Genetic diagnostic technologies are rapidly changing the way medicine is practiced. Preimplantati... more Genetic diagnostic technologies are rapidly changing the way medicine is practiced. Preimplantation genetic testing is a well established application of genetic testing within the context of in vitro fertilization cycles. It involves obtaining a cell(s) from a developing embryo in culture, which is then subjected to genetic diagnostic analysis; the resulting information is used to guide which embryos are transferred into the uterus. The potential applications and use of this technology have increased in recent years. Experts agree that preimplantation genetic diagnosis is clinically appropriate for many known genetic disorders. However, some applications of such testing, such as preimplantation genetic screening for aneuploidy, remain controversial. Clinical data suggest that preimplantation genetic screening may be useful, but further studies are needed to quantify the size of the effect and who would benefit most.
Obstetrics and Gynecology Clinics of North America, 2015
The desire to reproduce is one of the strongest human instincts. Many men and women in our societ... more The desire to reproduce is one of the strongest human instincts. Many men and women in our society may experience situations that compromise their future fertility. The past several decades have seen an explosion of technologies that have changed the historical limitations regarding fertility preservation. This review offers an overview of the state of the art within fertility preservation including surgical and medical interventions and therapies that necessitate the need for cryopreservation of eggs, sperm, and embryos. The review also addresses the psychological consequences of banking/not banking materials among patients in need of fertility preservation, particularly in the oncofertility context.
Clinical Medicine Insights: Reproductive Health, 2013
The past several decades have seen tremendous advances in the field of medical genetics. The appl... more The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.
Obstetrics and Gynecology Clinics of North America, 2014
There are few conditions in medicine associated with more heartache to patients than recurrent pr... more There are few conditions in medicine associated with more heartache to patients than recurrent pregnancy loss (RPL). The management of early RPL is a formidable clinical challenge for physicians. Great strides have been made in characterizing the incidence and diversity of this heterogeneous disorder, and a definite cause of pregnancy loss can be established in more than half of couples after a thorough evaluation. In this review, current data are evaluated and a clear roadmap is provided for the evaluation and treatment of RPL.
To test the hypothesis that in couples undergoing IUI, actively managed cycles using clomiphene c... more To test the hypothesis that in couples undergoing IUI, actively managed cycles using clomiphene citrate (CC) stimulation, ultrasound monitoring, and hCG timing will result in increased pregnancy rate (PR) per cycle compared with unstimulated urinary LH-timed cycles. Fifty-six couples with unexplained infertility (n = 26) or male factor infertility (n = 30) participated in the study. Tertiary academic medical center. Prospective, randomized, crossover. Couples were randomized initially to one of the two study groups (treatment A: LH-timed IUI; treatment B: CC-stimulated, hCG-timed IUI). If no pregnancy occurred, each couple alternated between the two regimens during subsequent cycles, up to a total of four cycles. Twenty-nine couples completed the study and the analysis of 95 cycles revealed that among the male factor infertility group, one pregnancy occurred during the 26 cycles of each treatment group (PR per cycle of 3.9% for both treatment groups). In contrast, among the unexplained infertility group, there was a marked difference in the effect of treatments. During treatment A only one pregnancy occurred in 20 cycles (PR of 5% per cycle) whereas during treatment B, six pregnancies occurred in 23 cycles (PR of 26.1% per cycle). If IUI is chosen as the treatment modality in unexplained infertility, the addition of active ovulation management that includes CC stimulation, ultrasound monitoring of folliculogenesis, and hCG timing of ovulation increases the PR per cycle. In couples with male infertility, PR per cycle is low and is apparently not affected by the addition of active ovulation management.
Several laboratories currently offer panels of serum autoantibody assays to screen women with une... more Several laboratories currently offer panels of serum autoantibody assays to screen women with unexplained infertility and those undergoing in vitro fertilization (IVF). Offering these tests implies that they have predictive value for the outcome of proposed infertility treatments such that the results of the testing would alter clinical management. Because screening for antiphospholipid antibodies adds expense to already costly procedures, it is an appropriate time to review the justification for the use of these panels.
The purpose of this study was to determine the efficacy of intestinal tract immunization in the i... more The purpose of this study was to determine the efficacy of intestinal tract immunization in the induction of specific antibodies in human female genital tract secretions. Live attenuated typhoid vaccine Ty 21a was administered to three groups of healthy female volunteers, who were not using hormonal contraceptives. Group 1 included 15 women vaccinated orally. Group 2 included seven of the same women, who were vaccinated rectally 6 months later. Group 3 included 11 volunteers, who were vaccinated rectally. Salmonella-specific antibodies of IgG and IgA were measured in vaginal lavage and cervical mucus after oral or rectal primary vaccination. Salmonella-specific antibodies measured 1 month after rectal booster vaccination demonstrated significant increases in vaginal fluids and cervical mucus and were dominated by IgA. These results indicate that specific antibodies in the human female genital tract induced by primary vaccination can be enhanced by subsequent rectal administration of vaccines.
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single... more To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). Both groups consented to obtaining fasting insulin and glucose levels. Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
Fertility and Sterility, Volume 78, Issue null, Pages S71-S72, September 2002, Authors:Rhonda L M... more Fertility and Sterility, Volume 78, Issue null, Pages S71-S72, September 2002, Authors:Rhonda L Markle; Patricia J King; Dana B Martin; William H Kutteh; Raymond W Ke.
Objective: In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinem... more Objective: In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS. Design: Double-blind, randomized, placebo-controlled trial. Setting: Academic reproductive endocrinology clinic. Patient(s): Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC. Intervention(s): Twenty-five women were randomized into two treatment groups. Subjects in Group I (n Ï 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n Ï 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months. Main Outcome Measure(s): The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens. Result(s): Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (PÏ.04, Fisher's exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 Ï® 13.8 U/mL to 17.3 Ï® 7.8 U/mL after rosiglitazone (PÏ.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 Ï® 0.3 g/dL to 1.0 Ï® 0.3 g/dL after rosiglitazone therapy (PÏ.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 Ï® 6.3 mU/mL to 7.2 Ï® 3.7 mU/mL (PÏ.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change. Conclusions: Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG. (Fertil Steril 2003;79:562-6.
Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associ... more Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associated with an increased risk of venous, arterial, and placental thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation [1691G3 A] in the factor V gene), the prothrombin 20210G3 A mutation, and homozygosity for a common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677C3 T) have been associated with arterial and venous thrombosis and arterial occlusive disease. We explored an association between these markers of thrombophilic states and RPL. Design: Prospective case-control evaluation. Setting: University-associated private practice. Patient(s): Fifty nonpregnant women with three or more pregnancy losses and 50 healthy, nonpregnant controls. Intervention(s): None. Main Outcome Measure(s): Anticardiolipin and antiphosphatidylserine antibodies were detected in serum by ELISA. Polymerase chain reaction was performed to identify the factor V Leiden (1691G3 A) mutation, the thermobile MTHFR (677C3 T) mutation, and the prothrombin 20210G3 A mutation.
To determine the predictive value of an embryonic heart rate (EHR) for a live birth in women with... more To determine the predictive value of an embryonic heart rate (EHR) for a live birth in women with and without a history of recurrent pregnancy loss (RPL). Prospective cohort study with concurrent controls. A subspecialty clinic for couples with RPL. Three hundred pregnant women who previously had been diagnosed with RPL, followed prospectively compared with 300 age-, race-, and gestational age-matched pregnant control women. Transvaginal sonography between 6 to 8 weeks of gestation. The EHR was determined between 6 and 8 weeks of gestation by transvaginal sonography. Obstetrical history and current pregnancy outcome were evaluated. Data were analyzed by using the two-tailed t test and Fisher's exact test. In women with RPL, an EHR predicted a successful live birth in 246 (82%) of 300, compared with 294 (98%) of 300 in control women. The mean (+/- SD) EHR from successful pregnancies in the control group (143.2 +/- 20.8 beats per minute) was significantly higher than the mean in women with a history of RPL (131.4 +/- 22.9 beats per minute). An EHR in women with RPL is associated with a live birth rate of 82% and is significantly lower than EHR in controls. Clinicians should use this information to counsel patients with RPL.
Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation cla... more Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation classically begins after 3 consecutive miscarriages of less than 10 weeks of gestation but may be warranted earlier if a prior miscarriage was found to be euploid, or if there is concomitant infertility and/or advancing maternal age. The evaluation begins with an extensive history and physical, followed by a diagnostic screening protocol. Management must be evidence-based; unproven treatments should be avoided. If no factor is identified, many couples will still eventually have a successful pregnancy outcome with supportive therapy alone.
Genetic diagnostic technologies are rapidly changing the way medicine is practiced. Preimplantati... more Genetic diagnostic technologies are rapidly changing the way medicine is practiced. Preimplantation genetic testing is a well established application of genetic testing within the context of in vitro fertilization cycles. It involves obtaining a cell(s) from a developing embryo in culture, which is then subjected to genetic diagnostic analysis; the resulting information is used to guide which embryos are transferred into the uterus. The potential applications and use of this technology have increased in recent years. Experts agree that preimplantation genetic diagnosis is clinically appropriate for many known genetic disorders. However, some applications of such testing, such as preimplantation genetic screening for aneuploidy, remain controversial. Clinical data suggest that preimplantation genetic screening may be useful, but further studies are needed to quantify the size of the effect and who would benefit most.
Obstetrics and Gynecology Clinics of North America, 2015
The desire to reproduce is one of the strongest human instincts. Many men and women in our societ... more The desire to reproduce is one of the strongest human instincts. Many men and women in our society may experience situations that compromise their future fertility. The past several decades have seen an explosion of technologies that have changed the historical limitations regarding fertility preservation. This review offers an overview of the state of the art within fertility preservation including surgical and medical interventions and therapies that necessitate the need for cryopreservation of eggs, sperm, and embryos. The review also addresses the psychological consequences of banking/not banking materials among patients in need of fertility preservation, particularly in the oncofertility context.
Clinical Medicine Insights: Reproductive Health, 2013
The past several decades have seen tremendous advances in the field of medical genetics. The appl... more The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.
Obstetrics and Gynecology Clinics of North America, 2014
There are few conditions in medicine associated with more heartache to patients than recurrent pr... more There are few conditions in medicine associated with more heartache to patients than recurrent pregnancy loss (RPL). The management of early RPL is a formidable clinical challenge for physicians. Great strides have been made in characterizing the incidence and diversity of this heterogeneous disorder, and a definite cause of pregnancy loss can be established in more than half of couples after a thorough evaluation. In this review, current data are evaluated and a clear roadmap is provided for the evaluation and treatment of RPL.
To test the hypothesis that in couples undergoing IUI, actively managed cycles using clomiphene c... more To test the hypothesis that in couples undergoing IUI, actively managed cycles using clomiphene citrate (CC) stimulation, ultrasound monitoring, and hCG timing will result in increased pregnancy rate (PR) per cycle compared with unstimulated urinary LH-timed cycles. Fifty-six couples with unexplained infertility (n = 26) or male factor infertility (n = 30) participated in the study. Tertiary academic medical center. Prospective, randomized, crossover. Couples were randomized initially to one of the two study groups (treatment A: LH-timed IUI; treatment B: CC-stimulated, hCG-timed IUI). If no pregnancy occurred, each couple alternated between the two regimens during subsequent cycles, up to a total of four cycles. Twenty-nine couples completed the study and the analysis of 95 cycles revealed that among the male factor infertility group, one pregnancy occurred during the 26 cycles of each treatment group (PR per cycle of 3.9% for both treatment groups). In contrast, among the unexplained infertility group, there was a marked difference in the effect of treatments. During treatment A only one pregnancy occurred in 20 cycles (PR of 5% per cycle) whereas during treatment B, six pregnancies occurred in 23 cycles (PR of 26.1% per cycle). If IUI is chosen as the treatment modality in unexplained infertility, the addition of active ovulation management that includes CC stimulation, ultrasound monitoring of folliculogenesis, and hCG timing of ovulation increases the PR per cycle. In couples with male infertility, PR per cycle is low and is apparently not affected by the addition of active ovulation management.
Several laboratories currently offer panels of serum autoantibody assays to screen women with une... more Several laboratories currently offer panels of serum autoantibody assays to screen women with unexplained infertility and those undergoing in vitro fertilization (IVF). Offering these tests implies that they have predictive value for the outcome of proposed infertility treatments such that the results of the testing would alter clinical management. Because screening for antiphospholipid antibodies adds expense to already costly procedures, it is an appropriate time to review the justification for the use of these panels.
The purpose of this study was to determine the efficacy of intestinal tract immunization in the i... more The purpose of this study was to determine the efficacy of intestinal tract immunization in the induction of specific antibodies in human female genital tract secretions. Live attenuated typhoid vaccine Ty 21a was administered to three groups of healthy female volunteers, who were not using hormonal contraceptives. Group 1 included 15 women vaccinated orally. Group 2 included seven of the same women, who were vaccinated rectally 6 months later. Group 3 included 11 volunteers, who were vaccinated rectally. Salmonella-specific antibodies of IgG and IgA were measured in vaginal lavage and cervical mucus after oral or rectal primary vaccination. Salmonella-specific antibodies measured 1 month after rectal booster vaccination demonstrated significant increases in vaginal fluids and cervical mucus and were dominated by IgA. These results indicate that specific antibodies in the human female genital tract induced by primary vaccination can be enhanced by subsequent rectal administration of vaccines.
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single... more To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). Both groups consented to obtaining fasting insulin and glucose levels. Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
Fertility and Sterility, Volume 78, Issue null, Pages S71-S72, September 2002, Authors:Rhonda L M... more Fertility and Sterility, Volume 78, Issue null, Pages S71-S72, September 2002, Authors:Rhonda L Markle; Patricia J King; Dana B Martin; William H Kutteh; Raymond W Ke.
Objective: In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinem... more Objective: In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS. Design: Double-blind, randomized, placebo-controlled trial. Setting: Academic reproductive endocrinology clinic. Patient(s): Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC. Intervention(s): Twenty-five women were randomized into two treatment groups. Subjects in Group I (n Ï 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n Ï 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months. Main Outcome Measure(s): The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens. Result(s): Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (PÏ.04, Fisher's exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 Ï® 13.8 U/mL to 17.3 Ï® 7.8 U/mL after rosiglitazone (PÏ.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 Ï® 0.3 g/dL to 1.0 Ï® 0.3 g/dL after rosiglitazone therapy (PÏ.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 Ï® 6.3 mU/mL to 7.2 Ï® 3.7 mU/mL (PÏ.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change. Conclusions: Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG. (Fertil Steril 2003;79:562-6.
Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associ... more Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associated with an increased risk of venous, arterial, and placental thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation [1691G3 A] in the factor V gene), the prothrombin 20210G3 A mutation, and homozygosity for a common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677C3 T) have been associated with arterial and venous thrombosis and arterial occlusive disease. We explored an association between these markers of thrombophilic states and RPL. Design: Prospective case-control evaluation. Setting: University-associated private practice. Patient(s): Fifty nonpregnant women with three or more pregnancy losses and 50 healthy, nonpregnant controls. Intervention(s): None. Main Outcome Measure(s): Anticardiolipin and antiphosphatidylserine antibodies were detected in serum by ELISA. Polymerase chain reaction was performed to identify the factor V Leiden (1691G3 A) mutation, the thermobile MTHFR (677C3 T) mutation, and the prothrombin 20210G3 A mutation.
To determine the predictive value of an embryonic heart rate (EHR) for a live birth in women with... more To determine the predictive value of an embryonic heart rate (EHR) for a live birth in women with and without a history of recurrent pregnancy loss (RPL). Prospective cohort study with concurrent controls. A subspecialty clinic for couples with RPL. Three hundred pregnant women who previously had been diagnosed with RPL, followed prospectively compared with 300 age-, race-, and gestational age-matched pregnant control women. Transvaginal sonography between 6 to 8 weeks of gestation. The EHR was determined between 6 and 8 weeks of gestation by transvaginal sonography. Obstetrical history and current pregnancy outcome were evaluated. Data were analyzed by using the two-tailed t test and Fisher's exact test. In women with RPL, an EHR predicted a successful live birth in 246 (82%) of 300, compared with 294 (98%) of 300 in control women. The mean (+/- SD) EHR from successful pregnancies in the control group (143.2 +/- 20.8 beats per minute) was significantly higher than the mean in women with a history of RPL (131.4 +/- 22.9 beats per minute). An EHR in women with RPL is associated with a live birth rate of 82% and is significantly lower than EHR in controls. Clinicians should use this information to counsel patients with RPL.
Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation cla... more Recurrent pregnancy loss affects up to 5% of couples trying to establish a family. Evaluation classically begins after 3 consecutive miscarriages of less than 10 weeks of gestation but may be warranted earlier if a prior miscarriage was found to be euploid, or if there is concomitant infertility and/or advancing maternal age. The evaluation begins with an extensive history and physical, followed by a diagnostic screening protocol. Management must be evidence-based; unproven treatments should be avoided. If no factor is identified, many couples will still eventually have a successful pregnancy outcome with supportive therapy alone.
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