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Chronic histiocytic intervillositis
(CHI): current treatments and
perinatal outcomes, a
systematic review and a
meta-analysis
Laurel Moar
1
†
, Chloe Simela
1
†
, Surabhi Nanda
1,2
,
Andreas Marnerides
3
, Mudher Al-Adnani
3
,
Catherine Nelson-Piercy
1,2
, Kypros H. Nicolaides
1,4
and Panicos Shangaris
1,2,5
*
1
School of Life Course and Population Sciences, King’s College London, London, United Kingdom,
2
Department of Women and Children, Guy’s and St. Thomas’NHS Foundation Trust, London,
United Kingdom,
3
Department of Histopathology, St. Thomas Hospital, Westminster Bridge Road,
London, United Kingdom,
4
Harris Birthright Research Centre for Fetal Medicine, King’s College
London, London, United Kingdom,
5
Peter Gorer Department of Immunobiology, School of
Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London,
London, United Kingdom
Background: Chronic histiocytic intervillositis (CHI) is a rare placental lesion
with a high recurrence rate and poor perinatal outcomes. There are currently
limited guidelines regarding the diagnosis of this condition in the index
pregnancy and treatment where recurrence is suspected.
Objective: The primary objective of this systematic review and meta-analysis
was to determine the perinatal outcomes of pregnancies affected by chronic
histiocytic intervillositis and to what extent they can be improved with
treatment. The secondary objective was to assess the relationship between
CHI lesion severity and pregnancy loss.
Methods: A systematic search of Ovid Embase, Web of Science, Science Direct,
PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. Case
reports, cohort, case-control and randomised controlled trials (RCT) detailing
the perinatal outcomes of CHI pregnancies, both treated and untreated, were
included.
Results: No RCTs were identified. However, in a review population of 659
pregnancies, with additional 7 in case reports, CHI treatments included aspirin,
prednisone, prednisolone, low molecular weight heparin (LMWH),
hydroxychloroquine and adalimumab. A descriptive synthesis of data found
mixed results for treatments in relation to live birth, miscarriage and fetal
growth restriction outcomes. Furthermore, quantitative synthesis of 38
pregnancies revealed a non-significant improvement in live birth rate with
CHI targeted treatment (OR 1.79 [95% CI 0.33-9.61] (p=0.50), while meta-
Frontiers in Endocrinology frontiersin.org01
OPEN ACCESS
EDITED BY
Reinaldo Marı
´n,
Instituto Venezolano de
Investigaciones Cientı
´ficas (IVIC),
Venezuela
REVIEWED BY
Chloe A. Brady,
The University of Manchester,
United Kingdom
Marta Cohen,
Sheffield Children’s Hospital,
United Kingdom
*CORRESPONDENCE
Panicos Shangaris
panicos.shangaris@kcl.ac.uk
†
These authors share first authorship
SPECIALTY SECTION
This article was submitted to
Developmental Endocrinology,
a section of the journal
Frontiers in Endocrinology
RECEIVED 16 May 2022
ACCEPTED 29 June 2022
PUBLISHED 22 July 2022
CITATION
Moar L, Simela C, Nanda S,
Marnerides A, Al-Adnani M,
Nelson-Piercy C, Nicolaides KH and
Shangaris P (2022) Chronic histiocytic
intervillositis (CHI): current treatments
and perinatal outcomes, a systematic
review and a meta-analysis.
Front. Endocrinol. 13:945543.
doi: 10.3389/fendo.2022.945543
COPYRIGHT
©2022Moar,Simela,Nanda,
Marnerides, Al-Adnani, Nelson-Piercy,
Nicolaides and Shangaris. This is an
open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use,
distribution or reproduction is
permitted which does not comply with
these terms.
TYPE Systematic Review
PUBLISHED 22 July 2022
DOI 10.3389/fendo.2022.945543
analysis of CHI severity in line with pregnancy loss, in a sample of 231
pregnancies, revealed lower odds of pregnancy loss with less severe lesions
(OR: 0.17 [0.03-0.80], p=0.03).
Conclusions: This systematic review and meta-analysis reinforce notions
surrounding the insufficient evidence for CHI treatment. It also strengthens
previous hypotheses detailing the positive association between CHI lesion
severity and odds of pregnancy loss. Aspirin, LMWH, prednisolone,
hydroxychloroquine and adalimumab are candidates with varying levels of
weak to moderate evidence supporting their use. Further prospective research
is required to obtain robust evidence pertaining to treatment safety and
efficacy and optimal drug regimes.
Systematic Review Registration: [website], identifier CRD42021237604
KEYWORDS
CHI, recurrent miscarriage, intervillositis, stillbirth, small gestation age (SGA)
Introduction
Chronic histiocytic intervillositis (CHI) (also referred as
CHIV) is a rare but severe placental condition characterised by
the presence of an inflammatory mononuclear infiltrate in the
intervillous space. CHI has been estimated to affect 6 in every 10
000 pregnancies that reach 12 weeks gestation (1,2) and the term
was first introduced by Labarrere and Mullen in 1987 as massive
chronic intervillositis (3). This pathology has since been referred
to by several names across the literature, including chronic
intervillositis of unknown aetiology (CIUE), massive chronic
intervillositis, massive perivillous histiocytosis and shortened
forms - chronic intervillositisorintervillitis.Diagnostic
understanding has also grown in differentiating CHI from other
placental lesions through its non-infectious origin and minimal
involvement of the villi or basal plate (1). Although the lesion is
well described in the placental pathology literature, there is no
agreed standardised diagnostic criteria or grading system for the
severity of this lesion (4–7). However, the paucity of knowledge
surrounding CHI biomarkers only permits retrospective diagnosis
following examination of the placenta postpartum.
Furthermore, while the aetiology of CHI remains undetermined,
the pathology’s high recurrence rate, reported to lie between 70 and
100% (8), highlights the need for effective treatment in future
pregnancies. Some evidence of pathogenic immune mechanisms
has been proposed, including an absence of the usual Th1 to Th2
immune response shift observed in normal pregnancy (1,9–13).
This raises the question of possible therapeutic benefits for
immunologically based CHI treatments, with steroids and other
immunosuppressants having been used in some cases.
Objectives
This systematic review summarises the available research on
treatment approaches for gravid women diagnosed with CHI in
a previous pregnancy, including antithrombotic and
immunosuppressive drug combinations. Primary objectives
include quantifying the effectiveness of these therapies in
improving perinatal outcomes compared to baseline data
without treatment. Moreover, further analysis was undertaken
to determine how CHI severity impacts perinatal outcomes.
Methods
Search strategy
PROSPERO registration for the review was fulfilled following
the completion of the protocol form (CRD42021237604).
The literature search was carried out by the two reviewers, CS
and LM, across seven databases: PubMed, OVID MEDLINE,
Google Scholar, OVID EMBASE, Web of Science, Science Direct
and CENTRAL (Cochrane Central Register of Controlled Trials)
between 15
th
February and 16
th
February 2021. Each reviewer used
the search strategy (1) comprising all known terms for CHI and a
period spanning from Jan 1990 to December 2020, in three
databases. CENTRAL was searched by both reviewers.
Formatting adjustments weremadetothesearchtermsto
optimise the strategy for each database, and email alerts were put
in place to notify the reviewers of new results after the search period
(Table 1). The two reviewers screened the search results
Moar et al. 10.3389/fendo.2022.945543
Frontiers in Endocrinology frontiersin.org02
independently, and discussions were held at both screening stages
to resolve any disagreements before the final papers were decided.
Study selection
Selection criteria were based on the following predetermined
characteristics from the protocol, starting with the population in
question being identified as pregnant women of any age diagnosed
with CHI in a previous pregnancy.CHI was defined as an idiopathic
inflammatory lesionin the intervillousspace in line withthe criteria
devised by Bos and colleagues (4). All other similar but distinct
placental lesions were excluded, including villitis, even if in co-
occurrence with CHI. Interventions described included varying
doses of drug-based mono or combination therapy for CHI.
However, studies without interventions were also included for
comparison. Outcomes assessing the efficacy of treatment and
impact of disease severity included, but were not limited to,
quantitative measures such as live birth rate and birth weight.
Only randomised controlled trials, cohort,case-control studies and
case reports were included, with abstracts excluded. While there
were no geographical limits, time constraints enforced excluding
texts not in English.
Data extraction
A modified Cochrane Public Health Group (CPHG) data
extraction form was used to collect population, intervention and
outcome data from the chosen papers independently by both
reviewers (C.S and L.M). Additionally, each structure underwent
a data checking process against the original article to detect and
minimise human error. The specific information collected for
each study included authors, publication year; study design,
location; the number of women, number of CHI pregnancies,
and number undergoing treatment. Authors were contacted to
confirm information regarding population data where
clarification was needed (14,15).
Outcome measures
Outcome measures reported in the systematic review included
growth restriction and preterm birth, while those of interest in the
meta-analysis were live birth rate and pregnancy loss. The preterm
birth rate was definedasalivebirthbefore37+0weeksgestation.
Fetal growth restriction (FGR) or intrauterine growth restriction
(IUGR) was defined as a birth weight below the 10
th
percentile (16).
Several terms were used when determining rates of
pregnancy loss in CHI. In this paper, pregnancy loss data were
divided into early miscarriage (before 14 + 0 weeks gestation),
late miscarriages (14 + 1 to 24 + 0 weeks gestation) and stillbirths
(intrauterine death after 24 + 0 weeks gestation). Some studies
also included neonatal deaths as an outcome, where this term
described the loss of an infant within seven days of birth (17).
In some cases (such as with FGR), there was variation in how
outcomes were classified (e.g., birth weight below 10
th
percentile
versus 3
rd
percentile, stillbirth including pregnancy loss as early as
20 weeks versus after 24 weeks) in different studies. Such instances
of outcome measure variation are indicated in the review.
The measure of CHI lesion severity
The extent of intervillous space involvement defined CHI
lesion severity as a quantifiable and standard measure. In this
case, low to moderate grading referred to infiltrate occupying
less than 50% of the intervillous space, and severe grading
infiltrate more than 50% of the intervillous space [Parant (18),
Simula (6), Sauvestre (15) but not Marchaudon (19)].
Risk of bias and quality assessment
The risk of bias and quality of included studies was assessed
independently by both reviewers using adapted versions of the
Newcastle-Ottawa scale (20) and Critical Appraisal Skills
Programme (CASP) checklist (21).
The 7-point system of the Newcastle Ottawa scale contained
domains of selection, comparability, and outcome, while the CASP
checklist aimed to detect instances of selection, measurement,
classification or reporting bias. Additional consideration was
given to the lack of accountability for confounding factors.
Analysis and data synthesis
The Cohen kappa coefficient was used to assess agreement
between the two reviewers at the full-text eligibility stage before
TABLE 1 Search strategy for database.
No. Science Direct, Ovid Embase, Web of Science search strategy
1(((chronic histiocytic intervill*) OR (chronic intervill*)) OR (chronic intervill* of unknown?etiology)) OR (massive chronic intervill*)) OR (massive perivillous
histiocyt*)
2“chronic histiocytic intervillositis”[All Fields] OR “chronic histiocytic intervillositis chi”[All Fields] OR “chronic histiocytosis”[All Fields] OR “chronic
histiocytosis x”[All Fields]
3Search 1 OR 2
Moar et al. 10.3389/fendo.2022.945543
Frontiers in Endocrinology frontiersin.org03
generating a narrative synthesis of the findings. A high ratio
indicated a reasonable level of agreement between the reviewers.
Inclusion in the meta-analysis component depended on
cohort studies with a suitable differentiation of outcomes
according to the presence of treatment or severity of lesions.
The chosen effect measures for the meta-analyses were relative
risk (RR) of pregnancy loss in moderate vs severe CHI and odds
ratios (OR) for live births in treated vs untreated pregnancies,
each with a 95% confidence interval and calculated based on the
number of pregnancies and events. All analyses herein were
carried out using RevMan (Review Manager (RevMan) Version
5.4.1, The Cochrane Collaboration 2020). Heterogeneity was
measured using the I
2
statistic, with an I
2
>50% indicating
significant heterogeneity, not due to chance. As recommended,
random-effects models were used to determine the summary
effect estimate where considerable heterogeneity was detected
(I
2
>30%) (22).
Due to the small meta-analysis population, no additional
sensitivity, subgroup, or meta-regression analyses were undertaken.
Results
Study selection
Figure 1 summarises (23) the study selection process and its
outcomes. In total, 805 papers were found, and of these, 384
remained for the title and abstract screening once duplicates
were removed. Titles and abstracts were excluded for review
format, language limitation and lack of relevance leading to 66
full texts, which were narrowed down to the final 20 for
systematic review inclusion. Reasons for exclusion included
irrelevance, language limitation, conference abstract, poster or
thesis format, full-text unavailability, and data insufficiency.
The Cohen kappa coefficient for full-text screening between
the two reviewers was 0.81, indicating almost perfect agreement
at this stage of study selection.
Study characteristics
The final twenty papers comprised 12 cohort studies and 8
case reports as no RCTs were identified. The characteristics of
these mainly retrospective studies and case reports are
summarised in Table 2. Five of the twelve cohort studies were
selected for inclusion in either meta-analysis. The limited
number of studies selected for meta-analysis was due to
treated vs untreated outcomes being unavailable for pooling in
the other seven studies.
Excluding case reports and series, the review population
included the outcomes of 527 pregnancies affected by CHI in 439
women with a mean age of approximately 31.9 years. Fifty-eight
of these cohort study pregnancies were treated, and sample size
ranged from 6 to 122 pregnancies. A further 6 instances of
treatment were reported in case reports and series. In total, 64
pregnancies were treated out of 554 across cohort studies, case
reports and case series.
Email correspondence with authors confirmed a shared
cohort between two papers, and this is highlighted in all
subsequent results tables to avoid duplication and reporting
errors. For review population totals, these cohorts have been
counted as one (14,15).
Risk of bias of included studies
The risk of bias scores for each case-control and cohort study
can be seen in Table 3. Following a judgement by both reviewers,
the risk of bias was considered generally low, with an average
bias score of 1.83 out of 4 across the twelve studies.
Selection bias was reported in four of the twelve studies due to
how participants were selected from a pathology database (15,18,37,
39). Furthermore, in other cases, selection bias was detected because
of limited search terms comprising only of ‘CIUE and chronic
intervillositis’in one study and ‘intervillositis’in another (15,39).
Seven studies indicated measurement/classification bias in
diagnosis and grading of CHI, whereby pathologists were aware
of and not blinded to the previous CHI diagnosis.
Reporting bias was undetected. However, ten out of twelve
studies did not state accountability for confounding variables.
Study quality assessment outcomes are shown in Table 4.High
scores were obtained in the selection domain, with participants seen
FIGURE 1
Study selection process of the systematic review and meta-
analysis into outcomes of pregnancies affected by CHI.
Moar et al. 10.3389/fendo.2022.945543
Frontiers in Endocrinology frontiersin.org04
as broadly representative of the population in question. The area in
which numerous studies were deficient was comparability and
outcome measures. Lack of differentiation between early and late
miscarriage outcomes and methods that did not describe the
assessment of lesion severity as a possible mediator of perinatal
outcome was also suboptimal. Furthermore, lack of information on
population comorbidities or medication also led to lower quality
scores in the outcome domain.
Treatment combinations
None of the cohorts included in the systematic review was
fully treated. The proportion of the four cohorts receiving
targeted treatment for CHI ranged from 18-88%, and the
other eight cohorts were labelled as untreated. Table 5
summarises the treatment combination details in the
treated pregnancies.
TABLE 2 Characteristics of studies included.
Study Location Study
design
Duration N
women
N CHI
pregnancies
Mean age Ethnicity BMI n/N
pregnancies treated
Doss 1995
(9)
USA Case report 1974-1994 1 4 36 NR NR 1/4
Parant 2009
(18)*s
France retrospective
cohort
2000-2006 10 14 30 (24-39) 99% white 21 (19-27) 6/14
Marchaudon
2011 (19)s
France retrospective 1997-2006 50 69 31 (16-43) NR NR NONE
Reus 2013
(11)
Netherlands retrospective
cohort study
2000-2010 22 30 31.8
(22-45)
NR NR NONE
Ramya 2014
(24)
India Case report 2014 1 1 22 NR NR NR
Mekinian
2015 (25)s
France multi-centre
prospective
2011-2013 24 24 34 46% white 26 NONE
Crawford
2016 (26)
Australia Case report 2016 1 4 28 NR NR NONE
Nowak 2016
(27)
France retrospective
cohort
1998-2010 NR 24 NR NR NR NONE
Sabra 2016
(28)
Spain retrospective 2012-2016 6 6 34.83
(32-39)
83.3% European
16.7% Latinx
NR NONE
Ozawa 2017
(29)
Japan Case report 2010-2017 1 3 29 NR NR 1/1
Vardi 2017
(30)
New
Zealand
Case report 2003-2013 1 6 31 NR NR 1
Koby 2018
(31)
Canada retrospective
observational
2001-2014 29 33 Median 31
(IQR 28.5-
34.5)
45.5% white, 42.4%
African, 12.1% Asian
median
29.8 (26-
31.7)
NONE
Mekinian
2019 (32)
France Case report 2019 2 3 38.5 (33–36) NR NR 2/2
Bos 2020
(37)
Netherlands Observational
cohort
2000-2015 38 38 34 (24-43) NR NR NONE
Homatter
2020 (38)
France retrospective
case-control
2000-2016 111 111 30.8 72.1% white NR 21/111
Mattuizzi
2020 (14)†
France retrospective 1997-2018 102 122 Median 32
(IQR 28-36)
61.6% white,
2% Asian
19.2% North African,
15.2% South African,
2% Hispanic
median 22 21/24
Nohr 2020
(33)
Canada Case report 2020 1 2 34 NR NR 1/1
Sauvestre
2020 (15)s†
France multi-centre
retrospective
1997-2018 102 122 31.7 NR 23.1 NONE
Simula 2020
(39)s
Canada retrospective
cohort
2006-2019 47 56 33.2 NR 25.9 10/56
Traeder 2010
(40)
Germany case series 1994-2008 4 4 34 (30-40) NR NR NONE
N CHI pregnancies –only includes pregnancies diagnosed with CHI, NR –not reported, * - pregnancies with villitis excluded, all ages are means with range included in brackets if reported,
** - median and IQR used where mean and range not available, sincluded in either one or both of the meta-analyses, †studies share same cohort.
Moar et al. 10.3389/fendo.2022.945543
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There was a variation of gestational ranges when the
treatment was commenced. Those containing aspirin were the
most common of the treatment regimes, followed by low
molecular weight heparin (LMWH) and finally corticosteroid
regimes (prednisone/corticoid), either alone or in combination.
Outcomes
Table 6 summarises the perinatal outcomes of these studies.
Continuous variables are reported as means followed by the
standard deviation and range in brackets if available.
Live births
The live birth rate varied considerably between studies,
ranging from 30.4% to 100%. Interestingly, neither of the
cohorts displaying results at these extremes were indicated as
receiving target CHI treatment (19,40). There was also variance
within similar populations, as several of the papers were based
within the same countries yet yielded different live birth rates for
example the study by Bos et al., 2020 reported a live birth rate
more than twice as high as that reported by Reus et al., 2013 (11,
37). Comparable live birth rates of 67% and 70% were observed
in two studies with a similar cohort size despite 88% of one
cohort receiving targeted treatment (25) versus none of the other
(27). Overall, the average live birth rate for cohorts in which no
treatment was stated was 58.3% versus 40.9% in cohorts with a
partial treatment.
Birth weight
Data on average live birth weight were available in seven
studies, three of which had a proportion receiving treatment. In
most cases, this outcome rarely reached 2500g however, the
highest mean birth weight of 2493g was achieved in one study in
which 88% of the cohort received treatment (25). Furthermore, a
low average birth weight of 995g was reported by Traeder and
TABLE 3 Risk of bias.
Study selection bias measurement/classification
bias
reporting
bias
confounding not accounted for
(no regression model)
score*
Parant 2009
(18)
✓×
No mention of blinding
✓×2
Reus 2013
(11)
✓✓ ✓ ×1
Mekinian
2015 (25)
✓✓✓1
Nowak 2016
(27)
✓×
No mention of blinding
✓×2
Sabra 2016
(28)
✓×
No blinding mentioned
✓×2
Koby 2018
(31)
✓×
Investigator was aware of diagnosis no
mention of blinding
✓×2
Marchaudon
2011 (19)
✓×
Histology in conjunction with fetal
autopsy so outcome known
✓×2
Bos 2020 (37)✓×
No mention of blinding when
pathologist reviewed slides
✓✓1
Homatter
2020 (38)
✓×
Only CHI positive cases assessed
histologically
✓×2
Mattuizzi
2020 (14)
✓×
No blinding to CHI diagnosis
✓×2
Sauvestre
2020 (15)
×
Only database search term was
‘intervillositis’
✓
All 3 pathologists blinded to diagnosis
✓×2
Simula 2020
(39)
×
Database search was for CIUE and
chronic intervillositis
×✓×3
*Risk of bias score is out of a total of 4.
✓Low risk of bias.
× High risk of bias.
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TABLE 4 Quality assessment using Newcastle-Ottawa scoring system.
Study year Study
design
Selection
(3)
Comparability
(2)
Outcome
(2)
total
(7)
Comment
Parant 2009
(18)
2009 retrospective
cohort
3 2 1 6 No details of whether pathologists were blinded
Marchaudon
2011 (19)
2011 retrospective 3 1 1 5 Pathologists carried out histological analysis in conjunction with
autopsy - no blinding, no mention of medications
Reus 2013
(11)
2013 retrospective 3 1 2 6
Mekinian
2015 (25)
2015 prospective 3 2 2 7
Nowak 2016
(27)
2016 retrospective
cohort
3216
Sabra 2016
(28)
2016 retrospective 2 1 1 4 No blinding mentioned, and only 6 patients
Koby 2018
(31)
2018 retrospective
observational
3 1 1 5 Pathologist was aware of diagnosis, no details on medication
Bos 2020
(37)
2020 observational
cohort
3 1 1 5 No comment on whether pathologists were blinded to prior
diagnosis.
Homatter
2020 (38)
2020 retrospective
case-control
2 1 2 5 Early miscarriage excluded
Mattuizzi
2020 (14)
2020 retrospective 3 1 1 5 No comments on anyon any blinding
Sauvestre
2020 (15)
2020 retrospective 2 1 1 4 Only histological database search term was ‘intervillositis’, live
birth outcomes unclear in table, 10 placentas missing
Simula 2020
(39)
2020 retrospective
cohort
3 2 1 6 No comment on whether pathologist was blinded
TABLE 5 Treatment combinations used in case pregnancies affected by CHI.
Author/Year Intervention details
N Untreated Treatment details
Parant 2009 (18) 14 8 aspirin (n=4)
aspirin + corticoid (n=2)
Traeder 2010 (40) 4 4 NONE
Marchaudon 2011 (19) 69 69 NONE
A. Reus 2013 (11) 30 30 NONE
Mekinian 2015 (25) 24 3 aspirin/LMWH (n=4)
aspirin + prednisone (n=6)
aspirin+ prednisone+ LMWH (n=5)
aspirin +prednisone+ LMWH+ hydroxychloroquine (n=6)
Nowak 2016 (27) 24 24 NONE
Sabra 2016 (28) 6 6 NONE
Koby 2018 (31) 33 33 NONE
Bos 2020 (37) 38 38 NONE
Homatter 2020* (38) 111 90 aspirin (n=18)
LMWH (n=7)
corticosteroids(n=6)
Mattuizzi 2020 (14) 122 122 NONE
N.K Simula 2020 (39) 56 37 aspirin 81mg +dalteparin 7500 IU+ hydroxychloroquine 400mg (n=2)
aspirin 81mg (n=3)
dalteparin (n=1)
prednisone (n=1)
aspirin + dalteparin (n=3)
Sauvestre 2020 (15) 122 122 NONE
* in combination but assessed separately.
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colleagues (40) across a case series of four untreated pregnancies.
However, this positive treatment effect was not always reflected,
with higher birth weight observed in untreated cohorts (19,27,
28) compared to partially treated cohorts (18,38).
Preterm birth
In five out of six studies, a low average birth weight was
accompanied by an average gestational age at delivery <37+0
weeks. The general trend towards high preterm birth in both
untreated and treated CHI pregnancies is also evident in a
preterm birth rate of 40.2% across the twelve studies.
Interestingly, the study by Mekinian and colleagues in which
the largest proportion of the cohort was treated (88%) had a
lower preterm birth rate of 31.25% (25). However, this was not
the case for all partially treated cohorts, which, for the most
part, had a lower mean gestational age at delivery (38)and
higher preterm live birth rate than the untreated cohort (19,
27,28).
TABLE 6 Perinatal outcomes for CHI pregnancy cohorts.
Study Year n/N
pregnancies
treated
Live
Birth
Rate
Avg.
Live
Birth
weight
(g)
Gestational
age at
delivery
(weeks)
Spontaneous
preterm live
birth
FGR
(<10
th
centile)
live or not
Miscarriage
< 14 weeks
Miscarriage
14 -24 weeks
Still
birth
IUD >
24 weeks
Parant 2009
(18)
2009 6/14 5/14 1550
(590-2760)
34.6
(27.5-37)
10/10 8/11 2/14 1/14 2/14
Traeder 2010
(40)
2010 NONE 4/4 995
(495-1640)
31.2
(27-35.6)
4/4 3/4
(<10th
percentile) 2/
4
(<3rd
percentile)
NO NO NO
Marchaudon
2011 (19)
2011 NONE 21/69 1780 ± 590
(920-2830)
35.0 ± 2.5
(30.6-39.0)
13/21 24/69
(<3rd
percentile)
21/69
(<12 weeks)
9/69
(12-22 weeks)
18/69
(>22
weeks)
Reus 2013
(11)
2013 NONE 10/30 NR NR 6/10 NR 4/30
(<12 weeks)
2/30
(12-16 weeks)
NR
Mekinian
2015 (25)
2015 21/24 16/24 2493 ± 678 38 ± 1.6 5/16 3/24 4/24
(<10 weeks)
4/24
(>10 weeks)
NR
Nowak 2016
(27)
2016 NONE 17/24 1634
(610-2875)
34.3± 3.7 11/17 14/21 /1/24 2/24 2/24
Sabra 2016
(28)
2016 NONE 2/6 1695
(1290-
2100)
35.5
(33-38)
1/2 2/6 4/6 NO NO
Koby 2018
(31)
2018 NONE 20/33 NR NR 16/20 23/33
(<10th
percentile),
15/33
(<3rd
percentile)
2/33
(<20 weeks)
NR 11/31
(>20
weeks)
Bos 2020
(37)
2020 NONE 31/38 NR NR 21/31 16/38
(<3rd
percentile)
NR 1/38 3/38
Homatter
2020 (38)
2020 21/111 62/111 1500 ± 885 33.6 ± 4.7 4/62 62/111
(<3rd
percentile)
NR 6/111
(14-21 weeks)
22/111
(22-42
weeks)
Mattuizzi
2020 (14)
2020 NONE 70/122 NR NR 38/70 81/122 17/122 17/122 NR
Simula 2020
(39)
2020 10/56 3/56 NR NR 1/6 7/15 at 20
weeks
29/56
(<12 weeks)
13/56
(12-22 weeks)
6/56
(>23
weeks)
Sauvestre
2020 (15)
2020 NONE 70/122 NR NR 5/70 46/70 (alive) 17/122 1/122 16/122
Total 58 336/659 1679.68 34.47 135/336 289/424 101 56 80
Live birth rate is as a fraction over total CHI pregnancies in each study, * pregnancies with villitis excluded, NR –not reported, average birth weight and gestational age at delivery with
standard deviation if reported and range in parentheses. Parentheses in miscarriage and FGR indicate differing classification criteria.
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Fetal growth restriction
Many infants were small for gestational age. Studies reported
fetal growth restriction of below 10
th
centile (with some even
below 3
rd
centile) in both live and stillborn or neonatal
death groups.
Similar prevalence of FGR < 10
th
centiles was reported in
two studies (66.7% and 69.7%, respectively), both of which had
entirely untreated cohorts (27,31). In treated cohorts, this same
variable ranged from 12.5% (25) to 72.7% (18)
19
with treated
proportions being 88% and 42.8%, respectively.
Severe FGR, <3
rd
centile, was only reported as an outcome in
5 studies (19,31,37,40). Of these, one study had an 18.9%
treated cohort with a severe FGR prevalence of 55.9% (38). Four
untreated study cohorts have reported an occurrence rate of
severe FGR as 69.7%, 42.1%, 34.8% and 50% (19,31,37,
40) respectively.
Miscarriage, stillbirth and neonatal death
Overall, miscarriage rates ranged between 2.63% and 20% in
untreated cohorts (11,37). The miscarriage rate was much wider
in treated cohorts (range between 5.4% and 75%). In some cases,
miscarriage timing was before 14 weeks rather than after 14
weeks, but this was only in five out of the twelve cohorts (11,15,
18,28,39).
Stillbirth rates varied between 10.7% and 19.8% in treated
pregnancies (38,39). Like miscarriage rates, this was
comparatively higher than the untreated cohort range of 7.9%
to 13.1% (15,22). Interestingly, there were also instances of no
reported stillbirths in untreated populations with small sample
sizes (28,40).
Neonatal death
Neonatal death was not widely reported as an outcome and
ranged from 1.11% up to 23.3% across four studies (11,14,15,
38). There are no reported cases in both partially treated and
untreated cohorts (18,27).
Individual pregnancy outcomes
As shown in Table 7, individual patient outcomes were
available from seven case reports, one case series, and two
retrospective cohort studies that reported individual patient
details. 21 of the 31 case pregnancies were treated, and 9 of
these resulted in a live birth, of which 4 were at term. This is
compared to 6 out of 10 untreated pregnancies resulting in live
births and 1 of these 6 occurring at term.
Meta-analysis
Meta-analysis of live birth outcomes in two studies in which
treated and untreated data was available revealed a non-
significant improvement in live birth rates with treatment
(Odds Ratio: 1.79 [0.33-9.61], p=0.50) (Figure 2). The pooled
population included 27 treated and 11 untreated pregnancies.
Heterogeneity (I
2
) was estimated to be 6%, using fixed
effect model.
Meta-analysis of pregnancy loss in relation to CHI severity
across four studies with a pooled population of 174 low to
moderate severity cases and 84 severe cases indicated
significantly lower odds of pregnancy loss in cases with less
severe lesions vs those with increased severity (Odds Ratio: 0.17
[0.03-0.80], p=0.03) (Figure 3). Largely homogenous grading
criteria in all four studies permitted low to moderate lesions to
be defined as <50% intervillous infiltrate involvement and >50%
leading to a severe classification (supplementary data file).
Discussion
Principle findings
The primary objective of this systematic review and meta-
analysis was to identify and quantify the effectiveness of current
treatment regimens for pregnant women diagnosed with CHI
following a previous pregnancy. Effectiveness was quantified by
comparing perinatal outcomes, including live birth, miscarriage,
stillbirth rates and neonatal death in treated and untreated
pregnancies, birth weight (normal, IUGR), as well as preterm
birth rate, with a positive effect in such measures indicating
effective treatment.
The commonly used treatment regimens for CHI, either as
standalone or as combination therapy include aspirin, prednisone,
low molecular weight heparin, biological agents most commonly
adalimumab and hydroxychloroquine (Table 8). The partially
treated cohorts often performed equally or even worse in the
outcome domains of live birth rates, preterm birth, fetal growth
restriction, miscarriage and stillbirth rates. Indeed, the pooled
treatment effect for live birth rates in treated vs untreated
pregnancies produced an odds ratio of 1.79 [95% CI 0.33-9.61]
(p=0.50). This converts to a risk ratio of 1.4 [95% CI 0.48-4.05]
(p=0.54), which reveals the likelihood of live births in the treated
group was 1.4 times that in the untreated, although this was not
statistically significant. Taken collectively, this suggests that
antithrombotic and immunosuppressive treatment for CHI
cannot be significantly effective in improving perinatal outcomes
in affected pregnancies. However, classifying these results as
clinically insignificant due to exceeding the arbitrary cut off
p=0.05 would be misleading as such a small, pooled population
of 27 treated and 11 untreated pregnancies suggests a degree of
imprecision. Consequently, we can conclude that these findings are
inconclusive, and there is insufficient evidence of a treatment effect,
as opposed to proof of no treatment effect (34).
The secondary objective of this review was to determine the
extent to which CHI severity –measured as a percentage of
intervillous space occupied by infiltrate- impacts perinatal
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TABLE 7 Individual patient outcomes in pregnancies affected by CHI.
Author/
Year
Maternal
Age
G P No. previ-
ous CHI
pregnancies
Case Pregnancy Treatment Treatment duration Case Pregnancy
Outcome
Doss
1995 (9)
36 13 2 4/12 Prednisone NR Live birth, 2170g
Parant
2009 (18)
a
35 8 5 NR None listed –Miscarriage 14 weeks
Parant
2009 (18)
b
25 5 0 NR Aspirin/corticoid (prednisone 20mg) Full gestation Miscarriage 8 weeks
Parant
2009 (18)
c
29 2 1 NR None listed - Live birth, 2310g, 34
weeks
Parant
2009 (18)
d
31 2 1 NR None listed - IUFD (Intrauterine fetal
death), 180g, 23 weeks
severe IUGR
Parant
2009 (18)
e
31 2 1 NR None listed - TOP, 190g fetal weight, 22
weeks, severe IUGR
Parant
2009 (18)
f
29 1 0 NR None listed - Live birth, 2080g, 37
weeks, severe IUGR
Parant
2009 (18)
g
24 4 0 NR Aspirin Full gestation Miscarriage 10 weeks
Parant
2009 (18)
h
25 2 0 NR Aspirin Full gestation IUFD, 330g, 26.5 weeks
FGR
Parant
2009 (18)
i
31 3 1 NR Aspirin/corticoid (prednisone 5mg) Full gestation TOP, 215g, 22.5 weeks,
FGR
Parant
2009 (18)
j
28 3 2 NR Aspirin Full gestation Live birth, 2760g, 37
weeks
Parant
2009 (18)
k
27 2 1 NR Aspirin Full gestation Live birth, 2320g, 37.5
weeks, IUGR
Parant
2009 (18)
l
33 3 2 NR None listed - TOP, 392g fetal weight, 26
weeks, FGR
Parant
2009 (18)
m
25 3 0 NR None listed –Live birth, 590g, 27.5
weeks, FGR
Parant
2009 (18)
n
31 2 0 NR None listed - IUFD, 160g, 28.5 weeks,
FGR
Traeder
2010 (40)
a
30 2 2 NR NONE NONE Live birth, 1640g, 32
weeks
Traeder
2010 (40)
b
40 4 1 NR NONE NONE Live birth FGR, 1440g, 35
weeks
Traeder
2010 (40)
c
30 1 1 NR NONE NONE Live birth FGR, 405g, 29
weeks
(Continued)
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TABLE 7 Continued
Author/
Year
Maternal
Age
G P No. previ-
ous CHI
pregnancies
Case Pregnancy Treatment Treatment duration Case Pregnancy
Outcome
Traeder
2010 (40)
d
36 1 1 NR NONE NONE Live birth FGR, 495g, 27
weeks
Ramya
2014 (24)
22 1 0 NR None listed –IUD 460g, 24 weeks
Crawford
2016 (26)
28 5 1 3/4 None listed - TOP 21 weeks
Ozawa
2017 (29)
29 7 0 2/6 ** Prednisolone 20mg + LDA 4 - 29 weeks Live birth, 2051g, 35
weeks
Vardi
2017 (30)
31 6 0 3/5 20mg oral prednisone OD, 40mg LMWH
(enoxaparin) subcutaneously OD, aspirin
100mg OD
Prednisone conception-20weeks and
decreasing dose to 28 weeks; LMWH 6
weeks onwards
Live birth, 2200g, 34
weeks
Mekinian
2019 (32)
a
37 13 1 NR Adalimumab + aspirin 100mg/day +
prednisone 10mg/day
2 months preconception - 9 weeks
gestation
Live birth, 2960g 38 weeks
Mekinian
2019 (32)
b
40 NR NR NR Adalimumab 40mg every 2 weeks
subcutaneously
2 months prior to oocyte donation - 9
weeks gestation
Live birth, - g, 39 weeks
NK
Simula
2020 (39)
a
NR 6 1 5/5* Aspirin 81mg daily, dalteparin 7500 IU
daily, hydroxychloroquine
From positive pregnancy test - delivery Live birth, -g, - weeks
NK
Simula
2020 (39)
b
NR NR NR NR Aspirin 81mg daily From positive pregnancy test - delivery Live birth at term, - g
NK
Simula
2020 (39)
c
NR NR NR NR Aspirin 81mg daily From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
d
NR NR NR NR Aspirin 81mg daily From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
e
NR NR NR NR Dalteparin 5000-7500 IU daily From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
f
NR NR NR NR Prednisone From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
g
NR NR NR NR Aspirin 81mg daily, dalteparin 5000-7500
IU daily
From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
h
NR NR NR NR Aspirin 81mg daily, dalteparin 5000-7500
IU daily
From positive pregnancy test - delivery Pregnancy loss
NK
Simula
2020 (39)
i
NR NR NR NR Aspirin 81mg daily, dalteparin 5000-7500
IU daily
From positive pregnancy test - delivery Pregnancy loss
NK
Simula
NR NR NR NR Aspirin 81mg daily, dalteparin 7500 IU
daily, hydroxychloroquine
From positive pregnancy test - delivery Ongoing?
(Continued)
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TABLE 7 Continued
Author/
Year
Maternal
Age
G P No. previ-
ous CHI
pregnancies
Case Pregnancy Treatment Treatment duration Case Pregnancy
Outcome
2020 (39)
j
Nohr
2020 (33)
34 4 1 2/3 IVIg therapy, prednisone, LMWH,
Aspirin
NR IUGR, IUFD 25 weeks
Live birth rate as a fraction over total CHI pregnancies in study, * 3/5 treated with Aspirin 81mg daily, dalteparin 5000-7500 IU daily, prednisone 10-40mg daily; 1/5 treated with aspirin
81mg daily, dalteparin 7500 IU daily, hydroxychloroquine 400mg daily.** pregnancy 5 treated with aspirin 81mg/ day resulted in IUD and IUGR 210g at 17 weeks; pregnancy 6 treated with
aspirin 81mg/day, heparin 10 000-15 000IU/day IUGR 33 weeks 1032g.
FIGURE 3
Forest plot summarising risk ratios of pregnancy loss in low/moderate vs severe CHI.
FIGURE 2
Forest plot summarising odds of live birth rates in treated vs untreated pregnancies.
TABLE 8 Summary of CHI treatments, their indication in mild, moderate, or severe cases and the strength of evidence surrounding each.
Treatment Dose Indication Strength of Evidence
Aspirin 75-100mg Low, moderate, severe Moderate
Dalteparin ——— Low, moderate, severe Moderate
Enoxaparin ——— Low, moderate, severe Moderate
Prednisone/Prednisolone 10-20mg Low, moderate, severe Moderate
Adalimumab ——— Moderate to severe Weak
Hydroxychloroquine ——— Moderate to severe Weak
Tacrolimus ——— Moderate to severe Weak
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outcomes. It was anticipated that establishing a relationship
between progression of placental pathology, in subsequent
pregnancies, and extent of adverse outcomes would improve
understanding of treatment potential as seen by the effect of
treatment (monotherapy or combination therapy) on the
placental tissue. This in turn would help to explore if
improvements in lesions (with or without complete remission)
positively correlate with more favourable perinatal outcomes.
Results demonstrate a small severity effect in relation to
pregnancy loss (Odds Ratio: 0.17 [0.03-0.80], (p=0.03). The
larger pooled population of 174 low or moderately affected
pregnancies and 84 pregnancies affected with severe CHI
infers a more reliable evidence that any improvement in the
severity of lesions correlates to a reduction (albeit small) in the
odds of miscarriage or stillbirth.
The proposed hypothesis around the effect of treatment
regimens is the reduction in the severity of lesions through
targeted anti-inflammatory, immunosuppressive and anti-
thrombotic mechanisms, which in turn would help improve
the perinatal outcome.
The discrepancies in severity classification systems between
papers cannot be ignored. It is known that CHI can exist with or
without fibrin deposition and so while it is not necessary for
diagnosis, the role of fibrin in severity classification systems is
interesting. While in some, fibrin was acknowledged, this was not
the case in studies with methods that did not call for fibrin to be
noted (19,39). Table 9 illustrates the varying inclusion and
exclusion criteria for CHI classification in all the studies included.
In retrospective studies, it was not possible for all placentas
in the database to be examined for CHI. Therefore, many relied
on the assumption that CHI placentas had accurately been
documented as such and the search terms used to recover
them were adequate (38).
Furthermore, there was an invariable absence of adjustment
for confounders known to increase risk of adverse perinatal
outcomes such as maternal BMI and smoking which at times,
were not measured during the process of data gathering in some
cases or noted in many of the case reports.
Comparison with existing literature
Overall, the findings of this review were consistent with
those previously available evidence. For instance, the strong
association between FGR, miscarriage, and stillbirth reflected
in Table 6 (2). FGR frequency <10
th
percentile, was estimated at
TABLE 9 Different diagnostic criteria for CHI among included studies in which it was stated.
Doss
1995
(9)
Parant
2009
(18)
Traeder
2010
(40)
Marchaudon
2011 (19)
Reus
2013
(11)
Ramya
2014
(24)
Mekinian
2015 (25)
Nowak
2016
(27)
Sabra
2016
(28)
Vardi
2017
(30)
Koby
2018
(31)
Bos
2020
(37)
Homatter
2020 (38)
Matuizzi
2020 (14)
Simula
2020
(39)
Nohr
2020
(33)
Sauvestre
2020 (15)
Inclusion
Infiltrate in
intervillous
space
++ + + + + + + + ++ + + + + +
Mononuclear
infiltrate
++ + + + + ++ ++ + + + + +
Histiocytic
CD68+
marker
++++ +
Massive/
diffuse
infiltrate
++ +
Fibrin
deposits
++ + +/-
Trophoblastic
necrosis
+
Maternal
origin of
infiltrate
Exclusion
Signs of
infection
++ + + ++ +
Villitis
Presence of
other
placental
lesions
+
Malaria + + +
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61% across nine studies in our review population compared to
48% in a previous meta-analysis (35). The total population in
our review did not confirm a higher prevalence of early
miscarriage compared to late, as was seen by Rota and
colleagues (5), however it was found that there was a higher
rate of intrauterine deaths in the remit of early miscarriage
rather than stillbirth or late miscarriage. Nevertheless, the
relatively high incidence of either early or late pregnancy loss
emphasises the impact of placental insufficiency without
maternal vascular malperfusion on increased adverse
pregnancy outcomes.
Interestingly, our conclusion that increased CHI lesion
severity correlates with increased risk of pregnancy loss
disagrees with the findings of the most prominent prospective
study in the area (25) which states that maintenance of visible
CHI pathology is not always indicative of adverse outcomes.
However, this study did find that the absence of these lesions was
linked to more positive outcomes. Further investigation may be
required to find a more definitive answer. It is worth
acknowledging here that there has previously been a lack of
international consensus on indications for sending placental
pathology (and for reporting by perinatal pathologists),
following an adverse pregnancy outcome, and therefore CHI
itself may be under-reported. However, there has been a reform
in this area more recently due to the creation of the international
Amsterdam consensus criteria in 2016 (36).
The lack of significant treatment effects in CHI, though
cautiously interpreted by our review, was also highlighted by
Contro et al (41). This 2010 review on CHI concluded that
treatments investigated at the time had no significant, and even a
detrimental, effect on perinatal outcome. Our review provides
evidence supporting this conclusion, despite numerous novel
studies conducted in the 10-years since the last systematic review
(41). However, one of the explanations for this may be a lack of
consensus about the case selection for treatment, gestation of
commencing treatment (and stopping), and treatment regimens
(monotherapy or combination therapy). Further explanation for
individual worse outcomes in combination therapy pregnancies
has been highlighted by Mekinian et al., pertaining to
confounding by indication and severity –whereby pregnancies
with worse prognoses (maternal history of previous IUD) are
targeted with combination treatment, while those with
prognostically better outcomes are not (25).
Historically, there has been a lack of evidence around the
generic use of immunosuppressive therapies in the management
of recurrent pregnancy loss (42). A previous study, albeit with
suboptimal case selection and design, highlighted a possible
association between first-trimester prednisone exposure and
cleftlipsandpalatesininfants(43). This has since been
disputed (44), and there is considerable experience in the use
of oral steroids for many a condition in pregnancy, including
lupus, transplants, severe asthma, etc. Nevertheless, long term
use of steroids has been linked with increased preterm delivery
rates (secondary to preterm prelabour rupture of membranes),
neonatal intensive care admission and low birth weights in the
neonates, and increased chance of maternal dependence on
steroids and steroid induced diabetes (and its associated
complications) (45–47). While it is not clear whether any of
these adverse outcomes were documented as a result of oral
steroids like prednisone in our review studies, its use in the
management of pregnancies previously affected by CHI as a part
of off-label treatment regimes in the UK, in order to optimise
pregnancy outcome (improve live birth rate, and prolong
gestation at delivery), is still surrounded by controversy (48).
Antithrombotic therapy is relatively effective in treating
pregnancy loss, particularly in those with associated
antiphospholipid syndrome (42,46). A recent Cochrane
review concluded that combined treatment of aspirin with
heparin is more likely to lead to higher birth rates in women
with recurrent pregnancy loss associated with antiphospholipid
antibodies, compared to aspirin alone (49). Though still yet to be
confirmed, this offers a potential means of treating the proposed
antibody mediated and pro-inflammatory pathophysiology
of CHI. A recent review drew upon the application of
immunomodulatory drugs in autoimmune conditions
during pregnancy to emphasise the safety and merit of
hydroxychloroquine in CHI (50).
Additionally, CHI has been associated with maternal
hypertensive disorders in some studies but evaluating this was
outside the remit of this paper (8). Antithrombotic therapy such
as aspirin is also cited by The American College of Obstetricians
and Gynaecologists as appropriate in the prevention of fetal
growth restriction, which in some cases is due to placental
insufficiency (16,51). Hence, despite further research being
warranted, the practice of the use of aspirin and heparin in the
management of pregnancies affected by CHI, is not discordant
with current practice. Anti-thrombotic drugs such as
unfractionated and low molecular weight heparin, adjunctive
low dose aspirin (with or without other immunosuppressive
agents such as hydroxychloroquine, azathioprine, adalimumab,
tacrolimus) currently form the basis of off-label CHI treatment
in the UK (48). A 2021 study by Brady and colleagues has
however offered some promising results in the application of
hydroxychloroquine and prednisolone (in conjunction with
mainstay aspirin and heparin) in improving CHI lesion
severity and bringing about a 62.3% reduction in subsequent
pregnancy loss (52). The study reported lower FGR, preterm,
stillbirth and neonatal death rates in treated pregnancies
although statistical significance was restricted by the small
sample size (52).
Co-occurrence of placental lesions was encountered as
frequently as 30% in one study and 25% in another (5,18).
While these cases were beyond the scope of the review, the
reality of coexisting pathology is worth recognising (50). In one
study, combined lesions formed a considerable proportion of
placental samples (35%). Although these were excluded from
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our data, the debate on viewing combined lesions as separate
entities continues (27). The application of aspirin and
corticosteroids in a pregnancy affected by both villitis and CHI
was documented as having a positive outcome in one case report
(53). It is questionable whether the same treatment effect would
be observed in pregnancies affected by other placental lesions
adjunct to CHI, and further research into this should be
encouraged. We stress the value of a multidisciplinary
discussion involving perinatal pathologists in such cases,
where there are such services available, to have a case-based
consensus of treatment regimes (36).
Strengths and limitations
This is a rare condition. As discussed above, there is a lack of
consensus and guidance on indications for placental pathology
following pregnancy loss or adverse pregnancy outcomes. Not all
placental pathology is assessed by perinatal pathologists.
Therefore, it can be acknowledged that the actual incidence of
CHI is underreported. There is only a small amount of literature
on CHI, and it is unlikely that any relevant studies were omitted
through the search strategy. It has been noted that observational
study titles can be misleading and require full-text screening for
relevance (22). The manageable number of search results
enabled manual screening and several checking processes to be
carried out to ensure that no relevant studies were missed. Saved
search alerts permitted new papers released after the search
period to be identified and screened equally.
However, it must be acknowledged that there was an
enforcement of an English-language criterion due to time
constraints, and it is possible that this introduced a level of
selection bias to this systematic review and meta-analysis.
Lastly, not all relevant data, i.e., treated vs untreated
outcomes, appeared to be included in studies, and although
raw data were requested through email correspondence, this was
not available. As a result, only 38 untreated and treated cases
across two studies could be included in the meta-analysis for
treatment effect concerning live birth rates specifically, and while
data from individual studies appeared to favour untreated
cohorts, pooled data in the meta-analysis revealed a non-
significant improvement in treated outcomes may suggest
publication bias. This is likely due to the exclusion of multiple
studies from the meta-analysis. There was a lack of data
distinguishing treated vs untreated outcomes in all these other
partially treated cohorts (18,25).
Associated maternal outcomes like hypertensive disorders in
pregnancy and treatment-related adverse effects like steroid-
induced diabetes have been noted in case reports and from
experience with our group. However, evaluating this was outside
the remit of this review (54).
Conclusion
This review examined the outcomes of 554 pregnancies, 64
of which were treated by either aspirin, prednisolone or LMWH
alone or in conjunction. Additional therapies included
hydroxychloroquine and adalimumab. Based on efficacy being
defined as significantly reducing the prevalence of adverse
perinatal outcomes in affected pregnancies, the findings have
further strengthened the available evidence that there is no
known effective treatment for CHI in pregnancy. The paucity
of research using comparison groups in a case-control design has
led to challenging analysis and equivocal results. Gaining a
deeper insight into novel, effective therapeutics will require
international collaboration due to the rare nature of
this pathology.
Current therapies for the general treatment of recurrent
pregnancy loss form a basis for building these next steps for CHI
treatment. Existing recommendations support the use of
antithrombotic therapies more than immunosuppressants. The
likely need for combination therapy in the event of previous
IUFD has been highlighted (25), and this review showed the
general value of combination therapy in current practice. Novel
therapies not previously reviewed, such as adalimumab and
hydroxychloroquine, warrant further research as uncertainty
surrounding their efficacy and safety has led to their
application only informally recommended in moderate to
severe cases.
Compared to other lesions, the high recurrence rate and
more severe perinatal outcomes associated with CHI underscore
the value of a precise differential diagnosis. Further research may
permit a stepwise approach utilising aspirin, heparin, and
hydroxychloroquine to form the basis of individualised
treatment plans with cost/benefitanalysisinlinewiththe
previous pregnancy outcomes and multidisciplinary
treatment counselling.
Fundamentally, research needs to address the aetiology of
CHI to gain a complete understanding of possible ways to treat
it. Once this is achieved, observational studies are of value, and
even if still retrospective, augmentation of database results with
additional hospital data will help account for confounding. Our
review only identified one complete and one ongoing
prospective multi-centre study. A prospective registry of
women with pregnancies previously affected by CHI, involving
non-profit organisations like CHI support (48), who may
provide ongoing support to these families, may help with a
holistic multidisciplinary approach to the management of these
pregnancies and improve our understanding of this rare
pathology. Equally, a prospective multi-centre design should
be the objective model of future studies with additional outcome
measures such as Apgar Scores and NICU admissions and later
achievement of neurodevelopmental milestones.
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Frontiers in Endocrinology frontiersin.org15
Interventions should include, but not be limited to, aspirin,
prednisone, and heparin, with or without other immunosuppressive
agents such as hydroxychloroquine, azathioprine, adalimumab,
tacrolimus). Researchers should be attentive to side effects caused
by therapies and their comparative effectiveness in combination or
alone. This will help develop future guidelines for CHI treatment,
and hopefully, long-term follow-up data regarding childhood
outcomes in untreated versus treated CHI pregnancies will also
become available.
The best effort to improve pregnancy outcomes in pregnancies
associated with CHI is surveillance and identification of screening
tools in the index pregnancy, where CHI is suspected. Equally,
where CHI has been previously identified, screening tools may
help increase surveillance and tailor treatment modalities and
regimens. Use of first-trimester markers (55,56)likeplacental
growth factor or second-trimester markers like alkaline
phosphatase, ultrasound markers like increased uterine artery
pulsatility index and reduction in amniotic fluid in the third
trimester, and use of fetal placental MRI using diffusion imaging
have all been reported either alone or in conjunction with each
other. Although a single sufficiently specific biomarker is yet to be
identified (31), further research into these potential prognostic
biomarkers would be invaluable (54)inreducingtheprevalenceof
adverse perinatal outcomes in this pathology by permitting earlier
intervention and better treatment.
Author contributions
PS, LM and CS conceptualized the topic and structure of the
systematic review. LM and CS drafted and revised the manuscript.
SN, AM, MA-A, CN-P, KN and PS provided expert opinion, edited,
and approved the finalmanuscript.Allauthorscontributedtothe
article and approved the submitted version.
Funding
PS is funded by an NIHR Clinical Lectureship (CL-2018-17-
002). This study was funded by the Fetal Medicine Foundation
(KHN) (registered charity 1037116), National Institute for Health
Research (NIHR) Biomedical Research Centre at Guy’s and St
Thomas’National Health Service Foundation Trust and King’s
College London (IS-BRC-1215–20006). The viewsexpressed in this
Article are those of the authors and not necessarily those of the
National Health Service, the NIHR, or the Department of Health.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fendo.2022.945543/
full#supplementary-material
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