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|Year : 2007
: 10 | Issue : 2 | Page
|Anticoagulation for pregnant patients with mechanical heart valves
Aseem R Srivastava, Pranav Modi, Sudhir Sahi, Yogesh Niwariya, Harpreet Singh, Amit Banerjee
Department of Cardiovascular and Thoracic Surgery, G. B. Pant Hospital, New Delhi., India
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| Abstract|| |
Management of a pregnant patient with mechanical heart valve is a complex issue for all health care providers involved in the care of such patients. Complications may arise at any stage due to the increased haemodynamic load imposed by pregnancy or because of impaired cardiac performance often seen in these patients. In addition, the use of various cardiovascular drugs in pregnancy (especially anticoagulants) may lead to foetal loss or teratogenic complications. Additionally, the risk of thrombo-embolic complications in the mother is increased by the hypercoagulable state of pregnancy. In this review, we have attempted to draw inferences to guide management of such patients based on the available literature. It seems that in pregnant women with mechanical heart valves, recent data support warfarin use throughout pregnancy, followed by a switch to heparin and planned induction of labour. However, the complexity of this situation demands a cafeteria approach where the patient herself can choose from the available options that are supported by evidence-based information. Unfortunately there is no consensus on such data. An overview of the available literature forms the basis of this review. In conclusion, a guideline comprising pragmatic considerations is proffered.
Keywords: Anticoagulation, Heparin, Warfarin, Pregnancy
|How to cite this article:|
Srivastava AR, Modi P, Sahi S, Niwariya Y, Singh H, Banerjee A. Anticoagulation for pregnant patients with mechanical heart valves. Ann Card Anaesth 2007;10:95-107
|How to cite this URL:|
Srivastava AR, Modi P, Sahi S, Niwariya Y, Singh H, Banerjee A. Anticoagulation for pregnant patients with mechanical heart valves. Ann Card Anaesth [serial online] 2007 [cited 2020 Feb 20];10:95-107. Available from: http://www.annals.in/text.asp?2007/10/2/95/37934
Expectant women with mechanical heart valves need to undergo an event-free period of gestation with a successful outcome for both mother and child. Unfortunately, pregnancy in these patients does not follow its usual benign course and is associated with high maternal and foetal risks. 
The incidence of rheumatic heart disease has declined dramatically in the industrialised nations. However, in India it has not shown a similar decline,  with hospital admissions ranging from 16.5-50.6% of all cardiac in-patients.  As rheumatic heart disease primarily affects younger patients, most women undergoing a heart valve replacement belong to the child-bearing age group and this potentially magnifies this problem in the developing countries.
During pregnancy there is a 50% increase in blood volume, an increase in cardiac output and a decrease in systemic vascular resistance (from uterine circulation and hormonal changes). During labour and delivery, cardiac output increases abruptly followed by a sudden increase in preload (due to autotransfusion of uterine blood and caval decompression). This increased haemodynamic burden, which is well tolerated by most women, may lead to cardiac decompensation in patients with prosthetic valves, especially those with left ventricular (LV) dysfunction or a relatively smallsized valve prosthesis. 
For patients with mechanical heart valve, lifelong anticoagulation is mandatory.  However in pregnant women, anticoagulation management is a complex issue. Pregnancy is a hypercoagulable state, due to increase in fibrinogen, factors VII, VIII and X, von Willebrand factor and relative decrease in protein S activity, stasis and venous hypertension.  This further increases the already existing risk of thrombo-embolic complications (TEC) in these patients. This state of hypercoagulability extends into the postpartum period too and requires a persistently higher maintenance dose of warfarin.  Similarly, increase in total blood volume affects the distribution of heparin and low molecular weight heparin (LMWH ). The presence of placental heparinase ,, further contributes to unpredictable changes in the quantum of medication required. Thus, optimal anticoagulation therapy is considered essential, but the appropriate choice of agent among the options available (warfarin, heparin or LMWH) is highly debatable.
Traditionally, a causal relationship between warfarin and embryopathy is well established, whereas anticoagulation by heparin is considered a substitute below par, since it is associated with a higher risk of TEC for the mother. The role of LMWH too has not been explored adequately under these settings, and even the manufacturers discourage its use in pregnant patients with mechanical heart valves. A school of thought that considers the teratogenic potentials of warfarin as negligible, further complicates the scenario. Consequently, there is no unanimity on the ideal anticoagulation protocol for pregnant valve prosthesis recipients.
We have searched the available literature on this complex issue, while attempting to draw inferences to guide management of such patients.
| Risk assessment|| |
The risk of complications during pregnancy in patients with mechanical heart valve depends on the patient's symptoms, cardiac function, and her functional capacity as well as on the type of valve prosthesis, its position and function.
There is an increased haemodynamic load during pregnancy, labour and delivery. The published experience indicates that most patients that were asymptomatic or only mildly symptomatic before conception, tolerate this haemodynamic burden well. ,,,,, However, cardiac decompensation may occur, especially in patients with impaired LV function and/or possible patientprosthesis mismatch.  In addition, an increased incidence of arrhythmia is reported during pregnancy  and may add to patient discomfort. Thus it is not surprising that decreased functional capacity, pulmonary oedema and death are not uncommon in pregnant women with mechanical valves. ,,,,, Patients with prosthetic heart valves and markedly impaired LV function that are moderately or severely symptomatic (New York Heart Association, class III and IV) are best advised against pregnancy. 
Residual tricuspid incompetence often co-exists in patients with prosthetic heart valves. The reported incidence of foetal loss in mothers suffering from tricuspid incompetence severe enough to require diuretics is around 73%.  This risk is significantly higher when compared with foetal loss in pregnancies in which the mother did not exhibit tricuspid incompetence. 
Prosthesis related factors
The commonest cause of maternal death in patients with mechanical heart valves is the device thrombosis. In addition, there is also a high incidence of thromboembolic events in these patients, ranging from 7% to 23%. ,,,, Mechanical prostheses in aortic position have a lower thromboembolic risk than in mitral position. Also, the relatively older prostheses (StarrEdwards, Bjork-Shiley standard, and Omniscience) have a higher thromboembolic risk than the subsequent generation valves (St Jude Medical or Medtronic Hall). However, thromboses of these newer valves, including those in aortic position, are not unknown. ,,,,,,
Foetal complications related to maternal anticoagulant therapy are teratogenicity and foetal loss. The incidence of abortion or foetal wastage (resulting from retroplacental haemorrhage, congenital malformations, etc) in these patients is high, with reported rates ranging between 23% and 50 %. ,,,,,
Maternal risk of haemorrhage while on anticoagulation is estimated at around 2.5%, with majority of such episodes (almost 80%) occurring in association with delivery. 
Moreover, in addition to anticoagulants, the use of other cardiovascular drugs during pregnancy may also adversely affect the foetal outcome [Table 1]. Cardiac drugs that are relatively safe during pregnancy include heparin, propranolol (and other beta blockers), verapamil, digoxin and few antihypertensives such as labetolol, methyldopa, hydralazine, nifedipine and prazosin. Amiodarone is associated with foetal hypothyroidism and intrauterine growth retardation. It should be reserved only for cases with refractory arrhythmias.
In these patients, a planned pregnancy is preferred to an unplanned one. Evaluation of pregnant women with prosthetic heart valves should include information about her prepregnancy functional capacity, ongoing drug treatment, a full clinical assessment, details of valvular prosthesis, an ECG, as well as an echoDoppler study to evaluate cardiac status. A fairly good estimate of maternal and foetal risk can then be made.
Patient should also be advised on the potential complications that may occur during pregnancy: symptomatic worsening, higher incidence of thromboembolism, and potential harmful effects to the foetus.
| Anticoagulants and pregnancy|| |
Choice of anticoagulant is limited to warfarin, heparin or LMWH. The advantage of warfarin lies in its ease of administration, dependability and low cost. However, the associated risk of embryopathy has limited its use in pregnant women, particularly in the first trimester. Heparins need to be administered parenterally and produce less dependable anticoagulation, but are not teratogenic.
Oral anticoagulants interfere with the cyclic inter-conversion of vitamin K and its epoxide, thus inhibiting the production of vitamin K dependant clotting factors. Dosage is adjusted to attain a desired international normalized ratio (INR) level [Table 2], which is calculated by the formula:
INR = (patient PT/mean normal PT) ISI
(PT stands for prothrombin time and ISI denotes International Sensitivity Index of thromboplastin used at the laboratory)
Measuring activated partial thromboplastin time (aPTT) remains the most frequently used method for monitoring the anticoagulant response of unfractionated heparin (UFH) and should be measured about 6 hours after the bolus dose, the continuous intravenous dose is adjusted accordingly. Long-term heparin therapy may cause osteoporosis. ,, Dahlman has studied 184 women receiving long-term prophylactic UFH therapy during pregnancy, and has reported a 2.2% incidence of vertebral fracture.  Approximately 3% patients on UFH acquire immune, IgG-mediated thrombocytopaenia. It should be suspected  when platelet count decreases to <100,000/mm 3 or <50% of the baseline value within 5 to 15 days after commencing heparin (sooner with recent heparin exposure) .
Low molecular weight heparin
LMWH has a better bioavailability than unfractionated heparin, and may also have a lower risk of bleeding, thrombocytopaenia and osteoporosis. These advantages, however, are partly offset by its longer half life (making it more difficult to handle during premature labour), and its unpredictable reversal with protamine. As already mentioned, because of an increased volume of distribution of LMWH in pregnancy and placental heparinase ,, , dose adjustments based on plasma anti-Xa levels 4 hours after the morning dose are essential. The target is to achieve an antiXa level of 1.0 to 1.2 units per ml. 
In 2002, Food and Drug Administration mandated a warning in the package insert of enoxaparin, which stated that the product is not recommended for anti-thrombotic prophylaxis in patients with prosthetic heart valves; that cases of prosthetic valve thrombosis, maternal and foetal deaths are reported with the use of this drug; and that in pregnant women who received this drug, both teratogenic and non-teratogenic effects have been reported. Even so, the data on the use of enoxaparin in this subgroup of patients is mixed, with literature available to both support ,, and contraindicate ,,,  its use.
Since heparin and LMWH do not cross the placenta, teratogenic effects are very unlikely. Moreover, in a review of 624 pregnancies  in which LMWH was used, no relationship between its use and foetal / neonatal adverse effects was noted. In 2002, a cardiology consensus statement  concluded that the role of enoxaparin in pregnant women with mechanical valves should be more appropriately considered unproven and imperfectly studied alternative among a trio of suboptimal and potentially unfavourable options.
In view of these reports, the labelling has been rephrased in 2004, suggesting that its use for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied.
Small-doses of aspirin are safe during the 2nd and 3rd trimesters of pregnancy. ,, Aspirin reduces the incidence of systemic embolization or death when added to oral anticoagulation in the non-pregnant population with mechanical heart valve. 
Thus, based on current data, 80-100 mg of aspirin during the second and third trimesters may be added to improve antithrombotic effects. Dipyridamole should not be considered an alternative antiplatelet agent because of its harmful effects on the foetus.
| Embryopathy|| |
Heparin (both UFH and LMWH) does not cross the placenta, and does not cause teratogenicity. On the contrary, warfarin readily crosses the placenta. Vitamin K acts as a co-factor for carboxylation of glutamic acid residues of osteocalcin and matrix Gla protein, which modulate calcium deposition.  Oral anticoagulants when used during the first trimester, may thus cause a failure in the synthesis of osteocalcin and Gla matrix protein resulting in nasal hypoplasia and stippling seen on X-ray of proximal epiphyseal growth areas (Chondroplasia punctata). Exposure during the second and third trimesters may lead to central nervous system and eye abnormalities (optic atrophy, cataract, blindness, microphthalmia, intraventricular haemorrhage, microcephaly, hydrocephalus, seizures, and growth/mental retardation). ,,,,
Incidence of coumarin embryopathy is a subject of intense debate, with reports ranging from none to almost 30%.  This probably reflects the lack of properly conducted trials and inadequate nature of current studies. Several studies did not find cases of embryopathy associated with warfarin use in pregnancy.10, ,,,, However, a recent review of 1234 pregnancies calculates a risk of about 6 %.  This incidence decreased to 3.4% when heparin was used during the first trimester, and more significantly, if warfarin was replaced with heparin prior to or at 6 th week, no foetal anomalies were seen. Similarly, no congenital anomalies were reported in patients exclusively on heparin, throughout the pregnancy. This review thus upholds the suggestion of previous studies , that warfarin embryopathy may be prevented if oral anticoagulants are discontinued before 6th week and until the 12th week of pregnancy, albeit with an increased risk of TEC.
Recently, Vitale et al  have made an important contribution to our understanding of coumarin embryopathy. They demonstrated a close relationship between warfarin dose and foetal complications. They report an 88% risk of foetal complications and a 9% incidence of warfarin embryopathy in women on a warfarin dose exceeding 5 mg/day. In contrast, only 15% of women on warfarin doses of <5 mg/day had foetal complications with no incidence of embryopathy. This may suggest the possibility of a risk free use of warfarin during pregnancy in patients who are adequately anticoagulated at lower doses of warfarin. However, there are data that are both in agreement ,, and against these findings. ,
Warfarin when used in the post-partum period does not cause an anticoagulant effect on the breast fed infant. , Likewise neither UFH nor LMWHs are secreted into breast milk. 
| Foetal Loss|| |
Spontaneous abortion is by far the most frequent foetal complication, associated with pregnancy in women with mechanical heart valves. Both oral anticoagulants and heparin carry this risk. Inhibition of the immature liver enzyme system of the foetus by warfarin may result into an increased risk of haemorrhagic complications and stillbirth. Although heparin will not cross the placenta, bleeding at the utero-placental junction is still possible.
Replacing warfarin with heparin during the first trimester prevents the occurrence of malformations, but this does not translate into an improved pregnancy outcome. ,,
Foetal loss in women receiving heparin predominantly occurs in the first trimester  , whereas in women receiving oral anticoagulants the frequency of foetal loss is similar in the first and second trimester and lower in the third trimester. In this regard, one important finding in a review by Chan et al  was that although the rates of spontaneous abortions were similar in the group using oral anticoagulants throughout pregnancy (24.7%) and those switching to heparin in the first trimester (23.8%), the subgroup where warfarin was discontinued and heparin used at or prior to 6 weeks of gestation, suffered least spontaneous abortions (14.7 %).
| Embolic complications|| |
Meschengieser et al,  in their prospective study of 92 pregnancies found that embolic complications were highest with low dose heparin (11.7 episodes/ 100 patient-months) than with adjusted subcutaneous heparin (4.92 episodes/100 patientmonths), and least with oral anticoagulation (0.33 episodes/100 patient-months). Many other studies report similar findings. ,,,
In Salazar's study  of 40 patients, which was terminated prematurely on account of two fatal incidences of massive thrombosis of mechanical valve, acenocoumarol was substituted with heparin between 6th to 12th weeks of pregnancy. Both patients with thrombosis had strictly followed their heparin treatment (aPTT 55 to 95 sec; control 30 to 35 sec). No thromboembolic events were observed, while the patients were receiving acenocoumarol. The authors concluded that subcutaneous heparin, with the doses adjusted to increase aPTT from 1.5 to 2.5 times the control was not effective in preventing thromboembolic phenomena in these patients.
A pooled result of 28 articles  has revealed a 3.9% risk of TEC in patients on oral anticoagulants throughout pregnancy versus a 33.3% risk when heparin alone was used. TEC risk was 9.2% when heparin was used in the first trimester and warfarin during the second and third. Maternal death occurred in 15% of patients treated with only heparin whereas such mortality with exclusive oral anticoagulant use was only 1.8% and 4.2%, when oral anticoagulants were replaced by heparin for the first trimester. The commonest cause of maternal death in this review was prosthetic valve thrombosis.
The 'HIP-CAT' study (Heparin in Pregnancy-Cardiac Valve Thromboprophylaxis)
This randomized controlled trial was designed to compare enoxaparin with warfarin and UFH in pregnant women with new-generation prosthetic heart valves.  Enoxaparin (1 mg/kg twice daily) was given subcutaneously and was adjusted to maintain a peak (3 hours post-dose) anti-Xa level below 1.2 U/mL. This study was prematurely discontinued after two of the seven patients who were treated with enoxaparin developed fatal valve dysfunction. None of the four patients in the heparin/warfarin group died. A review of anti-Xa levels in all seven patients treated with enoxaparin in this study demonstrated occasional sub therapeutic trough values in most of the patients. ,
Recently, Oran B et al  reviewed pregnancies in women with mechanical heart valves treated with LMWH. Among 81 pregnancies in 75 women, the proportion of valve thrombosis was 8.64%, whereas the overall frequency of TEC was 12.35%. More importantly, in the 51 pregnancies where anti Xa levels were monitored, only one patient had TEC. Also, the frequency of live births with LMWH was 87.65%.
Therefore, a very significant increase in thromboembolic events with heparin use is evident from the data available, and some recommend an exclusive oral anticoagulant use throughout the first trimester , banking on the relatively lower incidence of malformations reported in recent literature.
| Maternal bleeding complications|| |
In a systematic review by Chan and colleagues, the overall rate of major bleeding in pregnant females with mechanical heart valves was reported to be 2.5%.  This risk is similar to the risk of bleeding with either heparin therapy (2% in pregnant females with or without mechanical heart valves  and 3.7 in non pregnant females for deep vein thrombosis prophylaxis  ) or warfarin therapy (3.1% in non pregnant females with mechanical heart valves  ). Although there is no definite data on bleeding related to LMWH, bleeding complications appear to be rare with LMWH. Chan and colleagues further observed that out of a total of 31 episodes of bleeding, 25 occurred in patients on hepain. This may be related to the fact that most bleeding complications occur during delivery and warfarin is usually substituted with heparin during this period. However, there is no objective study in the literature, in this regard.
| Mode of delivery|| |
Several studies ,,, suggest that heparin therapy is safe for the foetus particularly at the time of delivery, when trans-placental transfer of oral anticoagulants may lead to bleeding in the neonate. Caesarean section is indicated, if labour starts while the mother is still on oral anticoagulants; rapid reversal of the mother's anticoagulation is attempted with liberal use of fresh frozen plasma. Avoiding vaginal delivery decreases birth trauma to the anticoagulated baby.
Recommendations on the management of elective deliveries, however, are more controversial. There are suggestions that continuing warfarin till 38 weeks of pregnancy, followed by a 2-day interruption of anticoagulant therapy and cesarean section , may improve outcome and decrease the time for which the mother remains unprotected. This represents a non-obstetrical indication for caesarean section, which is itself known to increase venous thromboembolic risk over that of natural childbirth. Also, anticoagulated preterm infants are at increased risk for intracranial haemorrhage during both vaginal and caesarean delivery. 
Therefore, stopping warfarin at the 36 th week, replacing it with adequate heparin and planned induction of labour at 38 th week is a more appealing alternative, and is recommended by most authorities on this subject.
| Available recommendations|| |
As in most areas of medicine, management of pregnant patients with mechanical heart valves is now covered by guidelines. Yet, this controversial issue remains unabated, partly from the need of well-designed prospective studies and partly due to the lack of consensus among various study groups. In this regard, the Task Force of the European Society of Cardiology, (ESC) On the Management of Cardiovascular Diseases during Pregnancy in its expert consensus statement  avers:
"In pregnant patients with mechanical prosthesis, the choice of anticoagulant therapy during the first trimester should take into account the greater thromboembolic risk with heparin and the risk of embryopathy with vitamin K antagonist. The use of vitamin K antagonist during the first trimester is the safest regimen for the mother."
[Table 3],[Table 4] and [Table 5] enumerate the guidelines of ESC, American Heart Association (AHA) and American College of Chest Physicians (ACCP) respectively. The divergence in opinion is clearly evident. ACCP considers heparin (LMWH or UFH) as the anticoagulant of choice during pregnancy (or at least until the 13th week). On the contrary ESC strongly recommends warfarin for the initial 35 weeks of pregnancy. AHA guidelines, however, have left much more room for the patient's preference, with a choice between continuous intravenous and dose adjusted subcutaneous heparin, dose adjusted LMWH or warfarin. AHA guidelines do not recommend LMWH use in these patients, unless anti-Xa levels are monitored 4 to 6 hours after administration. Moreover, LMWH, which is recommended by ACCP, is not yet approved by ESC, for use in pregnant patients with prosthetic valve, due to the high risk of valve thrombosis.
| Inferences|| |
Use of warfarin throughout pregnancy appears to confer the greatest protection to the mother against valve thrombosis and death.  Switching to heparin in the first trimester prior to 6 weeks of gestation avoids foetal embryopathy, but exposes the women to a period of increased risk of thrombosis.  The risks of bleeding complications in the mother are similar, irrespective of the type of anticoagulant chosen. Risks associated with oral anticoagulants occur primarily during the latter half of first trimester (embryopathy) and the peripartum period (maternal and foetal haemorrhages). Outside this, oral anticoagulants, compared to heparin, best stabilise the intensity of anticoagulation and thereby limit maternal thromboembolic events.
Therefore, a general consensus has emerged favouring the use of oral anticoagulants during the second and most of third trimester. Additionally, 80 -100 mg of aspirin during the second and third trimesters may be added, especially in patients at high thrombotic risk (mitral valve prosthesis, atrial fibrillation, older generation valve, previous thromboembolism, etc.).
Presently, there is a difference of opinion on the best possible approach between the 6th and 12th week of pregnancy and during the peripartum period. Anecdotal experiences all over the world tend to suggest that oral anticoagulants are probably the safest bet for the mother. ,,,, Although clinicians are chary about articulating their personal views in black and white, many do not interfere with the administration of warfarin during the first trimester. The confidence emanates from the low incidence of embryopathy in this cohort of patients. Switching to heparin in the first trimester does not dramatically improve the number of successful pregnancies.  Several documented papers tend to agree that the projected risk of warfarin embryopathy has probably been overstated in the past. ,,,,,, Too explicit information about the teratogenicity of this drug may lead to unnecessary anxiety and avoidable deprivation of a potentially beneficial therapy by prospective mothers.
The implications of these recent data suggesting a lower incidence of coumarin embryopathy than previously thought, ,,,,,, and better maternal protection against TEC by warfarin, , are thus far reaching and favour the ESC guidelines that recommend warfarin throughout the pregnancy. A few other studies further attest to the safety of this approach. ,[ 67],
Nonetheless, in today's litigation-riddled environs, the decision on whether to replace warfarin with heparin between 6 and 12 weeks of gestation or to continue with warfarin throughout pregnancy should be made after full discussion with the mother  and her partner. If she chooses to change to heparin, her wish must be respected, but she should be made fully aware that heparin is less safe for her and associated with a higher risk of TEC. The extreme rarity of warfarin embryopathy too must be clearly emphasized. Whenever UFH is used, it should be used in high doses (35,000 to 40,000 U in 24 hours) and the dose should be adjusted to keep the mid-interval aPTT at least twice of control  or to attain an anti-Xa heparin level of 0.35 to 0.70 U/mL. 
However, warfarin should preferably be substituted with heparin at 35 to 36 gestational weeks to avert bleeding accidents during delivery, with planned induction of labour or caesarean section at 38 weeks. To assure adequate anticoagulation, this 'switch' from coumarin to heparin should be done as an in-patient. The authors believe that echo-Doppler monitoring during these crucial weeks might be helpful in ensuring that prosthesis function is unaffected. Subcutaneous heparin is replaced with intravenous heparin for 48 hours and is stopped just before planned labour (or 4 hrs prior to caesarean section), and restarted 6-12 hours after delivery. It is rapidly re-switched to oral anticoagulants, over a period of 3 to 6 days, once the INR reaches a therapeutic level.
The advantage of intravenous UFH over LMWH (and subcutaneous heparin) is that it has a shorter half-life, making it easier to handle during premature labour and also decreases the time for which the mother remains unprotected. Caesarean section should best be reserved for usual obstetrical indications and when the labour starts while the mother is still on oral anticoagulants.
In summary, the threat of warfarin induced embryopathy during early pregnancy appears to be negligible vis-a-vis the looming threat of TEC. Hence, non-discontinuance of oral anticoagulation till the final weeks of gestation, maintaining the INR at a level appropriate for any valve-replaced patient may be the most pragmatic option. The change over from warfarin to heparin near term and vice versa following delivery, should be carried out in an institutional setting and monitored with relevant tests.
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Department of Cardiothoracic and Vascular Surgery, G. B. Pant Hospital, New Delhi-110002
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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