Surveillance for gestational trophoblastic neoplasia following molar pregnancy: a cost-effectiveness analysis.

BACKGROUND: Historically, published guidelines for care after molar pregnancy recommended monitoring human chorionic gonadotropin levels for the development of gestational trophoblastic neoplasia until normal and then for 6 months after the first normal human chorionic gonadotropin. However, there are little data underlying such recommendations, and recent evidence has demonstrated that gestational trophoblastic neoplasia diagnosis after human chorionic gonadotropin normalization is rare. OBJECTIVE: We sought to estimate the cost-effectiveness of alternative strategies for surveillance for gestational trophoblastic neoplasia after human chorionic gonadotropin normalization after complete and partial molar pregnancy. STUDY DESIGN: A Markov-based cost-effectiveness model, using monthly cycles and terminating after 36 months/cycles, was constructed to compare alternative strategies for asymptomatic human chorionic gonadotropin surveillance after the first normal (none; monthly testing for 1, 3, 6, and 12 months; or every 3-month testing for 3, 6, and 12 months) for both complete and partial molar pregnancy. The risk of reduced surveillance was modeled by increasing the probability of high-risk disease at diagnosis. Probabilities, costs, and utilities were estimated from peer-reviewed literature, with all cost data applicable to the United States and adjusted to 2020 US dollars. The primary outcome was cost per quality-adjusted life year ($/quality-adjusted life year) with a $100,000/quality-adjusted life year willingness-to-pay threshold. RESULTS: Under base-case assumptions, we found no further surveillance after the first normal human chorionic gonadotropin to be the dominant strategy from both the healthcare system and societal perspectives, for both complete and partial molar pregnancy. After complete mole, this strategy had the lowest average cost (healthcare system, $144 vs maximum $283; societal, $152 vs maximum $443) and highest effectiveness (2.711 vs minimum 2.682 quality-adjusted life years). This strategy led to a slightly higher rate of death from gestational trophoblastic neoplasia (0.013% vs minimum 0.009%), although with high costs per gestational trophoblastic neoplasia death avoided (range, $214,000 to >$4 million). Societal perspective costs of lost wages had a greater impact on frequent surveillance costs than rare gestational trophoblastic neoplasia treatment costs, and no further surveillance was more favorable from this perspective in otherwise identical analyses. No further surveillance remained dominant or preferred with incremental cost-effectiveness ratio of <$100,000 in all analyses for partial mole, and most sensitivity analyses for complete mole. Under the assumption of no disutility from surveillance, surveillance strategies were more effective (by quality-adjusted life year) than no further surveillance, and a single human chorionic gonadotropin test at 3 months was found to be cost-effective after complete mole with incremental cost-effectiveness ratio of $53,261 from the healthcare perspective, but not from the societal perspective (incremental cost-effectiveness ratio, $288,783). CONCLUSION: Largely owing to the rare incidence of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization after molar pregnancy, prolonged surveillance is not cost-effective under most assumptions. It would be reasonable to reduce, and potentially eliminate, current recommendations for surveillance after human chorionic gonadotropin normalization after molar pregnancy, particularly among partial moles. With any reduction in surveillance, patients should be counseled on symptoms of gestational trophoblastic neoplasia and established in routine gynecologic care.

Beneficial effect of l-arginine in women using assisted reproductive technologies: a small-scale randomized controlled trial.

This small-scale randomized controlled study aimed to examine the effect of l-arginine supplementation on the human chorionic gonadotropin (hCG)-positive rate and clinical pregnancy rate (CPR) in women undergoing assisted reproductive technology (ART) treatment for 3 months. From November 2017 to March 2018, 120 patients aged less than 40 years and planning for egg retrieval for embryo transfer were enrolled. The patients were divided into the AS2000 group (n = 36; l-arginine, 2 g; folate, 400 µg; and vitamin E, 10 mg), AS1000 group (n = 37; l-arginine, 1 g; and folate, 200 µg), and control group (n = 36). The main outcome was the hCG-positive rate or CPR in 3 months. The cumulative hCG-positive rates during the administration period were 44.2%, 54.2%, and 52.1%, and the CPRs were 39.5%, 41.7%, and 47.9% in the control, AS1000, and AS2000 groups, respectively. Odds ratios of the hCG-positive rate and CPR in the global l-arginine group (AS1000 and AS2000) versus those in the control group were 1.33 (95% confidence interval [CI], 0.62-2.90) and 1.11 (95% CI, 0.51-2.46), respectively. In the subgroup of women receiving ART because of male infertility, the hCG-positive rate and CPR were significantly increased in the l-arginine groups compared to those in the control group (13.42 [95% CI, 1.42-366.9] and 13.62 (95% CI, 1.42-367.6), respectively). Thus, arginine supplementation may be an option for women who desire pregnancy, especially those undergoing an ART program because of male infertility.

Evaluation of High-Dose Vitamin A Treatment in Postmolar Patients with Low and Plateauing Serum Human Chorionic Gonadotropin Levels.

OBJECTIVE: To compare the effect of high-dose vitamin A (HD Vit-A) use during postmolar follow-up of patients with low and plateauing (L&P) serum human chorionic gonadotropin (hCG) levels, from the moment serum hCG plateaued (P-hCG) to the first normal serum hCG value (< 5 IU/L). METHODS: The present retrospective series case study compared two nonconcurrent cohorts of patients. Control group (CG): 34 patients with L&P serum hCG levels who underwent expectant management for 6 months after uterine evacuation, from 1992 to 2010; study group (SG): 32 patients in similar conditions who received 200,000 IU of Vit-A daily, from the identification of a P-hCG level to the first normal hCG value or the diagnosis of progression to gestational trophoblastic neoplasia (GTN), from 2011 to 2017. The present study was approved by the Ethics Committee of the institution where it was conducted. RESULTS: In both groups, the prevalence of persistent L&P serum hCG levels was < 5%. In the SG, hCG levels at plateau were higher (CG = 85.5 versus SG = 195 IU/L; p = 0.028), the rate of postmolar GTN was lower (CG = 29.4% versus SG = 6.3%, p = 0.034) and follow-up was shorter (CG = 14 versus SG = 10 months, p < 0.001). During GTN follow-up, there were no differences in GTN staging or treatment aggressiveness in both groups. High-dose Vit-A use did not have any relevant toxic effect. There were no GTN relapses or deaths. CONCLUSION: The limited use of HD Vit-A seems to have a safe and significant effect on the treatment of postmolar patients with L&P serum hCG levels and may decrease the development of postmolar GTN in this population.

OBJETIVO: Comparar o efeito de alta dose de vitamina A (VitA) no seguimento pós-molar de pacientes com gonadotrofina coriônica humana (hCG) sérica apresentando valores baixos e em platô (L&P). MéTODOS: Estudo retrospectivo de série de casos comparando duas coortes não simultâneas. Grupo controle (CG): 34 pacientes com títulos de hCG sérico L&P submetidos a manejo expectante por 6 meses após o esvaziamento uterino, de 1992 a 2010; Grupo de Estudo (SG): de 2011 a 2017, 32 pacientes em condições semelhantes de hCG receberam Vit-A na dose de 200.000 IU por dia, do momento da identificação do hCG em platô ate o primeiro hCG normal ou diagnóstico de progressão para neoplasia trofoblástica gestacional (NTG). O presente estudo foi aprovado pelo Comitê de Ética da Instituição na qual foi desenvolvido. RESULTADOS: Em ambos os grupos, a prevalência de hCG L&P foi < 5%. No SG, os níveis de hCG em platô foram maiores (CG = 85.5 versus SG = 195 IU/L; p = 0,028), e foram significantemente menores tanto a prevalência de NTG pós-molar (CG = 29.4% versus SG = 6.3%, p = 0,034) como o tempo de seguimento (CG = 14 versus SG = 10 meses, p < 0.001). Na evolução para NTG não houve diferença no estadiamento da International Federation of Gynecology and Obstetrics (FIGO, na sigla em inglês) ou na agressividade do tratamento. Com altas doses de Vit-A não houve qualquer efeito tóxico relevante. Não houve casos de recidiva de NTG ou de óbito. CONCLUSãO: O uso limitado de altas doses de Vit-A parace ser seguro e apresenta efeitos significativos na evolução de pacientes em controle pós-molar com títulos de hCG sérico L&P, e pode diminuir o desenvolvimento de NTG pós-molar nessa população.

Evaluation of high-dose vitamin A treatment in postmolar patients with low and plateauing serum human chorionic gonadotropin levels / Avaliação de alta dose de vitamina A em pacientes pósmola hidatiforme, com valores baixos e em platô de gonadotrofina coriônica humana

Abstract Objective To compare the effect of high-dose vitamin A (HD Vit-A) use during postmolar follow-up of patients with low and plateauing (L&P) serum human chorionic gonadotropin (hCG) levels, from the moment serum hCG plateaued (P-hCG) to the first normal serum hCG value (< 5IU/L). Methods The present retrospective series case study compared two nonconcurrent cohorts of patients. Control group (CG): 34 patients with L&P serum hCG levels who underwent expectant management for 6 months after uterine evacuation, from 1992 to 2010; study group (SG): 32 patients in similar conditions who received 200,000 IU of Vit-A daily, from the identification of a P-hCG level to the first normal hCG value or the diagnosis of progression to gestational trophoblastic neoplasia (GTN), from 2011 to 2017. The present study was approved by the Ethics Committee of the institution where it was conducted. Results In both groups, the prevalence of persistent L&P serum hCG levels was < 5%. In the SG, hCG levels at plateau were higher (CG = 85.5 versus SG = 195 IU/L; p = 0.028), the rate of postmolar GTN was lower (CG = 29.4% versus SG = 6.3%, p = 0.034) and follow-up was shorter (CG = 14 versus SG = 10 months, p < 0.001). During GTN follow-up, there were no differences in GTN staging or treatment aggressiveness in both groups. High-dose Vit-A use did not have any relevant toxic effect. There were no GTN relapses or deaths. Conclusion The limited use of HD Vit-A seems to have a safe and significant effect on the treatment of postmolar patients with L&P serum hCG levels and may decrease the development of postmolar GTN in this population.

Resumo Objetivo Comparar o efeito de alta dose de vitamina A (VitA) no seguimento pósmolar de pacientes com gonadotrofina coriônica humana (hCG) sérica apresentando valoresbaixoseem platô(L&P). Métodos Estudo retrospectivo de série de casos comparando duas coortes não simultâneas. Grupo controle (CG): 34 pacientes com títulos de hCG sérico L&P submetidos a manejo expectante por 6 meses após o esvaziamento uterino, de 1992 a 2010; Grupo de Estudo (SG): de 2011 a 2017, 32 pacientes em condições semelhantes de hCG receberam Vit-A na dose de 200.000 IU por dia, do momento da identificação dohCG em platôate o primeirohCG normaloudiagnóstico de progressão para neoplasia trofoblástica gestacional (NTG). O presente estudo foi aprovado pelo Comitê de Ética da Instituição na qual foi desenvolvido. Resultados Em ambososgrupos, aprevalência de hCGL&P foi < 5%. No SG, os níveis de hCGemplatô forammaiores (CG = 85.5 versus SG = 195 IU/L; p = 0,028), e foram significantemente menores tanto a prevalência de NTG pós-molar (CG = 29.4% versus SG = 6.3%, p = 0,034) como o tempo de seguimento (CG = 14 versus SG = 10 meses, p < 0.001). Na evolução para NTG não houve diferença no estadiamento da Interna tional Federation of Gynecology and Obstetrics (FIGO, na sigla em inglês) ou na agressividade do tratamento. Com altas doses de Vit-A não houve qualquer efeito tóxico relevante. Não houve casos de recidiva de NTG ou de óbito. Conclusão O uso limitado de altas doses de Vit-A parace ser seguro e apresenta efeitos significativos na evolução de pacientes em controle pós-molar com títulos de hCG sérico L&P, e pode diminuir o desenvolvimento de NTG pós-molar nessa população.

Cell-free nucleic acids and melatonin levels in human follicular fluid predict embryo quality in patients undergoing in-vitro fertilization treatment.

Despite many advances in assisted reproductive technology (ART), the most viable embryo selection remains a challenge for infertility treatment. This study was designed to investigate whether intra-follicular circulating cell-free DNA (cfDNA) fragments and Melatonin levels predict embryo quality in patients undergoing IVF treatment. A total of eight hundred and ninety-five follicular fluid (ff) samples were collected from 325 infertile patients undergoing IVF treatment. Patients were enrolled from August 2017 to December 2018 in the infertility center of a tertiary care hospital. A clear non-hematic follicular fluid was aspirated after the removal of eggs from the dominant follicles (>18mm) of each patient. Melatonin and E2 levels in each follicular sample were estimated by immune-chemiluminescence using commercially available kits. ALU-qPCR evaluated cfDNA levels in individual follicular fluid samples. Our study presented a significant and negative relationship between intra-follicular cfDNA and melatonin concentration (-0.541: P<0.001). Each individual follicle contains measurable copy number of cfDNA [mean: 1.85±2.98ng/µl (median; 1.86ng/µl (95% Cl: 0.96-2.87)]. In pregnant women cfDNA copy number was significantly decreased in follicular fluid samples(ff) aspirated from matured oocytes than in immature ones [p<0.01; ß = -0.42±0.49; median; 1.45ng/ml (95% Cl: 0.36-2.97) vs. 3.57ng/µl (95% Cl: 0.37-4.01) respectively. While melatonin concentration in ff samples corresponding to mature oocytes was significantly higher than in ff samples related to immature oocytes (p<0.001). Moreover, in pregnant women cfDNA level was significantly lower in ff samples related to oocytes which produces top-quality embryos versus low quality embryos [p<0.001; ß=1.81±0.91; median; 1.25ng/µl (95% Cl: 0.35-1.97)] vs. [(median; 3.65ng/ml (95% Cl: 1.23-6.36)] respectively. Likewise, in non-pregnant women melatonin levels were significantly decreased in ff samples related to embryos with high fragmentation rate (≥25%) than embryos with low fragmentation rate (<25%; p<0.001). Conclusively, this study indicates that Intra-follicular cfDNA and melatonin concentration possibly a new supplemental tool that supports to establish an advanced non-invasive early prognostic test for the patients undergoing IVF/ICSI procedure.

Perception and knowledge of early pregnancy assessment units among perinatal practitioners in Europe.

OBJECTIVE: To investigate perceptions of early pregnancy assessment units (EPAUs) among perinatal practitioners working in Belgium, France, and Switzerland. METHODS: A prospective multinational survey was conducted between September 1, 2015, and May 21, 2016. Obstetricians, gynecologists, medical doctors, radiologists, and midwives were recruited during meetings, via e-mail invitations, or through the websites of regional obstetrics and gynecology scientific societies. The survey comprised 17 questions that assessed the participants' knowledge, interest, and management of early pregnancy. RESULTS: Of the 871 individuals invited to participate in the survey, 306 (35.1%) responded. Most of the participants were gynecologists and/or obstetricians (225 [73.5%]). A total of 258 (84.3%) participants had no or limited knowledge about EPAUs. Furthermore, 211 (69.0%) participants reported incorrect management when they visualized a gestational sac without embryo and 265 (86.6%) misinterpreted changes in serum levels of chorionic gonadotropin during early pregnancy. In all, 201 (65.7%) participants were interested in collaboration with an EPAU; however, only 125 (40.8%) had sufficient time and resources available to support a patient's psychological distress after early pregnancy loss or salpingectomy. CONCLUSION: Knowledge about early management of pregnancy was limited among the perinatal practitioners surveyed; however, the concept of EPAUs was welcomed by many.

Labor induction versus expectant management at early term in pregnancies with second trimester elevated human chorionic gonadotropin or alpha fetoprotein.

AIM: Elevated human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) have been linked to placental dysfunction and associated morbidities. We aimed to compare the induction of labor with expectant management at term in those pregnancies for the prevention of neonatal and maternal morbidities. METHODS: Women with second trimester HCG ≥ 2 and/or AFP ≥ 2 multiples of the median, without additional maternal or fetal complications, from their 38th gestational week were offered the choice of labor induction or expectant management. The primary outcomes were maternal composite outcome (composed of cesarean deliveries, pre-eclampsia or placental abruption) and neonatal composite outcome (composed of antenatal or neonatal death, Apgar score at 5 min < 7, admission to the neonatal intensive care unit, need for phototherapy, respiratory abnormalities, birth trauma or neonatal infection). RESULTS: Of 305 women, 124 women chose to undergo labor induction, and 181 women chose expectant management. The composite maternal outcome in the expectant management group was twice the rate of the labor induction group, although it did not reach statistical significance (18 [10%] vs 6 [5%]; P = 0.1; relative risk [expectant/induced] 2.04; 95% confidence interval 0.8-5.0). Increased rate of phototherapy led to increased neonatal composite outcomes in the labor induction group compared with the expectant management group (34 [27%] vs 27 [15%], respectively = 0.007). CONCLUSION: In pregnancies with elevated AFP and/or HCG, early term labor induction initiated a trend towards improvement in maternal outcome but increased the rate of mild neonatal morbidity. The statistical insignificance of the large effect on the maternal outcome might reflect the lack of statistical power. Further research is needed to address this limitation.

The effectiveness of zinc supplementation in men with isolated hypogonadotropic hypogonadism.

A multicenter, open-label, randomized, controlled superiority trial with 18 months of follow-up was conducted to investigate whether oral zinc supplementation could further promote spermatogenesis in males with isolated hypogonadotropic hypogonadism (IHH) receiving sequential purified urinary follicular-stimulating hormone/human chorionic gonadotropin (uFSH/hCG) replacement. Sixty-seven Chinese male IHH patients were recruited from the Departments of Endocrinology in eight tertiary hospitals and randomly allocated into the sequential uFSH/hCG group (Group A, n = 34) or the sequential uFSH plus zinc supplementation group (Group B, n = 33). In Group A, patients received sequential uFSH (75 U, three times a week every other 3 months) and hCG (2000 U, twice a week) treatments. In Group B, patients received oral zinc supplementation (40 mg day-1 ) in addition to the sequential uFSH/hCG treatment given to patients in Group A. The primary outcome was the proportion of patients with a sperm concentration ≥1.0 × 106 ml-1 during the 18 months. The comparison of efficacy between Groups A and B was analyzed. Nineteen of 34 (55.9%) patients receiving sequential uFSH/hCG and 20 of 33 (60.6%) patients receiving sequential uFSH/hCG plus zinc supplementation achieved sperm concentrations ≥1.0 × 106 ml-1 by intention to treat analyses. No differences between Group A and Group B were observed as far as the efficacy of inducing spermatogenesis (P = 0.69). We concluded that the sequential uFSH/hCG plus zinc supplementation regimen had a similar efficacy to the sequential uFSH/hCG treatment alone. The additional improvement of 40 mg day-1 oral zinc supplementation on spermatogenesis and masculinization in male IHH patients is very subtle.

Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6months after uterine evacuation?

OBJECTIVE: To compare the outcomes of Brazilian patients with molar pregnancy who continue human chorionic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6months after uterine evacuation. METHODS: Retrospective chart review of 12,526 patients with hydatidiform mole treated at one of nine Brazilian reference centers from January 1990 to May 2016. RESULTS: At 6months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients were managed expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) developed postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectant management required more time for remission (11 versus 8months; p=0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6months; p<0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p=0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/16 patients, p=0.60). None of the women relapsed, and no deaths occurred in either group. CONCLUSION: In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients.

[Effects of electroacupuncture pretreatment on ovarian function and expression of VEGF in rats with ovulation induction].

OBJECTIVE: To explore the protective effect of electroacupuncture (EA) pretreatment on ovarian function in rats with ovulation induction. METHODS: Thirty SD female rats were numbered according to random number table. According to vaginal smear method, rats of estrus were divided into a normal group (10 rats) and cohabitated with male SD rats with the proportion of 1:1. With computer-generated random number, the remaining rats were divided into a model group and an EA group, 10 rats in each one. The model of superovulation was established with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (HCG) in the model group and EA group. Before model establishment and cohabitation, rats in the EA group were treated with EA at "Guanyuan (CV 4)" and "Sanyinjiao (SP 6)", once for 15 min, for consecutive 7 days. Rats in the normal group and model group received no further treatment. The third day 23:00 pm after cohabitation, blood samples in three groups were collected to test the level of estradiol (E2) and progesterone (P). After the rats were sacrificed, the HE staining method was applied to observe the morphological changes of ovarian tissue; the immunohistochemical method was applied to measure the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2; the real-time quantitative PCR technique was applied to measure the gene expression of VEGF and VEGFR-2. RESULTS: The number of ovarian follicle in the EA group was higher than that in the model group and normal group (all P < 0.05); the ratio of corpus luteum size to ovarian size in the EA group was lower than that in the model group (P < 0.01). The ratio of plasma estradiol to progesterone in the EA group tended to be normal group (P < 0.05) and lower than that in the model group (P < 0.01). The protein expression of VEGF and VEGFR-2 in lutein granulosa cell and follicular fluid in the EA group was lower than that in the model group (P < 0.05); gene level of VEGF and VEGFR-2 in ovarian tissue in the EA group was lower than that in the model group (P < 0.05, P < 0.01). CONCLUSION: EA pretreatment has certain protective effect on ovarian function in rats with ovulation induction, which is likely to be related to regulation of VEGF and its receptor.

[Protective Effect of Schisandra Extract on Embryotoxicity and Reproductive Toxicity in Early Pregnant Rats Exposed to Benzo [a] pyrene].

OBJECTIVE: To observe protective effects of Schisandra extract (SE) on embryotoxicity and reproductive toxicity of early pregnant rats exposed to Benzo[a]pyrene (Bap). METHODS: Pregnant rat model was prepared using periodic screening cage method. Totally 50 female pregnant SD rats were divided into five groups by randomized block design according to the weight, i.e., the BaP model group, the low dose SE group, the middle dose SE group, the high dose SE group, the normal control group, 10 rats in each group. Rats in the BaP model group were administered with BaP at a daily dose of 2 mg/kg by gastrogavage. Rats in low, middle, and high dose SE groups were administered by gastrogavage with BaP (at a daily dose of 2 mg/kg) plus SE at a daily dose of 40, 200, and 1 000 mg/kg, respectively. Equal volume of olive oil was administered to rats in the normal control group by gastrogavage. All medication was performed for 8 successive days. Changes of rat body weight in each period were observed. The uterus embryonic total quality and ovary quality were measured, and organ index calculated. The number of corpus luteum, the number of embryo implantation, and the number of absorbed embryo were statistically calculated respectively. The implantation rate and the absorbed embryos rate were calculated. Serum levels of human chorionic gonadotrophin ß (ß-HCG) and progesterone (PROG) were detected by ELISA. RESULTS: Compared with the normal control group, the weight of 9-day pregnant rats, the number of embryo implantation, the uterus embryonic total index, ovary index, serum levels of ß-HCG and PROG all decreased in the Bap model group with significant difference (P < 0.05, P < 0.01). Compared with the Bap model group, body weight, the uterus embryonic total index, and the PROG level increased in 3 dose SE groups (P < 0.05, P < 0.01). Ovary index and serum ß-HCG increased in middle and high dose SE groups (P < 0.05, P < 0.01). The number of implantation obviously increased in the high dose SE groups (P < 0.01). CONCLUSION: SE could reduce the embryotoxicity and reproductive toxicity of early pregnant rats exposed to Benzo[a]pyrene.

Massage therapy improves in vitro fertilization outcome in patients undergoing blastocyst transfer in a cryo-cycle.

CONTEXT: Massage therapy is increasingly used to relieve physical and mental discomfort and is suggested as a safe therapeutic modality, without any significant risks or any known side effects. Although a multitude of complementary therapies, such as acupuncture, are applied in reproductive medicine, no information is available with regard to the application of massage as an adjuvant therapy in assisted-reproduction techniques (ARTs). OBJECTIVES: This study was intended to assess the effectiveness of a deep relaxation (andullation) therapy based on oscillating vibrations when used prior to embryo transfer (ET) in in vitro fertilization (IVF) cryo-cycles. DESIGN: The research team designed a retrospective, observational study. Participants willing to undergo the massage treatment were allocated to the intervention (andullation) group. SETTING: The study was performed at the IVF Centers Prof. Zech-Bregenz in Bregenz, Austria. PARTICIPANTS: A total of 267 IVF patients, with a mean age of 36.3 y, participated in this single-center study. INTERVENTION: All patients receiving a transfer of vitrified and warmed blastocysts between January and December 2012 were included in the evaluation. Prior to ET, the andullation group received a standardized program of therapy-a 30-min, deep relaxation massage on an oscillating (vibrating) device, whereas the control group did not. OUTCOME MEASURES: To determine efficacy, the primary outcomes that the study measured were (1) pregnancy rates (PRs), by testing urine and obtaining a positive ß-human chorionic gonadotropin (ß-hCG); and (2) ongoing, pregnancies (oPR), by observation of fetal heartbeat and birth rates (BR) as well as miscarriage rates. The patients' medical histories and types of infertility as well as the quality of the embryo transfers (ETs) were evaluated. RESULTS: In patients using the massage therapy prior to ET, significantly higher PRs, oPRs, and BRs were observed compared with the control group-PR: 58.9% vs 41.7%, P<.05; oPR: 53.6% vs 33.2%, P<.01; and BR: 32.0% vs 20.3%, P<.05. No differences were detected among groups for patients' ages, hormonal substitution protocols, endometrium structures and buildups, quality of transferred embryos, or quality of transfers. No adverse effects were noted in the massage group. CONCLUSIONS: The research team's results suggested that andullation therapy prior to blastocyst transfer in a cryo-cycle improves embryo implantation, most likely due to a reduction in stress (ie, a relaxation effect on patients), a reduction in uterine contractions, and, probably, an enhancement of the blood flow in the abdominal region. These findings provide support for use of andullation as a complementary therapy for ART.

Potential benefit of dehydroepiandrosterone supplementation for infertile but not poor responder patients in a IVF program.

AIM: The aim of this paper was to evaluate the hypothesis that pretreatment with dehydroepiandrosterone (DEHA) may improve the result on in vitro fertilization (IVF) and the pregnancy outcome among infertile women with normal ovarian reserve. METHODS: Double-blind, randomized, placebo-controlled study; 52 infertile patients received the long protocol IVF. Patients in Group 1, received 75 mg of DHEA once a day, 8 weeks before starting the IVF cycle and during treatment; control group (Group 2) received placebo. The primary endpoint was pregnancy, live birth and miscarriage rates, secondary endpoint was standard IVF parameters such us stimulation duration (hCG day), E2 on HCG-day, endometrial thickness, number of retrieved oocytes, metaphase II oocytes, embryos transferred and score of leading embryos transferred. RESULTS: Patients in the DHEA group had a significantly higher live birth rate compared with controls (P<0.05). Miscarriage rate was higher in control group (P<0.05). CONCLUSION: DHEA supplementation could have a beneficial effect on IVF outcome in infertile women with normal ovarian reserve.

The HAPPY study (Holistic Approach to Pregnancy and the first Postpartum Year): design of a large prospective cohort study.

BACKGROUND: The HAPPY study is a large prospective longitudinal cohort study in which pregnant women (N ≈ 2,500) are followed during the entire pregnancy and the whole first year postpartum. The study collects a substantial amount of psychological and physiological data investigating all kinds of determinants that might interfere with general well-being during pregnancy and postpartum, with special attention to the effect of maternal mood, pregnancy-related somatic symptoms (including nausea and vomiting (NVP) and carpal tunnel syndrome (CTS) symptoms), thyroid function, and human chorionic gonadotropin (HCG) on pregnancy outcome of mother and foetus. METHODS/DESIGN: During pregnancy, participants receive questionnaires at 12, 22 and 32 weeks of gestation. Apart from a previous obstetric history, demographic features, distress symptoms, and pregnancy-related somatic symptoms are assessed. Furthermore, obstetrical data of the obstetric record form and ultrasound data are collected during pregnancy. At 12 and 30 weeks, thyroid function is assessed by blood analysis of thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibodies (TPO-Ab), as well as HCG. Also, depression is assessed with special focus on the two key symptoms: depressed mood and anhedonia. After childbirth, cord blood, neonatal heel screening results and all obstetrical data with regard to start of labour, mode of delivery and complications are collected. Moreover, mothers receive questionnaires at one week, six weeks, four, eight, and twelve months postpartum, to investigate recovery after pregnancy and delivery, including postpartum mood changes, emotional distress, feeding and development of the newborn. DISCUSSION: The key strength of this large prospective cohort study is the holistic (multifactorial) approach on perinatal well-being combined with a longitudinal design with measurements during all trimesters of pregnancy and the whole first year postpartum, taking into account two physiological possible markers of complaints and symptoms throughout gestation: thyroid function and HCG. The HAPPY study is among the first to investigate within one design physiological and psychological aspects of NVP and CTS symptoms during pregnancy. Finally, the concept of anhedonia and depressed mood as two distinct aspects of depression and its possible relation on obstetric outcome, breastfeeding, and postpartum well-being will be studied.

Effect of Chinese herbal treatment on Th1- and Th2-type cytokines, progesterone and beta-human chorionic gonadotropin in early pregnant women of threatened abortion.

OBJECTIVE: To study the clinical effects of Prescription Zhuyun-III (ZYIII) on early pregnant women diagnosed as threatened abortion, and its mechanism in immunity and endocrine by determining serum Th1- and Th2-type cytokines, progesterone, and beta-human chorionic gonadotropin (beta-HCG). METHODS: The treatment group comprised 30 early pregnant women diagnosed as threatened abortion of deficiency syndrome of Pi, Shen, or both. The control group consisted of 20 normal early pregnant women of similar gestational age. Patients in the treatment group were administered with ZYIII for 4 weeks. Peripheral blood samples were collected pre- and post-treatment from both the treatment and the control groups. Serum Th1-type cytokine [interleukin-2 (IL-2)] and Th2-type cytokine [interleukin-10 (IL-10)] were determined by flow cytometry, and serum progesterone and beta-HCG were determined by ELISA. RESULTS: (1) The treatment was effective in 26 and ineffective in 4 patients of the treatment group. Therefore, the cure percentage was 86.67%. (2) In the treatment group before the treatment, IL-2 was significantly higher, IL-10 tended to be less, and the Th1/Th2 balance shifted toward Th1 compared with those in the control group. (3) After the treatment, IL-2 was decreased, IL-10 was increased, and IL-2/IL-10 was decreased. Both progesterone and beta-HCG were increased. Changes of progesterone were positively correlated with changes of IL-10, whereas changes of beta-HCG were negatively correlated with changes of IL-2. CONCLUSIONS: Our study suggests that ZYIII has an evident function of protecting the fetus, and one of its mechanisms is inhibiting the secretion of Th1 cytokines, promoting the secretion of Th2 cytokines, and recovering the pathological shift of the Th1/Th2 balance. The other possible mechanism is increasing serum progesterone and beta-HCG concentrations. Moreover, there are some correlations between the above two effects.

The METEX study: methotrexate versus expectant management in women with ectopic pregnancy: a randomised controlled trial.

BACKGROUND: Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. METHODS/DESIGN: A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment. DISCUSSION: This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 48210491.

Gonadotrophin-releasing hormone (GnRH) release in marmosets II: pulsatile release of GnRH and pituitary gonadotrophin in adult females.

Unlike other mammals, including rodents, Old World primates and humans, common marmosets and probably all other New World primates synthesise and release chorionic gonadotrophin (CG), and not luteinising hormone (LH) from pituitary gonadotrophs. However, little is known about the physiological dynamics of gonadotrophin-releasing hormone (GnRH)-regulated CG release from gonadotrophs and whether such CG release has pulsatile release characteristics similar to those of LH in other mammalian species. Consequently, we performed a series of in vivo and in vitro studies in ovariectomised laboratory rats and female marmosets to compare GnRH-induced pituitary LH and CG release characteristics, respectively. Exogenous GnRH stimulated a slower onset of release of marmoset pituitary CG, both in vivo and in vitro, and induced an approximately 400% greater increase in the duration of marmoset pituitary CG release compared to that for rat LH. Not surprisingly, hypothalamic pulsatile release of GnRH in vivo was not obviously concordant with endogenous episodic changes in circulating levels of CG in marmosets, in contrast to the clear concordance observed between in vivo GnRH and LH release previously demonstrated in rats and other mammals. Pituitary CG release in marmosets thus demonstrates considerable divergence from the timely hypothalamic GnRH-regulated LH release in other female mammals, implying potentially different physiological dynamics in gonadotrophin regulation of marmoset ovarian function.

Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease.

PURPOSE: A generally accepted definition for resistance to first-line single-agent chemotherapy for persistent trophoblastic disease (PTD) is lacking. In the present study, a normogram for serum human chorionic gonadotropin (hCG) from patients with normalization of serum hCG after first-line single-agent chemotherapy for PTD was constructed to identify patients resistant to this chemotherapy. PATIENTS AND METHODS: Between 1987 and 2004, data from 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. A normal serum hCG regression corridor was constructed for 79 patients with low-risk PTD who were cured by single-agent methotrexate (MTX) chemotherapy (control group). Another group of 29 patients with low-risk PTD needed additional alternative therapies (dactinomycin and multiagent chemotherapy) for failure of serum hCG to normalize with single-agent chemotherapy (study group). RESULTS: Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy course proved to have excellent diagnostic accuracy for identifying resistance to single-agent chemotherapy, with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively. At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity. CONCLUSION: In the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD successfully treated with MTX. At high specificity, hCG levels in the first few courses of MTX can identify half the number of patients who are extremely likely to need alternative chemotherapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.

Maternal serum screening in Ontario using the triple marker test.

OBJECTIVES: To summarise the experience and evaluate the performance of the Ontario maternal serum screening (MSS) programme. SETTING: The Ontario MSS programme between October 1993 and September 2000. METHODS: This study used information collected in the Ontario MSS database, which contains data on each screened pregnancy. In the Ontario MSS programme, women are screened between 15 and 20 weeks of gestation. The risk cut-off for Down's syndrome was >or= 1 in 385 at term and women with a serum alpha-fetoprotein >or= 2.2 multiples of the unaffected population median were defined as screen-positive for open neural tube defects. RESULTS: Between 1 October 1993 and 30 September 2000, 428410 women residing in Ontario were screened for open neural tube defects, and 423895 women were screened for Down's syndrome and trisomy 18. Approximately 48% of all pregnant women in the province had MSS. The uptake rate of amniocentesis following a positive Down's syndrome screening was 67%. Of 717 cases of Down's syndrome ascertained in the screened population, 531 were detected by MSS, giving a term detection rate (DR) of 70.6%, with a false-positive rate (FPR) of 7.2%. For neural tube defects, the DR was 72.7%, with a FPR of 2.0%. The screen also detected 50% of cases of trisomy 18 at term, with a FPR of 0.2%. Coincidentally, 113 cases of chromosome aneuploidies other than Down's syndrome and trisomy 18 were detected. DISCUSSION: In the Ontario MSS programme, MSS performed as expected in the detection of Down's syndrome, open neural tube defects and trisomy 18. MSS is an effective and practical method for large-scale second trimester screening for Down's syndrome, open neural tube defects and trisomy 18, and the MSS database is an extremely useful tool in monitoring the performance of this screen.