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Placental infarction identified by macroscopic examination and risk of cerebral palsy in infants at 35 weeks of gestational age and over

      Objective

      We sought to investigate whether placental infarction determined by macroscopic examination was associated with risk of cerebral palsy (CP).

      Study Design

      This was a population-based study of macroscopic placental infarcts in singletons >35 weeks' gestational age, in 158 perinatal deaths, 445 infants with CP, and 491 controls matched with CP cases for gestational age.

      Results

      Placental infarcts were recorded in 2.0% of controls, 4.4% of deaths (relative risk [RR], 2.2; 95% confidence interval [CI], 0.8–5.6]), 5.2% of infants with CP (P < .05, RR, 2.5; 95% CI, 1.2–5.3), and 8.4% with spastic quadriplegic CP (P = .0026; RR, 4.4; 95% CI, 1.8–10.6). In children with CP, unlike controls, placental infarction was associated with reduced fetal growth, older maternal age, more prior miscarriages, and poor neonatal condition, but not with maternal preeclampsia.

      Conclusion

      Placental infarction identified by macroscopic examination was associated with increased risk of CP and the CP subtype, spastic quadriplegic CP. Antecedents of placental infarction differed in children with CP compared with control children.

      Key words

      The placenta is the life support system for the fetus in utero. Disorders of the placenta may contribute to neurologic abnormalities manifested soon after birth, such as neonatal encephalopathy (NE)
      • McDonald D.G.
      • Kelehan P.
      • McMenamin J.B.
      • et al.
      Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy.
      • Shalak L.
      • Johnson-Welch S.
      • Perlman J.M.
      Chorioamnionitis and neonatal encephalopathy in term infants with fetal acidemia: histopathologic correlations.
      • Blume H.K.
      • Li C.I.
      • Loch C.M.
      • Koepsell T.D.
      Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case-control study.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for neonatal encephalopathy: the Western Australian case-control study.
      • Wintermark P.
      • Boyd T.
      • Gregas M.C.
      • Labrecque M.
      • Hansen A.
      Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia.
      or perinatal stroke.
      • Dueck C.C.
      • Grynspan D.
      • Eisenstat D.D.
      • Caces R.
      • Rafay M.F.
      Ischemic perinatal stroke secondary to chorioamnionitis: a histopathological case presentation.
      • Curry C.J.
      • Bhullar S.
      • Holmes J.
      • Delozier C.D.
      • Roeder E.R.
      • Hutchison H.T.
      Risk factors for perinatal arterial stroke: a study of 60 mother-child pairs.
      • Thorarensen O.
      • Ryan S.
      • Hunter J.
      • Younkin D.P.
      Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis.
      • Redline R.W.
      • Sagar P.
      • King M.E.
      • Krishnamoorthy K.S.
      • Grabowski E.F.
      • Roberts D.J.
      Case records of the Massachusetts General Hospital, case 12-2008: a newborn infant with intermittent apnea and seizures.
      • Lee J.
      • Croen L.A.
      • Backstrand K.H.
      • Yoshida C.K.
      • et al.
      Maternal and infant characteristics associated with perinatal arterial stroke in the infant.
      • Elbers J.
      • Viero S.
      • Macgregor D.
      • Deveber G.
      • Moore A.M.
      Placental pathology in neonatal stroke.
      For Editors' Commentary, see Table of Contents
      Several clinical case series
      • Grafe M.
      The correlation of prenatal brain damage with placental pathology.
      • Burke C.J.
      • Tannenberg A.E.
      • Payton D.J.
      Ischemic cerebral injury, intrauterine growth retardation, and placental infarction.
      • Becher J.C.
      • Bell J.E.
      • Keeling J.W.
      • Liston W.A.
      • McIntosh N.
      • Wyatt B.
      The Scottish perinatal neuropathology study–clinicopathological correlation in stillbirths.
      have linked infarction of the placenta with brain lesions in infants who died in the perinatal period. There are indications that placental infarction may also play a role in long-term neurologic disability in survivors: in 2 population-based studies, term-born children with later-diagnosed cerebral palsy (CP) had a higher rate of macroscopically identified placental infarcts than controls.
      • Walstab J.
      • Bell R.
      • Reddihough D.
      • Brennecke S.
      • Bessell C.
      • Beischer N.
      Antenatal and intrapartum antecedents of cerebral palsy: a case-control study.
      • Nielsen L.F.
      • Schendel D.
      • Grove J.
      • et al.
      Asphyxia-related risk factors and their timing in spastic cerebral palsy.
      One of these, a study from the Danish Cerebral Palsy Registry, found macroscopic placental infarction in growth-restricted (GR) infants to be associated especially with the spastic quadriplegic (SQ) subtype of CP.
      • Nielsen L.F.
      • Schendel D.
      • Grove J.
      • et al.
      Asphyxia-related risk factors and their timing in spastic cerebral palsy.
      In a prospective case-control investigation within a population-based study of placental infarction identified on macroscopic examination, we asked 2 questions. First, can we confirm that placental infarcts are associated with increased risk of adverse outcome: perinatal death, neurologic abnormality in the newborn period, or later CP? Second, is the association, if any, of placental infarcts with outcome influenced by the presence of fetal GR or maternal preeclampsia or both?

      Materials and Methods

      The case-control study of CP and perinatal death from which this report comes was designed to investigate factors associated with risk of CP, defined as a disorder of movement and/or posture and of motor function due to a nonprogressive interference/lesion or abnormality of the developing immature brain. Including all births in Western Australia from 1980 through 1995 (n = 380,918), perinatal and vital outcome data are available in a database linking birth and death registries with pregnancy and delivery information collected by the attending midwife, and including >99.5% of registered births.
      In Western Australia, each birth is attended by a midwife regardless of whether a physician is in attendance. This midwife is responsible for completing the statutory “notification of birth attended” form that is filed with the Western Australian Department of Health. Midwives receive instruction on normal placental anatomy during university training. Midwives observing abnormalities may consult with senior nurses and with physicians, who are often present for deliveries, especially in urban areas where the majority of births occur, concerning placental description. The information collected on placental infarction consisted of a yes/no item asking the presence of infarction. Except for placental weight, further information on placental features including number or size of infarcts was not gathered, and submission of placentas to the laboratory was not mandated.
      The other information requested on this form included hospital of delivery, gestational duration, date and plurality of birth, and pregnancy complications. More detailed clinical data were collected from medical records for 3 groups: (1) all children with CP not acquired postneonatally and whose functional motor impairment was evident in activities of daily living; (2) neonatal survivors without CP, individually matched to each CP case for date of birth (within 12 months), gestational age (GA) at delivery (within 1 week), and plurality of birth; and (3) a representative sample of intrapartum stillbirths or neonatal deaths delivered during study years and not the result of medical termination of pregnancy or lethal birth defects.
      For each study pregnancy, medical records were sought from the hospitals of birth and any additional transferring or receiving hospitals, general practitioners, or obstetricians identified in the medical record as involved. Data were collected by reviewers blind to case status.
      Preeclampsia was considered present if blood pressure exceeded 140/90 mm Hg or there was a rise of 20 mm Hg systolic or 15 mm Hg diastolic. GR was considered present if the birthweight fell <2 SD below estimated optimal (ie, a proportion of optimal birthweight [POBW] <77.3%), or, to minimize false negatives, if the neonatal notes recorded that the neonate appeared GR, whether or not birthweight met the first criterion. Optimal birthweight for singletons was estimated from a statistical model with terms for fetal gender, maternal height and parity, and gestational duration, derived from a population of births not exposed to commonly occurring pathological factors associated with growth abnormality, including maternal smoking.
      • Blair E.
      • Liu Y.
      • de Klerk N.
      • Lawrence D.
      Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: analysis of a total population perinatal database.
      This estimate of optimal birthweight is therefore a standard rather than a population reference
      • Iams J.D.
      Small for gestational age and fetal growth restriction.
      and POBW constitutes a measure of appropriateness of intrauterine growth.
      Although we prefer the more general term “neonatal encephalopathy,”
      • Nelson K.B.
      Is it HIE? And why that matters.
      a diagnosis of hypoxic-ischemic encephalopathy (HIE) was recorded if there was a clinical diagnosis in the newborn period of birth asphyxia or HIE.
      This study was approved by the Princess Margaret Hospital/King Edward Memorial Hospital Ethics Committee, the Confidentiality of Health Information Committee of the Western Australia Department of Health, and by individual hospital and regional ethics committees, whose documents can be provided on request.

      Statistics

      The frequency of reported placental infarction was compared between case status groups (control, perinatal death, and CP) and comparisons reported as relative risks (RRs) (with 95% confidence interval [CI]). Similarly the frequencies of placental infarction were compared within case groups stratified by other exposures.

      Results

      Among the 386,159 infants born in Western Australia from 1980 through 1995, there were 376,541 (97.5%) singleton births of whom 363,747 (96.6%) delivered ≥35 weeks' gestation. This cohort included 688 neonatal deaths, 993 intrapartum stillbirths, and 362,126 neonatal survivors of whom 539 (1.4 per thousand) were included on the Western Australia Cerebral Palsy Register, and of whom 445 (82.6%) had a description of the placenta available. From neonatal survivors not on the CP register, 508 were selected as controls, of whom 491 (96.7%) had a description of the placenta available. A sample of 175 singleton perinatal deaths without lethal malformations born ≥35 weeks' gestation was selected for more detailed study, of whom 158 (90.3%) had available information on placental infarction.
      Placental infarcts were associated with adverse outcome, being reported in 2.0% (10/491) of control infants, in 4.4% of perinatal deaths (compared with controls, RR, 2.2; 95% CI, 0.8–5.6), and in 5.2% (23/445) of those with later-diagnosed CP (P < .05, RR, = 2.5; 95% CI, 1.2–5.3) (Figure 1, A ). Of the 107 children with SQ CP, 9 (8.4%) had placental infarction (P = .0026, RR 4.1; 95% CI, 1.7–9.9).
      Figure thumbnail gr1
      FIGURE 1Placental infarction by case groups
      A, Proportion of singleton infants ≥35 weeks' gestational age with placental infarction in control infants, perinatal deaths, and children with cerebral palsy (CP) or CP subtype spastic quadriplegia (SQ). B, Proportion of infants in each group in presence or absence of growth restriction.
      *Comparison with controls differs P < .05.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      Mean maternal age was comparable in all groups without infarcts. Among controls, mothers with infarcts tended to be younger than those without infarcts, while mothers with CP infants with infarcts were statistically significantly older. Among perinatal deaths mean maternal age did not differ between those with and without infarcts, but was more widely dispersed (Table 1). Primiparity was significantly associated with placental infarction only in controls. Multiparous mothers of children with CP who had infarcted placentas had twice the rate of prior spontaneous miscarriages as those with CP but no placental infarction. Smoking was more frequent among mothers of infants with placental infarction in all 3 groups but statistically significantly more frequent only in controls.
      TABLE 1Characteristics of mothers
      OutcomeControlPerinatal deathCerebral palsy
      Placental infarct, nNo: 481Yes: 10No: 151Yes: 7No: 422Yes: 23
      Age, mean (SD)27.4 (4.9)25.9 (4.4)27.8 (6.0)27.3 (8.5)26.7 (5.5)30.2 (5.3)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      Primiparity, % (n)39.5 (189)70 (7)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      39.7 (60)57.1 (4)45.7 (193)43.5 (10)
      Prior miscarriage, %
      Percent of women who had previously been pregnant;
      (n)
      29.3 (99/338)16.7 (1/6)27.7 (31/112)0.0 (0/4)25.9 (71/274)50.0 (8/16)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      PE <30 w,
      Preeclampsia first identified at <30 weeks' gestation, or later;
      % (n)
      1.3 (6)0 (0/10)0.7 (1)0 (0/7)0.7 (3)4.4 (1)
      PE ≥30 w,
      Preeclampsia first identified at <30 weeks' gestation, or later;
      % (n)
      8.8 (42)40 (4)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      21.3 (32)57.1 (4)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      14.5 (61)17.4 (4)
      Diabetes,
      Either preexisting or gestational;
      % (n)
      Preeclampsia first identified at <30 weeks' gestation, or later;
      4.8 (23)10 (1)2.7 (4)0 (0/7)1.9 (8)4.4 (1)
      Smoking, %
      Percent of those with nonmissing data for smoking during pregnancy, missing for one-third of participants.
      (n)
      Either preexisting or gestational;
      27.7 (88/318)75 (3/4)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      29.6 (34/115)50 (2/4)33.0 (99/300)41.2 (7/17)
      PE, preeclampsia.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      a Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      b Percent of women who had previously been pregnant;
      c Preeclampsia first identified at <30 weeks' gestation, or later;
      d Either preexisting or gestational;
      e Percent of those with nonmissing data for smoking during pregnancy, missing for one-third of participants.
      Few infants born to women with preeclampsia presenting <30 weeks' GA remained undelivered until 35 weeks to enter this cohort. Preeclampsia beginning ≥30 weeks' GA was strongly associated with infarction in controls and deaths, being recorded in 40% of controls with infarction and in 57.1% of perinatal deaths with infarction (RR, 4.5; 95% CI, 2–10 and RR, 2.7; 95% CI, 1.3–5.5 for controls and deaths, respectively), but in a smaller proportion–17.4%–of children with CP. Conversely, significantly more CP infants without infarction had preeclamptic mothers than control infants without infarction (RR, 1.6; 95% CI, 1.1–2.4). Thus, although maternal preeclampsia was strongly associated with infarction in both control and perinatal death groups, there was little association of preeclampsia with infarction within the CP group (Figure 2).
      Figure thumbnail gr2
      FIGURE 2Placental infarction by presence or absence of HIE and of CP
      Proportion of infants with placental infarction among those with and without neonatal diagnosis of hypoxic-ischemic encephalopathy (HIE) and with and without later diagnosis of cerebral palsy (CP).
      *Comparison with no HIE, no CP = P < .05.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      In examining the association of infant characteristics with outcome, we observed that male infants in all groups (control, perinatal death, and CP) had a higher rate of infarcted placenta than females (pooled RR, 1.3; 95% CI, 1.1–1.6; P = .045) (Table 2). In all groups infants with a clinical diagnosis of GR had a substantially higher frequency of placental infarction, reaching statistical significance in deaths: RR, 2.8 (95% CI, 0.4–21) for controls, RR, 6.4 (95% CI, 1.3–32) for perinatal deaths, and RR, 1.8 (95% CI, 0.7–4.4) for CP cases.
      TABLE 2Characteristics of infants
      OutcomeControlPerinatal deathCerebral palsy
      Placental infarct, nNo: 481Yes: 10No: 151Yes: 7No: 422Yes: 23
      Male, % (n)51.6 (248)70 (7)58.3 (88)71.4 (5)55.0 (232)69 (16)
      Birthweight, g, mean (SD)3359 (516)3115
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
       (559)
      3093 (767)2338
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
       (789)
      3233 (565)3050 (739)
      GA wks, mean (SD)39.1 (1.6)37.6 (1.7)38.5 (1.9)37.0 (2.4)39.0 (1.6)39.1 (1.7)
      POBWz
      Z score of POBW, a continuous measure of appropriateness of intrauterine growth (Blair et al17);
      mean (SD)
      −0.26 (1.14)−0.24 (0.86)−0.74 (1.66)−2.1 (1.54)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      −0.54 (1.30)−1.11 (1.72)
      GR,
      POBWz <−2 or neonate clinically considered growth restricted;
      % (n)
      5.2 (25)10 (1)26.0 (39)71.4 (5)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      15.9 (67)26.1 (6)
      Apgar 5 <7, %
      Denominator including only livebirths;
      (n)
      1.8 (9)0 (0/10)46.6 (41/88)75 (3/4)21.0 (88)34.8 (8)
      Apgar 5 <4, %
      Denominator including only livebirths;
      (n)
      0.6 (3)0 (0/10)20.5 (18)50 (2)8.6 (36)8.7 (2)
      Seizures, %
      Denominator including only livebirths;
      (n)
      0.0 (0)0 (0/10)27.6 (24)50 (2)27.9 (115)47.8 (11)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      HIE,
      Clinically diagnosed HIE.
      %
      Denominator including only livebirths;
      (n)
      0.2 (1)0 (0/10)26.8 (22)66.7 (2)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      22.1 (91)40.9 (9)
      Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      GA, gestational age; GR, growth restriction; HIE, hypoxic-ischaemic encephalopathy; POBW, proportional of optimal birthweight.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      a Statistically significantly different (P < .05) between those with and without placental infarcts within case status;
      b Z score of POBW, a continuous measure of appropriateness of intrauterine growth (Blair et al
      • Blair E.
      • Liu Y.
      • de Klerk N.
      • Lawrence D.
      Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: analysis of a total population perinatal database.
      );
      c POBWz <−2 or neonate clinically considered growth restricted;
      d Denominator including only livebirths;
      e Clinically diagnosed HIE.
      The mean POBW did not differ between controls with and without infarction, suggesting that in this large group infarction was not generally associated with reduced growth. Mean POBW in CP cases and in perinatal deaths without infarcted placentas was significantly lower (P < .05) than in controls, suggesting that CP cases and perinatal deaths tended to have reduced growth whether or not their placentas were infarcted. However, growth reduction was further exacerbated in these groups in the presence of an infarcted placenta, the within group mean POBW of those with a infarcted placenta being statistically significantly below those without infarction in deaths and close to statistical significance in CP cases.
      Low Apgar scores were uncommon in control infants, and for death and CP groups the higher frequency of Apgar scores <7 at 5 minutes in the presence of placental infarction did not reach statistical significance. Neonatal seizures and clinically diagnosed HIE, almost all of which occurred in the death or CP groups, were associated with higher rates of placental infarctions, the differences being statistically significant in 3 of those 4 comparisons (Table 2).
      Children who had both a clinical diagnosis of HIE in the neonatal period and later-diagnosed CP had placental infarcts 4 times more frequently than those with neither HIE nor CP (Figure 2). The increase in macroscopically identified infarct frequency in non-GR infants with HIE-associated CP, as compared with those with neither HIE nor CP, was statistically significant (RR, 4.2; 95% CI, 1.6–10.8). The form of CP in HIE-associated CP was predominantly SQ (39/107, 36.5%) or dyskinesia (27/107, 25.3%); few were hemiplegic (11/107, 10.3%). Those who had infarcts as well as HIE were even more likely to be SQ (5/9, 55.6%) or dyskinetic (3/9, 33%) with only 1 having hemiplegia.
      We examined the impact of GR, maternal preeclampsia, and placental infarction on outcome, alone and in combinations. One-third of children with CP and 46% of those who died in the perinatal period were GR or born to women with preeclampsia or had infarcted placentas, or had >1 of these characteristics (Table 2). Increase in rate of death with GR alone was 4-fold. The rate of CP was 3 times higher in those with than without GR, which increased for the subset with SQ CP to 4.6-fold.
      Preeclampsia alone was associated with only a small increase in risk of these outcomes. Infarction alone was associated with tripled risk of CP and a 4.6-fold increase in SQ CP. Of children with SQ, 4.7% had infarcts alone (no GR or maternal preeclampsia). Infarction was more frequent in non-GR children with CP than in non-GR control children (P < .05; RR, 2.33; 95% CI, 1.03–5.39).
      Infarction combined with maternal preeclampsia was associated with a nonsignificantly lower risk of CP as compared with infarction alone. Similarly, fetal GR with preeclampsia was associated with nonsignificantly lower CP risk than GR alone. Thus placental infarcts or GR resulting from preeclampsia were not more likely to result in CP than infarcts and GR due to other causes.
      GR plus preeclampsia but without placental infarction was observed in only 1.4% of children with CP, and was not associated with significant increase in CP risk; that combination was, however, linked with higher mortality (Table 2). The RR of perinatal death associated with GR plus infarction was 18.7, and for CP was 8.8, but CIs were wide and these results were not statistically significant. Considering CP and perinatal death together, the RR was 11.4 (95% CI, 0.65–200), suggestive but still far short of statistical significance.

      Comment

      The first question posed in this study, whether macroscopically described placental infarcts were associated with increased risk of perinatal death or adverse neurologic outcome in the infant (encephalopathy in the newborn, later-diagnosed CP), was answered in the affirmative. In examining the second question, we found that fetal GR and placental infarction appeared to be independently related to CP risk, and that presence of maternal preeclampsia did not contribute further to risk of HIE or CP. We address these issues separately.

      Placental infarction and outcome

      In agreement with Nielsen et al
      • Nielsen L.F.
      • Schendel D.
      • Grove J.
      • et al.
      Asphyxia-related risk factors and their timing in spastic cerebral palsy.
      in another population-based study, we found that prospective macroscopic identification of placental infarcts was a predictor of later-diagnosed CP, and especially of SQ CP. Further, we observed that placental infarction was associated with encephalopathy in the newborn period in perinatal deaths and in those with subsequent CP, especially SQ CP.
      The causes of NE, often called HIE (whether or not there is sufficient evidence to suggest a hypoxic etiology
      • Kurinczuk J.J.
      • White-Koning M.
      • Badia N.
      Epidemiology of neonatal encephalopathy and hypoxic-ischemic encephalopathy.
      ), and of CP are incompletely known, but placental abnormality was common in NE.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for neonatal encephalopathy: the Western Australian case-control study.
      It has been a consistent observation in controlled studies that a majority of children with HIE and with HIE-associated CP have not had recognized asphyxial births.
      • Kurinczuk J.J.
      • White-Koning M.
      • Badia N.
      Epidemiology of neonatal encephalopathy and hypoxic-ischemic encephalopathy.
      Evans et al
      • Evans K.
      • Rigby A.S.
      • Hamilton P.
      • Titchiner N.
      • Hall D.M.B.
      The relationships between neonatal encephalopathy and cerebral palsy: a cohort study.
      note that NE/HIE-associated CP occurring in the absence of asphyxial birth events is especially poorly understood: “we do not yet have an explanation for most cases of NE-associated cerebral palsy.” The data presented here suggest that placental pathology should be further investigated for its contribution to the syndrome of NE/HIE-associated CP that underlies an important share of CP in term infants.
      The placenta has many functions and substantial functional reserve. It cannot be assumed that placental infarction acts chiefly via interference with gas exchange. The observed preponderance of placental infarcts in boys and the association of infarction with prior miscarriage in mothers of infants with CP suggest a more complex pathophysiology involving a maternal vasculopathy. Whatever the underlying process was that harmed the vasculature of the placenta to cause infarction, that process may also have harmed the fetal cerebral vasculature or the brain directly.

      Placental infarction, fetal GR, maternal preeclampsia, and outcome

      In 1969, Wallenburg
      • Wallenburg H.C.S.
      Uber den Zusammenhang zwischen Spatgestose und Placentarinfarkt.
      reported that placental infarcts were more common in women with preeclampsia, were more often centrally located, and that infarctions in the placentas of hypertensive mothers were associated with lower Apgar scores in their offspring. The association of placental infarction with low Apgar scores in infants of hypertensive women was subsequently confirmed.
      • Salgado S.S.
      • Pathmeswaran A.
      Effects of placental infarctions on the fetal outcome in pregnancies complicated by hypertension.
      Infarcts were also related to significantly lower head circumference in that study
      • Salgado S.S.
      • Pathmeswaran A.
      Effects of placental infarctions on the fetal outcome in pregnancies complicated by hypertension.
      and in a subsequent investigation in very premature infants.
      • McElrath T.F.
      • Allred E.N.
      • Kuban K.
      • et al.
      ; ELGAN Study Investigators Factors associated with small head circumference at birth among infants born before the 28th week.
      A population-based study from South Australia related placental “infarcts/stasis” to risk of CP in term infants.
      • Walstab J.
      • Bell R.
      • Reddihough D.
      • Brennecke S.
      • Bessell C.
      • Beischer N.
      Antenatal and intrapartum antecedents of cerebral palsy: a case-control study.
      In the Danish study,
      • Nielsen L.F.
      • Schendel D.
      • Grove J.
      • et al.
      Asphyxia-related risk factors and their timing in spastic cerebral palsy.
      the combination of GR with placental infarction was associated with a 16-fold increase in risk of SQ CP, while in non-GR infants there was not a significant increase in risk of CP with placental infarction. Neither maternal hypertensive disorder in general nor severe hypertension was associated with significant increase in risk of CP in that study.
      In the present study with substantially larger sample size, the antecedents of infarction in controls appear to differ from those in infants with CP. Mothers of control infants were younger, more often primiparous, more often developed preeclampsia >30 weeks, had shorter pregnancies, and produced infants of significantly lower birthweight but without more GR; most such infants had normal Apgar scores and no neonatal seizures or HIE. Mothers of infants with CP were older, more often had prior miscarriages, and produced infants with lower birthweights although they were not more often premature, consistent with the clinical diagnosis of GR and lower birthweight optimality. Within the CP group, placental infarcts were associated with neonatal seizures and with a clinical diagnosis of HIE.
      Among infants with CP, those whose mothers were not preeclamptic had a higher rate of placental infarction than controls (Figure 3), and fewer CP cases than controls or perinatal deaths had maternal preeclampsia to account for their placental infarcts (Figure 3). Other causes of infarction such as chronic villitis, antiphospholipid antibodies and other thrombophilias, hyperhomocysteinemia, or endothelial dysfunction might be sought in placental infarction in children with CP and no maternal preeclampsia. In a recent study, nonhypertensive mothers of infants with GR more often had evidence of endothelial dysfunction than did hypertensive mothers of GR infants.
      • Yinon Y.L.
      • Kingdom J.C.
      • Odutayo A.
      • et al.
      Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk.
      Figure thumbnail gr3
      FIGURE 3Placental infarction by presence or absence of preeclampsia
      Proportion of infants with placental infarction among controls, perinatal deaths, and children with cerebral palsy (CP) according to presence or absence of maternal preeclampsia. Asterisk means statistically significant difference, P < .05 for percent of infarctions between controls with and without maternal preeclampsia.
      RR, relative risk, with and without preeclampsia.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      In our study, infarction plus preeclampsia was not associated with higher risk of CP than infarction alone (Table 3). The combination of placental infarction and fetal GR was too rare for reliable evaluation but the nearly statistically significant association of this combination with perinatal death, and the Danish finding that placental infarction in GR babies was associated with high risk of SQ CP, lend credence to the possibility that infarcted placenta is especially ominous in GR infants, and may be even more ominous in GR infants whose mothers were not hypertensive.
      TABLE 3Relative risks associated with placental infarcts, growth restriction, and preeclampsia
      OutcomeControlPerinatal deathAll CPSpastic quadriplegia
      n (%)RRn (%)RR (95%CI)n (%)RR (95%CI)n (%)RR (95%CI)
      Total n with data487 (100)156 (100)442 (100)107 (100)
      Exposure
       GR only21 (4.3)1 (ref)27 (17.3)4.0 (2.3–6.9)59 (13.4)3.1 (1.9–5.0)21 (19.6)4.6 (2.6–8.0)
       PE only50 (10.3)1 (ref)23 (14.7)1.4 (0.9–2.3)63 (14.3)1.4 (1.0–2.0)11 (10.3)1.0 (0.5–2.0)
       Infarct only5 (1.3)1 (ref)0 (0.0)14 (3.2)3.1 (1.1–8.5)5 (4.7)4.6 (1.4–15)
       GR + PE4 (0.8)1 (ref)11 (7.1)8.6 (2.8–27)6 (1.4)1.7 (0.5–5.8)2 (1.9)2.3 (0.4–12)
       Infarct + PE4 (0.8)1 (ref)2 (1.3)1.6 (0.3–8.5)3 (0.7)0.8 (0.2–3.7)2 (1.9)2.3 (0.4–12)
       GR + infarct0 (0.0)
      In order to estimate relative risks for this exposure, 0.5 was added to this cell.
      3 (1.9)18.7 (0.9–370)4 (0.9)8.8 (0.04–166)0 (0.0)
       GR + PE + infarct1 (0.2)1 (ref)2 (1.3)6.2 (0.6–6.8)2 (0.5)2.2 (0.2–2.4)2 (1.9)9.1 (0.8–100)
      None of these exposures402 (82.6)1 (ref)88 (56.4)0.7 (0.6–0.8)291 (65.8)0.8 (0.7–0.9)64 (59.8)0.7 (0.6–0.9)
      CI, confidence interval; CP, cerebral palsy; GR, growth restriction; PE, preeclampsia; RR, relative risk.
      Blair. Placental infarction on macroscopic examination and cerebral palsy. Am J Obstet Gynecol 2011.
      a In order to estimate relative risks for this exposure, 0.5 was added to this cell.
      Our study provides prospective controlled observations in a population-based sample. It has the marked limitation that it provides only macroscopic observations of placental infarction, without details as to number, size, recentness, or location of infarcts, which may be more sensitive predictors of outcome, and without histologic verification. Nor did this study include other features of placental pathology, as would be desirable as multiplicity of types of placental lesions has been related to adverse outcome.
      • Viscardi R.M.
      • Sun C.C.
      Placenta lesion multiplicity: risk factor for IUGR and neonatal cranial ultrasound abnormalities.
      Benirschke et al
      indicate that it is usually possible to identify placental infarction macroscopically. However, especially near the placental margins, the distinction must be made from perivillous fibrin deposition, thought to represent poor blood flow and therefore also a vascular lesion.
      • Kaplan C.G.
      Fetal and maternal vascular lesions.
      Histologic verification is certainly a goal for a future study; yet whatever was identified as placental infarction in both the Danish study and in ours does appear to predict outcome.
      Examination of the placenta can provide indicators of the pathobiology underlying adverse neurologic outcome and can contribute prognostic information. It remains a hypothesis for future study that GR infants with placental infarction born to women without preeclampsia–but with some other cause of GR and placental infarction–may face special risk of long-term neurologic disability.
      CP cannot be diagnosed until months or years after birth, long after placentas of most affected children have been discarded. CP is uncommon, so to relate placental characteristics to CP and its subtypes in a well-designed study would require examining all placentas in a huge and representative (preferably population-based) birth cohort, with mechanisms for connecting placental data with a well-characterized low-prevalence disorder recognizable only years later. Hopefully such a study would provide access to medical records of mother, pregnancy, birth, and neonatal period, as well as documentation of good interobserver reliability for both placental findings and neurologic classification. No contemporary study meets this goal. The study reported here is obviously an early step.
      Recent reports indicate that there are lesions in the placenta in three-quarters or more of infants with perinatal brain injury.
      • Wintermark P.
      • Boyd T.
      • Gregas M.C.
      • Labrecque M.
      • Hansen A.
      Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia.
      • Elbers J.
      • Viero S.
      • Macgregor D.
      • Deveber G.
      • Moore A.M.
      Placental pathology in neonatal stroke.
      • Rosier-van Dunne F.M.
      • van Wezel-Meijler G.
      • Kaschula R.O.
      • Wranz P.A.
      • Odendaal H.J.
      • de Vries J.I.
      Placental histology related to fetal brain sonography.
      • Chang K.T.
      • Keating S.
      • Costa S.
      • Machin G.
      • Kingdom J.
      • Shannon P.
      Third trimester stillbirths: correlative neuropathology and placental pathology.
      • Wong L.
      • MacLennan A.H.
      Gathering the evidence: cord gases and placental histology for births with low Apgar scores.
      If the placenta is as important a source of information about perinatal brain injury as emerging information suggests, then despite the challenges involved in their study, placental-clinical correlations are likely to play a significant future role in perinatal medicine.

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