Meconium-stained amniotic fluid and risk for cerebral palsy in preterm infants

Meconium-Stained Amniotic Fluid and Risk for Cerebral Palsy in Preterm Infants ARSENIO SPINILLO, MAURO STRONATI,

MD, ELI-SA FAZZI, MD, EZlO CAPUZZO, MD, .MD, GAIA PIAZ%I, MD,, A.N.D A.NTC?NFI IA FE.RRARI, .MD

Objective: To estimate the risk for cerebral palsy in preterm infants in relation to the presence of meconium in the amniotic fluid (AF). Methods: A cohort study was conducted of 404 consecutive preterm infants delivered between 24 and 33 weeks’ gestation at a single institution. Sociodemographic and clinical data were collected at birth. The diagnosis of cerebral palsy was made at 2 years’ corrected age. Politomous logistic regression models were used to evaluate the odds for cerebral palsy while adjusting for potential confounders. Results: The overall prevalence af cerebral palsy among survivors was 11.6% (40/345). The cereb:ral palsy rate was 41.2% (7/17) among infants who were meconium-stained at birth and 10% (33/328) among those who were not (P = ,006 by Fisher exact test). After adjustment for potential confounders (gestational age and fetal gender), the odds ratio of cerebral palsy among infants delivered to women with meconium-stained AF was 6.9 (95% confidence interval 2.32, 20.81, P = .OOl) relative to those delivered to women with clear AF. Conclusion: The results of the present study support the view that the presence of meconium in the .AF is a gestational age-independent risk factor fcr cerebral palsy among preterm infants. (Obstet Gynecol 1997;90:519-23. 0 1997 by The American College of Obstetricians and Gynecologists.)

In the literature on the origin of cerebral palsy, most data are based on studies of term infants.“’ There is little information on risk factors for the development of cerebral palsy in preterm babies, Recent investigations3-’ suggest that both the type and the impact of causal factors of cerebral palsy in i:Tfants delivered preterm are different from those in term infants. Meconium staining of the amniotic fluid (AF) has well-, known adverse effects on neonatal survival and neurologic outcome in term or postterm infa.nts,6,7but infant ---. ~ _-.-_- .---. -- _-From the Department Intensive Care Unit, Department of Child Paaia, Italy.

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outcome data are lacking for preterm deliveries. In addition to the association of meconium-stained AF with. cerebral palsy in term infants, there are several other theoretic arguments supporting the role of meconium exposure in the development of brain damage in preterm babies. Meconium-stained AF frequently is associated.with microbial invasion of the amniotic cavity,8 resu.lting in increased production of several cytokines (eg, tumor necrosis factor, interleukin-lp, and interleu.kin-6),9 which have been implicated as mediators for the development of ischemic brain lesions in preterm babies.‘O In addition, in vitro studies” have shown that meconium can stimulate vasoconstriction of plasental veins, thereby precipitating brain-damaging hypoxemia. We evaluated the prevalence of neonatal death and cerebral palsy at 2 years’ corrected age in a cohort of singleton preterm infants in relation to the presence of meconium in the AF.

Materials and Methods The initial population for this study was composed of 461 singleton preterm (24--33completed weeks) infants delivered at our institution during 1987-1993. Eleven (2.4%) infants were excluded because of severe malformations or chromosomal abnormalities. Gestational age was estimated by menstrual. dates, postnatal assessment, and an ultrasound scan performed before 20 weeks’ gestation. In particular, 410 (91..1%)patients had an ultrasound scan done before 20 weeks’ gestation. For the 40 subjects with uncertain dates or a. greater than Z-week discrepancy between last menstrual dates and ultrasonographic assessment, the date from the scan was used Maternal sociodemographic and rlinical variables were collected at birth and stored in a computer data base. Social class in pregnancy was ranked into five categories, with class I as the highest, according to the

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woman’s or her partner’s occupation. Preeclampsia was defined according to standard criteri.a.” A birth weight below the sex-specific tenth percentile of the Italian birth weight curves was used to identify small for gestational age infantsI To explore the effect of birth weight on the outcomes independently of gestational age, we also computed the birth weight standard deviation (SD) scores (differences between actual and mean birth weight divided by SD) for each gestational age category. Intrapartum fetal heart rate (FHR) abnormalities included late or variable decelerations, bradycardia (less than 100 beats per minute), and tachycardia (FHR greater than 160 beats per minute). The diagnosis of chorioamnionitis was based on ma,ternal temperature greater than 37.8~ plus two of the following: 1) maternal tachycardia (heart rate greater than 100 beats per minute), 2) baseline FHR greater than 160 beats per minute, 3) positive endocervical or high-vaginal swab culture, 4) maternal white blood cell count greater than 18,000/mm3, and 5) foul-smelling AF.i4 Neurodevelopmental evaluation cf the surviving infants was carried out by a child neuropsychiatrist not involved in the intensive care of the infants and unaware of maternal history. Evaluation of the infants was carried out at discharge from the hospital and at 3,6,12, and 24 months’ corrected age. Neurclogic evaluation of the newborns was based on the methods of Amiel-Tison and Grenier.i5 The Bayley scales of infant development were used to assess cognitive status (Mental Developmental Index) at 12 to 24 months. Fifty (11.1%) infants died within the first 28 days of life and nine (2%) died thereafter. Of the 391 survivors, 46 (‘11.8%) were lost to follow-up and their data were excluded from the study. At discharge from the hospital, 38 (821.6%) of these latter infants had been judged to be neurologically unimpaired (none of these infants had been delivered to mothers with stained AF), six had minor neurodevelopmental abnormalities (one infant had been delivered to a mother with stained fluid), and in two infants, both delivered to mothers with clear AF, neurologic examination was frankly abnormal. Of the 345 infants assessed at 2-years’ corrected age, 40 (11.6%) had cerebral palsy. Cerebral palsy cases included 27 infants with spastic quadriplegia and 14 with spastic diplegia or hemiplegia. Fourteen of 27 quadriplegic infants and two in the nonquadriplegic group also had severe mental impairment (Bayley Mental Developmental Index less than 71). Statistical analysis was carried out using KruskalWallis analysis of variance or the Ma.nn-Whitney ZI test, where appropriate, for continuous variables. Bonferroni correction was used for multiple comparisons. Fisher exact test was used to compare categorical variables. Politomous logistic regression analysis with continuous

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and coded terms was used to evaluate the simultaneous effects of antenatal variables on neonatal death and cerebral palsy, adjusting for confounders.i6 This approach was chosen to estimate the role of potential risk factors on both outcome measures while avoiding survival bias. Unlike conventional logistic regression, which evaluates the association between explanatory variables and a binary (yes/no) outcome, politomous logistic regression permits analysis of the simultaneous association between explanatory variables and nominal or ordinal scaled multiple outcome measures.16 Although previous studies have shown that 14% of the risk of quadriplegic cerebral palsy is associated with meconium in the AF,17 we are unaware of data in the literature on the strength of the association between cerebral palsy and meconium-stained fluid in preterm infants. Given our sample size and an assumed 10% prevalence of cerebral palsy among pregnancies with clear AF, we had an 80% power to detect a minimum fivefold increased risk of cerebral palsy among infants delivered to women with meconium-stained fluid at the usual alpha value of .05.

Results Infant outcome was tabulated by maternal sociodemographic characteristics, infant gestational age, and birth weight (Table 1). Gestational age and birth weight were significantly lower among infants who subsequently died than among both surviving infants and infants with cerebral palsy (P < .05 by Kruskal-Wallis analysis of variance and Mann-Whitney U test with Bonferroni correction). Birth weight SD score was lower among surviving infants than among those who died (P = .029 by Mann-Whitney U test with Bonferroni correction). Increasing gestational age and birth weight decreased the likelihood of neonatal death and cerebral palsy, whereas increasing birth weight SD score was associated with reduced likelihood of neonatal death only. Previous induced abortions were associated with increased odds for death and cerebral palsy. The prevalence of cerebral palsy was significantly higher in male infants than in female infants (29/181 versus 11/164, respectively; P = .007 by Fisher exact test). Table 2 reports the association of cerebral palsy and death with several antenatal and intrapartum variables. Preeclampsia was associated with a reduced risk for infant cerebral palsy. Classified as meconium-stained were six cases with evident brownish green discoloration of AF and 14 cases with thick, undiluted meconium. Five patients with slight meconium staining (one case of cerebral palsy) and another seven with uncertain meconium staining (no cases of cerebral palsy) were included in the category of clear AF. Among survivors,

Obstetrics & Gynecology

Table

1. Odds Ratios for Neonatal

Death

and

Cerebral

Palsy

in Relation

Survival, no cerebral palsy (N = 305)*

Characteristic Maternal age (y) Gestational age (wk) Birth weight SD score Birth weight (g) Education (y) >13 9-13 6-8 <6 Social class I-II (professional/managerial) III (nonmanual, skilled and unskilled) IV-V (manual, skilled and unskilled) Previous term pregnancy Previous preterm delivery Previous spontaneous abortion Previous voluntary abortion Maternal smoking Alcohol use Male fetal gender

29.1 2 27.6 I - -0.2944 k 997+

451

5

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4.7 2.3 0.81 328

1.02 0.64 0.68 0.74

(0.97,1.08) (0.56,0.73) (0.50,0.92) (0.67,0.82)

interval. regression

1997

(N = 40)* 30.3 29.6 -0.065 1317

+ + + 2

OR (95% CI)+

5.2 2.8 0.94 519

1.07 0.87 0.88 0.94

(1.0, 1.15) (0.76,0.99) (0.62,1.23) (0.87,l.O)

4 13 19 4

Reference 0.67 (0.20,2.55) 0.83 (0.26,2.66) 0.59 (0.13,2.59)

55 149 101 100 46 66 21 26 40 152

7 22 30 25 7 22 9 9 12 31

Reference 1.16 (0.47,2.87) 2.33 (0.96,5.65) 1.50 (0.85,2.663 0.76 (0.32, 1.77) 2.15 (1.19, 3.90) 2.43(1.05,5.62) 1.93 (0.85,4.37) 1.69 (0.83,3.42) 1.11 (0.64,1.95)

9 17 14 12 6 7 10 5 9 29

Reference 0.69 (0.29,1.66) 0.85 (0.34,2.08) 0.88 (0.43,1.80) 0.99 (0.39,2.50) 0.77 (0.32,1.81) 4.51 [1.94,10.5) 1.53 (0.55,4.25) 1.92 (0.85,4.34) 2.65 (1.28,5.50)

deviation.

logistic regression, stained AF was associated with a sixfold increased risk for cerebral palsy. Interestingly, four of seven infants with cerebral palsy delivered to women with meconium-stained AF had been delivered

Deatl- and Cerebral Palsy in Relation to Antenatal

Preeclampsia Diabetes First-trimester hemorrhage Premature rupture of membranes No. 12-48 h >48 h Tocolysis ND. 12-48 h r48 h Corticosteroids Cesarean delivery No labor Small for gestational age Abruptio placentae Placenta previa Nonvertex presentation Fetal heart rate abnormalities Meconium-stained amniotic fluid Clinical chorioamnionitis OR = odds ratio; CI = confidence * Obtained by politomous logistic

Cerebral palsy OR (95% CI)t

Reference 0.87CO.30, 2.55) 0.70 (0.24,2.04) 1.53 IO.48,4.86)

Survival, no cerebral palsy 07 = 3051

Variable

Characteristics

21 20 13

the prevalence of cerebral palsy was 41% (7/17) in infants delivered to women with stained AF compared with 13.4% (33/246) in those delivered to mothers with clear AF (P = .006 by Fisher exact test). In politomous 2. Odds Ratios for Neonatal

Neonatal

23 111 132 39

OR = odds ratio; CI = confidence interval; SD = standard * Data are presented as mean f SD or n. + Obtained by politomous logistic regression analysis.

Table

and

Death

(N = 59y

28.6 t 4.9 30.5 k 2.4 0.062 5 1.02 1451k

to Maternal

and

Death

Intrapartum

Variables

Cerebral palsy (N = 40)

(N = 59)

OR (95% CIY

59 2 72

10 4 14

0.85 (0.41,1.78) 11.0 (1.96,61.6) 1.0 (0.52,1.94)

2 1 14

0.22 (0.05,0.94) 3.88 (0.34,43.8) 1.74 (0.86, 3.52)

194 73 38

39 15 5

Reference 1.02 (0.53,1.96) 0.65 (0.24,1.77)

24 6 10

Reference 0.66 (0.26,1.69) 2.12 (0.94,4.81)

157 42 106 166 174 158 53 22 13 59 23 10 17

19

Reference 2.16 (0.96,4.84) 2.26 (1.20,4.24) 0.62 (0.35,1.08) 0.59 (0.34,1.04) 0.64 (0.36,1.12) 1.09 (0.53, 2.24) 0.69 (0.20, 2.38) 1.20 (0.33,4.36) 1.69 (0.90,3.17) 1.92 (0.81,4.53) 1.58 (0.42,5.92) 0.59 (0.06,2.62)

16 6 18 18 22 18 9 2 3 3 3 7 3

Reference 1.4 (0.52,3.80) 1.67 (0.81,3.411 0.69 (0.351.33) 0.92 (0.47,1.79) 0.76 (0.39,1.47) 1.38 (0.62,3.07) 0.68 (0.15,2.99) 1.82 (0.49, 6.69) 0.34 (0.1,1.141 0.99 (0.28,3.47) 6.26 (2.23,17.54) 1.37 (0.25,5.08)

11

29 25 26 24 11 3 3 17 8 3 2

OR (95% CIY

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Table 3.

Risk

Factors

for Cerebral Palsy by Amniotic Fluid

Staining Clear Meconium-stained amniotic fluid amniotic fluid (N = 384) (N = 20)

Factor Maternal age (y) Gestational age (wk) Birth weight SD score Birth weight (g) Preeclampsia Previous spontaneous abortion Previous voluntary abortion Male fetal gender Diabetes SD = standard deviation. Data are presented as mean

28.9 29.9 0.013 1368

f 4.9 + 2.4 f cl.97 + 463 69 93 38 196 6

29.3 31.2 -0.30 1439

2 i i i 2 2 2 16 1

5.2 2.4 1.38 599

P 77’ S-124 .2 .80 .54 .18 > ,999 ,012 .30

? SD or II.

by elective cesarean after prolonged (greater than 48 hours) membrane rupture, but in only one case with proven neonatal sepsis was chorioaevlionitis clinically evident. The other three infants had been delivered by elective cesarean because of fetal growth restriction or preeclampsia. The next step of our analysis was YOseewhether the association between cerebral palsy and meconiumstained AF was due to potential confounders. Table 3 shows the distribution of risk facto:-s associated with cerebral palsy in pregnancies with ,meconium-stained fluid. Meconium-exposed infants had longer gestations and were more frequently male than those delivered to women with clear AF. These two potlzntial confounders then were inserted in a multiple politomous logistic model. The multivariate odds ratios of death and cerebral palsy among meconium-stained infants were 3.24 (95% confidence interval [CI] 0.73,14.5, P = .12) and 6.9 (95% CI 2.32, 20.81, P = .OOl), respectively.

Discussion Ten to 15% of all pregnancies are complicated by meconium staining of the AF.” Meconium staining of the AF is common in term and postterm pregnancies but is relatively uncommon in preterm births. According to several authors,” meconium staining of the AF affects between 3 and 5% of preterm deliveries; this figure is consistent with that (4.95%:~found herein. The relationship between the presence of meconium in the AF and increased odds for bjrth asphyxia, neonatal mortality, and subsequent brain damage is well established in term infants.2,6,7 Ali:hough meconium alone is not a strong risk factor fol: cerebral palsy in infants weighing more than 2500 E;,~’ Nelson7 found that in a small subgroup of infani:s with meconium staining and birth asphyxia (Apgar score of O-3 at 5

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minutes), the incidence of cerebral palsy was 9.4%, with a fivefold increased risk compared with infants who had only birth asphyxia. Data from the National Collaborative Perinatal Study6,17 indicate that 14% of the risk for quadriplegic cerebral palsy is associated with meconium in the AF. We found that in the small subgroup of preterm infants with meconium staining, the prevalence of cerebral palsy was increased sixfold compared with controls delivered to women with clear fluid. Becausedata on delivery were collected prospectively and only cases with moderate to thick meconium were considered exposed, it seemsunlikely that biasesmight have been introduced by collection or classification of cases. In addition, the analysis of the main potential confounders (gestational age, birth weight, and birth weight SD score) indicates that meconium in the AF was an independent predictor of cerebral palsy. Two possible mechanisms exist that may explain the association between meconium-stained AF and infant brain damage. One mechanism relates to the possibility of an increased risk for subclinical chorioamnionitis among patients with meconium-stained fluid.21 Several authorsx,9,22have found that the presence of meconium in the AF is associatedwith increased rates of microbial invasion of the amniotic cavity, which, in turn, is associated with increased odds for cytokine-induced perinatal ischemic brain lesions” and cerebral palsy.” The finding that four of the seven casesof cerebral palsy associated with meconium-stained AF were infants who had been delivered after prolonged membrane rupture supports the concept of an adverse role of subclinical intra-amniotic infection on the neurologic outcome of preterm infants. One the other hand, in our study, clinically evident chorioamnionitis was not associated with an increased risk for cerebral palsy. However, this was not surprising given that only 12% of patients with proven microbial invasion of the uterine cavity develop clinical symptoms.** Becausewe did not perform routine amniocentesis to diagnose microbial invasion of the amniotic cavity, we have no data to confirm the association between subclinical intrauterine infection and fetal brain damage. The rate of microbial invasion of the uterine cavity is increased in pregnancies involving male fetuses.23In addition, AF and urine concentrations of interleukin-1 receptor antagonist are diminished in male fetuses.23 These observations, which suggest an increased susceptibility of male fetuses to the adverse effects of intrauterine infection, support our findings and those of other authors24 showing a heightened risk of cerebral palsy among male preterm infants. Interestingly, there also were more male fetuses among pregnancies complicated by stained AF in our series.

Obstetrics 6 Gynecology

Another mechanism for the association between meconium-stained AF and cerebral palsy relates to the direct toxic effect of meconium or its components on the placental vasculature.‘1,25 Meconium or bile acids can stimulate constriction of the umbilical vein, also causing cord vascular necrosis, thereby incrfeasing the likelihood of fetal hypoxemia.25 In a stuldy of 43 cases of cerebral palsy associated with meconium in the AF, Naeye17 found that following meconium passage, acidosis developed in utero and became evident at birth only in infants delivered within 12-14 hours of the start of ischemia. Whatever the mechanism involved,. the results of the present study support the view that meconium in the AF is a gestational age-independent risk factor for cerebral palsy among preterm infants. Although this finding might be helpful in the understanding of the disease process, its implications concerning the management of preterm deliveries with suspect intraamniotic infection remain unclear. Further trials using standard definitions of subclinical intra-amniotic infection could indicate whether early intervention may benefit preterm infants with infection-related brain damage.

12.

13.

14.

15. 16. 17. 18. 19.

20. 21. 22. 23.

References 24. 1. Gaffney

2. 3. 4.

5.

6. 7. 8.

9.

10.

Il.

VOL.

G, Sellers S, Flavell V, Squier M, Jchnson A. Case-control study of intrapartum care, cerebral palsy and perinatal death. Br Med J 1994;308:743-50. Nelson KB, ElIenberg JH. Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med 1986;31W?-6. Uvebrant I’, Hagberg G. Intrauterine grcwth in children with cerebral palsy. Acta Paediatr 1992;81:407-12. Topp M, Laghoff-Roos J, Uldall I’, Kristensen J. Intrauterine growth and gestational age in prcterm infants with cerebral palsy. Early Hum Dev 1996;44:27-36. Murphy DJ, Sellers S, MacKenzie IZ, Yuclkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346: 1449-54. Naeye RL, Peters EC, Bartholomew M, Landis JR. Origins of cerebral palsy. AJDC 1989;143:1154-61. Nelson KB. Relationship of intrapartum and delivery room events to long-term neurologic outcome. Clin Perinatol 1989;16:995-1007. Mazor M, Furman B, Wimiter A, Shoham-vardi I, Cohen J, Ghezzi F. Maternal and perinatal outcome of patients with preterm labor and meconium-stained amniotic fluid. Obstet Gynecol 1995;86: 830-3. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi J-H, et al. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterrn placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995;172:960-70. Yoon BH, Romero R, Yang SH, Jun JK, Kim I-O, Choi J-H, et al. Interleukin-6 concentrations in umbilical card plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:1433-40. Sepulveda WH, Gonzalez C, Cruz MA, Rut olph MI. Vasoconstric-

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25.

tive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991;42:211-5. World Health Organization Study Group. The hypertensive disorders of pregnancy. WHO technical report series no. 758. Geneva: World Health Organization, 1987. Parazzini F, Cortinovis I, Bortolus R, Fedele L. Standard di peso alla nascita in Italia. AM Ostet Ginecol Med Perinat 1991;112:20346. Gibbs RS, Duff I’. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991;164: 1317-26. Amiel-Tison C, Grenier A. Evaluation neurologique du nouveau-& et du nourrisson. Paris: Masson, 1980. Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley & Sons, 1989:216-38. Naeye RL. Can meconium in the amniotic fluid injure the fetal brain? Obstet Gynecol 1995;86:720-4. Wiswell TE, Tuggle JM, Turner SB. Meconium aspiration syndrome: Have we made a difference? Pediatrics 1990;85:715-21. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC III, eds. Williams Obstetrics. 19th ed. London: Prentice-Hall International Ltd, 1993:733-40. Nelson KB, Ellenberg JH. Obstetric complications as risk factors for cerebral palsy or seizure disorders. JAMA 1984;251:1843-8. Leviton A, Paneth N. White matter damage in preterm newborns: An epidemiologic perspective. Early Hum Dev 1990;24:1-22. Newton ER. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol 1993;36:795-808. Romero R, Gomez R, Galasso M, Mazor M, Berry SM, Quintero RA, et al. The natural interleukin-1 receptor antagonist in the fetal, maternal, and amniotic fluid compartments: The effect of gestational age, fetal gender, and intrauterine infection. Am J Obstet Gynecol 1994;171:912-21. Brothwood M, Wolke D, Gamsu H, Cooper D. Prognosis of the very low birthweight baby in relation to gender. Arch Dis Child 1986;61:559-64. Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: A potential link between the placenta and poor pregnancy outcome. Obstet Gynecol 1992;79:760 -6.

Address reprint requests to: Arsenio Spinillo, MD Clinica Ostetrico-Ginecologica IRCCS Policlinico San Matte0 Piazzale Golgi 2 27100 Pavia 1tLdlj

Receizled Februaq 20, 1997. Received in revised form May 23, 1997. Accepted May 24, 1997.

Copyright Q 1997 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.

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