Keywords
venous thromboembolism - birth cohort study - pregnancy - post-partum - recurrent
pregnancy loss
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.
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.