The association between chronic deciduitis and preeclampsia.

383

384

385

ANTON, L., BROWN, A. G., PARRY, S. & ELOVITZ, M. A. 2012. Lipopolysaccharide

induces cytokine production and decreases extravillous trophoblast invasion

through a mitogen-activated protein kinase-mediated pathway: possible

386

387

mechanisms of first trimester placental dysfunction. Hum Reprod, 27, 61-72.

BENDON, R. W. & MILLER, M. 1990. Routine pathological examination of placentae

388

389

390

from abnormal pregnancies. Placenta, 11, 369-70.

BENNER, M., FERWERDA, G., JOOSTEN, I. & VAN DER MOLEN, R. G. 2018. How

uterine microbiota might be responsible for a receptive, fertile endometrium. Hum

391

392

393

Reprod Update, 24, 393-415.

BLAZQUEZ, A., GARCIA, D., RODRIGUEZ, A., VASSENA, R., FIGUERAS, F. &

VERNAEVE, V. 2016. Is oocyte donation a risk factor for preeclampsia? A

394

395

396

397

398

systematic review and meta-analysis. J Assist Reprod Genet, 33, 855-63.

BROWN, M. A., MAGEE, L. A., KENNY, L. C., KARUMANCHI, S. A., MCCARTHY,

F. P., SAITO, S., HALL, D. R., WARREN, C. E., ADOYI, G., ISHAKU, S. &

INTERNATIONAL SOCIETY FOR THE STUDY OF HYPERTENSION IN, P.

2018. Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and

399

400

401

Management Recommendations for International Practice. Hypertension, 72, 2443.

BURTON, G. J., REDMAN, C. W., ROBERTS, J. M. & MOFFETT, A. 2019. Pre-

402

403

404

405

406

407

eclampsia: pathophysiology and clinical implications. BMJ, 366, l2381.

CHEN, C., SONG, X., WEI, W., ZHONG, H., DAI, J., LAN, Z., LI, F., YU, X., FENG,

Q., WANG, Z., XIE, H., CHEN, X., ZENG, C., WEN, B., ZENG, L., DU, H.,

TANG, H., XU, C., XIA, Y., XIA, H., YANG, H., WANG, J., WANG, J.,

MADSEN, L., BRIX, S., KRISTIANSEN, K., XU, X., LI, J., WU, R. & JIA, H.

2017. The microbiota continuum along the female reproductive tract and its

408

409

410

411

relation to uterine-related diseases. Nat Commun, 8, 875.

CICINELLI, E., MATTEO, M., TINELLI, R., LEPERA, A., ALFONSO, R.,

INDRACCOLO, U., MARROCCHELLA, S., GRECO, P. & RESTA, L. 2015.

Prevalence of chronic endometritis in repeated unexplained implantation failure

412

413

414

415

and the IVF success rate after antibiotic therapy. Hum Reprod, 30, 323-30.

COWLING, P., MCCOY, D. R., MARSHALL, R. J., PADFIELD, C. J. & REEVES, D.

S. 1992. Bacterial colonization of the non-pregnant uterus: a study of premenopausal abdominal hysterectomy specimens. Eur J Clin Microbiol Infect Dis,

416

417

11, 204-5.

DI PIETRO, C., CICINELLI, E., GUGLIELMINO, M. R., RAGUSA, M., FARINA, M.,

18

418

419

PALUMBO, M. A. & CIANCI, A. 2013. Altered transcriptional regulation of

cytokines, growth factors, and apoptotic proteins in the endometrium of infertile

420

421

women with chronic endometritis. Am J Reprod Immunol, 69, 509-17.

EDMONDSON, N., BOCKING, A., MACHIN, G., RIZEK, R., WATSON, C. &

422

KEATING, S. 2009. The prevalence of chronic deciduitis in cases of preterm labor

423

424

425

without clinical chorioamnionitis. Pediatr Dev Pathol, 12, 16-21.

GELDENHUYS, J., ROSSOUW, T. M., LOMBAARD, H. A., EHLERS, M. M. & KOCK,

M. M. 2018. Disruption in the Regulation of Immune Responses in the Placental

426

427

Subtype of Preeclampsia. Front Immunol, 9, 1659.

GUNDOGAN, F., BIANCHI, D. W., SCHERJON, S. A. & ROBERTS, D. J. 2010.

428

429

430

Placental pathology in egg donor pregnancies. Fertil Steril, 93, 397-404.

HUTCHEON, J. A., LISONKOVA, S. & JOSEPH, K. S. 2011. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin

431

432

433

434

Obstet Gynaecol, 25, 391-403.

KAKU, S., KUBO, T., KIMURA, F., NAKAMURA, A., KITAZAWA, J., MORIMUNE,

A., TAKAHASHI, A., TAKEBAYASHI, A., TAKASHIMA, A., KUSHIMA, R. &

MURAKAMI, T. 2020. Relationship of chronic endometritis with chronic

435

436

437

deciduitis in cases of miscarriage. BMC Womens Health, 20, 114.

KHONG, T. Y., BENDON, R. W., QURESHI, F., REDLINE, R. W., GOULD, S.,

STALLMACH, T., LIPSETT, J. & STAPLES, A. 2000. Chronic deciduitis in the

438

439

440

441

442

443

444

445

446

447

placental basal plate: definition and interobserver reliability. Hum Pathol, 31, 2925.

KHONG, T. Y., MOONEY, E. E., ARIEL, I., BALMUS, N. C., BOYD, T. K.,

BRUNDLER, M. A., DERRICOTT, H., EVANS, M. J., FAYE-PETERSEN, O.

M., GILLAN, J. E., HEAZELL, A. E., HELLER, D. S., JACQUES, S. M.,

KEATING, S., KELEHAN, P., MAES, A., MCKAY, E. M., MORGAN, T. K.,

NIKKELS, P. G., PARKS, W. T., REDLINE, R. W., SCHEIMBERG, I.,

SCHOOTS, M. H., SEBIRE, N. J., TIMMER, A., TUROWSKI, G., VAN DER

VOORN, J. P., VAN LIJNSCHOTEN, I. & GORDIJN, S. J. 2016. Sampling and

Definitions of Placental Lesions: Amsterdam Placental Workshop Group

448

449

450

Consensus Statement. Arch Pathol Lab Med, 140, 698-713.

KIM, C. J., ROMERO, R., CHAEMSAITHONG, P. & KIM, J. S. 2015. Chronic

inflammation of the placenta: definition, classification, pathogenesis, and clinical

451

452

453

significance. Am J Obstet Gynecol, 213, S53-69.

KIMURA, F., TAKEBAYASHI, A., ISHIDA, M., NAKAMURA, A., KITAZAWA, J.,

MORIMUNE, A., HIRATA, K., TAKAHASHI, A., TSUJI, S., TAKASHIMA, A.,

19

454

455

AMANO, T., TSUJI, S., ONO, T., KAKU, S., KASAHARA, K., MORITANI, S.,

KUSHIMA, R. & MURAKAMI, T. 2019. Review: Chronic endometritis and its

456

457

effect on reproduction. J Obstet Gynaecol Res, 45, 951-960.

KITAYA, K., MATSUBAYASHI, H., TAKAYA, Y., NISHIYAMA, R., YAMAGUCHI,

458

459

460

461

462

463

K., TAKEUCHI, T. & ISHIKAWA, T. 2017. Live birth rate following oral

antibiotic treatment for chronic endometritis in infertile women with repeated

implantation failure. Am J Reprod Immunol, 78.

KITAYA, K., MATSUBAYASHI, H., YAMAGUCHI, K., NISHIYAMA, R., TAKAYA,

Y., ISHIKAWA, T., YASUO, T. & YAMADA, H. 2016. Chronic Endometritis:

Potential Cause of Infertility and Obstetric and Neonatal Complications. Am J

464

465

466

467

Reprod Immunol, 75, 13-22.

KITAZAWA, J., KIMURA, F., NAKAMURA, A., MORIMUNE, A., HANADA, T.,

AMANO, T., TSUJI, S., KASAHARA, K., SATOOKA, H., HIRATA, T.,

KUSHIMA, R. & MURAKAMI, T. 2021. Alteration in endometrial helper T-cell

468

469

470

471

subgroups in chronic endometritis. Am J Reprod Immunol, 85, e13372.

LI, X., ZHANG, W., LIN, J., LIU, H., YANG, Z., TENG, Y., HUANG, J., PENG, Q., LIN,

X., ZHANG, J., XIE, L., XIE, Y., LI, Y., LUO, J., DUAN, W., CHEN, J. & DUAN,

S. 2021. Hypertensive disorders of pregnancy and risks of adverse pregnancy

472

473

474

475

outcomes: a retrospective cohort study of 2368 patients. J Hum Hypertens, 35, 6573.

LUCAS, D N., YENTIS, S M., KINSELLA, S M., HOLDCROFT, A., MAY, A E., WEE,

M., ROBINSON, P N. 2000. Urgency of caesarean section: a new classication. J

476

477

478

R Soc Med, 93, 346-50.

MAROUN, L. L., MATHIESEN, L., HEDEGAARD, M., KNUDSEN, L. E. & LARSEN,

L. G. 2014. Pathologic evaluation of normal and perfused term placental tissue.

479

480

481

482

Pediatr Dev Pathol, 17, 330-8.

MASOUDIAN, P., NASR, A., DE NANASSY, J., FUNG-KEE-FUNG, K.,

BAINBRIDGE, S. A. & EL DEMELLAWY, D. 2016. Oocyte donation

pregnancies and the risk of preeclampsia or gestational hypertension: a systematic

483

484

485

486

487

review and metaanalysis. Am J Obstet Gynecol, 214, 328-39.

MATTEO, M., CICINELLI, E., GRECO, P., MASSENZIO, F., BALDINI, D.,

FALAGARIO, T., ROSENBERG, P., CASTELLANA, L., SPECCHIA, G. &

LISO, A. 2009. Abnormal pattern of lymphocyte subpopulations in the

endometrium of infertile women with chronic endometritis. Am J Reprod Immunol,

488

489

61, 322-9.

MCQUEEN, D. B., PERFETTO, C. O., HAZARD, F. K. & LATHI, R. B. 2015.

20

490

Pregnancy outcomes in women with chronic endometritis and recurrent

491

492

pregnancy loss. Fertil Steril, 104, 927-931.

MOLLER, B. R., KRISTIANSEN, F. V., THORSEN, P., FROST, L. & MOGENSEN, S.

493

494

495

496

C. 1995. Sterility of the uterine cavity. Acta Obstet Gynecol Scand, 74, 216-9.

MORIMUNE, A., KIMURA, F., NAKAMURA, A., KITAZAWA, J., TAKASHIMA, A.,

AMANO, T., KAKU, S., MORITANI, S., KUSHIMA, R. & MURAKAMI, T.

2021. The effects of chronic endometritis on the pregnancy outcomes. Am J

497

498

499

500

501

Reprod Immunol, 85, e13357.

MORITA, K., TSUDA, S., KOBAYASHI, E., HAMANA, H., TSUDA, K., SHIMA, T.,

NAKASHIMA, A., USHIJIMA, A., KISHI, H. & SAITO, S. 2020. Analysis of

TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8(+) T Cells

Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia. Front

502

503

504

505

506

507

508

Immunol, 11, 1082.

NAKASHIMA, A., SHIMA, T., AOKI, A., KAWAGUCHI, M., YASUDA, I., TSUDA,

S., YONEDA, S., YAMAKI-USHIJIMA, A., CHENG, S., SHARMA, S. &

SAITO, S. 2020. Placental autophagy failure: A risk factor for preeclampsia. J

Obstet Gynaecol Res.

POLLHEIMER, J., VONDRA, S., BALTAYEVA, J., BERISTAIN, A. G. & KNOFLER,

M. 2018. Regulation of Placental Extravillous Trophoblasts by the Maternal

509

510

Uterine Environment. Front Immunol, 9, 2597.

RANA, S., LEMOINE, E., GRANGER, J. P. & KARUMANCHI, S. A. 2019.

511

512

513

Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res, 124,

1094-1112.

REDMAN, C. W. & SARGENT, I. L. 2010. Immunology of pre-eclampsia. Am J Reprod

514

515

Immunol, 63, 534-43.

SAITO, S. 2010. Th17 cells and regulatory T cells: new light on pathophysiology of

516

517

518

preeclampsia. Immunol Cell Biol, 88, 615-7.

SAITO, S., NAKABAYASHI, Y., NAKASHIMA, A., SHIMA, T. & YOSHINO, O. 2016.

A new era in reproductive medicine: consequences of third-party oocyte donation

519

520

for maternal and fetal health. Semin Immunopathol, 38, 687-697.

SHARMA, S., GODBOLE, G. & MODI, D. 2016. Decidual Control of Trophoblast

521

522

523

Invasion. Am J Reprod Immunol, 75, 341-50.

TANG, M. X., HU, X. H., LIU, Z. Z., KWAK-KIM, J. & LIAO, A. H. 2015. What are the

roles of macrophages and monocytes in human pregnancy? J Reprod Immunol,

524

525

112, 73-80.

TARANOVSKA OCAPITAL

O,

C.,

LIKHACHOV

VCAPITAL

KA,

C.,

21

526

527

528

DOBROVOLSKA LCAPITAL EM, C., MAKAROV, O. G. & SHYMANSKA, Y.

V. 2020. The Role of Secreting Function of Decidua in the Development of

Complications of Gestation Process in Pregnant Women with a Past History of

529

530

Chronic Endometritis. Wiad Lek, 73, 2416-2420.

TSUDA, S., NAKASHIMA, A., SHIMA, T. & SAITO, S. 2019. New Paradigm in the

531

532

533

534

Role of Regulatory T Cells During Pregnancy. Front Immunol, 10, 573.

TSUDA, S., ZHANG, X., HAMANA, H., SHIMA, T., USHIJIMA, A., TSUDA, K.,

MURAGUCHI, A., KISHI, H. & SAITO, S. 2018. Clonally Expanded Decidual

Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but

535

536

Not in Preeclampsia, in Humans. Front Immunol, 9, 1934.

WANG, A., RANA, S. & KARUMANCHI, S. A. 2009. Preeclampsia: the role of

537

538

539

540

541

angiogenic factors in its pathogenesis. Physiology (Bethesda), 24, 147-58.

WU, D,. KIMURA, F., ZHENG, L., ISHIDA, M., NIWA, Y., HIRATA, K.,

TAKEBAYASHI, A., TAKASHIMA, A., TAKAHASHI, K., KUSHIMA, R.,

ZHANG, G., MURAKAMI, T. 2017. Chronic endometritis modifies

decidualization in human endometrial stromal cells. Reproductive Biology and

542

543

544

545

Endocrinology, 15.

ZOLGHADRI, J., MOMTAHAN, M., AMINIAN, K., GHAFFARPASAND, F. &

TAVANA, Z. 2011. The value of hysteroscopy in diagnosis of chronic

endometritis in patients with unexplained recurrent spontaneous abortion. Eur J

546

547

548

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552

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554

555

556

557

558

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Obstet Gynecol Reprod Biol, 155, 217-20.

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Figure Legends

563

Figure 1. Immunohistochemistry of CD138 for placenta.

564

a. b. Plasma cells in the decidua immunostained by CD138 are detected in chronic

565

deciduitis.

566

c. d. Plasma cells in the decidua are not detected in non-chronic deciduitis.

567

a. c. Bar = 500 μm

568

b. d. Bar = 100 μm

569

570

Figure 2. The number of CD138-positive cells in 10 HPFs.

571

The number of CD138-positive cells in 10 random HPFs was significantly higher in the

572

preeclampsia group than in the non- HDP group.

573

There was a case with a markedly high number of CD138-positive cells. Five sections

574

from different placental parts were pathologically examined to confirm the result

575

(Supplemental figure 1) . As results, over 100 CD138-positive cells in 10 random HPFs

576

were found to have infiltrated into the decidua in all specimens. This was a case of

577

preeclampsia with delivery at 32 weeks’ gestation in which the fetal heart rate pattern

578

rapidly deteriorated. Among all cases examined in the present study, this was the only one

579

for whom category-1 emergency caesarean section(Lucas et al., 2000) was performed in

580

the preterm period. The infant was LFD, and the Apgar scores at 1 and 5 minutes (1 point,

581

5 points) and umbilical arterial blood pH (6.882) were extremely low. This result might

582

therefore indicate the serious effects of CD138-positive cells in the decidua on the

583

pathophysiology of HDP and/or the prognosis of the affected fetus.

584

585

Supplemental figure 1. Immunohistochemistry of CD138 for the placenta of the case

23

586

with markedly high numbers of CD138-positive cells.

587

Over 100 CD138-positive cells in 10 random HPFs were found to have infiltrated into the

588

decidua of the placenta preserved in paraffin-embedded specimens.

589

a. b. c. d. e. Bar = 500 μm

590

f. Bar = 100 μm

Table 1. Characteristics and delivery outcomes in the non-CD and CD groups

non-CD

N=54

Age (years)

CD

N=22

P value

33.98±5.11

33.82±5.73

NS

2.00 (1.00-2.00)

1.50 (1.00-2.00)

NS

0 (0-1.00)

0 (0-1.00)

NS

22.19±3.88

22.05±3.66

NS

IVF pregnancy

31.5% (17/54)

27.2% (6/22)

NS

HDP

35.2% (19/54)

72.7% (16/22)

<.01

27.8% (15/54)

72.7% (16/22)

<.001

7.4% (4/54)

0% (0/22)

NS

0% (0/54)

0% (0/22)

NS

29.6% (16/54)

72.7% (16/22)

<.001

GDM

9.2% (5/54)

9.0% (2/22)

NS

Gestational age at delivery

35.30±2.57

33.73±3.67

<.05

Birth weight (g)

2270±645.28

1752±596.24

0.001

LFD

26.9% (18/67)

60.9% (14/23)

<.01

7.48 ±1.19

5.96 ±2.56

<.001

Gravity, median (IQR)

Parity, median (IQR)

BMI (kg/m )

Preeclampsia

Gestational hypertension

Chronic hypertension

Severe HDP

Apgar score at 1 minute

Apgar score at 5 minutes,

9.00 (9.00-9.00)

9.00 (8.00-9.00)

<.03

median (IQR)

Umbilical artery pH,

7.281 (7.2067.313 (7.281-7.343)

<.01

median (IQR)

7.301)

BMI, Body mass index; CD, Chronic deciduitis; GDM, Gestational diabetes mellitus;

HDP, Hypertensive disorders of pregnancy; IVF, In vitro fertilization; LFD, Light-for-

date infant; NS, Not significant

Table 2. Logistic regression analysis of factors associated with preeclampsia and CD

Preeclampsia

CD

Variable

Odds ratio

95% CI

P value

Age ≥40 years

BMI ≥25

Multigravida

CD

57.3

16.36

0.08

12.1

3.7-877.7

1.8-147.5

0.01-0.4

1.9-73.7

<.01

<.03

<.01

<.01

Multiparity

4.9

1.1-20.8

<.03

Preeclampsia

7.7

1.9-30.2

<.01

LFD

5.9

1.6-21.3

<.01

BMI, Body mass index; CD, Chronic deciduitis; CI, Confidence interval; LFD, Light-for-

date infant.

10

11

12

Table 3. Characteristics and outcomes of the preeclampsia patients in the non-CD

13

and CD groups .

non-CD

N=15

CD

N=16

P value

Age (y)

36.80±4.32

34.25±6.46

NS

Gravity

1.53±0.63

1.81±1.33

NS

0.0 (0.0-0.0)

0.0 (0.0-1.0)

NS

24.94±5.30

22.37±4.04

NS

40.0% (6/15)

37.5% (6/16)

NS

35.07±3.32

33.13±4.06

NS

Preterm birth

53.3% (8/15)

81.2% (13/16)

NS

Birth weight (g)

2116±816.70

1577±562.23

<.05

LFD

40.0% (6/15)

62.5% (10/16)

NS

7.53±0.91

6.18±2.65

<.1

9.00 (9.00-9.00)

9.00 (8.25-9.00)

NS

Umbilical artery pH

7.306±0.04

7.228±0.13

<.05

Early-onset type PE

40.0% (6/15)

75.0% (12/16)

<.1

Parity, median (IQR)

BMI (kg/m )

IVF pregnancy

Gestational age at delivery

Apgar score at 1 minute

Apgar score at 5 minutes,

median (IQR)

14

FVM

60.0% (9/15)

87.5% (14/16)

NS

BMI, Body mass index; CD, Chronic deciduitis; FVM, Fetal vascular malperfusion; IVF,

15

In vitro fertilization; LFD, Light-for-date infant; NS, Not significant.

16

17

Table 4. Characteristics and delivery outcomes of the non-HDP and preeclampsia

18

groups

non- HDP

N=41

preeclampsia

N=31

P value

Age (y)

32.8±4.91

35.4±5.65

<.05

Gravidity

2.34±1.37

1.67±1.07

<.05

0.0 (0.0-1.0)

0.0 (0.0-1.0)

<.1

21.34 ±2.56

23.61±4.85

<.03

26.8% (11/41)

38.7% (12/31)

<.1

35.34±2.17

34.06±3.86

NS

Birth weight (g)

2280±575.56

1838±745.10

<.01

LFD

27.8% (15/54)

51.6% (16/31)

<.05

8.00 (6.00-8.00)

8.00 (7.00-8.00)

NS

9.00 (8.00-9.00)

9.00 (8.00-9.00)

NS

7.316 (7.289-7.343)

7.293 (7.2587.325)

<.05

Parity, median (IQR)

BMI (kg/m )

IVF pregnancy

Gestational age at delivery

Apgar score at 1 minute,

median (IQR)

Apgar score at 5 minutes,

median (IQR)

Umbilical artery pH,

median (IQR)

19

CD

17.1% (7/41)

51.6% (16/31)

<.01

BMI, Body mass index; CD, Chronic deciduitis; HDP, Hypertensive disorders of

20

pregnancy; IVF, In vitro fertilization; LFD, Light-for-date infant; NS, Not significant.

21

22

...