Therapy In Pregnant Patients Research Articles

Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve Thrombosis in Pregnancy With Low-Dose, Slow Infusion of Tissue-Type Plasminogen Activator

Prosthetic valve thrombosis during pregnancy is life-threatening for mother and fetus, and the treatment of this complication is unclear. Cardiac surgery in pregnancy is associated with very high maternal and fetal mortality and morbidity. Thrombolytic therapy has rarely been used in these patients. The aim of this study is to evaluate the safety and efficacy of low-dose (25 mg), slow infusion (6 hours) of tissue-type plasminogen activator for the treatment of prosthetic valve thrombosis in pregnant women. Between 2004 and 2012, tissue-type plasminogen activator was administered to 24 consecutive women in 25 pregnancies with 28 prosthetic valve thrombosis episodes (obstructive, n=15; nonobstructive, n=13). Mean age of the patients was 29±6 years. Thrombolytic therapy sessions were performed under transesophageal echocardiography guidance. The mean dose of tissue-type plasminogen activator used was 48.7±29.5 mg (range, 25-100 mg). All episodes resulted in complete thrombus lysis after thrombolytic therapy. One patient had placental hemorrhage with preterm live birth at the 30th week, and 1 patient had minor bleeding. Low-dose, slow infusion of tissue-type plasminogen activator with repeated doses as needed is an effective therapy with an excellent thrombolytic success rate for the treatment of prosthetic valve thrombosis in pregnant women. This protocol also seems to be safer than cardiac surgery or any alternative medical strategies published to date. Thrombolytic therapy should be considered first-line therapy in pregnant patients with prosthetic valve thrombosis.

Prosthetic Valve Thrombosis in Pregnancy

Prosthetic heart valve thrombosis (PVT) is a rare complication, with an estimated incidence of 0.1% to 5.7% per patient-year.1 However, during pregnancy, changes in the hemostatic system lead to a procoagulant state that increases the risk of PVT up to 10%.2 This maternal and fetal life-threatening complication is mostly preventable with long-term adequate anticoagulation therapy. When anticoagulation fails, treatment focuses on choosing between cardiac surgery and thrombolysis, 2 therapeutic strategies with risks and benefits for the mother and fetus that are difficult to assess. Article see p 532 The study by Ozkan et al3 in this issue of Circulation is the largest series of pregnant patients with prosthetic mitral valve thrombosis reported to date and offers interesting results in a scenario in which randomized, clinical trials are not feasible. A protocol of low-dose, slow infusion of tissue-type plasminogen activator with repeated doses as needed that was guided by transesophageal echocardiography was associated with a successful thrombolysis in all episodes, with no maternal deaths and a fetal mortality rate of 20%, results that seem to be better than those obtained with other thrombolytic strategies reported. The authors’ conclusions on the superiority of thrombolysis over surgery and the redefinition of the lytic option as a first-line therapy in pregnant patients with PVT require careful evaluation. Previous studies of cardiac surgery showing maternal and fetal mortality rates of 6% and 30%, respectively, were published a decade ago and were based mostly on coronary revascularization procedures. Since then, some recommendations have been included, such as appointing the procedure during the second …

Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease

ObjectiveSeveral studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using...

A randomised controlled trial to compare intravenous iron sucrose and oral iron in treatment of iron deficiency anemia in pregnancy.

The aim of this study was to compare the efficacy and safety of intravenous iron sucrose with oral iron therapy in pregnant patients with anemia. The primary outcome of the study was increase in haemoglobin on day 7, 14 & 28 and rise of serum ferritin over 28 days. The study population consisted of 100 patients with singleton pregnancy between 24 and 34 weeks, hemoglobin levels between 7.0-9.0gm/dL and serum ferritin levels less than 15ng/mL. The participants in the oral group were given daily 180mg elemental iron in three divided oral doses for 4 weeks. Total calculated dose of iron sucrose with a target hemoglobin of 11gm%, was given in 200 mg dose on alternate days. Mean haemoglobin rise was 0.58gm/dL in the IV group as compared to 0.23gm/dL in the oral group on day 14 and 1.9gm/dL in the IV group & 1.3gm/dL in the oral group on day 28, (p <0.05). In the IV group, 76% of the subjects achieved haemoglobin levels of ≥11gm% at the time of delivery, as compared to only 54% of the subjects in the oral group who achieved these levels. Serum ferritin value was significantly higher in the IV group, 37.45 ± 5.73 ng/mL as compared to 13.96 ± 1.88 ng/mL in the oral group at 4th week (p <0.001). There was no major side effect in the IV group. 36% subjects in the oral group developed gastrointestinal side effects & 10% of the subjects were non compliant. The rate of hemoglobin rise is faster with intravenous iron sucrose therapy as compared to oral iron therapy which can be beneficial in pregnant women presenting with anemia at a later period of gestation. Intravenous iron sucrose is very well tolerated during pregnancy.

Acute Revascularization Therapy in Pregnant Patients

Ischemic stroke is uncommon during pregnancy, but decision making for acute revascularization therapy including intravenous recombinant tissue plasminogen activator (rt-PA) is difficult. The use of rt-PA remains controversial, but a systematic review of 16 patients (mean age 31.7 years) showed good results for both maternal (77.8%) and fetal (56.3%) outcomes. Pregnancy alone is not a solid contraindication for acute revascularization therapy including rt-PA. An endovascular approach might be beneficial for reducing the hemorrhagic complication; however, the treatment strategy should be considered based on the available treatment facility. Close cooperation with obstetrics is essential for the successful management of saving the lives of both the mother and the fetus.

Involvement of anticentromere antibody in interference with oocyte meiosis and embryo cleavage

The aim of this study was to investigate the clinical significance of anticentromere antibody (ACA) among types of antinuclear antibody (ANA) in the properties of oocytes retrieved from infertile women. The rate of metaphase II oocytes or embryo cleavage was significantly decreased in patients with positive ACA compared with patients with negative ACA, suggesting that ACA is an essential marker for flawed oocytes in infertile women with any type of ANA.

Perturbation of the Developmental Potential of Preimplantation Mouse Embryos by Hydroxyurea

Women are advised not to attempt pregnancy while on hydroxyurea (HU) due to the teratogenic effects of this agent, based on results obtained from animal studies. Several case reports suggest that HU may have minimal or no teratogenic effects on the developing human fetus. Fourteen cases of HU therapy in pregnant patients diagnosed with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease (SCD) have been reported. Three pregnancies were terminated by elective abortion; 1 woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. We contend that case studies such as these have too few patients and cannot effectively address the adverse effect of HU on preimplantation embryo or fetuses. The objective of this study was to assess the risks associated with a clinically relevant dose of HU used for the treatment of SCD, on ovulation rate and embryo development, using adult C57BL/6J female mice as a model. In Experiment 1, adult female mice were randomly assigned to a treatment or a control group (N = 20/group). Treatment consisted of oral HU (30 mg/kg) for 28 days; while control mice received saline (HU vehicle). Five days to the cessation of HU dosing, all mice were subjected to folliculogenesis induction with pregnant mare serum gonadotropin (PMSG). Five mice/group were anesthetized at 48 hours post PMSG to facilitate blood collection via cardiac puncture for estradiol-17β (E2) measurement by RIA. Ovulation was induced in the remaining mice at 48 hours post PMSG with human chorionic gonadotropin (hCG) and immediately caged with adult males for mating. Five plugged female mice/group were sacrificed for the determination of ovulation rate. The remaining mated mice were sacrificed about 26 hours post hCG, ovaries excised and weighed and embryos harvested and cultured in Whitten’s medium (WM) supplemented with CZBt. In Experiments 2 and 3, (N = 10/Experiment) folliculogenesis and ovulation were induced in untreated mice followed by mating. Recovered embryos were either exposed continuously (Experiment 2) or intermittently (Experiment 3) to bioavailable HU (18 μg HU/mL of WM + CZBt) or WM + CZBt only (control). Treated mice sustained decreased ovarian wt, ovulation rate and circulating E2 compared with controls (P < 0.05). Fewer embryos retrieved from HU-treated mice developed to blastocyst stage (32%) compared with those from controls (60%; P < 0.05). Furthermore, continuous or intermittent in vitro exposures of embryos to HU also resulted in reduced development to blastocyst stage (continuous HU, 9 vs. control, 63%; P < 0.05; intermittent HU, 20 vs. control, 62%; P < 0.05) with embryos exposed continuously to HU in vitro fairing worse. Even though HU is well tolerated, our data suggest that it compromises folliculogenesis and the ability of generated embryos to develop. Therefore, designed studies with larger numbers of patients receiving HU during pregnancy, with longer follow-up of exposed children and more careful assessment of embryo/fetotoxic effects, are required before this agent can be promoted as safe in pregnancy.

The Safety of Ureteroscopy During Pregnancy: A Systematic Review and Meta-Analysis

We performed a literature review and analysis to compare the safety of ureteroscopic stone removal during pregnancy with findings from a set of contemporary studies of that procedure in nonpregnant patients. A systematic review of MEDLINE(R) and EMBASE(R) was done to identify all reports of ureteroscopic stone removal in pregnant women. Complications were stratified according to modified Clavien criteria. We then reviewed a contemporary, multi-national meta-analysis of ureteroscopic stone removal (American Urological Association/European Association of Urology 2007 Guideline for the Management of Ureteral Calculi) to define the complication rate in a series of nonpregnant patients. Complication rates in the 2 reviews were compared using Fisher's exact test. A total of 14 reports of ureteroscopic stone removal in pregnant women were identified, representing 108 patients. Nine complications were noted. By Clavien criteria 2 complications were level 1, 6 were level 2 and 1 was level 3. When compared to the multinational meta-analysis of ureteroscopy in nonpregnant women, there was no significant difference in the ureteral injury and urinary tract infection complication rates (p = 0.191 and 0.597, respectively). Our analysis shows that the safety of ureteroscopic stone removal in pregnant patients is not significantly different from the safety of that procedure in nonpregnant patients and in each cohort the complication rate is low. Therefore, ureteroscopic stone removal may reasonably be considered appropriate first line therapy in pregnant patients with stone disease.

Antithrombotic Therapy and Pregnancy: Consensus Report and Recommendations for Prevention and Treatment of Venous Thromboembolism and Adverse Pregnancy Outcomes

Duhl, A.J.; Paidas, M.J.; Ural, S.H.; Branch, W.; Casele, H.; Cox-Gill, J.; Hamersley, S.L.; Hyers, T.M.; Katz, V.; Kuhlmann, R.; Nutescu, E.A.; Thorp, J.A.; Zehnder, J.L. ; Pregnancy and Thrombosis Working GroupAuthor Information

Comment on: Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion: reply

Comment on: Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion: reply

Comment on: Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion

Objectives. We aimed to test the maternal and fetal outcome of SLE patients who suffered from recurrent spontaneous abortion (RSA) treated with intravenous immunoglobulin (IVIg) alone during pregnancy and whether the clinical response to IVIg treatment is accompanied by modifications of SLE-associated antibodies and of complement levels. Methods. Twelve SLE-RSA pregnant patients were treated with high-dose IVIg and compared with 12 SLE-RSA pregnant patients treated with prednisolone and NSAIDs. They were evaluated for the clinical response [lupus activity index-pregnancy (LAI-P) scale] and for ANA, anti-dsDNA, anti Ro/SS-A or La/SS-B, aCL, LAC, C4, C3 before and during pregnancy, and before and after each treatment course. Pregnancy outcome in the two groups was also evaluated. Results. The groups characteristics were homogeneous at the beginning of pregnancy. A beneficial clinical response following IVIg treatment was noted in all patients and mean LAI-P decreased from 0.72 +/- 0.43 at the beginning of pregnancy to 0.13 +/- 0.19 at the end of pregnancy (P < 0.0001). Antibodies and complement levels tended to normalize in most of the patients. These clinical and laboratory improvements were significant with respect to the control group. Pregnancy was successfully carried out in 12/12 (100%) SLE-RSA patients with a mean Apgar score of 8.92. Three patients in the control group got aborted (25%). Conclusions. IVIg has a high response rate among SLE-RSA pregnant patients and may be considered safe and effective.

Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion

We aimed to test the maternal and fetal outcome of SLE patients who suffered from recurrent spontaneous abortion (RSA) treated with intravenous immunoglobulin (IVIg) alone during pregnancy and whether the clinical response to IVIg treatment is accompanied by modifications of SLE-associated antibodies and of complement levels. Twelve SLE-RSA pregnant patients were treated with high-dose IVIg and compared with 12 SLE-RSA pregnant patients treated with prednisolone and NSAIDs. They were evaluated for the clinical response [lupus activity index-pregnancy (LAI-P) scale] and for ANA, anti-dsDNA, anti Ro/SS-A or La/SS-B, aCL, LAC, C4, C3 before and during pregnancy, and before and after each treatment course. Pregnancy outcome in the two groups was also evaluated. The groups characteristics were homogeneous at the beginning of pregnancy. A beneficial clinical response following IVIg treatment was noted in all patients and mean LAI-P decreased from 0.72 +/- 0.43 at the beginning of pregnancy to 0.13 +/- 0.19 at the end of pregnancy (P < 0.0001). Antibodies and complement levels tended to normalize in most of the patients. These clinical and laboratory improvements were significant with respect to the control group. Pregnancy was successfully carried out in 12/12 (100%) SLE-RSA patients with a mean Apgar score of 8.92. Three patients in the control group got aborted (25%). IVIg has a high response rate among SLE-RSA pregnant patients and may be considered safe and effective.

Chemoradiation therapy in pregnant patients treated for advanced-stage cervical carcinoma during the first trimester of pregnancy: report of two cases

Two patients treated using chemoradiation therapy (CRT) (with fetus in utero) for advanced-stage squamous cell cervical carcinoma diagnosed during the first trimester of pregnancy are reported. One patient with a stage IVA disease diagnosed at 12 weeks of gestation was treated by exclusive CRT with the fetus in utero. She recurred 20 months after the end of the treatment. The second patient had a stage IIB disease diagnosed at 12 weeks of gestation and was treated by CRT with the fetus in utero followed by completion surgery (radical hysterectomy and para-aortic lymphadenectomy) due to the presence of a suspicious residual disease. No residual disease was observed during the histologic analysis of hysterectomy and nodes specimens. This patient is alive and free of disease 24 months after surgery. Our observations could suggest that CRT in pregnant patients with fetus in utero is feasible without major short-term toxicity. Such management could be proposed in patients with a bulky cervical cancer diagnosed during the first trimester of the pregnancy. Management of the uterine evacuation depends on the local tumor spread.

Treatment of Wilson's disease: what are the relative roles of penicillamine, trientine, and zinc supplementation?

New options are available for the medical treatment of patients with Wilson's disease. Penicillamine is no longer the treatment of choice, as there is a growing experience with safer and more effective alternatives. Trientine may be the best choice for initial therapy in symptomatic patients requiring chelation therapy, and it may be even more effective when used in combination with zinc, which is recommended for maintenance therapy. Further studies are needed to determine the best therapy for pregnant patients with Wilson's disease, and whether combination therapy using trientine and zinc will be the next treatment of choice for all symptomatic patients with liver or neurologic disease.

Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?

The interaction of pregnancy and the rheumatic diseases varies, ranging from life-threatening conditions such as thromboembolic events and progressive renal disease in some autoimmune disorders, to minor flares of peripheral arthritis in inflammatory rheumatic disease. As a consequence, treatment strategy will vary according to the maternal or fetal compromise expected. All nonsteroidal anti-inflammatory drugs (NSAIDs), including high dose aspirin (acetylsalicylic acid), can cause adverse effects during pregnancy related to the inhibition of prostaglandin synthesis. Prolongation of gestation and labour, constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding are risks of third trimester exposure of pregnant women to all inhibitors of cyclo-oxygenase. Most of these adverse effects can be prevented by discontinuing NSAIDs 8 weeks prior to delivery. Low dose aspirin has not been associated with fetal or neonatal toxicity. Some corticosteroids such as prednisone and prednisolone do not readily cross the placenta and can be safely used during pregnancy as immunosuppressive drugs. Maternal complications related to corticosteroids may occur and close monitoring is therefore mandatory. There is limited information on the safety of disease-modifying antirheumatic drugs including gold, antimalarials, penicillamine (D-penicillamine), sulfasalazine and cyclosporin. Of these agents, sulfasalazine has the best record for tolerability and can be used by pregnant patients. Gold compounds and penicillamine should be discontinued when pregnancy is recognised. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine in patients requiring treatment with antimalarials. Use of cyclosporin may be an alternative to other therapy in pregnant patients with severe rheumatic disease. Indications for treatment with colchicine during pregnancy are few, except for familial Mediterranean fever. Azathioprine can be used when the maternal condition requires a cytotoxic drug during the first trimester. Cyclophosphamide, chlorambucil and methotrexate are contraindicated during pregnancy because of their teratogenic potential. Their use may be considered in late pregnancy if the mother has a life-threatening condition.

Management of Thromboembolic Disease Associated with Pregnancy

Our objective was to identify practice patterns of members of the Society of Perinatal Obstetricians with regard to the management of thromboembolic disease in pregnant women.We sent survey-questionnaires to members of the Society of Perinatal Obstetricians and requested information on antepartum and postpartum management of four clinical case scenarios. We also requested information on the evaluation of hypercoagulability and on the dosing and monitoring of heparin during pregnancy.We received 515 responses after a single mailing (47%). Most respondents utilize some form of anticoagulation in pregnant women with a history of thromboembolic disease, although there was variation in the duration and intensity of anticoagulation. Nearly all respondents (96%) use full anticoagulation with heparin for pregnant women with prosthetic heart valves. Most respondents evaluate pregnant women for hypercoagulable disorders who present with a thromboembolism or have a history of thromboembolic disease. There is considerable variation with respect to the dosing and monitoring of heparin therapy during pregnancy.Although most SPO members recommend anticoagulation in pregnant women with a history of venous thromboembolism, there is marked variation in the intensity, duration, and monitoring of heparin therapy in pregnant patients. Randomized prospective studies are needed to establish accurate recurrence risks and to evaluate the efficacy of anticoagulation in pregnant women with a history of venous thromboembolism.

Management of thromboembolic disease associated with pregnancy.

Our objective was to identify practice patterns of members of the Society of Perinatal Obstetricians with regard to the management of thromboembolic disease in pregnant women. We sent survey-questionnaires to members of the Society of Perinatal Obstetricians and requested information on antepartum and postpartum management of four clinical case scenarios. We also requested information on the evaluation of hypercoagulability and on the dosing and monitoring of heparin during pregnancy. We received 515 responses after a single mailing (47%). Most respondents utilize some form of anticoagulation in pregnant women with a history of thromboembolic disease, although there was variation in the duration and intensity of anticoagulation. Nearly all respondents (96%) use full anticoagulation with heparin for pregnant women with prosthetic heart valves. Most respondents evaluate pregnant women for hypercoagulable disorders who present with a thromboembolism or have a history of thromboembolic disease. There is considerable variation with respect to the dosing and monitoring of heparin therapy during pregnancy. Although most SPO members recommend anticoagulation in pregnant women with a history of venous thromboembolism, there is marked variation in the intensity, duration, and monitoring of heparin therapy in pregnant patients. Randomized prospective studies are needed to establish accurate recurrence risks and to evaluate the efficacy of anticoagulation in pregnant women with a history of venous thromboembolism.

Management of Thyroxine Therapy During Pregnancy

To review the management of thyroxine (T4) therapy in pregnant patients with hypothyroidism. The results of pertinent published studies are summarized, and practical recommendations are presented. The conditions for which T4 therapy is administered during pregnancy are the same as those in nonpregnant patients: hypothyroidism, thyrotropin or thyroid-stimulating hormone (TSH) control after surgical treatment of thyroid cancer, and, in selected patients, suppression treatment for postsurgical thyroid remnants, thyroid nodules, or goiter. Untreated hypothyroidism during pregnancy can potentially cause adverse effects in both mother and fetus. Up to 75% of T4-treated women with hypothyroidism require higher doses of T4 during pregnancy than before or after conception, to maintain serum TSH levels in the normal range. Otherwise, in a substantial percentage of these women, subnormal serum free T4 levels, TSH elevations >20 microIU/L, or both will develop. The mean T4 dose needed to correct hypothyroidism during pregnancy is about 150 microg/day, but individual dose requirements vary widely. The increment in T4 dose needed to normalize an increased TSH level in women taking T4 can be estimated from the serum TSH concentration during pregnancy. Increased TSH levels can appear as early as 4 to 8 weeks of gestation or as late as the third trimester. Although the optimal schedule is uncertain, assessing the TSH once each trimester seems reasonable. After pregnancy, the T4 dose should be reduced to the preconception level, and postpartum reassessment should be done at 6 to 12 weeks.

Thyroxine requirement during pregnancy for replacement therapy of hypothyroidism

We examined the dose requirements of thyroxine (T4) and desiccated thyroid during eight pregnancies of six women who had undergone total thyroidectomy for thyroid carcinoma. In five pregnancies from four patients treated with T4, serum free T4, which was measured by a newly developed radioimmunoassay, decreased during pregnancy but increased above the normal range after delivery. Consistent with these changes in free T4, serum TSH (measured by a highly sensitive immunoradiometric assay) increased during pregnancy but returned to an undetectable level after delivery, with one exception. The serum triiodothyronine (T3)-to-T4 ratio, which is related to peripheral conversion of T4 to T3, was lower in patients treated with T4 than in normal controls, regardless of pregnancy. The ratio decreased further during pregnancy, and so relative deficiency of T3 during pregnancy was suspected, especially in T4-treated patients. On the other hand, in two pregnancies from two other patients treated with desiccated thyroid at a dose most equivalent to that of T4, serum free T4 decreased to a low-normal value during gestation but returned to the normal range after delivery, whereas serum TSH scarcely changed during pregnancy. These findings indicate that replacement therapy for pregnant patients with hypothyroidism after total thyroidectomy should include an increased dose of T4; in contrast, the dose of desiccated thyroid need not be changed.

Serial impedance plethysmography in pregnant patients with clinically suspected deep-vein thrombosis. Clinical validity of negative findings

STUDY OBJECTIVE To determine the safety of withholding anticoagulant therapy in pregnant patients with clinically suspected deep-vein thrombosis who have negative results by serial impedance plethysmography. DESIGN Prospective study evaluating prognosis by long-term follow-up to 3 months postpartum in all patients. SETTING University-affiliated community hospital and referral center. PATIENTS One hundred fifty-two consecutive pregnant patients referred with clinically suspected deep-vein thrombosis. All patients completed the study. INTERVENTIONS Anticoagulant therapy was withheld in 139 patients negative by serial impedance plethysmography, and the patients were followed long term. MEASUREMENTS AND MAIN RESULTS None of 139 patients (0%; 95% CI, 0% to 2.6%) had symptomatic pulmonary embolism or recurrent venous thrombosis. CONCLUSIONS The findings establish the safety of withholding anticoagulant therapy in pregnant patients who have negative results after serial impedance plethysmography. Sufficient patients were entered to provide narrow confidence intervals on the outcomes observed in patients with negative findings by impedance plethysmography. These findings are similar to those seen after venography in symptomatic patients. These data extend the role of non-invasive testing in patients with clinically suspected deep-vein thrombosis to the pregnant symptomatic patient.