Johnny S. Younis

Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage

OBJECTIVE To describe the characteristics of thrombophilia in women with idiopathic pregnancy loss. DESIGN Prospective observational study. SETTING Tertiary referral center in a teaching academic hospital. PATIENT(S) One hundred forty-five patients with repeated pregnancy loss and 145 matched controls. INTERVENTION(S) Prospective assessment of thrombophilia in patients and controls. MAIN OUTCOME MEASURE(S) Prevalence of activated protein C (APC) resistance, protein C, protein S, and antithrombin III deficiencies, antiphospholipid antibodies, factor V Leiden, factor II G20210A, and MTHFR C677T mutations. RESULT(S) At least one thrombophilic defect was found in 66% of study group patients compared with 28% in control group patients. Combined thrombophilic defects were documented in 21% of women with pregnancy loss compared with 5.5% of control patients. Late pregnancy wastage occurred more frequently in women with thrombophilia compared with women without thrombophilia (160/429 [37%] vs. 39/162 [24%], respectively). APC resistance was documented in 39% of women with pregnancy loss compared with 3% of the control patients. APC resistance without factor V Leiden mutation was documented in 18% of women with pregnancy loss compared with none of the controls. While factor V Leiden mutation was more common in women with pregnancy loss (25% vs. 7.6%), factor II G20210A and homozygosity for MTHFR C677T contributed to pregnancy loss only in the presence of other thrombophilia. CONCLUSION(S) Thrombophilia was found in the majority (66%) of women with idiopathic pregnancy loss. APC resistance with or without factor V Leiden mutation is the most common thrombophilic defect, and combined thrombophilia is a frequent finding in women with pregnancy loss. Thrombophilia is associated with increased frequency of late pregnancy wastage.

Activated protein C resistance can be associated with recurrent fetal loss

As thrombosis of placental vessels may result in recurrent fetal loss, we analysed 39 consecutive women with recurrent fetal loss of unknown cause for activated protein C resistance. Factor V Leiden (FVL) mutation (19 cases) or APC resistance without FVL (nine cases) were found among these 39 women.  Evaluation of 128 pregnancies in 19 patients with factor V Leiden mutation and 56 gestations in nine women with acquired APC resistance, revealed over 50% first‐trimester abortions and 17% late abortions. Intra‐uterine fetal death occurred in nine out of 19 FVL patients (47%). Only 34 of 184 gestations (18%) in hereditary or acquired APC‐resistance women resulted in a live birth, with 11 of the 34 (32%) being premature deliveries. These data suggest that, in some patients with recurrent fetal loss, hereditary and acquired APC resistance are potential causes of vascular placental insufficiency.

Activated Protein C Resistance and Factor V Leiden Mutation can be Associated with First‐ as well as Second‐Trimester Recurrent Pregnancy Loss

PROBLEM: To examine whether the occurrence of activated protein C resistance (APCR) and factor V Leiden mutation differs in women with first‐ compared to women with second‐trimester unexplained recurrent pregnancy loss. METHOD OF STUDY: Seventy eight consecutive women with two or more unexplained post‐embryonic recurrent pregnancy losses and 139 fertile women with at least one successful pregnancy and no abortions were prospectively investigated for APCR and the factor V Leiden mutation. No women were pregnant at the time of investigation. APCR was defined as APC–sensitivity ratio (APC–SR) of ≤2.0. All patients with an APC–SR ≤2.4 were investigated for the factor V Leiden mutation. Women in this study were divided into three groups. Group A included only women with a history of recurrent first‐trimester embryonic loss (37 women) and Group B included women with second‐trimester abortions with or without additional first‐trimester abortions (41 women). Group C included the controls (139 women). RESULTS: APCR and factor V Leiden mutations were significantly more prevalent in all recurrent pregnancy loss patients in this study as compared to controls, 38% (30/78) and 19% (15/78) in contrast to 8% (11/139) and 6% (8/139), respectively. All three groups in the study were comparable regarding age, parity, and number of living children, whereas Groups A and B were also comparable regarding gravidity. Mean APC–SRs were significantly higher in Group C as compared to Groups A and B. The incidence of APCR was significantly higher in Groups A and B, as compared to controls, 27 and 49% in contrast to 8%, respectively. Moreover, the incidence of the factor V Leiden mutation was significantly higher in Groups A and B as compared to Group C, 16 and 22% as distinct from 6%, respectively. The incidence of APCR was higher in Group B as compared to Group A, 49% in contrast to 27%, with borderline significance; however, the factor V Leiden mutation did not significantly differ between the two groups. CONCLUSIONS: APCR and factor V Leiden are associated with unexplained recurrent pregnancy loss. The occurrence of APCR and factor V Leiden seems to be linked to post‐embryonic first‐trimester as well as second‐trimester recurrent pregnancy loss. The significance of acquired, non‐heritable APCR in recurrent fetal loss patients, especially in the second‐trimester aborters, is still to be determined.

Endometrial preparation: lessons from oocyte donation

OBJECTIVE To gain insight into the physiology of human endometrial development after artificial preparation with estrogen (E) and P, before oocyte donation. DESIGN Review and analysis of relevant studies published in the last decade, identified through the literature and Medline searches. RESULTS Oocyte donation represents a unique in vivo experimental model in the human that permits the study of endometrial development under controlled variable conditions. Early studies have shown that adequate endometrial preparation can be achieved by sequential E and P only. The successful implementation of the simplified approach to oocyte donation demonstrated that satisfactory endometrial receptivity is not dependent on incremental administration of E and P and similarly can be achieved by fixed dosages of these steroids. Moreover, numerous clinical oocyte donation studies have shown that both physiologic and supraphysiologic levels of E and P have resulted in good endometrial development and pregnancy rates, underlining the relative insensitivity of the endometrium to extreme hormonal conditions. In addition, it has been clarified that the endometrium is tolerant of some manipulations during the follicular phase. Contrary to morphological studies that demonstrated preservation of endometrial preparation after luteal E depletion, preliminary evidence suggests that the functional capacity of the endometrium could be affected adversely. CONCLUSION In contrast to early oocyte donation studies, which indicated a correlation between morphologic integrity and functional capacity of the endometrium, some evidence presented in this review demonstrates that adequate endometrial morphology does not always imply normal endometrial receptivity.

Late manifestation of pelvic abscess following oocyte retrieval, for in vitro fertilization, in patients with severe endometriosis and ovarian endometriomata

AbstractPurpose: Our purpose was to study the unusual and rare late manifestation of severe pelvic abscess, following oocyte pickup (OPU), for in vitro fertilization and embryo transfer (IVF-ET). Patients: The patients were three infertile women with stage IV endometriosis and ovarian endometriomata, as the sole reason for their infertility. Medical and surgical modalities to treat endometriosis and infertility proved to be unsuccessful. Interventions: All patients were prepared for IVF-ET employing a long GnRH-a and hMG protocol. Transvaginal OPU was performed under ultrasound guidance. Intravenous (iv) prophylactic antibiotic was routinely administered. Results: All women underwent ET, and one conceived. Forty, 24, and 22 days after OPU, respectively, these patients presented with acute symptoms of severe pelvic inflammatory disease (PID) and were found to have pelvic abscess. Broad-spectrum iv antibiotics were employed in all cases, however, two patients did not respond and bilateral adnexectomy was eventually performed. Conclusions: Severe endometriosis with ovarian endometriomata seems to be a significant risk factor for pelvic abscess development, following transvaginal OPU for IVF-ET. Prophylactic IV cefazolin does not seem to prevent this complication. Late manifestation of pelvic abscess supports the notion that the presence of old blood in an endometrioma provides a culture medium for bacteria to grow slowly after transvaginal inoculation.

The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.

Objective To observe the effect of thrombophylaxis on pregnancy in women with a history of unexplained recurrent pregnancy loss also carrying the factor V Leiden mutation.

The effect of estradiol depletion during the luteal phase on endometrial development

OBJECTIVE To examine whether luteal E2 is obligatory for obtaining an adequately developed endometrium. DESIGN Survey of women with premature ovarian failure (POF) in a prospective, controlled, randomized study. SETTING In vitro fertilization unit in a tertiary care university medical center. PATIENTS Fourteen amenorrheic women with POF, candidates for oocyte donation, were divided into two distinct groups with seven women in each subgroup. INTERVENTIONS Endometrial priming with a fixed dose of oral micronized E2, 4 mg/d for 14 days, was similarly performed in the study and the control groups. Progesterone replacement during the luteal phase was also identical in the two groups and was accomplished by IM P in oil, 50 mg/d for another 14 days. Only the control group continued to have the same E2 regimen during the luteal phase. MAIN OUTCOME MEASURES AND RESULTS Follicular phase mean E2 levels as well as luteal phase mean P levels were similar in both groups. However, luteal E2 levels differed significantly between the study and the control groups (21 +/- 5 and 692 +/- 199 pg/mL, respectively; conversion factor to SI units, 3.671). Nevertheless, histologic evaluation of endometrial biopsies on days 21 and 26 were similar for both groups. Endometrial gland dating, using light microscopy in the study and the control groups, on day 21, was 19.1 +/- 0.8 and 18.4 +/- 0.5, respectively, and on day 26, 25.4 +/- 0.8 and 25.9 +/- 0.5, respectively. Dating of the stroma in the two biopsies was also similar in both groups. Moreover, transmission electron microscopy performed in two patients of the study group showed typical characteristics of a secretory endometrium. CONCLUSIONS Luteal E2 depletion in the human does not seem to adversely affect the morphological developmental capacity of the endometrium. Our results suggest that E2 secretion by the corpus luteum in the human does not appear to be obligatory for the development of a normal secretory endometrium. The actual receptivity of the endometrium after such preparation needs to be evaluated.

The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study *

OBJECTIVE To determine the effect of growth hormone (GH) supplementation to a long gonadotropin-releasing hormone agonist (GnRH-a)/human menopausal gonadotropin (hMG) treatment protocol, on ovarian response, embryo quality, and clinical outcome in in vitro fertilization (IVF). DESIGN Growth hormone or placebo were administered in a prospective randomized double-blind manner. PATIENTS Forty-two normal ovulatory, women who were 38 years of age or less with mechanical factor infertility and a normal male factor were selected for this study. INTERVENTIONS Gonadotropin-releasing hormone agonist, 0.5 mg/d, was initiated in the midluteal phase of the preceding cycle and continued until the day of human chorionic gonadotropin (hCG) administration. Ovulation induction with hMG was started 14 days after pituitary down regulation (17 beta-estradiol [E2] serum level less than 30 pg/mL). Growth hormone (12 IU/d) or placebo were administered on days 1, 3, 5, and 7 of hMG treatment. RESULTS Breaking the code at the completion of the study revealed that 20 women received GH and 22 placebo. The age and duration of infertility did not differ between the two groups. Follicular phase duration, hMG ampules used, serum E2, and number of follicles (greater than or equal to 14 mm) on day of hCG as well as number of oocytes and embryos achieved were similar in both groups. Embryo morphology and rate of cleavage were also similar. Insulin-like growth factor-I (IGF-I) serum levels did not change after pituitary down regulation and increased significantly both after GH/hMG and placebo/hMG ovulation induction treatment. Clinical pregnancy rate (PR) per embryo transfer and implantation rate were 40% versus 32% and 17.9% versus 11.3% in the GH and placebo groups, respectively, and were not statistically different. CONCLUSIONS In normo-ovulatory women undergoing ovulation induction for IVF, GH supplementation to hMG after GnRH-a pituitary down regulation does not seem to augment ovarian response or improve embryo quality. The effect of this regimen on actual PRs and implantation rates needs further clarification.

Gestational vascular complications

Severe pregnancy complications, primarily severe pre-eclampsia, placental abruption, intrauterine growth restriction (IUGR) and intrauterine fetal death (IUFD) occur in about 1-5% of gestations. This rate is even higher in special medical situations. These pregnancy complications have been shown to increase maternal and fetal morbidity and mortality considerably. Severe pregnancy complications have also been shown to be associated with deficient uteroplacental circulation and are linked with intervillous and spiral vessel thrombosis. Moreover, it has been suggested that these complications could have their basis in a deficient trophoblast invasion in the uterine spiral arteries at a stage much earlier than the clinical manifestations become evident. In the last few years, evidence has accumulated to suggest that severe pregnancy complications could have a common thrombogenic basis associated with inherited and acquired thrombophilia. In this chapter we present a comprehensive update of the aetiology, pathophysiology, clinical manifestations, diagnosis and treatment of these severe pregnancy complications.

Artificial endometrial preparation for oocyte donation: the effect of estrogen stimulation on clinical outcome.

Morphologic studies of the endometrium have demonstrated that varying the duration of an artificial follicular phase (AFP) in women with ovarian failure did not adversely affect its developmental capacity. The aim of this study was to evaluate whether such manipulations of endometrial stimulation could influence the pregnancy rate in women undergoing oocyte donation (OD). Twenty-nine women were investigated in 51 cycles of OD. Endometrial preparation was performed with a fixed dose of micronized estradiol, 4 mg/day, administered for 5–35 days in accordance with oocyte availability. On the day of donation progesterone in oil, 50 mg/day, was added to the regimen. Oocytes were donated anonymously by patients undergoing routine in vitro fertilization. Fifteen clinical pregnancies were achieved, for a success rate of 29.4%. Using logistic regression analysis the success rate was found to be closely associated with the duration of estrogen stimulation. The pregnancy rate was 7.7, 52, and 7.7% after an AFP of 4–11, 12–19, and 20–29 days, respectively. It seems that for optimal results in an OD program, estrogen stimulation should be kept at between 12 and 19 days. These results also imply that, contrary to endometrial morphology, which seems to be tolerant to extreme AFP durations, functional receptivity is less permissive and is adversely affected by such manipulations.