exclusions described above.

Preterm birth was defined as any birth occurring before 37 weeks of gestation, term birth as occurring between 37 and 41 completed weeks of gestation, and post-term birth as occurring between 42 completed weeks and 44 weeks of gestation. Very low birth weight was defined as less than 1,500 g.

Among term infants, the effect of birth weight on the risk of neonatal seizures was evaluated on the basis of whether the infant was small, appropriate, or large for gestational age. Infants were classified as small for gestational age if their birth weight was less than the 10th percentile for gestational age and as large for gestational age if their birth weight was more than the 90th percentile for gestational age. The remaining infants were considered appropriate for gestational age. These percentiles were based on ethnic-, gender-, and parity-specific birth weights for each gestational age between 25 and 42 weeks for 3,427,009 infants born in the United States in 1989 (13Go). Similar analysis was not performed for preterm infants because of the inaccuracy associated with estimating gestational age in this group of infants (11Go, 14Go). Level I, II, and III nurseries were defined according to American Academy of Pediatrics guidelines (15Go).

Significant risk factors for neonatal seizures were identified by univariate analysis on the basis of the relative risk estimates and 95 percent confidence intervals calculated by using the Cornfield method (16Go). Logistic regression analysis was performed to evaluate the independent effects of the risk factors identified as significant by univariate analysis or reported as such in the literature. Given that neonatal seizures are rare, the odds ratios derived from logistic regression analysis are a close approximation of the relative risk estimates. Associations were considered significant if the 95 percent confidence interval around the relative risk estimate did not contain 1 and marginally significant if the lower limit of the confidence interval was 0.9–1.0. Stata 5.0 statistical software was used for the analysis (17Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Preterm infants
For preterm infants, the risk of clinical seizures increased with decreasing birth weight and ranged from 0.8 per 1,000 livebirths for infants weighing 3,500 g or more to 23.4 per 1,000 livebirths for those weighing less than 1,500 g (table 1). For infants weighing less than 1,500 g, we observed a significantly lower risk for those born to White mothers (6.8 per 1,000 livebirths (2/294)) than for those born to Black mothers (31.5 per 1,000 livebirths (14/445)), Hispanic mothers (27.2 per 1,000 livebirths (7/257)), or mothers of other ethnicity (33.3 per 1,000 livebirths (1/30)) (relative risk (RR) for White vs. non-White = 0.2, 95 percent confidence interval (CI): 0.05, 1.0). This effect was independent of hospital of birth. The ethnic-specific distribution of birth weight and gestational age among infants weighing less than 1,500 g did not account for these differences either. There were no ethnic differences in the incidence of seizures among preterm infants weighing 1,500 g or more (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Risk of neonatal seizures* according to gestational age and birth weight,{dagger} Harris County, Texas, 1992–1994

 
Univariate analysis showed that preterm infants delivered at a level III private/university hospital and those delivered at a level III community hospital were at a significantly higher risk than infants delivered at hospitals with a level II nursery (RR = 9.5, 95 percent CI: 3.3, 27.1 and RR = 4.8, 95 percent CI: 1.5, 15, respectively). Home birth was associated with a substantially high risk: 32.5 per 1,000 livebirths (2 of 46 home births). Both infants who were born at home and had seizures weighed less than 1,500 g and were born before 33 weeks of gestation. Information was not available to verify whether the home deliveries were planned as such. Preterm infants delivered by cesarean section had an increased risk for seizures compared with those born by spontaneous vaginal delivery (RR = 1.8, 95 percent CI: 1.1, 3.2), and male infants were 1.8 times as likely to have seizures (95 percent CI: 1.0, 3.1). No significant association was found between seizures and mother's age, parity, or multiple births (table 2).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Risk factors for neonatal seizures in preterm infants (20–36 weeks of gestation), Harris County, Texas, 1992–1994

 
In multivariate analysis, birth weight, gender, and birth in a level III private/university hospital remained significant risk factors after adjustment for confounding, whereas birth in a level III community hospital and birth by cesarean section were no longer significant and were dropped from the final model. The risk associated with birth in a level III private/university hospital was lower in multivariate analysis. This finding indicates that the high risk found in univariate analysis can partly be explained by other factors retained in the final model. Although home birth was associated with a high risk in univariate analysis, it was not considered in multivariate analysis because of the low level of precision associated with this estimate (95 percent CI: 6.1, 173.3 (table 2)).

Term infants
For term infants, those who were small for gestational age were about two times as likely to have seizures as infants who were appropriate for gestational age (RR = 1.8, 95 percent CI: 1.2, 2.9). This effect was consistent across ethnic groups (data not shown). Post-term infants had the same risk of seizures as term, appropriate-for-gestational-age infants (table 1).

In univariate analysis, significant risk factors (table 3) included cesarean section compared with spontaneous vaginal delivery (RR = 2.0, 95 percent CI: 1.4, 2.9) and maternal age of 18–24 compared with 25–29 years (RR = 1.7, 95 percent CI: 1.1, 2.7). Birth in a hospital with a level III nursery (private/university, public/university, or community hospital) in comparison with a level II nursery, primiparity, and male gender were only marginally significant risk factors in univariate analysis. The increased risk associated with primiparity (RR = 1.5, 95 percent CI: 1.0, 2.1) was consistent across mothers' age groups (data not shown). Assisted vaginal delivery was not associated with a significantly higher risk when compared with spontaneous delivery (RR = 1.6, 95 percent CI: 0.8, 2.9); however, it was evaluated in multivariate analysis because of significant findings reported in the literature in addition to biologic plausibility. Multiple births were not considered in this analysis, because all term infants with seizures were singletons.


View this table:
[in this window]
[in a new window]
 
TABLE 3. Risk factors for neonatal seizures in term infants (37–41 weeks of gestation), Harris County, Texas, 1992–1994

 
The effects of birth weight, hospital of birth, maternal age, cesarean section, assisted vaginal delivery, and primiparity did not change substantially by multivariate analysis after adjustment for confounding. Gender was no longer a significant risk factor and was excluded from the final model. Although birth in a level III public/university or community hospital, birth by assisted vaginal delivery, and primiparity remained only marginally significant, they were retained in the final model as potential prognostic factors to be evaluated in further studies.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our data show that birth weight is a risk factor for clinical neonatal seizures in both preterm and term infants. For preterm infants, the risk of seizures increased significantly with decreasing birth weight; for term infants, those who were small for gestational age were two times as likely to have seizures as those whose birth weight was appropriate for their gestational age. Forty-six percent (11/24) of seizures in term, small-for-gestational-age infants in our study occurred within the first 2 days of life. This finding is consistent with the McIntire et al. (18Go) data showing a twofold incidence of seizures occurring during the first 24 hours of life in 82,361 term infants weighing less than the 11th percentile for their gestational age and with Minchom et al. (7Go), who reported an odds ratio of 2.6 (95 percent CI: 0.9, 6.3) for seizures occurring within the first 48 hours of life in "light-for-dates" term infants. The substantially increased risk of seizures among preterm infants weighing less than 1,500 g is not surprising, because these infants are at high risk for intraventricular hemorrhage and encephalopathy, which are frequently seen in conjunction with seizures (9Go, 10Go, 19Go).

We observed a significantly lower risk for very low birth weight infants born to White mothers compared with those born to Black mothers, Hispanic mothers, or mothers of other ethnicity. To the best of our knowledge, there are no published reports whose findings can be compared with ours. The observed ethnic discrepancy was independent of birth weight, gestational age, or hospital of birth, and it was unlikely to be due to differential underascertainment based on ethnicity. However, it might be partly explained by the higher neonatal mortality of White, very low birth weight infants compared with other infants, which has been reported both nationally (20GoGo–22Go) and for the state of Texas (23Go). With higher mortality, the opportunity for occurrence of seizures might be reduced. Data collected for this study were not sufficient to evaluate this effect, and validation of our findings requires further studies.

While this study found a higher risk of clinical seizures for preterm compared with term infants, it did not address whether the seizures were epileptic (i.e., hypersynchronous cortical neuron discharges) or nonepileptic (i.e., subcortical mechanisms or brainstem release phenomenon) in origin. It also did not address the gestational age at which the premature brain begins to generate typical epileptic seizures (10Go, 24Go). A recent prospective study of clinical seizures in very low birth weight infants documented by electroencephalographic-video monitoring found that almost all of the seizure types were not associated with simultaneously recorded electroencephalographic seizure activity (the hallmark of an epileptic seizure) and were best characterized as myoclonus (25Go, 26Go). Thus, while the current study indicates an increased incidence of clinical seizures in preterm infants, it does not support the notion of increased epileptogenesis in this group.

Birth in a level III private/university hospital was independently associated with an increased risk of seizures for both preterm and term infants. Factors that could explain this higher risk include referral of high-risk pregnancies, longer periods of surveillance, and more-consistent identification and documentation of neonatal seizures, especially in preterm infants in whom neonatal seizures are not easily recognized (9Go). This increased risk could also be due to relatively better survival rates for high-risk infants in level III nurseries compared with other nurseries. Delineation of the role of these and other factors in the increased risk of seizures observed in level III private/university hospitals warrants further evaluation.

For term infants, birth by cesarean section was associated with a twofold risk compared with birth by spontaneous vaginal delivery. This finding is consistent with previous findings showing a significant association between emergency cesarean section and seizures occurring within the first 72 hours of life in term infants (5GoGo–7Go). We could not evaluate the risk according to the indication for cesarean section because such information was not available on the birth certificates. In our study, assisted vaginal delivery and primiparity were only marginally related to the risk of seizures in multivariate analysis, but we kept them in the final model as potential risk factors. Minchom et al. (7Go) reported that in univariate analysis, these two factors were significant for seizures occurring within the first 48 hours of life in term infants (odds ratio = 3.5, 95 percent CI: 1.9, 6.1 and odds ratio = 2.9, 95 percent CI: 1.6, 5.4, respectively). Curtis et al. (6Go) also reported primiparity to be associated with asphyxial seizures (p value < 0.05). The effects of cesarean section and assisted vaginal delivery suggest a role for labor and delivery complications in the risk of neonatal seizures, which require further detailed evaluation. The effect of primiparity could be explained by the more difficult labor and delivery experienced by primiparous mothers.

We limited our analysis to factors that have been shown to be reliable on birth certificates. These factors included mainly demographic characteristics. Information regarding pregnancy and delivery complications, although relevant, was not considered in our study because of the low reliability of birth certificate information reported for these factors (27Go, 28Go). By using the same source of information for infants with and without seizures, we minimized the chance of misclassifying exposure differently for these two groups. Therefore, if misclassification of exposure occurred, we expect that it was nondifferential. This type of bias usually results in underestimation of the magnitude of the associations and, if present, would suggest that the associations reported here are even stronger.

In conclusion, this study confirmed the effect of low birth weight on the risk of clinical neonatal seizures in preterm and term infants. The association of seizures with the method of delivery, and birth in hospitals with a level III nursery, indicate the need for further evaluation of the role of labor and delivery complications in the risk of neonatal seizures in light of current neonatal care.


    ACKNOWLEDGMENTS
 
This study was supported by grant NO1-NS-1-2316 from the National Institute of Neurologic Disorders and Stroke. Research in the Section of Neurophysiology, Department of Neurology, Baylor College of Medicine is supported in part by the Peter Kellaway, Ph.D. Endowment for Research.

The authors thank the staff of the medical records sections at the participating hospitals for their valuable cooperation and Sharon Coan and Tony Lam at The University of Texas School of Public Health for their assistance with data management.


    NOTES
 
Reprint requests to Dr. Rima M. Saliba, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 423, Houston, TX 77030 (e-mail: rsaliba{at}mdanderson.org).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Saliba RM, Annegers JF, Waller DK, et al. Incidence of neonatal seizures in Harris County, Texas, 1992–1994. Am J Epidemiol 1999;150:763–9.[Abstract]
  2. Lanska MJ, Lanska DJ, Braumann RJ, et al. A population based study of neonatal seizures in Fayette County, Kentucky. Neurology 1995;45:724–32.[Abstract]
  3. Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 1999;134:71–5.[ISI][Medline]
  4. Lien JM, Towers GV, Quilligan EJ. Term early-onset neonatal seizures: obstetric characteristics, etiologic classification, and perinatal care. Obstet Gynecol 1995;85:163–9.[Abstract/Free Full Text]
  5. Patterson CA, Graves WL, Bugg G, et al. Antenatal and intrapartum factors associated with the occurrence of seizures in term infant. Obstet Gynecol 1989;74:361–5.[Abstract]
  6. Curtis PD, Matthews TG, Clarke TA, et al. Neonatal seizures: the Dublin Collaborative Study. Arch Dis Child 1988;63:1065–8.[Abstract]
  7. Minchom P, Niswander K, Chalmers I, et al. Antecedents and outcome of very early neonatal seizures in infants born at or after term. Br J Obstet Gynaecol 1987;94:431–9.[ISI][Medline]
  8. Derham RJ, Matthews TG, Clarke TA. Early seizures indicate quality of perinatal care. Arch Dis Child 1985;60:809–13.[Abstract]
  9. Volpe JJ. Neonatal seizures. In: Neurology of the newborn. 3rd ed. Philadelphia, PA: WB Saunders, 1995:172–207.
  10. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837–44.[Abstract]
  11. Kramer MS, McLean FH, Boyd ME, et al. The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations. JAMA 1988;260:3306–8.[Abstract]
  12. Alexander GR, Himes JH, Kaufman RB, et al. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–8.[Abstract/Free Full Text]
  13. Zhang J, Bowes WA. Birth weight for gestational age patterns by race, sex, and parity in the United States population. Obstet Gynecol 1995;86:200–8.[Abstract/Free Full Text]
  14. Milner RD, Richards B. An analysis of birth weight by gestational age of infants born in England and Wales, 1967 to 1971. J Obstet Gynaecol Br Commonw 1974;81:956–67.[ISI][Medline]
  15. Freeman RK, Poland RL, eds. Guidelines for perinatal care. 3rd ed. Elk Grove Village, IL: American Academy of Pediatrics; Washington, DC: American College of Obstetricians and Gynecologists, 1992.
  16. Cornfield J. A statistical problem arising from retrospective studies. In: Neyman J, ed. Proceedings of the Third Berkeley Symposium. Vol 4. Berkeley, CA: University of California Press, 1956:135–48.
  17. Stata Corporation. 1997 Stata statistical software, release 5.0 ed. College Station, TX: Stata Corporation, 1997.
  18. McIntire DD, Bloom SL, Casey BM, et al. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234–8.[Abstract/Free Full Text]
  19. Hack M, Hobar JD, Malloy MH, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Network. Pediatrics 1991;87:587–97.[Abstract]
  20. Guyer B, MacDorman MF, Martin JA, et al. Annual summary of vital statistics--1997. Pediatrics 1998;102:1333–49.[Abstract/Free Full Text]
  21. Sappenfield WM, Buehler JW, Binkin NJ, et al. Differences in neonatal mortality by race, birth weight and gestational age. Public Health Rep 1987;102:182–92.[ISI][Medline]
  22. Iyasu S, Becerra JE, Rowley DL, et al. Impact of very low birth weight on the black-white infant mortality gap. Am J Prev Med 1992;8:271–7.[ISI][Medline]
  23. Kerr GR, Ying J, Spears W. Ethnic differences in causes of infant mortality: Texas births, 1989 through 1991. Texas Med 1995;91:50–6.
  24. Mizrahi EM, Kellaway P. Pathophysiology. In: Diagnosis and management of neonatal seizures. Philadelphia, PA: Lippincott-Raven Publishers, 1998:181.
  25. Wise MS, Mizrahi EM, Hrachovy RA, et al. Seizures in very low birth weight infants. (Abstract). Ann Neurol 1999;46:525.
  26. Wise MS, Mizrahi EM, Hrachovy RA, et al. Seizures in very low birth weight (VLBW) infants: seizure characterization using bedside EEG/video/polygraphic monitoring. (Abstract). Epilepsia 1999;40:161.
  27. Selwyn BJ, Ethen MK. The validity of information on the Texas birth certificate. Report to the Texas Department of Health, Bureau of Vital Statistics. Houston, TX: The University of Texas School of Public Health, October 1999.
  28. Piper JM, Mitchel EF Jr, Snowden M, et al. Validation of 1989 Tennessee birth certificates using maternal and newborn hospital records. Am J Epidemiol 1993;137:758–68.[Abstract]
Received for publication October 19, 1999. Accepted for publication November 15, 2000.





This Article
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (5)
Disclaimer
Request Permissions
Google Scholar
Articles by Saliba, R. M.
Articles by Mizrahi, E. M.
PubMed
PubMed Citation
Articles by Saliba, R. M.
Articles by Mizrahi, E. M.