A total of 105 pregnant women were enrolled in this study, including 137 pregnancies, 96 in the warfarin group, 28 in the LMWH group, and 13 in the sequential treatment group. A total of 27 cases of spontaneous abortion in 3 groups, 3 cases of stillbirth (Table 1), including 23 cases of parous women, 7 cases of primiparas; 26 cases of long-term oral warfarin during pregnancy (6 cases greater than 5 mg, 20 cases less than 5 mg), 4 cases of LMWH only users during pregnancy; 5 cases of gynecological and obstetric diseases (4 cases of endometriosis, 1 case of multiple uterine fibroids), 3 cases of severe infection (1 case of sepsis, 1 case of acute pelvic inflammatory disease, 1 case of acute chorioitis), 1 case of hypothyroidism, 0 cases of NYHA ≥3, 6 cases of multiple spontaneous abortions with unknown causes, 1 case of fetal nervous system malformation, and 1 case of mechanical heart valve replacement during pregnancy. There was 51 artificial abortion.
A total of 8 cases of malformations (5.84%) (4 cases of cardiovascular system, 2 cases of skeletal deformity, 3 cases of nervous system malformation, and 1 case of intestinal malformation) (Table 1).
A total of 56 live births, including 28 cases in the warfarin group, 18 cases in the LMWH group, and 10 cases in the sequential treatment group (Table 2); 53 cases of cesarean section, 3 cases of natural delivery, 7 cases of premature babies, and 5 cases of LBW , 2 cases of SGA, 3 cases of neonatal asphyxia, 5 cases of pulmonary insufficiency, 3 cases of sepsis, 3 cases of neonatal encephalopathy, 18 cases of blood spots on skin, 2 cases of gastrointestinal bleeding, 5 cases of cranial hematoma, 1 case of disseminated intravascular coagulation, and 13 cases of pathological jaundice. The comparison of the neonatal indicators of the three groups is shown in Table 2. 22 neonates were admitted to the general neonatal ward, 7 were admitted to ICU treatment, and one of them gave up treatment 1 day later. All children admitted to the hospital were monitored for coagulation function. The coagulation indexes of the three groups were compared, and it was found that the INR (P <0.001), PT (P = 0.014), and APTT (P = 0.035) of newborns in the warfarin group were higher than those in the other two groups.
In the offspring of the warfarin group, 7 newborns had significantly increased INR on the first day after birth (2-7.11) (Table 3), which was significantly higher than that of the mother on the same day before delivery (1.1-2.8 fold). Except for 1 case that was changed to LMHW 1 week before delivery, the rest of the cases were withdrawn from warfarin for a short period of time, of which pregnancy was discontinued with 4 cases due to premature rupture of membrane (PROM) and 1 case due to fetal distress with emergency. One case of maternal pregnancy with warfarin dosage > 5mg, 2 cases of maternal pregnancy with acute chorioamnionitis, 1 case with preeclampsia, cardiac insufficiency (grade 3). Of these 7 newborns, 5 were admitted to the general neonatal ward, and 2 were admitted to the ICU (1 premature infant, LBW, with mild asphyxia, respiratory distress syndrome, and gastrointestinal bleeding, gave up treatment 1 day later; 1 case of diagnosed pyaemia, with atelectasis, respiratory failure, encephaledema, gastrointestinal bleeding, discharged after 15 days of treatment).
The dosage of warfarin is 1.5 mg-7.5 mg in the first trimester, with an average of 3.57 ± 1.21 mg. There were 14 cases greater than 5 mg (Table 4). Among the offspring, 1 case was live birth, 4 cases of spontaneous abortion, 1 case of stillbirth, and the remaining 8 cases were medically terminated pregnancy in the first trimester. There were 4 cases of the first pregnancy, with the average age of 26.21 ± 7.39 years old at the time of heart valve surgery (ranging at 19-43 years old).
Using logistics single factor regression analysis, we found that the higher the heart function level and the longer the gestational age, the lower the probability of spontaneous abortion/stillbirth (Table 5), the ORs were 0.35 (0.16, 0.77) and 0.95 (0.91, 0.98), respectively. The higher the INR of the coagulation index before delivery, the higher the probability of spontaneous abortion/stillbirth. The OR was 6.54 (1.30, 33.00). Multi-factor Tobit regression analysis showed that the probability of spontaneous abortion/stillbirth was still negatively correlated with gestational age and positively correlated with the coagulation index INR before delivery (P < 0.05). In addition, the longer the valve usage time, the higher the rate of spontaneous abortion/stillbirth (OR 1.13, P = 0.009).
What’s more, it was found that the worse level of cardiac function, the higher the probability of fetal malformation, with the OR of 5.25 (1.51, 18.27) (Table 6). Multi-factor Tobit regression analysis showed that the probability of malformation was not only positively correlated with the worse of cardiac function, but also positively correlated with the coagulation index INR at delivery (P < 0.05).
Table 1 General information of women with different anticoagulant treatment regimens
Index
|
Warfarin
n = 96
|
Low molecular weight heparin
n = 28
|
Sequential treatment
n = 13
|
F/H/χ2
|
P
|
Age (years)
|
32.00±5.68
|
30.39±3.35
|
30.85±3.56
|
1.21
|
0.302
|
Occupation
|
|
|
|
6.91
|
0.141
|
Staff
|
45(46.88)
|
14(51.85)
|
11(84.62)
|
|
|
Farmer
|
2(2.08)
|
1(3.70)
|
0(0.00)
|
|
|
Others
|
49(51.04)
|
12(44.44)
|
2(15.38)
|
|
|
Systolic blood pressure
|
116.66±11.11
|
116.86±13.55
|
122.46±10.83
|
1.45
|
0.239
|
Diastolic blood pressure
|
70.11±7.71
|
68.43±9.85
|
71.85±6.91
|
0.86
|
0.424
|
Gestational week
|
18.07±13.21
|
27.43±12.80a
|
35.46±6.23ab
|
14.51
|
<0.001
|
Gravidity
|
2.90±1.71
|
2.21±1.03a
|
2.00±1.29a
|
3.38
|
0.037
|
Parity
|
0.88±0.73
|
1.00±0.94
|
1.23±0.83
|
1.30
|
0.277
|
Mechanical heart valve
|
|
|
|
3.84
|
0.698
|
Mitral valve
|
43(44.79)
|
14(50.00)
|
8(61.54)
|
|
|
Aortic valve
|
30(31.25)
|
7(25.00)
|
1(7.69)
|
|
|
Mitral valve and aortic valve
|
22(22.92)
|
7(25.00)
|
4(30.77)
|
|
|
Cardiac Function
|
|
|
|
9.20
|
0.163
|
1
|
41(42.71)
|
7(25.00)
|
3(23.08)
|
|
|
2
|
52(54.17)
|
18(64.29)
|
10(76.92)
|
|
|
≥3
|
3(3.12)
|
3(10.71)
|
0(0.00)
|
|
|
Thrombotic or embolic events
|
4(4.17)
|
2(7.14)
|
0(0.00)
|
1.11
|
0.572
|
Bleeding event
|
1(1.04)
|
2(7.14)
|
0(0.00)
|
4.09
|
0.129
|
Live birth
|
28(29.17)
|
18(64.29)
|
10(76.92)
|
18.79
|
<0.001
|
Stillbirth/Spontaneous abortion
|
23(23.96)
|
4(14.29)
|
3(23.08)
|
1.20
|
0.549
|
Fetal/Newborn Malformation
|
4(4.17)c
|
3(10.71) d
|
1(7.69) e
|
1.78
|
0.411
|
INR before delivery
|
1.30±0.54
|
1.11±0.39
|
1.32±0.73
|
0.85
|
0.435
|
Premature rupture of membranes
|
6(6.25)
|
4(14.29)
|
1(7.69)
|
1.90
|
0.387
|
Abnormal placenta
|
|
|
|
12.33
|
0.055
|
Placenta previa
|
1(1.04)
|
0(0.00)
|
0(0.00)
|
|
|
Placenta implantation
|
0(0.00)
|
1(3.57)
|
0(0.00)
|
|
|
Placenta previa and placenta implantation
|
0(0.00)
|
2(7.14)
|
0(0.00)
|
|
|
Postpartum hemorrhage
|
1(1.04)
|
4(14.29)a
|
1(7.69)ab
|
9.46
|
0.009
|
Gestational diabetes mellitus
|
3(3.13)
|
3(10.71)
|
2(15.38)
|
4.65
|
0.098
|
Pregnancy induced hypertension
|
3(3.13)
|
0(0.00)
|
0(0.00)
|
1.31
|
0.519
|
Chronic hypertension
|
1(1.04)
|
1(3.57)
|
1(7.69)
|
2.68
|
0.262
|
Preeclampsia
|
2(2.08)
|
0(0.00)
|
0(0.00)
|
0.87
|
0.648
|
Infection during pregnancy
|
7(7.29)
|
4(14.29)
|
2(15.38)
|
1.82
|
0.403
|
Autoimmune disease
|
5(5.21)
|
7(25.00)a
|
0(0.00)ab
|
12.00
|
0.002
|
Arrhythmia
|
7(7.29)
|
3(10.71)
|
0(0.00)
|
1.51
|
0.471
|
MPHV usage time (years)
|
5.78±4.11
|
7.02±5.02
|
8.62±4.15
|
2.98
|
0.054
|
a, significantly different compared with the warfarin group.
b, significantly different the LMWH group.
c Multiple deformities (nose bone loss, complete endocardial pad defect, duodenal atresia) in 1 case, cerebellar vermis missing in 1 case, nasal bone abnormality in 1 case, right ventricle hydrocephalus in 1 case.
d Atrial septal defect combined with ventricular septal defect in 1 case, atrial septal defect in 1 case, and ventricular septal defect in 1 case.
e 1 case of cerebrovascular malformation.
MPHV: mechanical prosthetic heart valves
Table 2 Comparison of neonates in different anticoagulant treatment groups.
Index
|
Warfarin
n = 28
|
Low molecular weight heparin
n = 18
|
Sequential treatment
n = 10
|
F/H/χ2
|
P
|
Premature delivery
|
4(14.29)
|
3(16.67)
|
0(0.00)
|
1.80
|
0.407
|
Newborn weight (g)
|
2838.67±643.85
|
2791.94±528.31
|
3245.00±372.48
|
2.31
|
0.109
|
Newborn length (cm)
|
48.90±2.72
|
48.33±2.95
|
46.91±10.93ab
|
41.79
|
<0.001
|
Small for gestational age
|
0(0.00)
|
2(11.11)
|
0(0.00)
|
4.38
|
0.112
|
Low birth weight infant
|
2(7.14)
|
3(16.67)
|
0(0.00)
|
2.42
|
0.299
|
ICU admission
|
4(14.29)
|
2(11.11)
|
1(10.00)
|
0.17
|
0.918
|
Neonatal coagulation index
|
n = 13
|
n = 10
|
n = 6
|
|
|
INR
|
3.01±1.83
|
1.63±0.31a
|
1.64±0.47a
|
25.23
|
<0.001
|
PT
|
36.96±23.25
|
17.80±3.50a
|
17.90±5.67a
|
5.05
|
0.014
|
APTT
|
101.00±45.11
|
71.91±18.74a
|
59.55±20.93a
|
3.81
|
0.035
|
a, significantly different compared with the warfarin group.
b, significantly different the LMMH group.
Table 3 Cases of INR > 2 on the first day of newborns in the Warfarin group.
Patient
|
Neonatal
INR
|
Maternal prenatal
INR
|
Gestational week
|
Pregnancy comorbidity
|
Warfarin dosage (mg)
|
Duration of LMWH treatment post-warfarin
|
1
|
3.2
|
1.63
|
30
|
Pre-eclampsia, cardiac insufficiency, fetal distress
|
3
|
< 24 hrs
|
2
|
3.86
|
2.06
|
37
|
Acute chorioamnionitis, PROM
|
3
|
< 24 hrs
|
3
|
2
|
1.7
|
37
|
Acute chorioamnionitis
|
4.875
|
1 week
|
4
|
4
|
2.93
|
39
|
Moderate anemia
|
4.5
|
< 24 hrs
|
5
|
7.11
|
2.49
|
34
|
Mitral valve neoplasms, PROM
|
6
|
< 24 hrs
|
6
|
4.9
|
1.87
|
36
|
PROM
|
2.6
|
< 24 hrs
|
7
|
4.9
|
1.93
|
36
|
PROM
|
2.6
|
< 24 hrs
|
PROM: Premature rupture of membrane
Table 4 Cases with dosage of warfarin greater than 5 mg in early pregnancy
Patient
|
Age (years)
|
Age at valve replacement (years)
|
Valve replacement site
|
Gestational week
|
Pregnancy and childbirth history
|
Warfarin dosage (mg)
|
NYHA
|
Complications
|
Fetal / newborn outcome
|
1
|
29
|
22
|
MVR
|
7
|
G3P1
|
5.25
|
1
|
-
|
Spontaneous abortion
|
2
|
34
|
34
|
AVR
|
10
|
G5P3
|
7.5
|
2
|
Marfan syndrome
|
Abortion
|
3
|
29
|
25
|
MVR
|
9
|
G3P1
|
6.5
|
2
|
-
|
Spontaneous abortion
|
4
|
36
|
26
|
MVR+ AVR
|
8
|
G4P0
|
6.5
|
1
|
Endometriosis
|
Spontaneous abortion
|
5
|
34
|
12
|
MVR+ AVR
|
38
|
G1P1
|
6
|
2
|
Preeclampsia, pelvic inflammatory disease, mild pulmonary hypertension
|
Live birth
|
6
|
30
|
27
|
MVR+ AVR
|
11
|
G1P0
|
6
|
1
|
-
|
Spontaneous abortion
|
7
|
26
|
25
|
MVR+ AVR
|
6
|
G1P0
|
5.25
|
1
|
Hypertension during pregnancy
|
Abortion
|
8
|
35
|
33
|
MVR
|
7
|
G4P2
|
6
|
1
|
-
|
Abortion
|
9
|
27
|
26
|
MVR+ AVR
|
7
|
G2P1
|
6
|
2
|
Marfan syndrome
|
Abortion
|
10
|
21
|
19
|
AVR
|
8
|
G2P1
|
5.25
|
1
|
-
|
Abortion
|
11
|
38
|
29
|
MVR
|
8
|
G7P1
|
6
|
1
|
Habitual abortion
|
Abortion
|
12
|
26
|
20
|
MVR+ AVR
|
7
|
G1P0
|
5.25
|
1
|
-
|
Abortion
|
13
|
45
|
43
|
MVR+ AVR
|
9
|
G4P2
|
5.25
|
1
|
-
|
Abortion
|
14
|
32
|
26
|
MVR
|
32
|
G4P0
|
5.25
|
1
|
-
|
Stillbirth
|
MVR, mitral valve replacement; AVR, aortic valve replacement; NYHA, New York Heart Association
Table 5 Influencing factors of neonatal spontaneous abortion/stillbirth (single factor, multi-factor)
Index
|
Single factor
|
|
Multi-factor
|
|
|
OR (95%CI)
|
P
|
OR (95%CI)
|
P
|
NYHA
|
0.35 (0.16, 0.77)
|
0.009
|
0.94 (0.85, 1.04)
|
0.266
|
Gestational week
|
0.95 (0.91, 0.98)
|
0.002
|
0.95 (0.93, 0.97)
|
<0.001
|
Anticoagulation method
|
0.83 (0.43, 1.59)
|
0.566
|
1.02 (0.96, 1.08)
|
0.575
|
INR before delivery
|
6.54 (1.30, 33.00)
|
0.023
|
1.14 (1.05, 1.24)
|
0.003
|
Number of mechanical valve
|
1.19 (0.47, 3.01)
|
0.709
|
1.02 (0.91, 1.14)
|
0.779
|
Mechanical valve usage time (years)
|
0.82 (0.39, 1.75)
|
0.615
|
1.13 (1.03, 1.24)
|
0.009
|
NYHA, New York Heart Association
Table 6 Influencing factors of neonatal malformations (single factor, multi-factor)
Index
|
Single factor
|
|
Multi-factor
|
|
|
OR (95%CI)
|
P
|
OR (95%CI)
|
P
|
NYHA
|
5.25 (1.51, 18.27)
|
0.009
|
1.20 (1.03, 1.40)
|
0.025
|
Gestational week
|
1.07 (1.00, 1.14)
|
0.054
|
1.03 (0.99, 1.06)
|
0.151
|
Anticoagulation method
|
1.62 (0.64, 4.12)
|
0.313
|
1.05 (0.96, 1.14)
|
0.305
|
INR before delivery
|
3.60 (0.98, 13.17)
|
0.053
|
1.18 (1.04, 1.34)
|
0.011
|
Number of mechanical valve
|
0.43 (0.05, 3.66)
|
0.442
|
0.89 (0.75, 1.05)
|
0.167
|
Mechanical valve usage time
|
0.85 (0.23, 3.21)
|
0.813
|
1.03 (0.90, 1.18)
|
0.677
|
NYHA, New York Heart Association