Gynecology_Novak

Gynecology_Novak. The importance of obtaining karyotypic analysis from tissues obtained after pregnancy demise in a woman experiencing recurrent losses cannot be overemphasized. Results may suggest karyotypic anomalies in the parents. The documentation of aneuploidy may have important prognostic implications and may direct future interventions. Cost analysis has demonstrated that karyotypic analysis is financially prudent among patients with histories of recurrent pregnancy loss (342). Obtaining karyotypic data from aborted specimens incurs many difficulties in culturing cells from tissues that may have significant inﬂammation or necrosis and contamination of specimens with maternal cells. Efforts to develop methods that avoid such difficulties include the application of comparative genomic hybridization technology to recurrent pregnancy loss (343). This technology was used successfully on archived and paraffin-embedded pregnancy tissues (344). In the future, fetal karyotype assessment may also be


Gynecology_Novak

Gynecology_Novak. technology to recurrent pregnancy loss (343). This technology was used successfully on archived and paraffin-embedded pregnancy tissues (344). In the future, fetal karyotype assessment may also be performed using DNA isolated from nucleated fetal erythrocytes in maternal blood (345)


Gynecology_Novak

Gynecology_Novak. Advances in the treatment of patients with recurrent pregnancy loss have been regrettably slow. Despite a rapid expansion in understanding the molecular and subcellular mechanisms involved in implantation and early pregnancy maintenance, extension of these concepts to prevention of recurrent early pregnancy loss has lagged. In addition to these limitations, progress toward treatment of most causes of recurrent pregnancy loss has been hampered by a variety of factors. The condition itself has been inconsistently defined. The results of clinical trials involving recurrent pregnancy loss patients therefore are nearly impossible to compare and evaluate. Trial design is frequently substandard, with lack of rationale, lack of appropriate controls, and poor statistical analysis, limiting the ability to draw rational conclusions from reported results. Finally, epidemiologic data indicate that most patients with a history of recurrent pregnancy loss will, in fact, have a successful pregnancy


Gynecology_Novak

Gynecology_Novak. to draw rational conclusions from reported results. Finally, epidemiologic data indicate that most patients with a history of recurrent pregnancy loss will, in fact, have a successful pregnancy the next time they conceive (7). For these reasons, with few exceptions, most therapies for recurrent pregnancy loss must be considered experimental. Until further study is completed, treatment protocols involving these therapies should be undertaken only with informed consent and in the setting of a well-designed, double-blind, placebo-controlled clinical trial.


Gynecology_Novak

Gynecology_Novak. Common therapeutic options available for patients with recurrent pregnancy loss include the use of donor oocytes or sperm, the use of preimplantation genetic diagnosis, the use of antithrombotic interventions, the repair of anatomic anomalies, the correction of any endocrine abnormalities, the treatment of infections, and a variety of immunologic interventions and drug treatments. Psychologic counseling and support should be recommended for all patients.


Gynecology_Novak

Gynecology_Novak. Recent evidence suggests that, in women with a history of three or more spontaneous pregnancy losses, a subsequent pregnancy loss has a 58% chance of chromosomal abnormality (15). Among women with recurrent pregnancy loss who are age 35 or older, the aneuploidy rate is much higher (8). The majority of chromosomal abnormalities identified in miscarriages are autosomal trisomies and considered to result from maternal nondisjunction. Maternal age appears as a consistent and important risk factor for trisomy in the majority of studies. There are several options for patients who suffer from recurrent pregnancy loss who have an identified miscarriage due to trisomy. The first is to conceive again without any specific change in medical management, as these abnormalities are sporadic and unlikely to recur. Studies examining patients with recurrent pregnancy loss show that women who miscarry chromosomally abnormal conceptions are more likely to achieve a live birth with subsequent pregnancy


Gynecology_Novak

Gynecology_Novak. to recur. Studies examining patients with recurrent pregnancy loss show that women who miscarry chromosomally abnormal conceptions are more likely to achieve a live birth with subsequent pregnancy than those who miscarry chromosomally normal conceptions (13,346). A second involves preimplantation genetic diagnosis (PGD) or preimplantation screening, and a third involves the use of donor gametes.


Gynecology_Novak

Gynecology_Novak. Because chromosomal abnormalities are the most commonly identified cause of miscarriage, some have argued that the use of PGD is indicated for patients with recurrent pregnancy loss. PGD involves the removal of a single cell from an in vitro–matured embryo. Genetic testing can be performed on this cell to examine chromosomal composition for the presence of single gene disorders (e.g., cystic fibrosis) or abnormalities in chromosome number and morphology. Embryos that are diagnosed with genetic abnormalities would be discarded and only those embryos with normal results would be considered appropriate for transfer into the uterus. Use of PGD in patients with known heritable genetic disorders (e.g., cystic fibrosis, X-linked disorders) is presently in widespread use in internationally recognized assisted reproductive technology centers.


Gynecology_Novak

Gynecology_Novak. The use of PGD has the potential to reduce the incidence of pregnancy loss arising from a genetic etiology. However, definitive studies in this population have not yet been done. The use of PGD requires the patient to go through an IVF cycle to obtain embryos for biopsy, and the impact of the biopsy technique itself on the embryos’ viability is not known at this time. Although there are several retrospective studies showing reduced miscarriage rates with this technique, several prospective trials using the outcome of successful pregnancy per started cycle fail to show any benefit (347–357). IVF is invasive and costly and many patients with recurrent pregnancy loss conceive quickly without intervention and have a high likelihood of live birth with their subsequent pregnancy. Therefore, the optimal control group for a study of IVF PGD in the recurrent pregnancy loss population is debated. Should it be natural conceptions or IVF without PGD? Finally, the prognosis for a patient with


Gynecology_Novak

Gynecology_Novak. the optimal control group for a study of IVF PGD in the recurrent pregnancy loss population is debated. Should it be natural conceptions or IVF without PGD? Finally, the prognosis for a patient with recurrent pregnancy loss does seem to be linked to the chromosome analysis of prior miscarriages. Recurrent pregnancy loss patients who miscarry chromosomally abnormal embryos, seem to have better prognosis than those who miscarry chromosomally normal conceptions, again arguing for expectant management for recurrent pregnancy loss patients with a history of aneuploid loss. On the other hand, patients with poorer prognosis are those who miscarry chromosomally normal embryos and therefore would not benefit from PGD. The efficacy of PGD in the treatment of patients with recurrent pregnancy loss continues to be investigated, and the method of embryo biopsy and genetic testing continues to evolve (355,356). As these techniques improve and the understanding of aneuploidy and recurrence improves,


Gynecology_Novak

Gynecology_Novak. to be investigated, and the method of embryo biopsy and genetic testing continues to evolve (355,356). As these techniques improve and the understanding of aneuploidy and recurrence improves, there may be a subset of recurrent pregnancy loss patients, such as carriers of parental translocations, who might benefit from this intervention. At this time it cannot be recommended for all patients with a history of recurrent pregnancy loss.


Gynecology_Novak

Gynecology_Novak. The third approach is to use donor eggs or sperm. This treatment is particularly useful for patients with parental genetic factors and recurrent pregnancy loss, for example, a patient with Robertsonian translocations involving homologous chromosomes. In these patients, their genetic anomaly always results in unbalanced gametes, and the use of donor oocyte or donor sperm is recommended. Use of donor gametes among patients with a history of recurrent pregnancy loss can be useful in other cases where couples are at higher risk for unbalanced offspring because of carrying other forms of chromosomal rearrangements, such as reciprocal translocations or advanced maternal age. In these cases use of donor gametes was demonstrated to be as effective as its use in matched patients without such a history (358). In all cases of balanced translocations or embryonic aneuploidy, genetic counseling is recommended.


Gynecology_Novak

Gynecology_Novak. Anatomic Anomalies Hysteroscopic resection represents state-of-the-art therapy for submucous leiomyomas, intrauterine adhesions, and intrauterine septa. This approach appears to limit postoperative sequelae while maintaining efficacy in terms of reproductive outcome (72,76,77,358– 362). Use may be safely extended to patients with DES exposure, hypoplastic uteri, and complicated septal anomalies (76,77,363). Attempts to improve on standard hysteroscopic metroplasty, which is typically performed in the operating room using general anesthesia, often with laparoscopic guidance, are under investigation. Ultrasonographically guided transcervical metroplasty is reported to be safe and effective (359). Ambulatory, office-based procedures, including septum resection under ﬂuoroscopic guidance, are attractive options (360).


Gynecology_Novak

Gynecology_Novak. For patients with a history of loss secondary to cervical incompetence, placement of a cervical cerclage is indicated. This is usually performed early in the second trimester after documentation of fetal viability. Cervical cerclage should be considered as a primary intervention for women with DES-associated uterine anomalies.


Gynecology_Novak

Gynecology_Novak. Some investigators have proposed the use of ovulation induction for the treatment of recurrent pregnancy loss (361,362). The theory behind its use in these patients rests on hypotheses that ovulation induction is associated with healthier oocytes. Healthier oocytes, in turn, may decrease the incidence of luteal phase insufficiency, which should result in improved pregnancy maintenance. This approach grossly oversimplifies the mechanisms involved in implantation and early pregnancy maintenance. Until appropriately studied, use of empiric ovulation induction for treatment of unexplained recurrent pregnancy loss should be viewed with caution. Evidence from small studies indicates such use is not effective (361). Still, use of ovulation induction in some subsets of patients with recurrent pregnancy loss could be of benefit. For instance, stimulating folliculogenesis with ovulation induction or luteal phase support with progesterone should be considered for women with luteal phase


Gynecology_Novak

Gynecology_Novak. pregnancy loss could be of benefit. For instance, stimulating folliculogenesis with ovulation induction or luteal phase support with progesterone should be considered for women with luteal phase insufficiency. The efficacy of these therapies, however, is not substantiated (363). Ovulation induction might also be beneficial for women with hyper-androgen and LH hypersecretion disorders, especially following pituitary desensitization with gonadotropin-releasing hormone agonist therapy (112). This treatment remains controversial because the only large, prospective, randomized controlled trial to date reports no therapeutic efficacy; none for prepregnancy pituitary suppression nor for luteal phase progesterone supplementation (364).


Gynecology_Novak

Gynecology_Novak. Links between PCOS, hyperandrogenism, hyperinsulinemia, and recurrent pregnancy loss make use of insulin-sensitizing agents in the treatment of recurrent pregnancy loss associated with PCOS attractive (89–92). Although further study is needed, there are an increasing number of reports that support its use for this application (365,366). Prepregnancy glycemic control may be particularly important for women with overt diabetes mellitus (93,95). Thyroid hormone replacement with Synthroid may be helpful in cases of hypothyroidism. There are data indicating that thyroid hormone therapy may be of some benefit in euthyroid recurrent loss patients with antithyroid antibodies and possibly even in all pregnant women with “euthyroid” TSH levels between 2.5 and 5.0 mIU/L (98–100,272). There does not appear to be a place in the medical management of recurrent pregnancy loss for adding bromocriptine in women who do not have a prolactin disorder.


Gynecology_Novak

Gynecology_Novak. Infections Empiric antibiotic treatment has been used for couples with recurrent abortion. Its efficacy is unproven. Elaborate testing for infectious factors among recurrent pregnancy loss patients and use of therapeutic interventions is not justified unless a patient is immunocompromised or a specific infection has been documented (113). For cases in which an infectious organism has been identified, appropriate antibiotics should be administered to both partners, followed by posttreatment culture to verify eradication of the infectious agent before attempting conception.


Gynecology_Novak

Gynecology_Novak. Immunologic Factors Immune-mediated recurrent pregnancy loss has received more attention than any other single etiologic classification of recurrent pregnancy loss. Nevertheless, the diagnosis and subsequent treatment of the majority of cases remains unclear (102,367–370). Most therapies for proposed immune-related recurrent pregnancy loss must be considered experimental. As stated earlier, it is known that the developing conceptus contains paternally inherited gene products and Immunostimulating Therapies: Leukocyte Immunization tissue-specific differentiation antigens, and that there is maternal recognition of these antigens (216–218). Historically, it has been speculated that either inappropriately weak immune responses to these antigens or unusually strong responses could result in early pregnancy loss. As a consequence, both immunostimulating and immunosuppressive therapies have been proposed, but no conclusions about efficacy can be drawn.


Gynecology_Novak

Gynecology_Novak. Stimulation of the maternal immune system using alloantigens on either paternal or pooled donor leukocytes has been promoted for patients with immunologic recurrent pregnancy loss, and a number of reports support possible mechanisms for potential therapeutic value (371–375). Both individual clinical trials and meta-analyses, however, continue to report conﬂicting results concerning the efficacy of leukocyte alloimmunization in patients with recurrent pregnancy loss (25,364,365,372,376–379). This most certainly reﬂects the remarkable heterogeneity in study design, patient selection, and therapeutic protocols, as well as the typically small numbers of enrolled subjects in these investigations. One of the largest trials evaluating the efficacy of leukocyte immunization in patients with unexplained recurrent pregnancy loss is a part of the Recurrent Miscarriage (REMIS) study (380). This investigation was large (over 90 patients per treatment arm), prospective, placebo controlled,


Gynecology_Novak

Gynecology_Novak. unexplained recurrent pregnancy loss is a part of the Recurrent Miscarriage (REMIS) study (380). This investigation was large (over 90 patients per treatment arm), prospective, placebo controlled, randomized, and double blinded. It demonstrated no efficacy for paternal leukocyte immunization in couples with unexplained recurrent pregnancy loss. The most recent and best of the meta-analyses definitively rejects use of this therapy in patients with recurrent loss (381). Leukocyte immunization also poses a significant risk to both the mother and her fetus (344,345,382). Several cases of graft-versus-host disease, severe intrauterine growth retardation, and autoimmune and isoimmune complications have been reported (25,378,382–386). In addition, alloimmunization to platelets contained in the paternal leukocyte preparation is associated with cases of potentially fatal fetal thrombocytopenia. The routine use of this therapy for recurrent abortion cannot be clinically justified at this time.


Gynecology_Novak

Gynecology_Novak. leukocyte preparation is associated with cases of potentially fatal fetal thrombocytopenia. The routine use of this therapy for recurrent abortion cannot be clinically justified at this time. The procedure should be performed only as part of an appropriately controlled trial using informed consent. All costs associated with this treatment should be borne by the investigators until its efficacy has been demonstrated.


Gynecology_Novak

Gynecology_Novak. Other immunostimulating therapies have been proposed and abandoned. Intravenous preparations consisting of syncytiotrophoblast microvillus plasma membrane vesicles have been used to mimic the fetal cell contact with maternal blood that normally occurs in pregnancy (387). The efficacy of this therapy has not been established (381,387,388). The use of third-party seminal plasma suppositories has also been attempted, based on the misconception that TLX was part of an idiotype–anti-idiotype control system (389,390). Third-party seminal plasma suppositories for recurrent abortion have no scientifically credible rationale and should not be used.


Gynecology_Novak

Gynecology_Novak. Immunosuppressive and other immunoregulating therapies have been advocated for cases in which abortion was believed to result from antiphospholipid antibodies or inappropriate cellular immunity toward the implanting fetus. Again, study design problems, including small numbers of recruited patients, lack of prestratification by maternal age and number of prior losses before randomization, and other methodologic and statistical inaccuracies preclude definitive statements regarding therapeutic efficacy for most of the proposed immunosuppressive approaches.


Gynecology_Novak

Gynecology_Novak. Intravenous Immunoglobulin Intravenous immunoglobulins (IVIgs) are composed of pooled samples of immunoglobulins harvested from a large number of blood donors. Studies on the use of IVIg therapy in the treatment of recurrent pregnancy loss are based on the theory that some recurrent pregnancy loss patients have an overzealous immune reactivity to their implanting fetus. IVIgs do have immunosuppressive effects, but the mechanisms underlying this immune modulation are only partially understood. These mechanisms may include decreased autoantibody production and increased autoantibody clearance, T-cell and Fc-receptor regulation, complement inactivation, enhanced T-cell suppressor function, decreased T-cell adhesion to the extracellular matrix, and downregulation of TH1 cytokine synthesis (391–394). Based on a large number of relatively small studies using a variety of treatment protocols, there remains no conclusive evidence to suggest that use of IVIg in the treatment of patients with


Gynecology_Novak

Gynecology_Novak. Based on a large number of relatively small studies using a variety of treatment protocols, there remains no conclusive evidence to suggest that use of IVIg in the treatment of patients with unexplained (and presumed immunologic) recurrent pregnancy loss has any benefit (383,395–399). This includes a recent trial using IVIg in women with secondary recurrent pregnancy loss that was ended early because interim analyses revealed no effect (395). The Cochrane review of immune therapy for recurrent pregnancy loss also addressed IVIg therapy and reported that its use did not alter pregnancy outcomes in patients with otherwise unexplained recurrent pregnancy loss (381,388). Improved posttreatment pregnancy rates may be seen, however, when IVIg is used in those specific patients with autoimmune-mediated pregnancy loss associated with APS (400,401). Therapy with IVIgs for recurrent pregnancy loss is expensive, invasive, and time-consuming, requiring multiple intravenous infusions over the


Gynecology_Novak

Gynecology_Novak. pregnancy loss associated with APS (400,401). Therapy with IVIgs for recurrent pregnancy loss is expensive, invasive, and time-consuming, requiring multiple intravenous infusions over the course of pregnancy (402). Side effects of IVIg therapy include nausea, headache, myalgias, and hypotension. More serious adverse effects include anaphylaxis (particularly in patients with IgA deficiency) (403).


Gynecology_Novak

Gynecology_Novak. Progesterone As mentioned earlier, progesterone also has known immunosuppressive effects (220–223,227,228). A number of studies using in vitro cellular systems relevant to the maternal–fetal interface have now demonstrated that progesterone either inhibits TH1 immunity or causes a shift from TH1-to TH2-type responses (208,227,228,404). Although the mechanism of action remains unclear, a recent Cochrane review concluded that progesterone supplementation was effective in the treatment of recurrent, but not isolated, spontaneous pregnancy loss (405,406). The review makes no recommendations on dosage, timing of initiation, nor route of progesterone administration. Progesterone has been administered both intramuscularly and intravaginally for the treatment of recurrent pregnancy loss. It is thought that vaginal administration may increase local, intrauterine concentrations of progesterone better than systemic administration. Vaginal formulations may therefore provide a better method of


Gynecology_Novak

Gynecology_Novak. thought that vaginal administration may increase local, intrauterine concentrations of progesterone better than systemic administration. Vaginal formulations may therefore provide a better method of attaining local immunosuppressive levels of progesterone while averting any adverse systemic side effects.


Gynecology_Novak

Gynecology_Novak. Intralipid Infusion The relative paucity of inﬂammatory diseases among the Greenland Inuit population, who consume a diet high in fish oils, led investigators to study the immune modulatory effects of lipid emulsions in total parenteral nutrition preparations for preoperative patients and for burn and trauma victims (406–409). The wide range of demonstrated effects, including lipid preparations that reduced natural killer cell activity, reduced monocytes proinﬂammatory cytokine production and increased susceptibility to infection, led investigators to hypothesize, as early as 1994, that lipid infusions might promote an immune environment that would favor pregnancy maintenance (410). Since that time, a small number of publications have addressed the effects of lipid infusions (Intralipid) in women with a history of pregnancy loss (411,412). These investigations have demonstrated a decrease in peripheral natural killer cell activity in women treated with one to three infusions of


Gynecology_Novak

Gynecology_Novak. in women with a history of pregnancy loss (411,412). These investigations have demonstrated a decrease in peripheral natural killer cell activity in women treated with one to three infusions of Intralipid. This effect lasted from 4 to 9 weeks after the last infusion (411). The authors did not address NK cell cytokine secretion patterns nor did they assay decidual NK cell function. Despite this paucity of data, Intralipid infusions are being administered to recurrent pregnancy loss patients with increasing frequency. The existing data do not support this practice. At this time, Intralipid infusions in recurrent pregnancy loss patients should only be administered under an institutional review board–approved protocol and in a study setting. They should not generate clinical income.


Gynecology_Novak

Gynecology_Novak. TNF-α Inhibition Interest in the potent proinﬂammatory cytokine, TNF-α, as a mediator of pregnancy loss came out of the description of the TH1 and TH2 paradigm (209). Over the past 10 years, there have been several publications that link maternal serum TNF-α levels and activating TNF-α gene promoter polymorphisms to recurrent pregnancy loss (413–415). The development of antagonists of TNF-α in the form of blocking antibodies (adalimumab, inﬂiximab) and inhibitory recombinant proteins (etanercept) has allowed for successful treatment of several autoimmune disorders, including rheumatoid arthritis, psoriasis, and Crohn’s disease. Their use, however, has not been associated with universally positive outcomes and may worsen some disorders, including multiple sclerosis (416). These products are associated with rare but worrisome side effects, including liver failure, aplastic anemia, interstitial lung disease, and anaphylaxis (417). Although there exists only a single, small,


Gynecology_Novak

Gynecology_Novak. products are associated with rare but worrisome side effects, including liver failure, aplastic anemia, interstitial lung disease, and anaphylaxis (417). Although there exists only a single, small, retrospective, observational, nonrandomly assigned case series that involved treatment of recurrent pregnancy loss patients with inhibitors of TNF-α, these positive preliminary results have led a growing number of clinics to offer this therapy to patients, often at a significant cost (418). The safety of these compounds in pregnancy has not been appropriately studied, and preliminary reports associating exposure to TNF-α inhibitors during early pregnancy to fetal VACTERL syndrome is concerning (419). As with Intralipid therapy, use of TNF-α inhibition for the treatment of recurrent pregnancy loss should only be administered under an institutional review board–approved protocol in a study setting and should not generate clinical income.


Gynecology_Novak

Gynecology_Novak. Other immunoregulating therapies theoretically useful in treating recurrent pregnancy loss include the use of cyclosporine, pentoxifylline, and nifedipine, although maternal and fetal risks with these agents preclude their clinical use. Plasmaphoresis has also been used to treat women with recurrent abortion and antiphospholipid antibodies (420). Generalized immunosuppression with corticosteroids, such as prednisone, has been advocated during pregnancy for women with recurrent losses and chronic intervillositis and those with recurrent pregnancy loss and APS (421). Although corticosteroids have shown some treatment promise in these patients, maternal and fetal side effects and the availability of alternative therapies have limited their use (421,422). That said, in response to successful use of prednisolone in a woman with 10 prior losses, Quenby et al. have demonstrated that such treatment decreases the number of uterine NK cells in the peri-implantation decidua among women with a


Gynecology_Novak

Gynecology_Novak. use of prednisolone in a woman with 10 prior losses, Quenby et al. have demonstrated that such treatment decreases the number of uterine NK cells in the peri-implantation decidua among women with a history of recurrent loss and have plans for a trial of therapy using live birth as a secondary outcome (423–425). The efficacy and side effects of prednisone plus low-dose aspirin was examined in a recent, large, randomized, placebo-controlled trial treating patients with autoantibodies and recurrent pregnancy losses. Pregnancy outcomes for treated and control patients were similar; however, the incidence of maternal diabetes and hypertension and the risk of premature delivery were all increased among those treated with prednisone and aspirin (426).


Gynecology_Novak

Gynecology_Novak. Antithrombotic Therapy Therapy for patients with recurrent pregnancy losses associated with either APS or other thrombophilic disorders has now shifted toward the use of antithrombotic medications. Unlike immunosuppressive treatments, this approach appears to address the effect (hypercoagulability), but not the underlying cause (e.g., genetic, APS) of recurrent pregnancy loss. However, there are reports that heparin, one typical anticoagulant, may exert direct immunomodulatory effects by binding to antiphospholipid antibodies and may decrease movement of inﬂammatory cells to sites of alloantigen exposure (427,428). The combined use of low-dose aspirin (75 to 80 mg per day) and subcutaneous unfractionated heparin (5,000 to 10,000 units twice daily) during pregnancy has been best studied among women with APS and appears to be efficacious (429–433). A typical regimen for women with antiphospholipid antibody syndrome would include use of aspirin (80 mg every day) beginning with any


Gynecology_Novak

Gynecology_Novak. among women with APS and appears to be efficacious (429–433). A typical regimen for women with antiphospholipid antibody syndrome would include use of aspirin (80 mg every day) beginning with any attempts to conceive. After pregnancy has been confirmed, 10,000 IU unfractionated sodium heparin is administered subcutaneously twice daily, throughout gestation. An aPTT should be obtained weekly and dosages of heparin should be adjusted until anticoagulation is achieved. Patients using this therapy should be treated in conjunction with a perinatologist because of their increased risks for preterm labor, premature rupture of the membranes, intrauterine growth restriction, intrauterine fetal demise, and pre-eclampsia. Other potential risks include gastric bleeding, osteopenia, and abruptio placenta.


Gynecology_Novak

Gynecology_Novak. Attempts have recently been made to extend the finding that antithrombotic therapy is efficacious when used to treat patients with APS and recurrent pregnancy loss in a number of directions. These directions include the use of low-molecular weight heparins (LMWH), the use of antithrombotic therapy in non-APS patients with thrombophilia and recurrent pregnancy loss, and even its use among recurrent pregnancy loss patients without thrombophilia (unexplained recurrent losses).


Gynecology_Novak

Gynecology_Novak. New formulations of heparin, termed low-molecular weight heparins, have been demonstrated to be superior to unfractionated heparin in the treatment of many clotting disorders (434–436). LMWH has the advantage of an increased antithrombotic ratio when compared with unfractionated heparin. This results in improved treatment of inappropriate clotting but fewer bleeding side effects. In addition, LMWH has been associated with a decreased incidence of thrombocytopenia and osteoporosis when compared with its unfractionated counterpart. Finally, LMWH has a long half-life and requires less frequent dosing and monitoring, thereby improving patient compliance. LMWH appear to be safe for use in pregnancy, and LMWH has shown promise when combined with low-dose aspirin in the treatment of recurrent pregnancy loss associated with APS (430,435,437). Only a few studies have compared the use of unfractionated heparin and aspirin to LMWH and aspirin in the treatment of women with APS and adverse


Gynecology_Novak

Gynecology_Novak. pregnancy loss associated with APS (430,435,437). Only a few studies have compared the use of unfractionated heparin and aspirin to LMWH and aspirin in the treatment of women with APS and adverse pregnancy outcomes (433,438). The therapies had similar effects in one study (438). A meta-analysis suggested that unfractionated heparin was superior to LMWH, however, there was significant heterogenicity between studies (433). Efficacy has been suggested for LMWH treatment for patients with recurrent pregnancy loss associated with other thrombophilias, including activated protein C resistance associated with factor V Leiden, mutations in the promoter region of the prothrombin gene, and decreases in protein C and protein S activities (63,439–441). The use of LMWH for this indication appears to have an excellent safety profile for mother and fetus (437,442,443) .


Gynecology_Novak

Gynecology_Novak. The prophylactic use of daily-low dose aspirin has become common practice within the lay public based on its perceived cardiovascular effects combined with its low incidence of side effects. Its sole use in the treatment of recurrent pregnancy loss has likewise gained momentum, and many patients with histories of recurrent loss will either be self-prescribing this therapy or will inquire about its usefulness. At present, there are no good data supporting its use either in patients with heritable thrombophilias or in the general recurrent pregnancy loss population. Although studies are small, the use of low-dose aspirin alone has not been shown to be effective in the treatment of recurrent pregnancy loss associated with APS (431,444,445). When used in these patients, it should be in combination with unfractionated or LMWH. Large randomized prospective trials examining the empiric use of aspirin alone or in combination with prophylactic doses of heparin have shown no benefit of these


Gynecology_Novak

Gynecology_Novak. with unfractionated or LMWH. Large randomized prospective trials examining the empiric use of aspirin alone or in combination with prophylactic doses of heparin have shown no benefit of these therapies in unexplained recurrent pregnancy loss (445). In addition, the use of aspirin in early pregnancy has been called into question with reports of an increased incidence of isolated spontaneous pregnancy loss among women who used this medication (316,317). However, these reports are poorly designed and do not adequately address the level of aspirin exposure (81 mg vs. 325 mg). Although reviews have touted the overall safety of aspirin in pregnancy, outside of use in combination with heparin for patients with recurrent pregnancy loss and APS, this medication should be used only with justification in the well-informed patient during early pregnancy (446).


Gynecology_Novak

Gynecology_Novak. More directed antithrombotic therapies have also been described for the treatment of recurrent pregnancy loss among patients with thrombophilias. For instance, the use of protein C concentrates has been reported to be associated with favorable pregnancy outcome in a patient with a history of thrombosis, recurrent fetal losses, and protein C deficiency (447). As mentioned previously, vitamins B6,B12, and folate are important in homocysteine metabolism, and hyperhomocysteinemia is linked to recurrent pregnancy loss (21,23,38,66,68,72). Women with recurrent pregnancy loss and isolated fasting hyperhomocysteinemia should be offered supplemental folic acid (0.4 to 1.0 mg per day), vitamin B6 (6 mg per day), and possibly vitamin B12 (0.025 mg per day) (448–451). Fasting homocysteine levels should be retested after treatment. If levels are normalized or remain only marginally elevated, no further therapy is necessary. Homocysteine levels will predictably decrease during pregnancy.


Gynecology_Novak

Gynecology_Novak. Treatment of women with recurrent pregnancy loss and an identified inherited or acquired thrombophilia should be based on accompanying history. Currently, there are no prospective controlled trials examining the benefit of anticoagulation for the prevention of miscarriage in the absence of APS, and, therefore, anticoagulation recommendations for patients with inherited thrombophilias are based on individualized risk of venous thromboembolic events in pregnancy (28). If a venous thromboembolic event occurs during the index pregnancy, posthospi talization management requires therapeutic anticoagulation. UFH: 10,000 to 15,000 U subcutaneous every 8 to 12 hours (monitor to keep aPTT 1.5 to 2.5 times normal) OR LMWH: enoxaparin 40 to 80 mg subcutaneous twice a day or dalteparin 5,000 to 10,000 U subcutaneous twice a day). Consider monitoring trough factor Xa levels in the third trimester.


Gynecology_Novak

Gynecology_Novak. LMWH: enoxaparin 40 to 80 mg subcutaneous twice a day or dalteparin 5,000 to 10,000 U subcutaneous twice a day). Consider monitoring trough factor Xa levels in the third trimester. If there is a personal history of venous thromboembolic events (particularly in a previous pregnancy or with hormonal contraceptive use) or a strong thrombophilic family history, treat with therapeutic anticoagulation. Thrombotic risk is greatest during the postpartum period. Anticoagulation should be reinitiated after delivery in doses reﬂecting predelivery treatment regimens. Postpartum anticoagulation should be continued for 6 to 12 weeks postpartum (435). Women may continue injectable therapy or transition to oral anticoagulants (e.g., coumarin). Use of heparin or of coumarin derivatives does not prohibit breastfeeding.


Gynecology_Novak

Gynecology_Novak. Psychological Support There is no doubt that experiencing both isolated and recurrent losses can be emotionally devastating. The risk of major depression is increased greater than twofold among women with spontaneous pregnancy loss; in most women it arises in the first weeks following delivery (452). A caring and empathetic attitude is prerequisite to all healing. The acknowledgment of the pain and suffering couples have experienced as a result of recurrent abortion can be a cathartic catalyst enabling them to incorporate their experience of loss into their lives rather than their lives into their experience of loss (112). Referrals to support groups and counselors should be offered. Self-help measures, such as meditation, yoga, exercise, and biofeedback may also be useful.


Gynecology_Novak

Gynecology_Novak. The prognosis for successful pregnancy depends both on the potential underlying cause of pregnancy loss and (epidemiologically) on the number of prior losses (Table 33.4). As previously discussed, epidemiologic surveys indicate that the chance of a viable birth even after four prior losses may be as high as 60%. Depending on the study, the prognosis for successful pregnancy in couples with a cytogenetic etiology for reproductive loss varies from 20% to 80% (453– 455). Women with corrected anatomical anomalies may expect a successful pregnancy in 60% to 90% of cases (74,453,456–459). A success rate higher than 90% has been reported for women with corrected endocrinologic abnormalities (454). Between 70% to 90% of pregnancies reported among women receiving therapy for antiphospholipid antibodies have been viable (460,461).


Gynecology_Novak

Gynecology_Novak. Many forms of pre-or postconceptional tests have been proposed to help predict pregnancy outcome (201,219,327,462,463); none have been fully substantiated in large, prospective trials. The documentation of fetal cardiac activity on ultrasound may offer prognostic value; however, it appears that its predictions may be greatly affected by any underlying diagnosis. In one study, the live birth rate following documentation of fetal cardiac activity between 5 to 6 weeks from the last menstrual period was approximately 77% in women with two or more unexplained spontaneous abortions (464). It may be important to note that the majority of the patients in this study had evidence of inappropriate antitrophoblast cellular immunity. Others have shown that 86% of patients with antiphospholipid antibodies and recurrent pregnancy loss had fetal cardiac activity detected prior to subsequent demise (465). A prospective, longitudinal, observational study of 325 patients with unexplained recurrent


Gynecology_Novak

Gynecology_Novak. and recurrent pregnancy loss had fetal cardiac activity detected prior to subsequent demise (465). A prospective, longitudinal, observational study of 325 patients with unexplained recurrent pregnancy losses demonstrated that only 3% of 55 miscarriages occurred following the detection of fetal cardiac activity using transvaginal ultrasonography (466).


Gynecology_Novak

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