Pregnancy induces a hypercoagulable state and is therefore associated with an increased risk of valve thrombosis and thromboembolism; this is especially important with mechanical prosthetic heart valves that already cause a risk of clotting. During pregnancy, there is an increased concentration of clotting factors, decreased fi brinolysis, and increased platelet adhesive- ness. Anticoagulation management is thus critical, and one should not extrapolate the same therapies used for patients with mechanical prostheses having noncar- diac surgery to those in the pregnant state. Appropriate anticoagulation, however, is challenging because anticoagulation with warfarin can be associated with important fetal adverse eff ects, while heparin is a less eff ective anticoagulant and therefore associated with important maternal complications, particularly valve thrombosis and thromboembolism In many series, valve thrombosis and thromboembolic events occur in approximately 10% of cases and are oft en fatal.[ 8 ] Mitral tilting disk valves and older generation valves such as the Bjork–Shiley and Starr–Edwards valves appear to confer the highest risk of thrombotic com- plications. Th us, the anticoagulant strategy selected poses a diffi cult clinical dilemma for both women and the clinicians caring for them, and requires a detailed and informed discussion before pregnancy is contem- plated. What is considered to be an “acceptable risk”
to mother and baby may diff er from one clinician to another, and may be very diff erent between one woman and the next .[ 7 ]
Unfractionated heparin
Heparin is a large molecule that not cross the placenta to aff ect the fetus. It has a relatively short circulating half-life, however, and may be given either subcu- taneously or intravenously. Th e use of heparin can be associated with osteoporosis [ 9 ] and an immune
Section 4: Antenatal Care: Specifi c Maternal Conditions
immunoglobulin G mediated thrombocytopenia. In early series, it was oft en the anticoagulant of choice in pregnancy, particularly in the fi rst trimester, for women with mechanical prostheses in an eff ort to avoid the potential complications of fetal embryopa- thy due to warfarin . Th e laboratory control of anti- coagulation, however, is challenging and there is wide variability in the sensitivity of activated partial thromboplastin time (APTT) reagents for monitoring the dosage and considerable variability in response to standard dosing. In addition, the APTT may vary by as much as 50% in response to the same continuous intravenous dose of heparin, with a higher anticoagu- lant eff ect at night-time. Th is diurnal variation may relate to a circadian rhythm in the pharmacokinetics of heparin or, more likely, to a spontaneous circadian variation in coagulation also seen in normal controls.
[ 10 ] During pregnancy, the APTT response to hepa- rin is oft en attenuated because of increased levels of factor VIII and fi brinogen.[ 11 ] It is thus imperative that heparin should be given at an adequate intensity, with frequent measurements of trough and peak lev- els. Contemporary APTT reagents are more sensitive to the anticoagulant eff ect of heparin, and an APTT ratio of 1.5 is inadequate. Th e APTT ratio should be at least 2, which correlates with an anti-factor Xa (“anti-Xa”) level of >0.55 IU/ml in approximately 90%
of women.[ 12 ] Because of the variability in laboratory sensitivities for monitoring heparin, APTT alone may be insuffi cient and anti-Xa assays may periodically be more useful in guiding therapy. If this is done, it is recommended that the anti-Xa level be maintained between 0.35 and 0.7. It may be that suboptimal target APTT ratios account for some of the reported treat- ment failures .
In the author’s experience, unfractionated hepa- rin is diffi cult to manage via the subcutaneous route
because of wide peaks and troughs. In accordance with both the American Heart Association and American College of Cardiology Valvular Heart Disease Guidance [ 13 ] and the European Society of Cardiology Guidelines,[ 14 ] if unfractionated heparin is used, the intravenous route is preferable. Th e dose must be adjusted to achieve an APTT of at least two times the control (recommendation class IIa).
Chan et al. performed a meta-analysis from 1966 to 1997, looking at 976 women with 1234 pregnan- cies and comparing three management strategies [ 15 ]: (1) unfractionated heparin throughout preg- nancy; (2) subcutaneous unfractionated heparin in the fi rst trimester and warfarin thereaft er until just prior to delivery when intravenous heparin was adminis- tered; and (3) warfarin throughout pregnancy. Th e risks of miscarriage and fetal loss for those on warfa- rin throughout pregnancy were 25% and 34%, respec- tively, and (perhaps surprisingly from a theoretical point of view because heparin does not cross the pla- centa) the use of heparin in the fi rst trimester yielded similar results with a miscarriage rate of 25% and a fetal loss rate of 27% ( Table 11.1 ). Th ey reported that the use of warfarin throughout pregnancy was associated with embryopathy in 6.4% of live births but that if heparin were substituted at or prior to 6 weeks of gestation and continued up to 12 weeks then the risk of embryopathy was eliminated ( Table 11.2 ). Th e overall risks of fetal loss (miscarriage, stillbirth, and neonatal death) were similar in women treated with warfarin throughout compared with women treated with heparin in the fi rst trimester. Th e overall maternal mortality in this series was 2.9% and major bleeding events occurred in 2.5%
of all pregnancies, most commonly at the time of deliv- ery. Th e maternal risk, however, was quite diff erent among the various anticoagulant strategies: the regi- men associated with the lowest maternal risk of valve
Table 11.1 Frequency of fetal complications reported with various anticoagulant strategies
Regimen Miscarriage Fetal anomalies Fetal loss
Warfarin a 196/792 (25%) 35/549 (6%) 266/792 (34%)
Heparin/warfarin b 57/230 (25%) 6/174 (3%) 61/230 (27%)
Heparin c 5/21 (24%) 0/17 (0%) 9/21 (43%)
No anticoagulants d 10/102 (10%) 3/92 (3%) 20/102 (20%)
a Warfarin throughout pregnancy with or without heparin prior to delivery
b Heparin in the fi rst trimester and then warfarin throughout pregnancy, with or without heparin prior to delivery
c Heparin throughout pregnancy
d Including the use of antiplatelet agents alone
Modifi ed with permission from Chan et al . (2000), all rights reserved [ 15 ]
thrombosis was the use of oral anticoagulants through- out pregnancy, with a risk of 3.9% ( Table 11.3 ). While the use of heparin between 6 and 12 weeks of gesta- tion eliminated the risk of fetal embryopathy, the risk of maternal valve thrombosis was more than doubled, at 9.2% ( Table 11.3 ). It thus appears that the window between 6 and 12 weeks is pivotal, since the contin- ued exposure to warfarin resulted in an increase in the risk of fetal loss by >50%. Th e apparent advantages of reduced fetal loss and embryopathy gained from the use of heparin, however, appeared to be counterbal- anced by an increase in maternal complications and an increased risk of thromboembolism .
Th ese fi ndings were confi rmed by Meschengieser et al. in a study of 92 pregnancies in 59 women.[ 16 ] Th ey reported that miscarriage or fetal losses were similar in women exposed to oral anticoagulants in the fi rst trimester (15/61 [25%]) compared with those who received adjusted subcutaneous heparin (6/31 [19%];
p =0.5717). Embolic events, however, were more com- mon in women receiving heparin. Th e authors con- cluded that heparin did not off er a clear advantage over oral anticoagulants in the pregnancy outcome .
Th ese studies highlight the dilemma that caregivers face when managing pregnant women with mechani- cal heart valves. While the risk and severity of war- farin embryopathy may not be as high as previously reported, the continued use of warfarin until close to term can result in a high risk of fetal loss. Th e use of warfarin throughout pregnancy, however, confers the
greatest protection to the mother against valve throm- bosis and death. Substituting heparin in the fi rst tri- mester as early as possible avoids fetal embryopathy but exposes the woman to a period of increased risk of thrombosis. [ 15 ]
Intravenous unfractionated heparin is the appro- priate treatment of choice during the peripartum because it can be discontinued several hours before planned delivery and its anticoagulant eff ects disap- pear within 6 h. Th is helps to avoid complications of hemorrhage with epidural anesthesia and bleeding complications around the time of delivery. Early rein- stitution of anticoagulation postpartum is impor- tant, but almost certainly contributes to high rates of primary and secondary postpartum hemorrhage.[ 7 ] Heparin can be restarted approximately 6 h aft er deliv- ery, depending on the individual situation and bleed- ing complications .
Warfarin
Th e use of warfarin, particularly between the 6th and 12th week of pregnancy, is associated with embry- opathy (warfarin embryopathy). Th e manifestations of warfarin embryopathy can vary widely and range from minor stippling of the epiphyses on X-ray (chondro- dysplasia punctata) and/or nasal hypoplasia to serious central nervous system abnormalities and optic atro- phy.[ 17 , 18 ] Stippling of the epiphyses occurs during early childhood and disappears with age. Th e incidence
Table 11.2 Fetal outcomes of early anticoagulant strategies in the fi rst trimester a
Early anticoagulant strategy Miscarriage Fetal anomalies Fetal loss
Regimen 2: heparin for <6 weeks 19/129 (15%) 0/108 (0%) 21/129 (16%)
Heparin for >6 weeks 19/56 (34%) 4/36 (11%) 20/56 (36%)
aComparing the results of discontinuing warfarin in the fi rst 6 weeks and substituting heparin vs those who continued on warfarin beyond 6 weeks into the more vulnerable period before heparin was substituted
Modifi ed with permission from Chan et al . (2000), all rights reserved [ 15 ]
Table 11.3 Frequency of maternal complications reported with the various anticoagulation regimens a
Regimen Thromboembolic complications Death
Warfarin 31/788 (4%) 10/561 (2%)
Heparin/warfarin 21/229 (9%) 7/167 (4%)
Heparin 7/21 (33%) 3/20 (15%)
No anticoagulants 26/107 (24%) 5/106 (5%)
a As described in Table 11.1
Modifi ed with permission from Chan et al . (2000), all rights reserved [ 15 ]
Section 4: Antenatal Care: Specifi c Maternal Conditions
of embryopathy in reported series also varies widely, from 0% to >20%.[ 19 – 23 ] Th is has been the subject of considerable debate in the literature; the incidence of warfarin embryopathy varies by the degree of scru- tiny the baby receives (whether examined by a primary care physician or a geneticist) and whether the miscar- ried babies are examined for features of embryopa- thy. Concern has also been expressed that there may be long-term eff ects of warfarin exposure associated with minor neurological dysfunction and low intelli- gence quotients.[ 24 ] In addition to the fi rst-trimester embryopathy with warfarin exposure, there may be an associated “fetopathy” with exposure in the second and third trimesters. Th is poses an increased risk of fetal hemorrhage, central nervous system abnormalities, fetal loss, and stillbirth.[ 25 ] Many late fetal losses result from fetal intracranial hemorrhage.
It has been suggested that the risk of fetal embryo- pathy is related to the dose of warfarin used and that it mostly occurs in women taking a daily dose >5 mg.
[ 21 ] In a series of 58 pregnancies, women whose daily warfarin doses were >5 mg had 22 fetal compli- cations, whereas those taking a dose of 5 mg/day or less had only 5 fetal complications ( p =0.0001).[ 21 ] Th ese complications included four miscarriages and one woman with fetal growth restriction. None of the babies born to mothers taking a warfarin dose of 5 mg/day or less had evidence of embryopathy. In the higher dose group, two fetuses miscarried in the sixth month of pregnancy, showing typical features of war- farin embryopathy. In these women, the doses of war- farin were 6.5 and 7.5 mg/day.[ 21 ] Th e authors noted a relatively high miscarriage rate in this overall series, most commonly in the fi rst 3 months of pregnancy, but argued that it was similar to the miscarriage rate reported in other series of women treated with sub- cutaneous heparin in the fi rst trimester. Th e authors suggested, therefore, that there was no advantage in the use of heparin during the fi rst trimester to pre- vent fetal loss. Th is dose-related response to warfarin is not reported in all series, however. In a prospective South African study of 62 pregnancies, 41 fetuses were exposed to warfarin in the fi rst trimester, with fi ve (12%) cases of warfarin embryopathy.[ 26 ] Th is risk was present irrespective of the warfarin dose: 5% if the dose of warfarin was ≤5 mg/day and 7% for patients taking >5 mg/day warfarin. A dose-dependent diff er- ence was noted for stillbirths however; if the warfarin dose was <5 mg per day, the stillbirth rate was 3.6%
which rose to 38.5% if the daily dose was ≥7.5 mg
( p =0.01). Th is dose-dependent relationship of war- farin with increased fetal loss has also been shown in other studies; in one study, it was as high as 100% in women taking a daily dose ≥10 mg .[ 27 ]
While the dose-related response to warfarin is not reported in all series, it merits serious consideration and permits a risk stratifi cation approach for women who have high-risk prostheses. Th ese would include those with mitral tilting disk valves who might be at a greater risk of valve thrombosis, particularly those in atrial fi brillation or with a prior thromboembolic event.
Th erefore, if the potential mother is taking a low dose of warfarin, the possibility of continuing oral anticoag- ulants throughout the pregnancy to reduce the risk of valve thrombosis should be carefully discussed with the woman at the time of preconception counseling. Th is is in accordance with guidelines from both the American College of of Cardiology/American Heart Association and the European Society of Cardiology.[ 13 , 14 ] It also has medicolegal implications since in North America warfarin is sold on the basis that it is contraindicated in pregnancy, so the prospective mother must be well informed about the potential risks and benefi ts of each anticoagulant approach and must agree to its use on this basis if the practitioner is to avoid being sued .
Warfarin should certainly be discontinued at around 35 weeks of gestation prior to anticipated labor; heparin should be substituted at that point. Th e fetus is eff ectively “overdosed” on warfarin because of its immature liver enzyme systems and low levels of vitamin K dependent clotting factors. Warfarin takes some days to be eliminated from the fetus; as such, these babies are at increased risk of intracranial hem- orrhage and should not be allowed to deliver vaginally.
[ 28 ] Cesarean section is therefore indicated in this set- ting unless delivery can be delayed until the eff ects of the warfarin have worn off , despite the risk of increased surgical bleeding at the time of the cesarean section. In general, if there is an anticipated likelihood of preterm delivery, the change from oral anticoagulants to hep- arin should be initiated earlier .
Low-molecular-weight heparin
Compared with unfractionated heparin, low- molecular-weight heparin (LMWH) has superior bioavailability, is easier to use, does not cross the pla- centa, and is associated with a lower frequency of heparin-induced thrombocytopenia. In addition, there is probably a reduced risk of osteoporosis with its use.
Problems with its use include its long half-life and the fact that it is not easily reversed. Furthermore, a spec- trum of anticoagulation tests detect measurable phar- macodynamic diff erences between the various currently available LMWH preparations when they are adminis- tered so as to achieve equivalent anti-Xa doses.[ 29 ]
Data on the use of LMWH during pregnancy in the setting of mechanical heart valves are few and generally confi ned to small groups of women.[ 30 – 3 3 ] Both valve thrombosis and maternal death have been reported with its use.[ 30 , 33 , 34 ] Because of the risks of valve thrombosis, the manufacturers of enoxaparin issued a warning in 2002 against its use in pregnant women with mechanical prosthetic heart valves, although by 2013 this had changed to “Pregnant women with mechanical prosthetic heart valves and their fetuses, may be at increased risk and may need more frequent monitoring and dosage adjustment” ( http://products.
sanofi .us/lovenox/lovenox.html , accessed September 10, 2015). Th us, its use remains controversial because many reports comprise retrospective studies with small numbers of patients, oft en with incomplete data.
Patient compliance with treatment is not always fully documented, nor is the adequacy of the anticoagula- tion strategy .
Oran et al. reviewed pregnancy data published between 1989 and 2004 regarding LMWH.[ 35 ] Th ere were 74 women with 81 pregnancies, most of whom had a mitral valve prosthesis. In 60 pregnancies LMWH was used throughout, while in 21 pregnancies LMWH was used in the second half of the fi rst trimes- ter and again at term. In 51 pregnancies the anti-Xa levels were monitored to determine that dosage was adequate, while in 30 pregnancies a fi xed dose was used. Th romboemboli occurred in 10 of the 81 preg- nancies (12%). All of these women had mitral valve prostheses, again emphasizing that these valves are more vulnerable to thromboembolic complications.
All the women with thromboemboli were on LMWH throughout pregnancy and nine of the ten were on the fi xed dose regimen. Th ese results underscore the need for meticulous monitoring of anti-Xa levels; the rec- ommendation from these authors is that the anti-Xa levels 4–6 h postinjection should be maintained at a minimum of 1 IU/ml .
It seems, therefore, that LMWH is associated with an increased risk of valve thrombosis but that this risk is reduced (although not eliminated) if careful dose adjustment is accomplished according to anti-Xa
levels. Target anti-Xa levels 4–6 h postdose should be 0.8–1.2 U/ml and the recommendation is that the levels should be measured weekly.[ 14 ] Small studies have demonstrated good outcomes for mother and baby with meticulous anticoagulant monitoring and therapeutic anti-Xa levels, even with continuation of LMWH throughout pregnancy [ 16 ] and particularly in the context of second-generation prostheses.[ 36 ] Th is obviously introduces signifi cant issues with com- pliance for some women, which may have contributed to the incidence of thrombosis in some series.[ 8 , 31 , 37 ] Th is strategy could be used throughout pregnancy, or until the 13th week, when warfarin may be substituted until the middle of the third trimester, and then hepa- rin restarted .
Because the reported series are very small, how- ever, the value of antifactor Xa monitoring in terms of effi cacy and safety remains to be established, and no large series have been published. Concern remains as to whether the recommended target anti-Xa levels are really correct, whether safety might be improved if predose levels were also measured, and what the best time intervals for dosage and measurement might be.
Valve thrombosis and even maternal death has been reported even in the context of therapeutic anti-Xa levels.[ 27 , 34 ] As with unfractionated heparin, LMWH is cleared through the kidney and subject to pharma- cokinetics that vary during pregnancy.[ 38 ] Because of the physiological changes in pregnancy such as an increased plasma volume, increased glomerular fi ltra- tion rate, and the production of placental heparinase, enoxaparin appears to have a higher clearance and larger volume of distribution during early pregnancy compared with that in the same women postpartum.
[ 39 ] Between early and late pregnancy, the maximum concentration achieved decreases, consistent with the volume expansion of pregnancy.[ 39 ] Barbour et al.
reported considerable variability in the anti-Xa activ- ity with LMWH use throughout all three trimesters, and it was noteworthy that when using the manufac- turer’s recommended dosage for twice daily dalteparin of 100 IU/kg, only 54% of pregnancies achieved thera- peutic peak anti-Xa levels. [ 40 ]
Heparin should be withdrawn at least 24 h before delivery and changed to intravenous unfractionated heparin, which can be terminated abruptly. Th is per- mits more controlled cessation of anticoagulation, since there is concern about bleeding and hematoma development if epidural anesthesia is to be used .