The impact of unilateral oophorectomy on ovarian reserve in assisted reproduction: a systematic review and meta-analysis.

BACKGROUND: Women following unilateral oophorectomy (UO) are occasionally encountered during assisted reproduction treatment. OBJECTIVE: To explore the impact of UO on ovarian reserve in assisted reproduction. SEARCH STRATEGY: An electronic database search was performed using PubMed, EBSCO, ISI, Trip, ClinicalTrial.gov and the Cochrane library followed by a manual search to identify published research between January 1978 and December 2015. SELECTION CRITERIA: Controlled studies that compared infertile women following UO undergoing IVF-ET treatment with women with two intact ovaries. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data concerning the impact of UO on ovarian reserve tests, ovarian response to controlled ovarian hyperstimulation and clinical pregnancy rate. Meta-analysis was performed using these measures. MAIN RESULTS: Twenty-one studies were eligible for quantitative analysis. They included 1045 and 18 172 IVF cycles in women with one and two intact ovaries, respectively. Basal FSH weighted mean difference (WMD) was significant (2.01 IU/l; 95% CI: 0.24-3.79, P = 0.026). Similarly, the WMD of serum E2 level on the day of hCG administration was significant (WMD: -431 pg/ml; 95% CI: -616 to -246, P < 0.001). However, the weighted overall odds ratio (OR) of clinical pregnancy between women with a single ovary and women with two ovaries was comparable (overall OR: 0.76; 95% CI: 0.57-1.00, P = 0.054). All eligible studies were retrospectively conducted and the heterogeneity among ovarian response measures was high. CONCLUSIONS: Available pooled data supports an adverse effect of UO on ovarian reserve involving the quantity but not the quality of the ovarian pool. TWEETABLE ABSTRACT: Review finds women with one ovary removed have less IVF capacity but the same pregnancy rate as women with two ovaries.

The effect of rLH supplementation to the GnRH-antagonist protocol on endocrine dynamics in the advanced reproductive age.

PURPOSE: To explore serum endocrine dynamics, specifically LH levels, following rLH supplementation to rFSH following GnRH-antagonist treatment in the advance reproductive age. METHODS: Women were prospectively and similarly treated employing rFSH and the flexible GnRH-antagonist protocol, while rLH was supplemented only to the study group. Serum FSH, LH, E2, and P were evaluated throughout the follicular phase. Three strategies were a priori planned to examine endocrine dynamics among women enrolled. RESULTS: While serum LH drop were similar before GnRH-antagonist stimulation, it dropped more times in the control group compared to the study group. Among women receiving rFSH only, serum LH levels dropped ≤2, ≤1 and ≤0.5 mIU/mL in 71.4, 46.4, and 28.6% of cases, while this occurred only in 38.7% (P = 0.01), 6.5% (P = 0.0004) and 3.2% (P = 0.007) of women receiving combined rFSH and rLH treatment, respectively. The same trend was found when serum LH dropped in at least two occasions following the GnRH-antagonist administration. Conversely, serum LH diagrams throughout the follicular phase did not differ between the two groups. Furthermore, individual area under the curve values of LH, E2, and P was similar between the two groups following GnRH-antagonist initiation. CONCLUSIONS: Different strategies to explore LH dynamics following the GnRH-antagonist administration have resulted in diverse results, implying the need for a consensus definition of LH threshold for adequate folliculogenesis and steroidogenesis. Such action would pave the way for understanding which groups of patients may benefit from rLH supplementation.

Reverse breech extraction in cases of second stage caesarean section.

Our objective was to examine the feasibility of reverse breech extraction to disengage fetal head from the pelvis at second stage caesarean section (CS). A total of 50 consecutive women with singleton term pregnancies undergoing urgent CS at second stage were retrospectively evaluated. A total of 29 were delivered by the reverse breech manoeuvre (study group) and 21 women were delivered by the conventional approach (control group). The reverse breech extraction was successful in all cases of the study group. The mean estimated blood loss during operation, haemoglobin drop, Apgar scores at 1 and 5 min as well as cord PH were similar between the groups. The mean newborn weights were similar, 3492 ± 426 and 3610 ± 392 g in the study and control group, respectively. One case of an inadvertent extension of the low transverse incision was encountered in each group. Also, in three cases of the study group the incision was intentionally extended to an inverted T-shape to facilitate the manoeuvre. None of the newborns in both groups had trauma related to the extraction or were admitted to the neonatal intensive care unit. All women following CS had a low rate complication rate in the postpartum period. We conclude that reverse breech extraction seems to be feasible to disengage fetal head from the pelvis at second stage CS. Maternal and newborn complications following this manoeuvre seem to be low.

Ovarian aging and implications for fertility female health.

Ovarian aging is a major detrimental factor of pregnancy achievement and it is related to other issues of women's health. The purpose of this review is to present an update on ovarian aging risk factors followed by contemporary methods of its assessment and an overview of its current management strategies in assisted reproductive technologies (ART). Ovarian aging is a multifactorial trait governed by several factors including medical, lifestyle, genetic, autoimmune and idiopathic. There are several established risk factors and many others that are still being revealed. Heritability has a major influence on ovarian aging. Different genetic strategies and approaches for ovarian aging evaluation have been rapidly expanding; however the mission is far from complete. Genome-wide association studies seems to be the most applicable to advance this research. Although anti-Müllerian hormone and antral follicle count (AFC) biomarkers seems to be the most reliable predictors of ovarian aging, none has demonstrated conclusive evidence to predict pregnancy achievement in an ART setting. The debate continues which of the two predictors is the most suitable in ART as well as non-ART settings. Although multivariate models have been shown to be equally predictive to AFC, latest data support the notion that chronological age and genetic markers inclusion may increase their reliability. Several strategies have been suggested to manage ovarian aging in ART settings. None of the stimulation protocols or ART interventions has been shown to be convincingly beneficial to ovarian aging women and individualization of treatment is still recommended. Ovarian priming by different androgen preparations has been shown to be promising but more randomized controlled studies are required to substantiate these findings. Except for oocyte donation other ART strategies have not shown a persuasive evidence for advanced ovarian aging infertility patients. The new development of oocyte vitrification may well introduce opportunities for fertility preservation to woman at risk. It is concluded that proper assessment and detection of ovarian aging, employing current or developing biomarkers of ovarian reserve, may enable health providers to recommend, at appropriate biological time, early pregnancy achievement or fertility preservation in women at risk.

Increased progesterone/estradiol ratio in the late follicular phase could be related to low ovarian reserve in in vitro fertilization-embryo transfer cycles with a long gonadotropin-releasing hormone agonist.

OBJECTIVE: To gain insight into the physiologic as well as the clinical significance of premature luteinization in the long gonadotropin-releasing hormone agonist (GnRH-a) cycles and to evaluate whether it may be a manifestation of low ovarian reserve. DESIGN: Prospective evaluation. SETTING: A university-affiliated reproductive medicine unit. PATIENT(S): Seventy-six consecutive infertile women. INTERVENTION(S): The long GnRH-a protocol was used for IVF-ET treatment. MAIN OUTCOME MEASURE(S): Women in the study were prospectively evaluated in their first cycle of treatment and were divided into those with (study group) or without premature luteinization (control group). Premature luteinization was defined as P/E2 ratio of more than 1 on the day of hCG administration. RESULTS(S): Thirty-one (41%) of the women in the study demonstrated premature luteinization. Patients' characteristics were comparable between the two groups. Late follicular P/E2 ratio was significantly and considerably higher in the study as compared to the control group, 2.4 +/- 1.7 and 0.7 +/- 0.2, respectively. Ovarian reserve parameters including day 3 FSH, E2 level on hCG day, total amount of hMG, number of follicles, oocytes, and embryos were significantly inferior in the study as compared to the control group. P levels on hCG day were significantly higher in the study as compared to the control group, 1.9 +/- 0.7 ng/mL and 1.2 +/- 0.6 ng/mL, respectively. However, LH levels on hCG day did not differ between the groups, 1.4 +/- 0.7 mIU/mL and 1.2 +/- 0.7 mIU/mL, respectively. The clinical pregnancy rate was significantly lower in the premature luteinization group as opposed to controls, 13% and 42%, respectively. CONCLUSION(S): Premature luteinization, defined as late follicular P/E2 >1, in long GnRH-a cycles seems to adversely affect clinical outcome. Our findings in this setting support the notion that premature luteinization could be related to low ovarian reserve and that this manifestation is not necessarily an LH-dependent event.

Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss (RPL). We have evaluated the efficacy and safety of the low molecular weight heparin enoxaparin in 50 women, (mean age 26 +/- 3 years) with RPL (> or =3 losses in 1st, > or =2 losses in 2nd and > or =1 loss in 3rd trimester) who were found to harbor thrombophilia. Twenty-seven had a solitary thrombophilic defect, and twenty-three women had combined thrombophilic defects: 17--two defects and 6--three defects. Following diagnosis of thrombophilia, sixty-one subsequent pregnancies were treated with the low molecular weight heparin enoxaparin throughout gestation until 4 weeks after delivery. Dosage was 40 mg/day in women with solitary defect and 80 mg/day in combined defects. Aspirin, 75 mg daily was given in addition to enoxaparin to women with antiphospholipid syndrome. Forty-six out of 61 (75%) gestations treated by enoxaparin resulted in live birth compared to only 38/193 (20%) of the untreated pregnancies in these 50 women prior to diagnosis of thrombophilia (p <0.00001). In 23 women without a single living child following 82 untreated gestations, antithrombotic therapy resulted in 26/31 (84%) successful deliveries (p <0.0001). In 20 women with a prior living child, antithrombotic therapy improved successful delivery from 33/86 (38%) to 20/21 (95%) (p <0.0001). Enoxaparin dose of 40 mg/day resulted in live birth in 24/35 (69%) of gestations, compared to 19/23 (83%) gestations in women treated with 80 mg/day (p = 0.37). Only one thrombotic episode and one mild-bleeding episode were noticed during enoxaparin therapy. Enoxaparin is safe and effective in prevention of pregnancy loss in women with inherited and acquired thrombophilia.

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. METHODS: Between 1 January and 31 December 1996, activated protein C (APC) resistance and factor V Leiden mutation were prospectively measured in 56 nonpregnant women, with a history of two or more unexplained recurrent pregnancy losses. During the same study period, seven women carrying the factor V Leiden mutation conceived, and were subsequently followed throughout their pregnancy. Subcutaneous low molecular weight heparin (LMWH, enoxaparin, 40 mg/day) and oral low dose aspirin (100 mg/day) were administered throughout the pregnancies, starting at early first trimester. Ultrasound and Doppler umbilical and fetal middle cerebral arterial flow studies were performed in the second and third trimesters, and the course and outcome of the pregnancies were documented. RESULTS: Activated protein C resistance and factor V Leiden were found in 20 (36%) and 12 (21%) women of the study, respectively. Five of the seven pregnancies occuring progressed uneventfully to term with normal fetal growth, normal Doppler flow studies and uneventful neonatal outcome. Two of the seven women had early missed abortions. CONCLUSIONS: Thrombophylaxis, beginning in early pregnancy, in women with unexplained recurrent pregnancy loss associated with factor V Leiden mutation, seems to be safe and allow normal fetal development and good neonatal outcome. To prove the efficacy of thrombophylaxis by LMWH and low dose aspirin in this setting prospective controlled studies seem to be justified.

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 < or = 2.0. All patients with an APC SR < or = 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.

High prevalence of activated protein C resistance due to factor V leiden mutation in cases of intrauterine fetal death.

OBJECTIVE: To test a possible association between activated protein C resistance and intrauterine fetal death. METHODS: The activated protein C anticoagulant activity and factor V R506Q mutation were assessed in 14 nonpregnant women with a history of intrauterine fetal death and 14 healthy controls. RESULTS: Four women in the study group were heterozygotes for the factor V mutation and none of the controls. The mean activated protein C activity of the study group was statistically significantly lower than that of the controls (P = 0.013). CONCLUSION: Resistance to activated protein C activity may be of etiologic importance in some cases of intrauterine fetal death.

Thrombophilic polymorphisms are common in women with fetal loss without apparent cause.

An association between fetal loss and thrombophilia has recently been described but has not been yet fully elucidated. We have evaluated prospectively the prevalence of the three common thrombophilic polymorphisms (TP) factor V G1691A (Leiden), thermolabile-methylenetetrahydrofolate reductase (TL-MTHFR) C677T and factor II G20210A mutations, in 76 women with fetal loss (> or =3 in first, > or =2 in second, > or =1 in third trimester) without apparent cause and 106 controls without fetal loss. Thirty seven out of 76 (49%) of the women in the fetal loss group had at least one TP compared to only 23/106 (22%) in the control group (p = 0.0001 ). Factor V-Leiden was more common in the fetal loss group 24/76 (32%) compared to the control group 11/106 (10%) (OR = 4.0, 95% CI: 1.8-8.8, p <0.001). Five of the 76 patients (7%) were homozygous for factor V-Leiden compared to none of the controls (p = 0.012). A trend, albeit no statistically significant difference was found between women with fetal loss and control groups regarding factor II G20210A (8% vs. 4% respectively, OR = 2.2, 95% CI: 0.6-8.0, p = 0.23) and MTHFR C677T (18% vs. 10% respectively, OR = 1.95, 95% CI: 0.83-4.6, p = 0.12). Combined TP were documented in 6/76 (8%) patients compared to 1/106 (1%) in controls (OR = 9.0, 95% CI: 1.1-76, p = 0.02). Second or third trimester fetal loss were more common cause of pregnancy termination in 37 patients with TP compared to 39 patients without TP (57/158 (36%) vs. 23/135 (17%) respectively, (p = 0.0004). Thrombophilic polymorphisms are common in women with fetal loss without apparent cause and are associated with late pregnancy wastage. Combinations of TP increase the risk for fetal loss.

Premature luteinization: could it be an early manifestation of low ovarian reserve?

OBJECTIVE: To gain insight into the physiologic significance of premature luteinization and to evaluate whether it could be a manifestation of low ovarian reserve. DESIGN: Retrospective evaluation. SETTING: Reproductive medicine unit. PATIENT(S): Thirty-one consecutively seen women with normal ovulation and unexplained infertility. INTERVENTION(S): Induction of superovulation with hMG coupled with synchronized IUI. A GnRH agonist was not used during the study. MAIN OUTCOME MEASURE(S): Premature luteinization was defined as a progesterone/estradiol ratio of > 1 on the day of hCG administration. Patients were evaluated during their first cycles of hMG treatment and then were divided into those with (study group) and those without (control group) premature luteinization. The ovarian reserve parameters were compared between the two groups. RESULT(S): Nineteen of the 31 patients with unexplained infertility demonstrated premature luteinization. Patient characteristics were similar between the study and control groups. Mean (+/- SD) day 3 FSH levels were 8.2 +/- 3.3 and 6.6 +/- 1.7 mIU/mL in the study and control groups, respectively. Mean (+/- SD) day 3 estradiol levels were significantly higher in the study than in the control group (74 +/- 49 pg/mL vs. 30 +/- 17 pg/mL, respectively). Mean (+/- SD) estradiol levels on the day of hCG administration also differed significantly between the study and control groups (760 +/- 539 pg/mL vs. 1,568 +/- 675 pg/mL, respectively). Likewise, the number of follicles that were > or = 15 mm on the day of hCG administration was significantly lower in the study than in the control group (2.9 +/- 1.5 vs. 4.3 +/- 1.3, respectively). The total dose of hMG and duration of administration were similar in the two groups. The clinical pregnancy rates after four cycles of treatment were 15.8% and 41.7% in the study and control groups, respectively. CONCLUSION(S): This preliminary work suggests that, in cycles that are not treated with a GnRH agonist, signs of premature luteinization in patients with unexplained infertility could be an early manifestation of low ovarian reserve. It appears that hMG treatment in this group of patients could uncover the pathogenesis of their infertility.

A validation study of three indexes of orthodontic treatment need in the United States.

The purpose of this study was to compare the reliability and validity of three occlusal indexes of orthodontic treatment need in predicting the opinion of treatment need of a panel of 18 orthodontists. A set of 160 study casts representing all types of malocclusion was used. The casts were scored with the following occlusal indexes: the Index of Orthodontic Treatment Need (IOTN), the Handicapping Labio-Lingual Deviations index (HLD), and the Handicapping Malocclusion Assessment Record (HMAR modified). The diagnostic accuracy or validity of each index was calculated using the mean opinion of the orthodontic raters as a "gold standard". Receiver Operating Characteristic curves were plotted for each index. The overall diagnostic accuracy, as determined by percent area under the curve, was similar for each index: IOTN 98.6%; HLD 96.1%; HMAR 96.6%. The score optimizing the sensitivity and specificity relationship for each index was as follows: IOTN (dental health component) 4; HLD 13; HMAR 12. These results indicate that the three occlusal indexes provided valuable information for determining orthodontic treatment need.

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

PURPOSE: 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 (i.v.) 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 i.v. 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.

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.

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.

Double-layer closure of uterine incision with visceral and parietal peritoneal closure: are they obligatory steps of routine cesarean sections?

The objective of this study was to examine the feasibility of a modified technique of cesarean section in which the uterine incision is sutured in one layer and the visceral and parietal peritoneum are left open. Two hundred patients undergoing a low segment cesarean section were prospectively randomized (according to the patients' identity numbers) into two groups. The first group had standard cesarean section including a continuous double layer closure of uterine incision in addition to closure of visceral and parietal peritoneum. The second group underwent the modified procedure as described above. The modified technique compared to the standard technique, resulted in shorter operative time (32 +/- 11 versus 44 +/- 16 min, P < 0.0001) and a reduced need for postoperative sedation (P < 0.004). The operative procedure was shown, by multiple regression analysis, to be the significant factor that determined its length. Postoperative morbidity was similar in the two groups. The modified technique of cesarean section reduces operative time and postoperative narcotic requirement, and has no adverse affect on postoperative recovery. A double-layer closure of low uterine incision, re-approximation of bladder flap, and closure of parietal peritoneum, as in the standard technique, do not seem to be essential steps of cesarean section. Larger studies are needed to ensure the safety of one-layer uterine closure in future deliveries.