International Journal of Hematology
https://doi.org/10.1007/s12185-022-03354-4

ORIGINAL ARTICLE

Peripartum management of hereditary thrombophilia: resultsof primary surveillance in Japan
Takao Kobayashi1· Kazuko Sugiura2 · Toshiyuki Ojima3 · Kyuya Hirai1 · Eriko Morishita4

Received: 3 March 2022 / Revised: 12 April 2022 / Accepted: 12 April 2022
© Japanese Society of Hematology 2022

Abstract
This study investigated patients with thrombophilia and current peripartum management practices based on national surveillance in Japan. Between 2014 and 2018, antithrombin (AT), protein C (PC) and protein S (PS) deficiency were observedin 84, 67, and 443 pregnancies, respectively, with incidence rates among total deliveries at 0.012%, 0.009%, and 0.061%.
The percentage of institutions that measured both antigens and AT, PC, and PS activity for the diagnosis of thrombophilia
was 50.2%, and 46.9% of institutions did not perform gene analysis. Prophylactic anticoagulation therapy was used in theante- and postpartum management of patients with AT deficiency at 67.1% and 66.3% of institutions, most commonly with
10,000 units of unfractionated heparin. Ante- and postpartum management of PC and PS deficiency was performed at 75.3%
and 67.1% of institutions. Approximately half of the institutions performed peripartum prophylactic AT supplementation
for AT deficiency. Low trough AT activity before supplementation was most commonly 50 ≤  < 70%, and the highest AT
supplementation was 1500 ≤  < 3000 units. The number of pregnancies with AT, PC and PS deficiency might be as many as
29, 23 and 151 every year in Japan if complete answers were provided.
Keywords Antithrombin deficiency · Hereditary thrombophilia · Peripartum management · Protein C deficiency · Protein S
deficiency
Abbreviations
AT	Antithrombin
DVT	Deep vein thrombosis
FV	Factor V
Co-first author: Takao Kobayashi and Kazuko Sugiura.
Contributed equally to this work with: Takao Kobayashi and
Kazuko Sugiura.
* Takao Kobayashi
tkoba@hmedc.or.jp
Kazuko Sugiurasugiura@med.nagoya-cu.ac.jp
Toshiyuki Ojima
ojima@hama-med.ac.jp
Kyuya Hirai
kyuya@hmedc.or.jp
Eriko Morishita
eriko86@staff.kanazawa-u.ac.jp
1

JSOG	Japan Society of Obstetrics and Gynecology
LDA	Low dose aspirin
LMWH	Low molecular weight heparin
PC	Protein CPE	Pulmonary embolism
PS	Protein S
UFH	Unfractionated heparin
VTE	Venous thromboembolism
2

Department of Reproductive Health Nursing/Midwifery,
Nagoya City University Graduate School of Nursing,
1 Kawasumi, Mizuho‑cho, Mizuho‑ku, Nagoya,
Aichi 467‑8601, Japan3

Department of Community Health and Preventive Medicine,
Hamamatsu University School of Medicine, 1‑20‑1
Handayama, Higashi‑ku, Hamamatsu, Shizuoka 431‑3192,
Japan

4

Department of Laboratory Sciences, College of Medical,
Pharmaceutical and Health Sciences, Kanazawa University,
5‑11‑80 Kodatsuno, Kanazawa, Ishikawa 920‑0942, Japan

Director Emeritus, Department of Obstetrics
and Gynecology, Hamamatsu Medical Center, 328
Tomitsuka‑cho, Naka‑ku, Hamamatsu, Shizuoka 432‑8580,
Japan

13

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T. Kobayashi et al.

Introduction
Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due
to a hereditary deficiency in anticoagulant factors such as
antithrombin (AT), protein C (PC), or protein S (PS). It isa syndrome in which severe thrombosis may occur under
40 years of age [1–6]. In the neonatal stage and infancy,
it may lead to cerebral hemorrhage, cerebral infarction,
purpura fulminans or other conditions, and in children or
adults it sometimes causes early onset of venous thromboembolism (VTE) or repeated recurrences of VTE, which
can be fatal [7, 8]. VTE is usually either deep vein thrombosis (DVT) or pulmonary embolism (PE), but there arealso cases of thrombosis in unusual sites. Therefore, whena woman with thrombophilia becomes pregnant, thrombosis may develop during pregnancy or after delivery [9–11].
Racial differences are well known in hereditary
thrombophilia. Factor V (FV) Leiden mutation and prothrombin 20210G > A are major pathological variants ofthrombophilia in Western countries, but there are still noreports of them in Japanese people [12–15]. Therefore,
AT deficiency, PC deficiency and PS deficiency are themajor types of thrombophilia in the Japanese population.
Among them, PS Tokushima (PS p.K196E) is exclusive
to the Japanese people, and thrombosis sometimes occurs
during pregnancy [16–19].
Recently, we developed clinical guidance for peripartum management of patients with hereditary thrombophilia, referring to research articles and guidelines inJapan and other countries [1]. In past articles, however,
the reported number of pregnant patients with thrombophilia is limited, and no large-scale surveillance has been
carried out. This study aimed to investigate the number ofpatients with thrombophilia and their current peripartum
management in Japan.

Materials and methods
National surveillance questionnaireThis national surveillance was conducted in June 2019.
We sent paper surveillance questionnaires to 415 perinatal
medical centers and general hospitals that have the ability
to manage pregnant women with thrombophilia, listed asregistered institutions by the perinatal committee of Japan
Society of Obstetrics and Gynecology (JSOG). Institutions
were asked to provide information regarding all deliveries and the number of pregnant women with thrombophilia between January 1, 2014 and December 31, 2018.

13

They were also asked how such cases were diagnosed
and managed during pregnancy and after delivery. The
questionnaire included questions on antigen and/or activity measurements, gene analysis, peripartum prophylactic
anticoagulation or prophylactic supplementation. As forperipartum prophylactic anticoagulation, the questionnaire asked about two groups, one of patients with AT
deficiency, and one of patients with PC deficiency andPS deficiency (PC/PS deficiency), because peripartum
VTE risk in patients with AT deficiency was reported tobe higher than that with PC/PS deficiency [1]. All personal
information were anonymized in this surveillance.

Diagnosis of hereditary thrombophilia
In this primary survey, hereditary thrombophilia was diagnosed according to the criteria of each institution, based onthings such as low activities of AT, PC and PS, and family
history and previous history of thrombosis (early onset inyounger age, recurrence or unusual site of thrombosis). The
lower limits of the adult reference values are generally about
70% for AT, 55–70% for PC, and 60–70% for PS [1]. The
final diagnoses were confirmed by gene analyses.

Statistical analysis
The differences among antepartum, intrapartum and postpartum prophylactic anticoagulation, both in patients withAT deficiency and in those with PC/PS deficiency, wereassessed by the chi-square test. The differences in peripartum prophylactic anticoagulation between patients withAT deficiency and those with PC/PS deficiency were also
assessed. Statistical analysis was done using SPSS version
25. In these analyses, a p value of less than 0.05 indicatedstatistical significance.

Details of ethics approval
The study was approved by the Ethics Committee of Kanazawa University (approval number 890-1) and Hamamatsu
Medical Center (rapid approval number 78, 2018). It was
performed in compliance with the Declaration of Helsinki. Consent was not obtained, but the presented data areanonymized and there is no risk of identification.

Results
Participants
A flowchart of this study is shown in Fig. 1. Among the
415 institutions to which we sent a paper surveillancequestionnaire, 2 institutions were excluded from the study

Peripartum management of hereditary thrombophilia: results of primary surveillance in Japan﻿	Perinatal medical centers or general hospitals listed as registered institutions by the perinatal committee of Japan Society of
Obstetrics and Gynecology (n = 415; 100%)
Obstetric ward or hospital closed, 1 institution
each (n = 2; 0.5%)413 institutions (99.5%)

Institutions that did not respond to questionnaire(n = 170; 41.0%)

Cases unknown(n = 7; 2.9%)(Total deliveries = 20,710; 2.9%)

Institutions that responded to questionnaire(n = 243; 58.5%)(Total deliveries = 725,405; 100%)

No cases with thrombophilia(n = 134; 55.1%)(Total deliveries = 378,687; 52.2%)

Cases with thrombophilia(n = 102; 42.0%)(Total deliveries = 326,008; 44.9%)

Fig. 1  Flowchart of this study

because their obstetric ward or hospital was closed, and243 (58.5%) responded to the questionnaires. At these
institutions, 725,405 women delivered after 22 gestational
weeks; their infants represented 15.0% of all Japanese live
births between January 1, 2014 and December 31, 2018[20]. Among the 243 responding institutions, 134 (55.1%,
total deliveries; 378,687, 52.2%) had no cases of thrombophilia, 102 (42.0%, total deliveries; 326,008, 44.9%) hadcases of thrombophilia, and 7 did not know (2.9%, total
deliveries; 20,710, 2.9%).

Table 1  Reported cases andprevalence of pregnant womenwith thrombophilia from 2014
to 2018

Type of thrombophilia

Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Others*
Total

Reported cases and prevalence of pregnant womenwith thrombophilia
The number of reported cases and the prevalence of thrombophilia in pregnant women from 2014 to 2018 are shown in
Table 1. The number of cases of thrombophilia was counted
as one each when one woman delivered several times, orwhen one woman had combined thrombophilia deficiencies. In cases of multiple pregnancy, however, the numberof cases of thrombophilia was counted as one case. The
numbers of cases with AT deficiency, PC deficiency, PS

Cases of thrombophilia (from Jan 1, 2014 to Dec 31,
2018)
2014

2015

2016

2017

2018

Total

14
11
71
1
97

12
14
83
2
111

22
8
87
0
117

17
13
81
0
111

19
21
121
2
163

84
67
443
5
599

Prevalence in total
deliveries (%)**

0.012
0.009
0.061
0.001
0.083

The number of cases of thrombophilia was counted as one each when one woman delivered several times,
or when one woman had combined thrombophilia deficiencies. In cases of multiple pregnancies, however,the number of cases of thrombophilia was counted as one case*One case each of methylenetetrahydrofolate reductase gene polymorphism, factor V Leiden (a Russian
woman), Upshaw–Schulman syndrome, plasminogen deficiency, and essential thrombocythemia**The number of total deliveries in this survey was 725,405

13

T. Kobayashi et al.
Table 2  Thrombophilia diagnosis: antigen and/or activity measurement
Measurement

Institution%

Measurement of both antigen and activity
Measurement of antigen only
Measurement of activity only
Measurement of antigen and/or activity
No answer
Total

122
7
76
8
30
243

50.2
2.9
31.3
3.3
12.3
100

Table 3  Thrombophilia diagnosis: gene analysis

Peripartum prophylactic anticoagulation therapy

Gene analysis

Institution%

Analysis in all cases
Analysis if possible
No analysis
No answer
Total

6
102
114
21
243

2.5
42.0
46.9
8.6
100.0

Among 108 institutions that used gene analysis, 68 (63.0%) outsourced it to other institutions, and only 24 (22.2%) performed it intheir own institutions. The remaining 16 institutions (14.8%) did not
answerdeficiency and other abnormalities were 84, 67, 443 and 5(599 in total), respectively. The prevalence of AT deficiency,
PC deficiency, PS deficiency and other abnormalities among
total deliveries was 0.012%, 0.009, 0.061% and 0.001%(0.083% in total), respectively. Other reported abnormalities
were one case each of methylenetetrahydrofolate reductase
gene polymorphism, factor V Leiden (a Russian woman),Upshaw–Schulman syndrome, plasminogen deficiency, andessential thrombocythemia.

How thrombophilia was diagnosed—antigen and/or activity measurement, gene analysis
The methods of diagnosing thrombophilia are shown in
Table 2 (antigen and/or activity measurement) and in Table 3(gene analysis). Effective answers for antigen and/or activity
Table 4  Prophylactic
anticoagulation in patients withantithrombin (AT) deficiency.
Proportion of institutions
that performed prophylactic
anticoagulation

Prophylaxis

Anticoagulation
In all cases
Case by case
Clinical vigilance
No answer/no experience
Total

measurement were provided by 87.7% of institutions. To
diagnose thrombophilia, 122 institutions (50.2%) measured both antigen and activity, 76 (31.3%) measured activity only, 8 (3.3%) measured antigen and/or activity, and 7(2.9%) measured antigen only (Table 2). Effective answers
for gene analysis were provided by 91.4% of institutions.
One hundred fourteen institutions (46.9%) did not performgene analysis, 102 (42.0%) performed it if possible, and 6(2.5%) performed it in all cases. Among 108 institutions,
68 (63.0%) outsourced gene analysis to other institutions,and only 24 (22.2%) performed it in their own institutions(Table 3).

Prophylactic anticoagulation in patients with AT deficiency
is shown in Table 4 and Supplemental Table 1. In antepartum management, 100 institutions (41.2%) performed anticoagulation on a case by case basis, 63 (25.9%) performed
it in all cases, 22 (9.1%) performed only clinical vigilance,and 58 institutions (23.9%) did not respond and/or had noexperience of thrombophilia. Unfractionated heparin (UFH)
combined with low dose aspirin (LDA) was seen in 6 institutions. In intrapartum management, 93 institutions (38.3%)
performed only clinical vigilance, 70 (28.8%) performed
anticoagulation on a case by case basis, 21 (8.6%) performed
it in all cases, and 59 (24.3%) did not respond and/or had
no experience. In postpartum management, 100 institutions(41.2%) performed anticoagulation on a case by case basis,
61 (25.1%) performed it in all cases, 22 (9.1%) performed
only clinical vigilance, and 60 (24.7%) did not respond and/or had no experience. UFH combined with warfarin wasseen in 22 institutions. During peripartum management,
10,000 units of UFH were used the most often. Low molecular weight heparin (LMWH) was used after cesarean section in many institutions. In prophylactic anticoagulation,
there were significant differences between the antepartum
and intrapartum periods, and between the intrapartum andpostpartum periods (both p < 0.001 by the chi-square test).
However, the difference between antepartum and postpartum
was not significant (ns).

Antepartum

Intrapartum

Postpartum

Institution%

Institution%

Institution

%

163a
63
100
22a
58
243

67.1
25.9
41.2
9.1
23.9
100.1

91b
21
70
93b
59
243

37.4
8.6
28.8
38.3
24.3
100

161c
61
100
22c
60
243

66.3
25.1
41.2
9.1
24.7
100.1

a vs. b; p < 0.001, a vs. c; not significant, b vs. c; p < 0.001 by the chi-square test13Peripartum management of hereditary thrombophilia: results of primary surveillance in Japan﻿	Prophylactic anticoagulation in patients with PC/PS
deficiency is shown in Table 5 and supplemental Table 2.
In antepartum management, 132 institutions (54.3%) performed anticoagulation on a case by case basis, 51 (21.0%)
performed it in all cases, 19 (7.8%) performed only clinical vigilance, and 41 (16.9%) did not respond and/or had
no experience of thrombophilia. UFH combined with LDA
was seen in 17 institutions. In intrapartum management, 109
institutions (44.9%) performed only clinical vigilance, 75(30.9%) performed anticoagulation on a case by case basis,
17 (7.0%) performed it in all cases, and 42 (17.3%) did not
respond and/or had no experience. In postpartum management, 113 institutions (46.5%) performed anticoagulation
on a case by case basis, 50 (20.6%) performed it in allcases, 39 (16.0%) performed only clinical vigilance, and 41(16.9%) did not respond and/or had no experience. During
Table 5  Prophylactic
anticoagulation in patients withprotein C and protein S (PC/PS) deficiency. Proportion of
institutions that performed
prophylactic anticoagulation

Prophylaxis

Anticoagulation
In all cases
Case by case
Clinical vigilance
No answer/no experience
Total

peripartum management, 10,000 units of UFH were used
the most. LMWH was used after cesarean section in many
institutions. In prophylactic anticoagulation, there were significant differences between the antepartum and intrapartum
periods, between the intrapartum and postpartum periods(both p < 0.001), and between the antepartum and postpartum periods (p < 0.01). Postpartum anticoagulation only was
marginally significant lower (p = 0.0506) in patients with
PC/PS deficiency than in patients with AT deficiency.

Peripartum prophylactic supplementation
Peripartum prophylactic AT supplementation in patientswith AT deficiency is shown in Table 6. In antepartum management, 80 institutions (33.3%) performed supplementationin cases of lower activity, 50 (20.6%) performed clinical

Antepartum

Intrapartum

Postpartum

Institution%

Institution%

Institution

%

183d
51
132
19d
41
243

75.3
21.0
54.3
7.8
16.9
100

92e
17
75
109e
42
243

37.9
7.0
30.9
44.9
17.3
100.1

163f
50
113
39f
41
243

67.1
20.6
46.5
16.0
16.9
100

d vs. e; p < 0.001, d vs. f; p < 0.01, e vs. f; p < 0.001 by the chi-square test. a vs. d; not significant, b vs. e;
not significant, c vs. f; p = 0.0506 (marginally significantly lower) compared to AT deficiency (Table 4)
Table 6  Prophylactic
antithrombin (AT)supplementation in patientswith AT deficiency

Supplementation

Antepartum
Institution

Intrapartum%

Institution

Supplementation in all cases
41
16.5
49
Supplementation in cases of lower activity
80
33.3
79
Clinical vigilance
50
20.6
45
No answer/no experience
72
29.6
70
Total
243
100
243
Trough AT activity before supplementation in cases of lower activity (%)
< 50
8
10
6
50 ≦ < 70
17
21.3
13
70 ≦
10
12.5
16
Undetermined (case by case)2
2.5
4
No answer/no experience
43
53.8
40
Total
80
100.1
79
Amount of AT supplementation (units)< 15002
0.8
01500 ≦ < 3000
208.2
33000 ≦
8
3.3
2
Undetermined (case by case)2
0.8
1
No answer/no experience
211
86.8
237
Total
243
99.9
243

Postpartum%

Institution

%

19.8
32.5
18.5
29.2
100

40
77
55
71
243

16.1
31.7
22.6
29.6
100

7.6
16.5
20.3
5.1
50.6
100.1

6
16
14
2
39
77

7.8
20.8
18.2
2.6
50.6
100

0
1.2
0.8
0.4
97.5
99.9

2
21
8
2
210
243

0.8
8.6
3.3
0.8
86.4
99.9

13

T. Kobayashi et al.

vigilance only, 41 (16.5%) performed supplementation in allcases, and 72 (29.6%) did not respond and/or had no experience. In intrapartum management, 79 institutions (32.5%)
performed supplementation in cases of lower activity, 49(19.8%) performed supplementation in all cases, 45 (18.5%)
performed clinical vigilance only, and 70 (29.2%) did not
respond and/or had no experience. In postpartum management, 77 institutions (31.7%) performed supplementationin cases of lower activity, 55 (22.6%) performed clinicalvigilance only, 40 (16.1%) performed supplementation in
all cases, and 71 (29.6%) did not respond and/or had noexperience. The most common answer for the low troughAT activity criterion for the use of supplementation was
50 ≤  < 70%, and the most common amount of AT supplementation was 1500 ≤  < 3000 units among institutions thatprovided valid answers. No cases of supplementation withfreeze-dried concentrated human activated protein C werereported in PC deficiency.

Discussion
In this study, we conducted the first national surveillanceof peripartum management of hereditary thrombophilia inJapan. Between 2014 and 2018, AT, PC and PS deficiency
were observed in 84, 67, and 443 pregnancies, respectively,
with incidence rates among total deliveries at 0.012%,
0.009%, and 0.061%.
AT deficiency, PC deficiency and PS deficiency are themajor types of thrombophilia in the Japanese population[1–6, 15]. In this surveillance, 243 institutions (58.5%)
responded to the questionnaire and 102 (42.0%) of themhad cases with thrombophilia (Fig. 1). The number of pregnant women with AT, PC and PS deficiency was reported
to be 84, 67, and 443, respectively (Table 1). Though thenumber of reported cases fluctuated every year, the reason
why it was the highest in 2018 may be because that was theyear nearest to the year of the surveillance. At these institutions, 725,405 women delivered, representing 15.0% of all
Japanese live births between 2014 and 2018. As we senta paper surveillance questionnaire to all perinatal medical
centers and general hospitals that have the ability to manage
pregnant women with thrombophilia throughout Japan, there
might have been up to 144 cases of AT deficiency, 115 of PC
deficiency and 757 of PS deficiency in these 5 years if 100%of institutions had responded. Specifically, there could havebeen up to 29 cases of AT deficiency, 23 of PC deficiency
and 151 of PS deficiency every year. National surveys by
Ministry of Health, Labour and Welfare research groups andacademic societies have found that there are about 2,000
individuals with AT, PC, and PS deficiencies in all of Japan(total population was estimated at 124.2–125.4 million
between 2014 and 2018 [20]). The number of patients in

13

whom these conditions newly develop annually is estimatedto be less than 100 among neonates and infants, and about
500 among adults [21–23]. Accordingly, looking only at
women of reproductive age who hope to bear children, theestimated annual number of pregnant women with thrombophilias obtained from this surveillance (29 with AT deficiency, 23 with PC deficiency, 151 with PS deficiency, and
203 in total) would seem to be reasonable and to reflect thecurrent situation of Japan. The prevalence of AT, PC and PS
deficiency among total deliveries was 0.012%, 0.009% and0.061%, respectively (Table 1). In the general Japanese population, AT, PC and PS deficiency are thought to be present
in about 1 person per 650 people (0.15%), about 1 person
per 750 people (0.13%) [24], and about 10–20 persons per
1,000 people, respectively. Only PS deficiency is roughly 10
times higher than the 0.16–0.21% in Caucasians [25, 26].
The main reason for that is thought to be the PS gene polymorphism, PS p.K196E, which is exclusive to Japanese [16,18, 19]. A mutant allele of PS p.K196E is seen in 1 of about
55 people (about 2%) in the general population [17].
Only about a half of institutions (50.2%) measured bothantigen and activity for a diagnosis of thrombophilia; however, more than 80% of institutions measured at least activity (Table 2). The best way to diagnose thrombophilia is
to measure both antigen and activity, which leads to distinguishing between type I and type II subtypes of thrombophilia. However, this surveillance revealed that subtype
diagnosis of thrombophilia is difficult even if thrombophilia
itself can be diagnosed in Japan today. We recommend
the measurement of both antigen and activity to diagnose
thrombophilia at more institutions in the near future. Geneanalysis is the ultimate diagnosis of thrombophilia, however, this surveillance revealed that among the 108 institutions that used gene analysis, only 22.2% could performgene analysis in their own institutions (9.9% of the whole)(Table 3). Although genetic screening is currently very difficult in Japan, gene analysis for thrombophilia is expected
to become widespread in the near future as AT, PC, and PS
deficiency were added to the diseases targeted for genetic
testing in the 2020 revision of the medical payment system
in Japan [1].
In peripartum prophylactic anticoagulation in patientswith AT deficiency (Table 4), about two-thirds of institutions performed anticoagulation in the antepartum andpostpartum periods (67.1% antepartum and 66.3% postpartum; ns), while 37.4% did in the intrapartum period(p < 0.001 vs. antepartum and postpartum). As VTE risks
differ with factors such as type I deficiency, past history
or family history of thrombosis, prophylactic anticoagulation depends on individual VTE risk. According toclinical guidance for peripartum management of patientswith hereditary thrombophilia [1], both antepartum andpostpartum prophylactic doses of anticoagulation arePeripartum management of hereditary thrombophilia: results of primary surveillance in Japan﻿	suggested. However, it is recommended that they be discontinued with the onset of labor pains in cases of vaginal
delivery and 6 h before the start of delivery in cases ofplanned delivery or cesarean section. Although the proportion of institutions with postpartum prophylactic anticoagulation was not so high, the obtained data seem tobe satisfactory. The anticoagulation was stopped duringlabor in all institutions even when it was performed on thedate of delivery. UFH was used during pregnancy because
LMWH, which is widely used in Western countries, is notcovered by health insurance in Japan for either prophylaxis
or treatment of VTE, except for postoperative prophylactic
use for VTE. In the peripartum period, 10,000 units of
UFH was the most common dose for prophylactic anticoagulation. For the postpartum period only, UFH combinedwith warfarin was seen in some institutions and LMWH
was used after cesarean section in many institutions (supplemental Table 1). These data are thought to be in accordance with the abovementioned clinical guidance [1].
In peripartum prophylactic anticoagulation in patientswith PC/PS deficiency (Table 5), two-thirds to three-fourthsof institutions performed anticoagulation in the antepartum
and postpartum periods (75.3% antepartum and 67.1% postpartum; p < 0.01), while 37.9% performed anticoagulation in
the intrapartum period (p < 0.001 vs. antepartum and postpartum). Though the peripartum VTE risk in patients withAT deficiency is reported to be higher than that in patientswith PC/PS deficiency [1], the proportion of institutions performing antepartum anticoagulation for PC/PS deficiency
was slightly higher than that for AT deficiency. This data
may seem strange. The reasons for this are thought to be
the following: (1) The guideline for obstetrics practice inJapan recommends peripartum prophylactic anticoagulation
equally in patients with thrombophilia, regardless of whether
it is AT and PC/PS deficiency [27]. (2) Japanese physicians
have more occasions to encounter patients with PS deficiency because of the higher prevalence of PS deficiency
than of AT or PC deficiency in Japan [16–19, 25, 26]. (3)Prophylactic anticoagulation is suggested to prevent recurrent fetal loss in cases with PS deficiency [1]. Accordingly,
physicians tend to perform prophylactic anticoagulation inpatients with PS deficiency, especially in the antepartum
period. Two statistical findings, i.e., that the proportion of
institutions performing postpartum prophylactic anticoagulation was significantly lower than that performing antepartum prophylactic anticoagulation (p < 0.01), and that it was
marginally significant lower (p = 0.0506) compared to AT
deficiency, might demonstrate this tendency. In the peripartum period, doses of UFH were almost the same as for AT
deficiency. However, UFH combined with low dose aspirin(LDA) was seen in some institutions. It is thought that LDA
was used for the prevention of recurrent pregnancy loss inpatients with PS deficiency.

Approximately half of institutions performed peripartum
prophylactic AT supplementation in patients with AT deficiency (49.8% in the antepartum, 52.3% in the intrapartumand 47.8% in the postpartum period) (Table 6). According to
the abovementioned clinical guidance [1], supplementation
with an AT preparation is suggested in peripartum periods
depending on individual VTE risk. Although there is noestablished opinion with regard to AT supplementation, it
has been recommended in some reports in recent years [28,29]. The reason that only half of institutions currently perform AT supplementation in the peripartum periods in Japan
seems to be that there is no firm recommendation about it.
In this survey, low trough AT activity before supplementation was most commonly 50% ≤  < 70%, and the highest AT
supplementation was 1500 ≤  < 3000 units. Since administration of 1500 to 3000 units of AT concentrate are recommended so that AT activity levels are preferably maintained
at 70% or higher if possible [1, 30], the obtained data seem
satisfactory.
In conclusion, it is suggested that the number of pregnancies with AT, PC and PS deficiency might be as manyas 29, 23 and 151 every year in Japan. More than 80% of
institutions measured at least activity for the diagnosis ofthrombophilia; however, only about 10% of institutions
could perform gene analysis in their own institutions. The
obtained data on peripartum prophylactic anticoagulation
and AT supplementation are thought to be in accordancewith clinical guidance.

Study limitations
We revealed the number of patients with thrombophilia
and their current peripartum management in Japan for the
first time; however, (i) The rate of responding institutionsin this primary survey (243/415, 58.5%) was not very high.
(ii) Reported cases of thrombophilia may not have been
definitively diagnosed, since hereditary thrombophilia wasdiagnosed according to the criteria of each institution. In
addition, there might be considerable pregnant women withfalse PS deficiency, especially if PS activities were measured during pregnancy. (iii) Since this study was a primary
survey, detailed information other than the obtained data is
unknown.
Supplementary Information The online version contains supplementary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 12185-0​ 22-0​ 3354-4.
Acknowledgements This work was supported by the Research Grantsof the Ministry of Health, Labour and Welfare Science of Japan for
Blood Coagulation Abnormalities in the Research Program on Rareand Intractable Diseases.
Author contributions TK wrote the manuscript and researched data.
KS collected paper surveillance questionnaire and researched data. TO,

13

T. Kobayashi et al.
KH, and EM contributed to the discussion and reviewed or edited themanuscript.

Declarations
Disclosure No declaration.

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