CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(04): 606-617
DOI: 10.1055/s-0039-1677733
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Endometriosis and Recurrent Pregnancy Loss as New Risk Factors for Venous Thromboembolism during Pregnancy and Post-Partum: The JECS Birth Cohort

Mayumi Sugiura-Ogasawara
1  Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Takeshi Ebara
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Taro Matsuki
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Yasuyuki Yamada
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
3  Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
,
Toyonori Omori
4  Department of Health Care Policy and Management, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
5  National Center for Child Health and Development, Tokyo, Japan
,
Yosuke Matsumoto
1  Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Sayaka Kato
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
6  Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Hirohisa Kano
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Takahiro Kurihara
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Shinji Saitoh
6  Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
Michihiro Kamijima
2  Department of Occupational and Environmental Health, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
,
and the Japan Environment & Children's Study (JECS) Group› Author Affiliations
Funding This study was funded by the Ministry of the Environment, Government of Japan.
Further Information

Address for correspondence

Mayumi Sugiura-Ogasawara, MD, PhD
Department of Obstetrics and Gynecology, Graduate School of Medical Science, Nagoya City University
Mizuho-ku, Nagoya 4678601
Japan   

Publication History

11 October 2018

17 December 2018

Publication Date:
05 February 2019 (eFirst)

 

Abstract

Background Since venous thromboembolism (VTE) is one of the causes of maternal mortality, several guidelines recommend prophylaxis using low molecular weight heparin for women in high-risk groups. The number of large population-based studies examining predictors for VTE has been limited, and there has been no study based on a Japanese population.

Objective Our objective was to examine VTE risk factor during the pregnancy and post-partum period.

Materials and Methods A nationwide birth cohort study known as the ‘Japan Environment and Children's Study (JECS)’ was conducted by the Ministry of the Environment. The subjects consisted of 103,070 pregnancies recruited by the JECS between January 2011 and March 2014. Pregnant women completed the questionnaires during the first and second/third trimester. Their medical records were transcribed by physicians or research coordinators at registration, just after delivery and at 1 month after delivery.

Results The frequency of VTE was 7.5 per 10,000 pregnancies (77 of 103,070) during the pregnancy and post-partum period. After the adjustment of multiple covariates for each factor, endometriosis and recurrent pregnancy loss (RPL) were identified as novel independent risk factors for VTE. Adjusted odds ratios were as follows: 2.70 (95% confidence interval, 1.21–6.00) for endometriosis and 6.13 (2.48–15.16) for RPL. Threatened abortion, threatened pre-term birth, pre-term birth and caesarean section were ascertained to be risk factors for VTE.

Conclusion Careful attention should be given to novel predictors, such as endometriosis and a history of RPL, to prevent VTE during the pregnancy and post-partum period.


#

Introduction

It is well known that pregnancy and puerperium is associated with venous thromboembolism (VTE). The frequency of post-partum VTE was reported to be 7.2 per 10,000 deliveries in an English cohort registered between 1997 and 2014 and 7.9 in a Swedish cohort registered between 2005 and 2011.[1] Since VTE is one of the causes of maternal mortality, several guidelines recommend prophylaxis using low molecular weight heparin (LMWH) for women in the high-risk group.[2] [3] The strongest risk factor is a previous episode.[2] [3] The recurrence rate of withholding heparin was 2.4% in 125 pregnant women with previous VTE, 0% in 44 women without thrombophilia and 5.9% in 51 women with thrombophilia and/or previous episode of idiopathic thrombosis.[4] Pregnant women who have had two or more episodes, one episode plus thrombophilia associated with anti-phospholipid antibodies, protein C (PC), protein S (PS) or an anti-thrombin (AT) deficiency, and one episode plus a history of VTE in a first-degree relative are all included in the highest risk group.[2] [3] The second highest risk group includes women with an isolated episode during bed rest, dehydration and surgery, thrombophilia or with a complication such as heart disease, lung disease, systemic lupus erythematosus (SLE), cancer, inflammatory bowel disease or nephrotic syndrome.[2] [3] [5] The third highest group includes women with an age ≧ 35 years, a body mass index (BMI) of > 30 kg/m2, a smoker, parity ≧ 3, a systemic infection, gross varicose veins, paraplegia, pre-eclampsia, hyperemesis, ovarian hyperstimulation syndrome, multiple pregnancies, use of artificial reproductive technology, caesarean section and post-partum haemorrhage.[2] [3] [5] Accordingly, LMWH is recommended for pregnant women with three or more of these risk factors.

However, both the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines and the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines have recommended that LMWH use should be decided upon after discussion between two or more doctors in the case of the second and third highest risk groups since these guidelines were based on expert opinion due to limited evidence concerning the effect of thromboprophylaxis during pregnancy.[2] [3] [6]

The Japan Society of Obstetrics and Gynecology (JSOG) drew up guidelines in 2014 that conformed to the RCOG and ACCP guidelines due to a lack of evidence in Japan.[7] Before April 2014, thromboprophylaxis was performed according to the previous guidelines, under which an episode of VTE, thrombophilia, age ≧ 35 years, a caesarean section and obesity were considered to be risk factors for Japanese women.[8] For the highest risk group, low dose unfractionated heparin was recommended for women with a past episode of VTE or thrombophilia who underwent a caesarean section during the post-partum period. Unfractionated heparin or intermittent pneumatic compression was recommended for older obese women after caesarean section or for women with an episode of VTE or thrombophilia after vaginal delivery in the high-risk group. There has been no study of VTE risk factors in Japanese women during the pregnancy and post-partum period. Therefore, it was considered necessary to examine these factors because the frequency of VTE is smaller in Japanese populations than in Caucasian population and the frequency of thrombophilia depends on race.[9]

We have conducted a nationwide population-based birth cohort study known as the ‘Japan Environment and Children's Study (JECS)’, a project planned by the Ministry of the Environment, Government of Japan.[10] [11] [12] [13] [14] The study subjects consisted of 104,102 registered children or foetuses recruited during the first 3 years of the JECS, and the babies are now being followed up for 13 years mainly to examine the influence of the environment on the foetus.

This is the first birth cohort used to examine the frequency of VTE and to determine VTE risk factors during the pregnancy and post-partum period in a Japanese population.


#

Materials and Methods

Study Design and Participants

Pregnant women were recruited by the JECS between January 2011 and March 2014. Eligibility criteria for expectant mothers were as follows: that they (1) resided at the time of recruitment in any of the study areas selected by 15 regional JECS centres located countrywide; (2) had an expected delivery date after August 1, 2011; and (3) were capable of comprehending the Japanese language and completing the self-administered questionnaire.[10] [11] [12] [13] [14] The sample size has been calculated in the JECS protocol by the Ministry of the Environment.[15] In principle, pregnant women completed the questionnaires during the first (MT1) and second/third trimester (MT2). Their medical records were transcribed by physicians or research coordinators at registration (DrT1), just after delivery (Dr0m) and at 1 month after delivery (Dr1m).

This study was based on the jecs-ag-20160424 dataset, which includes 104,102 registered children (foetuses and embryos), and was released restrictively to all concerned in June 2016. The second and third children of multiple pregnancies were excluded and these numbered 1,003 (0.96%). Twenty-nine participants (0.03%) withdrew their consent completely. Finally, 103,070 pregnancies were included in the main analysis. The mean (standard deviation [SD]) age at registration was 30.7 (5.1) years. The mean (SD) gestational weeks at registration was 14.0 (5.7) weeks. The JECS population has been recognized as representative of the pregnant women in Japan.[11]

The JECS protocol was reviewed and approved by the Ministry of the Environment's Institutional Review Board on Epidemiological Studies and by the Ethics Committees of all participating institutions. Written informed consent was obtained from all participating women.


#

Data Collection

The first questionnaire (MT1) included socio-demographic characteristics, medical histories, the details of all previous pregnancies and exercise habits.

The socio-economic status was assessed by the education level and annual household income in the second questionnaire (MT2). The MT2 included lifestyle details.

The first medical record transcript (DrT1) included maternal age, gestational weeks at registration, maternal body weight, height, conception and details of all previous pregnancies (vaginal delivery/caesarean delivery/miscarriage/induced abortion/stillbirth).

The Dr0m included maternal age, gestational weeks at miscarriage and delivery, single/multiple pregnancies, live birth/stillbirth, miscarriage/induced abortion, male/female, birth weight, vaginal/caesarean delivery, pregnancy complications and perinatal outcome.

VTE was described in the Dr0m and in the third medical record transcription (Dr1m).


#

Exposures and Covariates

Potential exposures were compiled from medical and obstetrical histories as well as from information on gynaecological diseases, obstetric complications and lifestyle.

Potential covariates were maternal age at registration (categorized as < 20, 20–29, 30–39, ≧ 40 years), BMI (categorized as < 18.5, 18.5–25.0, ≧ 25.0), the presence/absence of in vitro fertilization and embryo transfer (IVF-ET), smoking status and income level (categorize as < 200, 200–< 400, 400–< 600, 600–< 800, 800–< 1,000 JPY × 10,000 [1 US$ = 114.66 JPY, November 13, 2018]).


#

Statistical Analysis

Details of potential exposures are listed in [Supplementary Table S1] (available in the online version).

Frequencies for discrete data between VTE and each factor were counted with proportion. To compare their respective distributions, a Fisher's exact test was performed. Crude odds ratios (ORs) for all exposures were calculated and multiple logistic regression analyses were further conducted to determine what kind of exposures was predictive of VTE after controlling for maternal age, BMI, the presence/absence of IVF-ET, smoking status and income level. In case the observed number of each factor and VTE was less than 6, adjusted ORs were not calculated because of potential biases depending on the number of cases in the less frequencies.

All calculations were conducted using SPSS version 23 and 24 (IBM Corp., Japan), and a p-value of < 0.05 was regarded as statistically significant.


#
#

Results

The frequency of VTE was 7.5 per 10,000 pregnancies (77 of 103,070) during the pregnancy and post-partum period. The presence/absence of VTE according to each factor is shown in [Tables 1] and [2]. Age, BMI, the presence of IVF-ET, smoking status and income level were significantly associated with VTE.

Table 1

The presence/absence of venous thromboembolism according to each factor

Factors

N

%

Venous thromboembolism

p-Value[a]

(Missing data)

Absence

Presence

Medical histories

Atopic dermatitis

98,766

95.8

Absence

83,178

60

0.207

(4,304)

(4.2)

Presence

15,512

16

Asthma

98,766

95.8

Absence

87,905

64

0.194

(4,304)

(4.2)

Presence

10,785

12

Collagen disease

98,766

95.8

Absence

98,560

76

(4,304)

(4.2)

Presence

130

0

Autoimmune disease

98,766

95.8

Absence

98,548

76

(4,304)

(4.2)

Presence

142

0

SLE

98,766

95.8

Absence

98,618

76

(4,304)

(4.2)

Presence

72

0

RA

98,766

95.8

Absence

98,483

76

(4,304)

(4.2)

Presence

207

0

IDDM

98,766

95.8

Absence

98,614

76

(4,304)

(4.2)

Presence

76

0

NIDDM

98,766

95.8

Absence

98,556

76

(4,304)

(4.2)

Presence

134

0

Gestational diabetes

98,766

95.8

Absence

97,950

75

0.436

(4,304)

(4.2)

Presence

740

1

Hyperthyroidism

98,766

95.8

Absence

97,635

76

(4,304)

(4.2)

Presence

1,055

0

Hypothyroidism

98,766

95.8

Absence

97,714

75

0.530

(4,304)

(4.2)

Presence

976

1

Anaemia

98,766

95.8

Absence

80,446

60

0.555

(4,304)

(4.2)

Presence

18,244

16

Hypertension

98,766

95.8

Absence

98,220

76

(4,304)

(4.2)

Presence

470

0

Hyperlipidaemia

98,766

95.8

Absence

98,206

76

(4,304)

(4.2)

Presence

484

0

Stroke

98,766

95.8

Absence

98,579

76

(4,304)

(4.2)

Presence

111

0

Myocardial infarction

98,766

95.8

Absence

98,628

76

(4,304)

(4.2)

Presence

62

0

Congenital heart disease

98,766

95.8

Absence

98,387

76

(4,304)

(4.2)

Presence

303

0

Kawasaki disease

98,766

95.8

Absence

98,271

76

(4,304)

(4.2)

Presence

419

0

Depression

98,766

95.8

Absence

95,701

72

0.295

(4,304)

(4.2)

Presence

2,989

4

Dysautonomia

98,766

95.8

Absence

95,044

72

0.366

(4,304)

(4.2)

Presence

3,646

4

Anxiety disorder

98,766

95.8

Absence

95,904

71

0.064

(4,304)

(4.2)

Presence

2,786

5

Gastritis

98,766

95.8

Absence

90,166

65

0.097

(4,304)

(4.2)

Presence

8,524

11

Gastric ulcer

98,766

95.8

Absence

96,998

73

0.142

(4,304)

(4.2)

Presence

1,692

3

Irritable colon

98,766

95.8

Absence

97,152

75

1.000

(4,304)

(4.2)

Presence

1,538

1

Crohn's disease

98,766

95.8

Absence

98,655

76

(4,304)

(4.2)

Presence

35

0

Ulcerative colitis

98,766

95.8

Absence

98,468

76

(4,304)

(4.2)

Presence

222

0

Fatty liver

98,766

95.8

Absence

98,446

76

(4,304)

(4.2)

Presence

244

0

Chronic nephritis

98,766

95.8

Absence

98,349

76

(4,304)

(4.2)

Presence

341

0

Nephrotic syndrome

98,766

95.8

Absence

98,599

76

(4,304)

(4.2)

Presence

91

0

Breast cancer

98,766

95.8

Absence

98,635

76

(4,304)

(4.2)

Presence

55

0

Cervical cancer

98,766

95.8

Absence

97,883

75

0.464

(4,304)

(4.2)

Presence

807

1

Endometrial cancer

98,766

95.8

Absence

98,682

76

(4,304)

(4.2)

Presence

8

0

Gastric cancer

98,766

95.8

Absence

98,687

76

(4,304)

(4.2)

Presence

3

0

Colorectal cancer

98,766

95.8

Absence

98,679

76

(4,304)

(4.2)

Presence

11

0

Blood cancer

98,766

95.8

Absence

98,650

76

(4,304)

(4.2)

Presence

40

0

Other cancers

98,766

95.8

Absence

98,515

76

(4,304)

(4.2)

Presence

175

0

Pregnancy histories

Pregnancy loss (total number)

99,687

96.7

Absence

76,885

50

0.012

(3,383)

(3.3)

Presence

22,725

27

Pregnancy loss (once)

94,645

91.8

Absence

76,885

50

0.343

(8,425)

(8.2)

Presence

17,695

15

Pregnancy loss (twice)

80,842

78.4

Absence

76,885

50

0.333

(22,228)

(21.6)

Presence

3,903

4

Pregnancy loss (three times or more)

78,070

75.7

Absence

76,885

50

< 0.001

(25,000)

(24.3)

Presence

1,127

8

Hypertensive disorders of pregnancy

98,766

95.8

Absence

96,791

76

(4,304)

(4.2)

Presence

1,899

0

Gestational diabetes

98,766

95.8

Absence

98,223

76

(4,304)

(4.2)

Presence

467

0

Abruptio placentae

98,766

95.8

Absence

98,455

75

0.166

(4,304)

(4.2)

Presence

235

1

Ectopic pregnancy

98,766

95.8

Absence

97,742

75

0.520

(4,304)

(4.2)

Presence

948

1

Placenta praevia

98,766

95.8

Absence

98,216

74

0.052

(4,304)

(4.2)

Presence

474

2

Hydatidiform mole

98,766

95.8

Absence

98,262

76

(4,304)

(4.2)

Presence

428

0

Gynaecological disease

Menstrual disorder

98,766

95.8

Absence

87,529

68

1.000

(4,304)

(4.2)

Presence

11,161

8

Endometriosis

98,766

95.8

Absence

95,088

69

0.021

(4,304)

(4.2)

Presence

3,602

7

Uterine fibroids

98,766

95.8

Absence

92,671

67

0.049

(4,304)

(4.2)

Presence

6,019

9

Adenomyosis

98,766

95.8

Absence

98,355

74

0.028

(4,304)

(4.2)

Presence

335

2

Uterine anomaly

98,766

95.8

Absence

98,408

76

(4,304)

(4.2)

Presence

282

0

Ovarian tumour

98,766

95.8

Absence

95,267

74

1.000

(4,304)

(4.2)

Presence

3,423

2

Polycystic ovarian syndrome

98,766

95.8

Absence

96,477

71

0.028

(4,304)

(4.2)

Presence

2,213

5

Lifestyle

Strong exercise during pregnancy

96,753

93.9

No

93,448

72

0.325

(6,317)

(6.1)

Yes

3,229

4

Moderate exercise during pregnancy

96,091

93.2

No

72,207

64

0.049

(6,979)

(6.8)

Yes

23,809

11

Walking during pregnancy

95,424

92.6

No

27,018

25

0.298

(7,646)

(7.4)

Yes

68,333

48

Night shift work during pregnancy

97,035

94.1

No

88,910

70

1.000

(6,035)

(5.9)

Yes

8,049

6

Breakfast during pregnancy

97,064

94.2

Everyday

69,100

58

0.374

(6,006)

(5.8)

Not everyday

27,888

18

Working h/wk (MT1)

59,428

57.7

0 h

37,614

28

0.995

(43,642)

(42.3)

0–35 h

21,770

16

Working h/wk (MT1)

63,449

61.6

0 h

37,614

28

0.878

(39,621)

(38.4)

36–45 h

25,789

18

Working h/wk (MT1)

49,807

48.3

0 h

37,614

28

0.277

(53,263)

(51.7)

> 46 h

12,152

13

Working h/wk (MT2)

64,615

62.7

0 h

45,672

33

1.000

(38,455)

(37.3)

0–35 h

18,896

14

Working h/wk (MT2)

68,246

66.2

0 h

45,672

33

0.663

(34,824)

(33.8)

36–45 h

22,522

19

Working h/wk (MT2)

55,240

53.6

0 h

45,672

33

0.311

(47,830)

(46.4)

> 46 h

9,525

10

Abbreviations: IDDM, insulin-dependent diabetes mellitus; MT1, maternal questionnaires during the first trimester; MT2, maternal questionnaires during the second/third trimester; NIDDM, non-insulin-dependent diabetes mellitus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.


a The p-value was not calculated when expected frequency is less than 1.


Table 2

The presence/absence of venous thromboembolism according to each factor

Factors

N

%

Venous thromboembolism

p-Value[d]

(Missing data)

Absence

Presence

Threatened abortion

100,818

97.8

Absence

88,624

52

< 0.001

(2,252)

(2.2)

Presence

12,117

25

Threatened pre-term labour

100,818

97.8

Absence

80,909

47

< 0.001

(2,252)

(2.2)

Presence

19,832

30

Hyperemesis

97,070

94.2

Absence

16,745

11

0.648

(6,000)

(5.8)

Presence

80,249

65

Early miscarriage (< 12 wk gestation)[a]

99,614

96.6

Absence

99,130

76

(3,456)

(3.4)

Presence

408

0

Stillbirth (≥ 12 wk gestation)[b]

100,048

97.1

Absence

99,130

76

0.478

(3,022)

(2.9)

Presence

841

1

Pre-term birth < 37 wk gestation[c]

99,475

96.5

Absence

94,090

67

0.020

(3,595)

(3.5)

Presence

5,309

9

Pre-term birth at 34–36 wk gestation[c]

98,196

95.3

Absence

94,090

67

0.539

(4,874)

(4.7)

Presence

4,035

4

Pre-term birth < 34 wk gestation[c]

95,436

92.6

Absence

94,090

67

0.003

(7,634)

(7.4)

Presence

1,274

5

Placenta praevia[c]

99,519

96.6

Absence

98,777

75

0.400

(3,551)

(3.4)

Presence

666

1

Abruptio placentae[c]

99,519

96.6

Absence

99,009

75

0.283

(3,551)

(3.4)

Presence

434

1

Adherent placenta[c]

99,519

96.6

Absence

99,209

76

(3,551)

(3.4)

Presence

234

0

Premature rupture[c]

99,519

96.6

Absence

90,648

68

0.545

(3,551)

(3.4)

Presence

8,795

8

Oligohydramnios[c]

99,519

96.6

Absence

98,169

72

0.017

(3,551)

(3.4)

Presence

1,274

4

Mild hypertensive disorders of pregnancy[c]

99,519

96.6

Absence

97,141

74

0.696

(3,551)

(3.4)

Presence

2,302

2

Severe hypertensive disorders of pregnancy[c]

99,519

96.6

Absence

98,469

72

0.007

(3,551)

(3.4)

Presence

974

4

Uterine infection

100,818

97.8

Absence

100,008

75

0.109

(2,252)

(2.2)

Presence

733

2

Caesarean section[c]

99,165

96.2

Vaginal

79,785

49

0.001

(3,905)

(3.8)

Caesarean

19,304

27

SFD (< 10%)[c]

99,360

96.4

Absence

89,385

69

1.000

(3,710)

(3.6)

Presence

9,899

7

Multiple pregnancy

100,733

97.7

Single

99,670

74

0.040

(2,337)

(2.3)

Multiple

986

3

Abbreviation: SFD, small for dates.


a Stillbirth (≥ 12 weeks' gestation) and artificial abortion were excluded from analyses.


b Early miscarriage (< 12 weeks' gestation) and artificial abortion were excluded from analyses.


c Miscarriage and artificial abortion were excluded from analyses.


d The p-value was not calculated when expected frequency is less than 1.


After the adjustment of multiple covariates for each factor, endometriosis and recurrent pregnancy loss (RPL) were judged to be novel independent predictors for VTE ([Table 3]). Adjusted ORs were as follows: 2.70 (95% confidence interval [CI], 1.21–6.00) for endometriosis and 6.13 (2.48–15.16) for RPL. There was no statistically significant risk related to any of the listed medical histories or lifestyle other than those mentioned above.

Table 3

An association of medical histories, gynaecological disease and lifestyle with venous thromboembolism

Factors

Crude ORs (95% CI)

p-Value

Adjusted ORs[a] (95% CI)

p-Value

Medical histories

Atopic dermatitis

1.43

(0.82−2.48)

0.204

1.58

(0.89−2.82)

0.119

Asthma

1.53

(0.83−2.83)

0.178

1.55

(0.81−2.96)

0.188

Gestational diabetes

1.77

(0.25−12.71)

0.573

Hypothyroidism

1.34

(0.19−9.61)

0.774

Anaemia

1.18

(0.68−2.04)

0.565

1.22

(0.68−2.21)

0.506

Depression

1.78

(0.65−4.87)

0.263

Dysautonomia

1.45

(0.53−3.97)

0.471

Anxiety disorder

2.42

(0.98−6.01)

0.056

Gastritis

1.79

(0.94−3.39)

0.074

1.80

(0.92−3.53)

0.089

Gastric ulcer

2.36

(0.74−7.48)

0.146

Irritable colon

0.84

(0.12−6.06)

0.865

Cervical cancer

1.62

(0.23−11.65)

0.633

Pregnancy histories

Pregnancy loss (total number)

1.83

(1.14−2.92)

0.012

1.42

(0.84−2.39)

0.186

Pregnancy loss (once)

1.30

(0.73−2.32)

0.368

1.11

(0.59−2.06)

0.755

Pregnancy loss (twice)

1.58

(0.57−4.37)

0.382

Pregnancy loss (three times or more)

10.92

(5.16−23.08)

< 0.001

6.13

(2.48−15.16)

< 0.001

Abruptio placentae

5.59

(0.77−40.34)

0.088

Ectopic pregnancy

1.38

(0.19−9.90)

0.752

Placenta praevia

5.60

(1.37−22.88)

0.016

Gynaecological disease

Menstrual disorder

0.92

(0.44−1.92)

0.829

0.93

(0.42−2.03)

0.851

Endometriosis

2.68

(1.23−5.83)

0.013

2.70

(1.21−6.00)

0.015

Uterine fibroids

2.07

(1.03−4.15)

0.041

1.73

(0.84−3.58)

0.139

Adenomyosis

7.94

(1.94−32.46)

< 0.001

Ovarian tumour

0.75

(0.19−3.07)

0.691

Polycystic ovarian syndrome

3.07

(1.24−7.61)

0.015

Lifestyle

Strong exercise during pregnancy

1.61

(0.59−4.40)

0.356

Moderate exercise during pregnancy

0.52

(0.28−0.99)

0.046

0.62

(0.33−1.19)

0.154

Walking during pregnancy

0.76

(0.47−1.23)

0.264

0.72

(0.43−1.19)

0.199

Night shift work during pregnancy

0.95

(0.41−2.18)

0.898

1.03

(0.44−2.39)

0.954

Breakfast during pregnancy

0.77

(0.45−1.31)

0.330

0.86

(0.48−1.54)

0.607

Working h/wk (MT1) (0 h vs. 1–35 h)

0.99

(0.53−1.83)

0.968

0.82

(0.42−1.60)

0.562

Working h/wk (MT1) (0 h vs. 36–45 h)

0.94

(0.52−1.70)

0.831

0.77

(0.40−1.50)

0.443

Working h/wk (MT1) (0 h vs. 46 h)

1.44

(0.74−2.78)

0.280

1.28

(0.62−2.63)

0.500

Working h/wk (MT2) (0 h vs. 1–35 h)

1.03

(0.55−1.92)

0.937

0.82

(0.41−1.64)

0.575

Working h/wk (MT2) (0 h vs. 36–45 h)

1.17

(0.66−2.05)

0.591

0.95

(0.50−1.82)

0.884

Working h/wk (MT2) (0 h vs. 46 h)

1.45

(0.72−2.95)

0.301

1.53

(0.72−3.25)

0.274

Abbreviations: BMI, body mass index; CI, confidence interval; IVF-ET, in vitro fertilization and embryo transfer; MT1, maternal questionnaires during the first trimester; MT2, maternal questionnaires during the second/third trimester; OR, odds ratio; VTE, venous thromboembolism.


a Adjusted for maternal age at registration, BMI, the presence/absence of IVF-ET, smoking and income. Only crude ORs were shown when the number of presence of both factor and VTE was less than 6.


Regarding pregnancy complications and outcomes, oligohydramnios might be a novel independent predictor for VTE though adjusted ORs were not shown since the number was less than 6 ([Table 4]). Threatened abortion, threatened pre-term birth, pre-term birth at < 37 weeks and caesarean section remained significantly associated with VTE. Adjusted ORs were as follows: 3.61 (95% CI, 2.16–6.02) for threatened abortion, 2.98 (1.83–4.86) for threatened pre-term birth, 2.64 (1.30–5.36) for pre-term birth both at < 37 weeks and 2.19 (1.32–3.63) for caesarean section.

Table 4

An association between pregnancy complication and venous thromboembolism

Factors

Crude ORs (95% CI)

p-Value

Adjusted ORs[a] (95% CI)

p-Value

Threatened abortion

3.52

(2.18−5.67)

< 0.001

3.61

(2.16−6.02)

< 0.001

Threatened pre-term labour

2.60

(1.65−4.12)

< 0.001

2.98

(1.83−4.85)

< 0.001

Hyperemesis

1.23

(0.65−2.34)

0.521

1.21

(0.62−2.38)

0.573

Stillbirth (≥ 12 wk gestation)

1.55

(0.22−11.17)

0.663

Pre-term birth < 37 wk gestation[b]

2.38

(1.19−4.78)

0.015

2.64

(1.30−5.36)

0.007

Pre-term birth 34–36 wk gestation[b]

1.39

(0.51−3.82)

0.521

Pre-term birth < 34 wk gestation[b]

5.51

(2.22−13.70)

< 0.001

Placenta praevia[b]

1.98

(0.28−14.24)

0.499

Abruptio placentae[b]

3.04

(0.42−21.93)

0.270

Premature rupture[b]

1.21

(0.58−2.52)

0.606

1.14

(0.52−2.50)

0.744

Oligohydramnios[b]

4.28

(1.56−11.73)

0.005

Mild hypertensive disorders of pregnancy[b]

1.14

(0.28−4.65)

0.854

Severe hypertensive disorders of pregnancy[b]

5.62

(2.05−15.40)

< 0.001

Uterine infection

3.64

(0.89−14.85)

0.072

Caesarean section[b]

2.28

(1.42−3.64)

< 0.001

2.19

(1.32−3.63)

< 0.001

SFD (< 10%)[b]

0.92

(0.42−1.99)

0.825

0.95

(0.41−2.20)

0.899

Multiple pregnancy

4.10

(1.29−13.02)

0.017

Abbreviations: BMI, body mass index; CI, confidence interval; IVF-ET, in vitro fertilization and embryo transfer; OR, odds ratio; SFD, small for dates; VTE, venous thromboembolism.


a Adjusted for maternal age at registration, BMI, the presence/absence of IVF-ET, smoking and income. Only crude ORs were shown when the number of presence of both factor and VTE was less than 6.


b Miscarriage and artificial abortion were excluded from analyses.


There was no association with hyperemesis or mild hypertensive disorders of pregnancy (HDP) with VTE. The association with a history of placenta praevia, adenomyosis and PCOS, pre-term birth < 34 weeks' gestation, severe HDP, placenta praevia, abruptio placenta, multiple pregnancy and VTE were unclear in this study because the sample size was relatively small. There were no cases of VTE in patients with a history of stroke, myocardial infarction, congenital heart disease, SLE, Crohn's disease, ulcerative colitis, nephrotic syndrome or various forms of cancer.


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Discussion

In the present cohort, we found endometriosis and three or more pregnancy losses as novel risk factors for VTE.

Endometriosis is characterized by endometrial-like tissue outside the uterine and is a major contributor to pelvic pain and infertility.[16] This is the first study that we know of to show that endometriosis is a VTE risk factor. In fact, there was one study in which no episode of deep vein thrombosis and VTE occurred after laparoscopic surgery in a group of 266 patients in which 21% had endometriosis.[17] Lesions and activated macrophages can secrete pro-inflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-8 and tumour necrosis factor α in the peritoneal cavity of patients with endometriosis.[16] These pro-inflammatory cytokines might trigger VTE during pregnancy.

With regard to RPL, to our knowledge, this is the first study to show that a history of RPL has a direct predictive value for assessing VTE risk. Stillbirth was not included in eight women with both a history of RPL and VTE, though stillbirth is well-known to be a strong risk factor for post-partum VTE.[1] RPL and VTE are considered to be associated with acquired and inheritable thrombophilia such as AT deficiency, PC deficiency, PS deficiency and homozygous factor V (FV) Leiden.[18] Clinical criteria for anti-phospholipid syndrome (APS) include thrombosis, recurrent miscarriage, intrauterine foetal death and early-onset pre-term birth following pre-eclampsia or placental insufficiency.[19] Patients with APS received combined therapy of low dose aspirin and heparin, and this applied to 162 women in the present cohort with APS. RPL was an independent predictor when APS was used as a covariate (not shown). Recently, 472 variants in 187 genes have been reported to be associated with RPL.[20] A meta-analysis revealed a significant association between RPL and 21 variants, including loss due to thrombophilia with ORs of 0.51 to 2.37. Thrombophilia related to FV Leiden mutation, pro-thrombin mutation, MTHFR and ANXA5 single-nucleotide polymorphisms is reported to be associated with RPL.[20] [21] Recent large cohort study proved that the rate of VTE within 42 days of an induced abortion was 3.0 per 10,000 women (hazard ratio, 0.16, 95% CI, 0·12–0·22) when compared with women in the live birth cohort, whose VTE rate was 18.5 per 10,000 women.[22] The risk might be due to pathologies common to RPL and VTE.

The frequency of VTE was found to be 7.5 per 10,000 pregnancies in the present Japanese population registered between 2011 and 2014. It was similar to that in Caucasian population,[1] but VTE has been speculated to be less frequent in the Japanese population due to the fact that no FV Leiden and pro-thrombin mutations were found in the Japanese population.[9] The frequency of PS deficiency was higher in the Japanese population because of a domestic mutation known as PS-Tokushima (K196E) which has a frequency of 1.8%.[23]

According to the old guidelines, thromboprophylaxis with the use of unfractionated heparin was speculated to be common for post-partum women with a previous episode of VTE or thrombophilia or for older obese women post-partum after a caesarean section that took place between 2011 and 2014.[8] After April 2014, thromboprophylaxis during pregnancy was introduced into the JSOG guidelines.[7] Thus, the effect of thromboprophylaxis during pregnancy might be small in this analysis, but we should consider that some portion of patients with an unexplained RPL may have received a combination of low dose aspirin and unfractionated heparin even though there was no recorded evidence.[24] Actually, 267 and 1,609 women in the two groups above received heparin and low dose aspirin in the present cohort. However, any indication of treatment after VTE, prophylaxis for VTE or prevention of APS or gestational weeks at the start of heparin therapy was not available. This is one of the limitations of this study.

Associations with pre-term birth, HDP, uterine infection, multiple pregnancies and caesarean section with VTE were reported in the previous studies.[2] [3] [5] A recent risk prediction model showed that emergency caesarean delivery, stillbirth, varicose veins, pre-eclampsia and post-partum infection were the strongest predictors of post-partum VTE.[1] A pre-conceptional history of VTE was reportedly associated with an increased risk of pre-eclampsia, stillbirth and placental abruption.[25] These might also be induced by common genetic factors.

An association with oligohydramnios was not confirmed by a logistic model because of the small sample size. The major limitation was that there was no distinction made between VTE during pregnancy and that occurring post-partum. Data on gestational weeks at the VTE occurrence were also not available. This might be a reason why hyperemesis were not associated with VTE in this study. Thus, we could not dismiss these associations. The majority of women were recruited at 14 weeks' gestation, therefore, we should keep in mind that we did not cover all early miscarriages or hyperemesis.

Endometriosis and a history of RPL were found to be novel risk factors for VTE. Endometriosis and RPL affect 6 to 10% and 4.2% of women of reproductive age, respectively.[16] [26] Consequently, we should pay careful attention to novel predictors, such as endometriosis and RPL, to prevent VTE in pregnant women.

What is known about this topic?

  • Venous thromboembolism (VTE) prophylaxis during pregnancy and post-partum is recommended for women in high-risk groups.

  • The strongest risk factor is a previous episode. Thrombophilia, an age ≧ 35 years, obesity, a smoker, parity ≧ 3, a systemic infection, gross varicose veins, paraplegia, pre-eclampsia, hyperemesis, multiple pregnancies, caesarean section, stillbirth and post-partum haemorrhage were considered to be risk factors.

  • The number of large population-based studies examining predictors for VTE has been limited, and there has been no study based on a Japanese population.

What does this paper add?

  • Endometriosis and recurrent pregnancy loss (RPL) were identified as novel independent risk factors for VTE.

  • Threatened abortion, threatened pre-term birth, pre-term birth and caesarean section were ascertained to be risk factors for VTE.


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Conflict of Interest

M.S.-O. received grants from the Japanese Ministry of Education, Science, and Technology for conducting studies on the topic of RPL in the different patient population, and payment for lectures from Kaken Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co., Aska Pharmaceutical Co. Ltd., Sekisui Medical Co. Ltd. and Siemens Japan. The remaining authors report no conflict of interest.

Acknowledgements

We would like to express our gratitude to all of the JECS participants and all obstetricians in the 15 areas.

The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Ministry of the Environment.

The chief members of the Japan Environment and Children's Study (JECS) as of 2017 are the National Institute for Environmental Studies, Tsukuba (principal investigator, Toshihiro Kawamoto); the National Center for Child Health and Development, Tokyo (Hirohisa Saito); Hokkaido University, Sapporo (Reiko Kishi); Tohoku University, Sendai (Nobuo Yaegashi); Fukushima Medical University, Fukushima (Koichi Hashimoto); Chiba University, Chiba (Chisato Mori); Yokohama City University, Yokohama (Shuichi Ito); University of Yamanashi, Chuo (Zentaro Yamagata); University of Toyama, Toyama (Hidekuni Inadera); Nagoya City University, Nagoya (Michihiro Kamijima); Kyoto University, Kyoto (Takeo Nakayama); Osaka University, Suita (Hiroyasu Iso); Hyogo College of Medicine, Nishinomiya (Masayuki Shima); Tottori University, Yonago (Yasuaki Hirooka); Kochi University, Nankoku (Narufumi Suganuma), University of Occupational and Environmental Health, Kitakyushu (Koichi Kusuhara); and Kumamoto University, Kumamoto (Takahiko Katoh).

Authors' Contributions

The JECS group conducted the nationwide study project. M.S.O. designed the present study, analysed the data and wrote the first draft of the manuscript. T.E. organized the study team and was responsible for obtaining and analysing the data. M.K., a member of the JECS Steering Committee, was responsible for data acquisition and supervision of the study. M.K. and T.O. took the initiative in the launch of the Aichi regional sub-cohort of JECS. T.M. analysed the data. Y.Y., T.O., Y.M., S.K. and S.S. were responsible for data acquisition. All authors interpreted the data, contributed to the writing of the manuscript and revised it critically for important intellectual content.


Note

Data sharing is not permitted by the JECS due to a government policy restricting the deposition of data containing personal information. See the reference for more details.[12]


Supplementary Material


Address for correspondence

Mayumi Sugiura-Ogasawara, MD, PhD
Department of Obstetrics and Gynecology, Graduate School of Medical Science, Nagoya City University
Mizuho-ku, Nagoya 4678601
Japan