university of groningen placental lesions and …abstract objective: to determine whether the...

University of Groningen

Placental lesions and outcome in preterm born childrenRoescher, Annemiek

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2014

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Roescher, A. (2014). Placental lesions and outcome in preterm born children: the relation betweenplacental lesions, neonatal morbidity and neurological development. [S.l.]: [S.n.].

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 10-10-2020

https://www.rug.nl/research/portal/en/publications/placental-lesions-and-outcome-in-preterm-born-children(68ac1fbd-b414-4122-acba-e48058a4ee65).html



113

General introduction and outline of the thesis

1

113

6Annemiek M Roescher

Albertus TimmerKoenraad NJA Van Braeckel

Elise A VerhagenJorien M Kerstjens

Sijmen A ReijneveldJan Jaap HM Erwich

Arend F Bos

Submitted

Placental lesions and functional outcomes at early school age of

children born between 32 and 35 weeks’ gestational age

Chapter 6

AbstractObjective: To determine whether the presence of placental lesions were associated with functional outcome at 7 years of age in children born between 32 and 35 weeks GA.Method: This study was part of a larger community based cohort study. We included 44 moderately and late preterm born, singleton children from whom the placenta was available for examination. The placentas were assessed for pathology. cognitive and motor outcomes were assessed at a median age of 6.9 years. Results: Almost 80 percent of the placentas showed one or more lesions. in the presence of maternal vascular underperfusion (mVU) we found lower total iQ scores (mean [sD] 97.8 [7.2] vs 105.0 [8.3]) and verbal iQ scores (mean 100.4 [8.9] vs 109.1 [9.1]) (P=.017 and, P=.003 respectively). in the presence of ascending intrauterine infection (AiUi) we found lower total motor outcome percentile scores (median 32.1 vs 53.5, P=.028). other placental lesions were not associated with cognitive or motor outcome.Conclusion: Placental lesions consistent with mVU are associated with lower iQ scores, whereas placental lesions indicating AiUi are associated with impaired motor skills at early schoolage. These findings suggest that placental lesions might be an early indicator for impaired outcome later in life.

115

Placental lesions and functional outcomes at early school aGe of children born between 32 and 35 weeks’ Gestational aGe

6

IntroductionPreterm birth is a major contributor to long-term neurodevelopmental problems.1 This not only holds true for early preterm birth, i.e. infants born at < 32 weeks’ gestational age (GA), but also for moderately preterm-born (GA 32-34 weeks) and late preterm-born (GA 34-36 weeks) children.2-4 The outcomes of moderately preterm-born and late preterm-born children as a group are less well studied than those of preterm-born children of < 32 weeks GA and fullterm-born children. it is known that compared to their fullterm-born counterparts, moderately preterm-born and late preterm-born children are at risk of developmental delays at preschool age2 and at early school age they obtain lower scores on intelligence tests and their neuropsychological functioning is poorer.3

Placental lesions may cause preterm birth and may have major implications for the child if placental function is impaired. Placental lesions are known to be associated with adverse functional outcomes in very preterm and fullterm infants.5-8 Whether this also holds for moderate and late preterm infants is unknown, but would seem likely. Available evidence suggests that several placental lesions are associated with neonatal morbidities in preterm infants.9 This association may be even more apparent in moderate and late preterm infants because rates of neonatal complications, which frequently confound findings on the association between placental lesions and functional outcomes, are much lower in these two groups. Moderate and late preterm birth offers an excellent opportunity to bypass this confounding effect of non-placenta-related neonatal complications.

A better understanding of the association between placental lesions and cognitive and motor outcomes in later life is necessary to identify placenta-related risks for developmental problems. such an understanding could provide clues for early interventions to improve functional outcomes. The objective of this study was, therefore, to determine whether the presence of placental lesions in general, and specific placental lesions in particular, were associated with functional outcomes at the age of seven in children born between 32 and 35 weeks’ GA. We hypothesized that in case of placental lesions functional outcomes would be poorer.

Methodsin this community-based cohort study we related placental lesions to functional outcomes at seven years of age.

Study populationour cohort consisted of forty-four moderate and late preterm-born, singleton children, who participated in the Longitudinal Preterm outcome Project (LoLLiPoP). LoLLiPoP is a large prospective, community-based cohort study designed to investigate the growth, development, and general health of preterm-born children. Within LoLLiPoP we focused moderately preterm-born and late preterm-born children. From the northern part of the netherlands, were our hospital is situated, we invited 248 moderate and late preterm-born children, born without major chromosomal and congenital abnormalities, to participate in

116


6

follow-up testing at seven years of age .3 For the study reported on here, we selected the singleton, moderately preterm-born

and late preterm-born children who had participated in the above mentioned follow-up study (181). of this group the placentas of 44 children, i.e. 24%, were available for pathological examination. We determined whether this group, who were included in this study, differed in terms of gender, GA, birth weight, small-for-gestational age (SGA), Apgar scores, age, length, and weight at follow-up from the children whose placentas were not available (excluded from this study). We found statistically significant lower mean GAs, BWs, and a higher incidence of sGA among children whose placentas were available (Table 1).

Table 1. Patient demographics, patient characteristics, and placental characteristics. Data are given as median (range) or numbers (percentage)Study populationa / exluded infantsb N = 44a N = 137b

Boys / girls 24/20 (55% / 45%) 71/66 (52% / 48%)Gestational age, weeks 34 (32-35) 34 (32-35) *Birth weight, grams 2000 (1190-3710) 2400 (975-3900)*Small for gestational age (P<10) 10 (22.7%) 12 (8.8%)*Apgar score at 5 min <6 2 (4.5%) 3 (2.2%)Parental education levelc

Low 6 (13.6%) Middle 16 (36.4%) High 20 (45.5%)Placental weight, grams 373 (170-680)Cord length, centimeters 33.5 (10-70)Placenal lesions† 35 (79.5%) Maternal vascular underperfusion 17 (38.6%) Ascending intrauterine infection 8 (18.2%) Fetal thrombotic vasculopathy 6 (13.6%) Villitis of unknown etiology 5 (11.4%) Chronic deciduitis 2 (4.5%) Perivillous fibrinoid 0 Chorioamniotic hemosiderosis 0 Meconium 4 (9.1%)Placental markers Elevated nucleated red blood cells 11 (25%) Chorangiosis 3 (6.8%)Follow up Age at follow up, years 6.9 (6.8-7.0) Length at follow up, centimeters 124 (111-135) Weigth af follow up, kilogram 23 (17-35)

* P<.05† The summed number exceeds the total numbers, because a single placenta can have more than one lesion.cParental education level is defined as the mean of the highest education completed by mother and father (low, elementary school; middle, high school or technical school; high, college or university), n=2 are missing.

117


6

Procedure and variablesPlacental lesionsPlacental lesions were assessed by using the histopathologic coupes of placentas that had been obtained from the hospitals where the infants were born. These coupes were reexamined by a perinatal pathologist (AT) in accordance with the guidelines published by the British Royal college of obstetricians and Gynaecologists and the Royal college of Pathologists, and by the college of American Pathologists.9,10 The pathologist was blinded as to clinical outcomes. We assessed all the placentas for lesions found in preterm and/or fullterm infants and that may possibly be associated with neurodevelopment.5-7 each lesion was scored as either resent or absent. The lesions were classified as placental pathology consistent with maternal vascular underperfusion (mVU),11 ascending intrauterine infection (AiUi) with a maternal and/or a fetal response,12 chronic villitis of unknown etiology (VUe),13 chronic deciduitis,14 perivillous fibrinoid,15 fetal thrombotic vasculopathy,16 meconium associated vascular necrosis,17 chorioamniotic hemosiderosis,18 increased nucleated red blood cells (nRBcs),19 chorangiosis,20 and umbilical cord abnormalities.21 Table 2 presents the definition and scoring criteria of these placental lesions. in addition, data on placental weights and umbilical cord lengths were obtained.

118


6

Table 2: Diagnostic terminology and definitions of the placental lesionsDiagnostic terminology Definition and scoring criteria

Maternal vascular underperfusion Decidual vasculopathy, e.g. incomplete or absent spiral artery remodeling, acute atherosis, fibrinoid necrosis, or thrombosis; parenchymal pathology such as placental hypoplasia, increased syncytial knotting, villous agglutination, increased perivillous fibrin, distal villous hypoplasia, infarction, retroplacental hematoma.11

Ascending intrauterine infection Acute inflammation of the extraplacental membranes and chorionic plate. Acute chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical vasculitis represents the fetal response.12

Villitis of unknown aetiology Chronic lymphohistiocytic inflammation of the stem and chorionic villi, with or without obliterative vasculopathy of stem villus vessels.13

Chronic deciduitis Chronic lymphohistiocytic or plasmacytic inflammation of placental decidua.14

Maternal floor infarction / massive perivillous fibrinoid deposition

Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least one slide (maternal floor infarction) or transmural encasing ≥50% of villi on at least one slide (massive perivillous fibrinoid deposition).15

Fetal thrombotic vasculopathy Fetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic endovasculitis and groups of at least five avascular fibrotic villi without inflammation or mineralization and/or adherent thrombi in stem vessels.16

Meconium associated vascular necrosis Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate vessels.17

Chorioamniotic hemosiderosis Presence of hemosiderophages in the amnion and chorion.18

Elevated nucleated red blood cells Only rare NRBCs are normal after the first trimester. More than two NRBC in a randomly selected field of 4.5 mm2, corresponding to 18 consecutive fields at 40x magnification, or one field at 10x magnification was considered as abnormal.19

Chorangiosis Diffuse increase in the number of villous capillaries.20

Umbilical cord abnormalities Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse, entanglement, knots, disrupted velamentous vessels, hyper/hypo-coiling).21

119


6

Assessment of functional outcomes at seven years of ageThe children and their parents were invited to visit University medical center Groningen or a well-infant clinic in their neighborhood for a three-hour assessment consisting of standardized neuropsychological tests. While their parents waited in the waiting room, each child was tested individually by a trained psychologist, who was blind as to gestational age and placental pathology . We assessed cognitive and motor outcomes.

With regards to cognitive outcomes we assessed total, verbal, and performance intelligence with a shortened version of the Wechsler intelligence scale, third edition, Dutch version (Wisc-iii-nL).22 We assessed visuomotor integration with the Design copying Test, a subtest of the Developmental neuropsychological Assessment Battery, second edition, Dutch version (nePsY-2-nL).23 Verbal memory, including learning capacity, long-term memory, and recognition, we assessed with the Dutch version of the Rey Auditory Verbal Learning Test (AVLT).24 We assessed the attention skills required for effective functioning at school with the following subtests of the Test of everyday Attention for children, Dutch version (TeA-ch-nL): map mission (selective attention), score! (sustained auditory attention), same World (attention control), and opposite World (inhibition).25

With regards to motor outcomes we used the Dutch version of the movement Assessment Battery for children (movement-ABc).26 We determined total motor performance, which is based on subscale scores for manual dexterity (fine motor skills), ball skills, and static and dynamic balance.

Additionally, we collected data on several neonatal and obstetrical characteristics such as mode of delivery, GA, birth weight, gender, sGA, Apgar scores, and parental education.

Statistical analysisWe used sPss 20.0 software for Windows (sPss inc chicago, illinois, UsA) for the statistical analyses. For demographic characteristics, placental lesions, and outcome scores at follow-up we used descriptive statistics . We present the outcome scores as raw scores and percentiles, where appropriate. on the basis of the test scores and following the tests’ manuals, we assigned the children to one of three categories: normal, borderline, or abnormal. subsequently, we assessed the association of outcome scores with placental lesions. We did this in two ways. First, we assessed outcome measures for no, one, or more than one placental lesion using regression analyses. Because GA and parental education are known to be associated with outcome measures, we adjusted for these variables. Finally, we assessed the association between outcome measures and each specific placental lesion. We used linear regression models (‘enter’ method) for all placental lesions occurring more than four times in the study group. We once again adjusted for GA and parental education and entered these variables into a second model. A predetermined P value of < .05 was considered statistically significant.

120


6

ResultsStudy population characteristicsWe present the perinatal and follow-up characteristics of the study population in Table 1 and the follow-up outcomes of the entire group, irrespective of placental lesions, in Table 3.

Table 3: outcome data at follow-up. We present raw test scores and percentiles of several tests (left part) and number of children categorized as normal, borderline or abnormal (right part)

VariablesTest scoresMean (SD)

Percentile scores Median (P25-75)

Number of children categorized

Normal Borderline Abnormal Total

WISCa

IQ-total 102.2 (8.6) - 44 0 0 44

IQ-verbal 105.7 (9.9) - 44 0 0 44

IQ-performance 98.5 (11.1) - 41 3 0 44

NEPSYb

Visuomotor 7.6 (2.3) - 29 14 1 44

TEAChc

Selective attention 11.8 (3.8) 37 (16-50) 34 7 3 44

Sustained attention 6.2 (2.7) 50 (18-75) 36 5 3 44

Attention control 37.3 (8.3) 50 (25-82) 41 3 0 44

Inhibition 48.6 (15.0) 50 (18-84) 37 4 3 44

AVLTc

Recall 36.2 (7.8) 55 (34-91) 41 2 0 43

Delayed recall 7.8 (2.2) 59 (25-75) 36 6 1 43

Recognition 28.1 (1.9) - - - - 43

Movement ABCc

Total motor skills 4.7 (4.6) 44 (26-78) 38 3 3 44

Manual dexterity 1.4 (2.2) - 41 0 3 44

Ball skills 1.7 (1.7) - 31 8 5 44

Balance 1.2 (2.1) - 36 4 4 44

Abbreviations: Wisc – Wechsler intelligence scale; nePsY – Developmental neuropsychological Assessment battery; TeAch – Test of everyday Attention for children; AVLT – Auditory Verbal Learning Test; movement ABc – movement Assessment Battery for children.

a: Test score: Intelligence quotient. Categorized: normal ≥85; borderline 70-84; abnormal <70.b: Test score: Scaled score. Categorized: normal ≥7; borderline 3-6; abnormal <3.c: Test score: raw scores. Categorized: normal p ≥15; borderline p5-14; abnormal p<5.

121


6

Placental lesionssee Table 1 for the distribution of placental lesions. We found no lesions in nine out of forty-four placentas (20.5%). eighteen placentas showed one lesion and seventeen showed more than one lesion. The maximum number of lesions was three. The largest group of placental lesions consisted of mVU, in seventeen placentas, followed by AiUi in eight. All eight placentas with AiUi showed a maternal response, while six placentas showed a fetal response in addition to the maternal response. chronic deciduitis occurred twice and chronic chorioamnionitis once. Both lesions were, therefore, not included in the analyses with outcome measures. Perivillous fibrinoid deposition, chorioamniotic hemosiderosis, and meconium-associated vascular necrosis did not occur in our study population.

Association between placental lesions and cognitive outcomes The number of placental lesions in general was not associated with cognitive outcomes (Table 4). After adjustment for gestational age and parental education, scores on selective attention became marginally better with more placental lesions (P = .048, Table 4).

Regarding specific placental lesions, only MVU was associated with IQ (Table 5). In the presence of mVU we found lower total iQ scores (mean 97.8, sD 7.2 versus mean 105.0, sD 8.3) and verbal iQ scores (mean 100.4, sD 8.9 versus mean 109.1, sD 9.1) (P = .017 and P = .003, respectively). In the presence of MVU the unstandardized coefficient (B) was -7.1 for total iQ, which explains a decline of 7.1 iQ points in the presence of mVU. For verbal iQ we found a B of -8.7. mVU was not associated with performance iQ (P = .340)

When we assigned the children to either one of the three categories normal, borderline, or abnormal in accordance with their outcomes scores, none of the placental lesions were associated with outcome.

122


6

Table 4 Relation of cognitive and motor outcomes and the presence of placental lesionsOutcome scores No placental lesions 1 placental lesion ≥2 placental lesions# F P F † P †

N= 9 (SD) N=18 (SD) N=17 (SD)

Intelligence (IQ)

IQ-total 106.1 (9.0) 99.6 (5.1) 102.9 (9.3) 1.934 .158 0.527 .595

IQ-verbal 110.6 (8.3) 104.4 (8.2) 104.6 (11.8) 1.379 .263 0.856 .434

IQ-performance 101.4 (12.9) 94.6 (9.7) 101.1 (10.9) 1.998 .149 0.503 .609

Visuomotora 7.7 (1.7) 7.7 (2.7) 7.4 (2.1) 0.085 .919 0.115 .892

Verbal memory

Recallb 46.9 (29.3) 63.2 (27.0) 60.9 (32.5) 0.964 .390 0.638 .535

Delayed recallb 59.1 (30.6) 57.0 (26.6) 48.5 (29.5) 0.539 .587 1.087 .349

Recognitionc 27.6 (2.7) 27.9 (1.8) 28.6 (1.4) 1.066 .354 0.363 .698

Attention

Selectiveb 23.8 (17.0) 34.0 (25.2) 41.7 (19.9) 1.992 .149 3.331 .048*

Sustainedb 43.4 (25.4) 43.3 (35.7) 53.4 (33.4) 0.486 .618 1.008 .376

Attention controlb 46.6 (33.7) 53.7 (23.2) 55.1 (31.3) 0.276 .761 0.540 .588

Inhibitionb 45.7 (35.4) 50.6 (36.3) 53.4 (30.7) 0.152 .859 0.375 .690

Motor skills

Totalb 54.1 (30.3) 48.0 (32.0) 48.9 (26.0) 0.137 .872 0.299 .744

Manual dexterityd 1.7 (2.2) 1.9 (2.8) 0.8 (1.2) 1.308 .281 0.079 .191

Ball skillsd 1.9 (2.1) 1.6 (1.6) 1.7 (1.6) 0.104 .902 0.106 .900

Balanced 0.7 (1.0) 1.1 (2.7) 1.6 (1.9) 0.681 .512 0.620 .544

Data are mean (sD). P values of the F tests in AnoVA. higher scores represent better performance on the subtests, except for Attention control, inhibition, and all motor skills.#: with a maximum of 3 placental lesions. †: adjusted for parental education and gestational age in AnoVA.*: P <.05a: scaled score, higher score represent better performanceb: percentile scoresc: raw scores, higher score represent better performanced: raw scores, higher scores represent worse performance

Association between placental lesions and motor outcomes The number of placental lesions in general was not associated with motor outcomes (Table 4).

With regards to specific placental lesions only AIUI was associated with motor outcomes (Table 5). in the presence of AiUi we found lower total motor outcome percentile scores (mean 32.1, sD 19.8 versus mean 53.5, sD 29.3, P = .048). AiUi with a fetal response was associated with lower total motor outcome scores (median 26.2, sD16.2 versus median 53.3 sD 28.8, P = .031) (Figure 1).

After assigning the children to one of the three categories normal, borderline, or abnormal, only AiUi and AiUi with a fetal response, were associated with poorer static and dynamic balance (P = .035 and P = .085, respectively), but not with total motor skills.

123


6

Table 5 Relation of cognitive and motor outcome scores and placental lesions, using multivariable linear regression models

Variable B† 95% CI for B† Beta† R2† P-value† Beta†† P-value††

IQ-totala

MVU -7.10 -12.86 to -1.34 -.41 17.8 .017* -.35 .033*

AIUI 0.74 -6.23 to 7.70 .03 17.8 .832 .15 .288

FTV 0.88 -7.11 to 8.87 .04 17.8 .825 -.04 .787

VUE 0.16 -8.15 to 8.46 .01 17.8 .969 .23 .119

↑NRBCs 1.39 -4.52 to 7.29 .07 17.8 .637 .01 .935

Visuomotor integrationb

MVU -0.69 -2.30 to 0.93 -.15 7.7 .396 -.31 .114

AIUI 1.08 -0.88 to 3.03 .19 7.7 .217 .19 .280

FTV 1.01 -1.23 to 3.25 .16 7.7 .366 .27 .176

VUE 0.12 -2.21 to 2.45 .02 7.7 .918 .01 .937

NRBCs -0.60 -2.26 to 1.06 -.12 7.7 .469 -.06 .743

Verbal memoryc

MVU -4.93 -26.73 to 16.72 -.08 3.6 .647 -.17 .394

AIUI -7.53 -33.68 to 18.62 -.10 3.6 .563 -.08 .674

FTV 5.37 -26.52 to 37.27 .06 3.6 .735 -.01 .976

VUE 10.60 -20.57 to 41.77 .12 3.6 .495 .20 .304

↑NRBCs 2.10 -20.10 to 24.29 .03 3.6 .849 .03 .860

Selective attentiond

MVU -2.66 -18.66 to 13.35 -.06 7.6 .739 -.13 .507

AIUI -0.63 -19.99 to 18.73 -.01 7.6 .948 .04 .818

FTV 12.57 -9.64 to 34.78 .20 7.6 .259 .28 .169

VUE 0.89 -22.19 to 23.97 .01 7.6 .938 .06 .729

↑NRBCs 10.85 -5.56 to 27.27 .21 7.6 .189 .28 .116

Total motor skillsd

MVU -11.01 -30.93 to 8.91 -.19 13.5 .270 -.27 .159

AIUI -27.22 -51.31 to -3.12 -.37 13.5 .028* -.36 .041*

FTV -4.93 -32.57 to 22.71 -.06 13.5 .720 -.06 .772

VUE -11.02 -39.74 to 17.71 -.12 13.5 .442 -.07 .671

↑NRBCs 3.34 -17.09 to 23.76 .05 13.5 .743 .05 .767

Abbreviations: mVU – maternal vascular underperfusion; AiUi – ascending intrauterine infection; FTV – fetal thrombotic vasculopathy; VUe – villitis of unknown etiology; nRBcs – nucleated red blood cells.† model 1: all placental lesions for outcome measures, method enter.†† model 2: all placental lesions, gestational age, and parental education for outcome measures, method enter.*: P <.05a: intelligence quotient b: scaled score, higher score represent better performancec: Verbal memory: recall, percentile scored: percentile scores

124


6

Figure 1: Total movement-ABc scores in the presence or absence of AiUi with and without a fetal response.Data are shown in box and whisker plots. Abbreviations: AiUi – ascending intrauterine infection; movement-ABc – movement Assessment Battery for children.

*

* P <.05

Mov

emen

t-ABC

perc

entil

esc

ore

absent present absent present

AIUI AIUI with fetal response

*100

80

60

40

20

0

125


6

Discussionour study showed that placental lesions in general hardly associated with functional outcomes in moderately preterm-born and late preterm-born children at early school age. only the presence of one or more placental lesions was marginally associated with better selective attention. On considering specific placental lesions, however, we found a strong association between the presence of mVU and lower total iQ scores and between the presence of AiUi and poorer motor skills. other placental lesions were not associated with cognitive or motor functioning. our hypothesis that functional outcomes would be poorer in the presence of placental lesions was thus confirmed for MVU and AIUI, but not for other placental lesions. The presence of placental lesions in general was not associated with outcome scores. We only found that the presence of one or more placental lesions in general were marginally associated with better selective attention. This is not supported by the literature and may be a chance finding due to multiple testing. The presence of any placental lesion, unspecified, might also be too broad an operationalization to find any associations. We draw attention to the fact that almost 80% of the moderately preterm-born and late preterm-born children in our study had one or more placental lesions.

We did find associations between specific placental lesions and functional outcomes, in particular for placental lesions with signs of mVU and AiUi. mVU was associated with lower iQ scores. We found a decline of 7.1 iQ points on total iQ in the presence of mVU. This is almost one sD lower compared to the group without mVU (sD = 8.3), which constitutes a relevant IQ difference. Only a few other studies addressed the association between mVU and cognition, albeit in early preterm infants.6,33 Van Vliet et al. found poorer mental development in the presence of mVU compared to AiUi at the age of two. At seven years they found better, although not significant, mental and motor development in the presence of AiUi compared to mVU, suggesting lower scores in the presence of mVU.33 These findings suggest a similar association between MVU and IQ in moderately preterm-born and late preterm-born children. Conversely, Redline et al. did not find an association at school age between mVU and cognitive measures, including executive functions and memory, in early preterm-born children.6 They did not, however, investigate IQ. We also did not find an association between MVU and memory tests, but we did find an association between mVU and iQ. iQ scores are a global indication for cognition, whereas visuomotor integration, memory, and attention tests are more specific. This may explain why we only found differences concerning MVU and cognition on IQ scores and not on specific subtests.

An explanation for lower iQ scores in the presence of mVU may be due to the chronic nature of mVU. The onset of mVU occurs more than one week prior to delivery,36 and is caused by inadequate spiral artery remodeling leading to decidual vasculopathy.11 Decidual vasculopathy may result in placental underperfusion leading to a lasting non-optimal intrauterine environment. This in turn may lead to some degree of cerebral underperfusion resulting in lower cognition scores at school age. Another possibility is that due to the

126


6

lasting non-optimal intrauterine environment the infant is more susceptible to the inherent stress of delivery leading to intrapartum complications.5 Finally, it might also be a chance finding since we assessed multiple associations. The second placental lesion that we found to be associated with outcome measures was AiUi. AiUi was associated with poorer motor skills, particular in the case of AiUi with a fetal response. These findings are consistent with the literature. AIUI is known to be associated with poorer motor outcomes in early preterm and in fullterm infants.5,7,8,37,38 We now add that this association is also potentially present in moderately preterm-born and late preterm-born children. notably, we found a stronger association between AiUi and motor outcomes in the presence of a fetal response. other studies also reported that the association between AiUi and motor outcomes is predominantly seen in the presence of AiUi with a fetal response in the placenta.5,7,8 several hypotheses have been proposed to explain the association between AiUi and motor outcomes. The first hypothesis concerns the presence of cytokines in fetal circulation and postulates that the elevated blood and brain cytokine levels resulting from AIUI might lead to central nervous system damage in the fetus. The inflammatory cytokines can be neurotoxic and inhibit oligodendrocytes from developing white matter.38-

41 Another possible explanation is the multiple hit hypothesis.42 This hypothesis addresses the etiology of retinopathy of prematurity. Dammann et al. explained that multiple hits of exposure to inflammation might contribute to the risk of retinopathy of prematurity.42 This might also be the case for motor outcome. Postnatal inflammatory exposure in addition to AiUi might be an additional risk factor for developing poorer motor skills in later life.

The strength of this study is that to the best of our knowledge we are the first to study the association between placental lesions and functional outcomes in moderate and late preterm infants. We do, however, point out a few limitations too. to. First, the placentas of only 24% of the children initially tested in LoLLiPoP and who met our inclusion criteria were available for pathological examination. This 24% may constitute a biased group because the placentas had probably not been submitted for examination without reason. in comparison to the children whose placentas had not been sent to the pathologist, we found that the children whose placentas were available had lower GAs, lower birth weights, and a higher percentage were sGA. This suggests that the children included in our study were more at risk of adverse outcomes than the children whose placentas were not available.

secondly, almost 80% of the children in our study group were born with one or more placental lesions. When determining the associations between a specific placental lesions and outcomes, the comparison group consisted partly of children with placental lesions other than the one under study, which may have led to a degree of underestimation of the real differences. in conclusion, our study indicated that in moderately preterm-born and late preterm-born children mVU was associated with lower iQ scores and AiUi with impaired motor skills at early school age. These findings suggest that placental lesions might be early

127


6

indicators of impaired outcome later in life. Placental lesions should, therefore, be taken into account when evaluating the functional outcomes of all preterm-born children.

AcknowledgementsThis study was part of the research program of the postgraduate school for Behavioral and Cognitive Neurosciences, University of Groningen. Annemiek Roescher received financial support from the Junior Scientific Master Class of the University of Groningen. We greatly acknowledge the help of Dr Titia van Wulfften Palthe in Utrecht for correcting the English manuscript.

128


6

References1. Romeo Dm, Guzzetta A, scoto m,

et al. early neurologic assessment in preterm-infants: integration of traditional neurologic examination and observation of general movements. eur J Paediatr neurol. 2008;12(3):183-189.

2. Potijk mR, kerstjens Jm, Bos AF, Reijneveld sA, de Winter AF. Developmental delay in moderately preterm-born children with low socioeconomic status: Risks multiply. J Pediatr. 2013;163(5):1289-1295.

3. cserjesi R, Van Braeckel kn, Butcher PR, et al. Functioning of 7-year-old children born at 32 to 35 weeks’ gestational age. Pediatrics. 2012;130(4):e838-46.

4. kerstjens Jm, Bocca-Tjeertes iF, de Winter AF, Reijneveld sA, Bos AF. neonatal morbidities and developmental delay in moderately preterm-born children. Pediatrics. 2012;130(2):e265-72.

5. Redline RW. severe fetal placental vascular lesions in term infants with neurologic impairment. Am J obstet Gynecol. 2005;192(2):452-457.

6. Redline RW, minich n, Taylor hG, hack m. Placental lesions as predictors of cerebral palsy and abnormal neurocognitive function at school age in extremely low birth weight infants (<1 kg). Pediatr Dev Pathol. 2007;10(4):282-292.

7. Redline RW, o’Riordan mA. Placental lesions associated with cerebral palsy and neurologic impairment following term birth. Arch Pathol Lab med. 2000;124(12):1785-1791.

8. Rovira n, Alarcon A, iriondo m, et al.

impact of histological chorioamnionitis, funisitis and clinical chorioamnionitis on neurodevelopmental outcome of preterm infants. early hum Dev. 2011;87(4):253-257.

9. Royal college of obstetricians and Gynaecologists. Fetal and perinatal pathology. Report of a joint working party. London, Uk: RcoG-press; 2001.

10. Langston c, kaplan c, macpherson T, et al. Practice guideline for examination of the placenta: Developed by the placental pathology practice guideline development task force of the college of american pathologists. Arch Pathol Lab med. 1997;121(5):449-476.

11. Redline RW, Boyd T, campbell V, et al. maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2004;7(3):237-249.

12. Redline RW, Faye-Petersen o, heller D, et al. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2003;6(5):435-448.

13. Redline RW. Villitis of unknown etiology: noninfectious chronic villitis in the placenta. hum Pathol. 2007;38(10):1439-1446.

14. khong TY, Bendon RW, Qureshi F, et al. chronic deciduitis in the placental basal plate: Definition and interobserver reliability. hum Pathol. 2000;31(3):292-295.

15. katzman PJ, Genest DR. maternal floor infarction and massive perivillous fibrin deposition: Histological definitions, association with intrauterine fetal growth restriction, and risk of recurrence. Pediatr Dev Pathol.

129


6

2002;5(2):159-164. 16. Redline RW, Ariel i, Baergen Rn, et

al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2004;7(5):443-452.

17. 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(5 ( Pt 1)):760-766.

18. ohyama m, itani Y, Yamanaka m, et al. maternal, neonatal, and placental features associated with diffuse chorioamniotic hemosiderosis, with special reference to neonatal morbidity and mortality. Pediatrics. 2004;113(4):800-805.

19. Lewis s, Perrin e. Pathology of the placenta. 2nd ed. churchill Livingstone; 1999.

20. ogino s, Redline RW. Villous capillary lesions of the placenta: Distinctions between chorangioma, chorangiomatosis, and chorangiosis. hum Pathol. 2000;31(8):945-954.

21. Baergen Rn. cord abnormalities, structural lesions, and cord “accidents”. semin Diagn Pathol. 2007;24(1):23-32.

22. kort W, compaan e, Bleichrodt n, et al. Wisc-iii nL: Wechsler intelligence scales for children. . 3rd, Dutch version ed. Amsterdam, the netherlands: niP Dienstencentrum; 2002.

23. korkman m, kirk U, kemp s. nePsY: A developmental neuropsychological assessment. san Antonio, TX, UsA:

Psychological corporation; 1998. 24. van den Burg W, kingma A.

Performance of 225 dutch school children on rey’s auditory verbal learning test (AVLT): Parallel test-retest reliabilities with an interval of 3 months and normative data. Arch clin neuropsychol. 1999;14(6):545-559.

25. manly T, Robertson i, Anderson V, nimmo-smith i. TeA-ch: Test of everyday attention for children, handleiding. The netherlands: harcourt Assessment; 2004.

26. smits-engelsman B. Dutch manual of the movement assessment battery for children. Lisse, the netherlands: swets & Zeitlinger; 1998.

27. kidron D, Bernheim J, Aviram R. Placental findings contributing to fetal death, a study of 120 stillbirths between 23 and 40 weeks gestation. Placenta. 2009;30(8):700-704.

28. horn Lc, Langner A, stiehl P, Wittekind C, Faber R. Identification of the causes of intrauterine death during 310 consecutive autopsies. eur J obstet Gynecol Reprod Biol. 2004;113(2):134-138.

29. korteweg FJ, erwich JJ, holm JP, et al. Diverse placental pathologies as the main causes of fetal death. obstet Gynecol. 2009;114(4):809-817.

30. ogunyemi D, murillo m, Jackson U, hunter n, Alperson B. The relationship between placental histopathology findings and perinatal outcome in preterm infants. J matern Fetal neonatal med. 2003;13(2):102-109.

31. Beebe LA, cowan LD, Altshuler G. The epidemiology of placental features: Associations with gestational age and

130


6

neonatal outcome. obstet Gynecol. 1996;87(5 Pt 1):771-778.

32. Beaudet L, karuri s, Lau J, magee F, Lee sk, von Dadelszen P. Placental pathology and clinical outcomes in a cohort of infants admitted to a neonatal intensive care unit. J obstet Gynaecol can. 2007;29(4):315-323.

33. van Vliet eo, de kieviet JF, van der Voorn JP, Been JV, oosterlaan J, van elburg Rm. Placental pathology and long-term neurodevelopment of very preterm infants. Am J obstet Gynecol. 2012;206(6):489.e1-489.e7.

34. Redline RW, Wilson-costello D, Borawski E, Fanaroff AA, Hack m. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab med. 1998;122(12):1091-1098.

35. Blair e, de Groot J, nelson kB. Placental infarction identified by macroscopic examination and risk of cerebral palsy in infants at 35 weeks of gestational age and over. Am J obstet Gynecol. 2011;205(2):124.e1-124.e7.

36. Redline RW. Disorders of placental circulation and the fetal brain. clin Perinatol. 2009;36(3):549-559.

37. shatrov JG, Birch sc, Lam LT, Quinlivan JA, mcintyre s, mendz GL. chorioamnionitis and cerebral palsy: A meta-analysis. obstet Gynecol. 2010;116(2 Pt 1):387-392.

38. soraisham As, Trevenen c, Wood s, singhal n, sauve R. histological chorioamnionitis and neurodevelopmental outcome in preterm infants. J Perinatol. 2013;33(1):70-75.

39. Wu YW, colford Jm,Jr. chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAmA. 2000;284(11):1417-1424.

40. Dammann o, Leviton A. maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997;42(1):1-8.

41. horvath B, Grasselly m, Bodecs T, Boncz i, Bodis J. histological chorioamnionitis is associated with cerebral palsy in preterm neonates. eur J obstet Gynecol Reprod Biol. 2012;163(2):160-164.

42. Dammann o, Brinkhaus mJ, Bartels DB, et al. immaturity, perinatal inflammation, and retinopathy of prematurity: A multi-hit hypothesis. early hum Dev. 2009;85(5):325-329.

43. Pathak s, Lees cc, hackett G, Jessop F, sebire nJ. Frequency and clinical significance of placental histological lesions in an unselected population at or near term. Virchows Arch. 2011;459(6):565-572.

131


6

133

Chapter 7 In preterm infants ascending intrauterine infection is associated with lower cerebral tissue oxygen saturation and higher oxygen extraction

Chapter 8 Cytokine Response in Preterm Infants with Placental Lesions

Disease Mechanisms of Placental Lesions Leading

to Neurological Morbidity

Part IV

134

General introduction and outline of the thesis

1

134

university of groningen placental lesions and …abstract objective: to determine whether the...

Documents