Low hCG Research Articles

Characteristics of relapse in patients with clinical stage I testis cancer undergoing primary surveillance

16040 Background: Primary active surveillance (PAS) has increasingly become standard of care for patients (pts) with clinical stage I testis cancer (CSITC), given the fact that 50–80% are cured with orchiectomy alone. This study investigated sites of relapse and prognostic status at time of relapse. Methods: Since 1998, Oregon Health & Science University's institutional policy has been to recommend active surveillance alone to all CSITC pts after orchiectomy, independent of known risk factors. We retrospectively identified and reviewed the charts of 85 pts with CSITC treated between 1998 and 2007. Site of relapse, prognostic category at relapse, and overall survival data were tabulated. Results: Of 44 pts with seminoma, 10 pts (23%) experienced relapse at a median of 10.5 months after orchiectomy. All 10 pts were good prognosis at time of relapse by the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system. Nine of 10 pts relapsed with low volume abdominal disease only. One patient relapsed with low volume abdominal disease and low level HCG elevation. Seven of ten pts received abdominal radiation. Three pts received 3 cycles of bleomycin, etoposide, and cisplatin (BEP) - two due to pt preference and one due to horseshoe kidney. Two of ten pts had subsequent relapses after radiation (one in thoracic spine and one in supraclavicular nodes) and both pts were rendered disease free with subsequent therapies. All 44 pts (100%) are alive with a median follow up of 28 months. Of 41 pts with nonseminomatous germ cell tumor, 14 pts (34%) experienced relapse at a median of 6 months after orchiectomy. All 14 pts were good prognosis at time of relapse by IGCCCG classification. Six pts relapsed with both low level marker elevation and low volume retroperitoneal disease. Five pts had low level serologic relapse only. Two pts had pulmonary metastic disease without serologic relapse. One pt had relapse in supraclavicular nodes without serologic relapse. All pts received 3 cycles of BEP. All 41 pts (100%) are alive with a median follow up of 28 months. Conclusions: In our series, all pts on PAS relapsed with good prognosis disease and were cured with subsequent therapies. PAS is a safe and reliable management method which reduces the overall burden of treatment in pts with CSITC. No significant financial relationships to disclose.

Persistent tubal pregnancy presenting with postcoital hemorrhage following laparoscopic linear salpingotomy: A case report

BACKGROUND: The use of conservative surgical techniques to treat ectopic pregnancies has been reported to increase the rate of incomplete trophoblastic tissue removal and subsequent regrowth.CASE: Postcoital acute abdominal pain occurred in a woman treated with a laparoscopic linear salpingotomy without suturing for an ampullary ectopic pregnancy 20 days previously. The patient developed clinical symptoms despite satisfactory declining hCG levels. An emergency laparotomy was performed and a 600 ml hemoperitoneum was present The bleeding site of the prior salpingotomy was identified and closed. A few trophoblastic cells were noted in the intratubal clot during pathologic evaluation.CONCLUSION: This case demonstrates that postoperative rupture and bleeding from the fallopian tube with an ectopic gestation can occur in spite of declining and low hCG values. It is conceivable that the hemorrhage at the site of the prior salpingotomy was caused by not only minimal residual trophoblastic tissue, but also mechanical stimulation during sexual intercourse. It is necessary to evaluate the additional benefit of suturing during linear salpingotomy for ectopic gestations.

Placental site trophoblastic tumor

Placental site trophoblastic tumor (PSTT) is a rare neoplasm that rises from intermediate trophoblasts and commonly presents with low and variable concentration of HCG immunoactivity in serum, which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease. PSTT can occur after a normal pregnancy, spontaneous abortion, termination of pregnancy, ectopic or molar pregnancy. There is a wide clinical spectrum of presentation and behavior ranging from a benign condition to an aggressive disease with fatal outcome. Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low HCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. Surgery is the cornerstone of treatment. Chemotherapeutic regimen should be EMA/CO for first line chemotherapy; EMA/EP should be used in EMA/CO refractory cases. This article reviews the literatures on this rare but fatal disease.

Human Placental Development Is Impaired by Abnormal Human Chorionic Gonadotropin Signaling in Trisomy 21 Pregnancies

Placental development is markedly abnormal in women bearing a fetus with trisomy 21, with defective syncytiotrophoblast (ST) formation and function. The ST occurs from cytotrophoblast (CT) fusion and plays an essential role by secreting human chorionic gonadotropin (hCG), which is essential to placental development. In trisomy of chromosome 21 (T21) pregnancies, CTs do not fuse and differentiate properly into STs, leading to the secretion of an abnormal and weakly bioactive hCG. In this study we report for the first time, a marked decrease in the number of mature hCG receptor (LH/CG-R) molecules expressed at the surface of T21-affected CTs. The LH/CG-R seems to be functional based on sequencing that revealed no mutations or deletions and binding of recombinant hCG as well as endogenous hCG. We hypothesize that weakly bioactive hCG and lower LH/CG-R expression may be involved in the defect of ST formation. Interestingly, the defective ST formation is mimicked in normal CT cultures by using LH/CG-R small interfering RNA, which result in a lower hCG secretion. Furthermore, treatment of T21-affected CTs with recombinant hCG overcomes in vitro the T21 phenotype, allowing CTs to fuse and form a large ST. These results illustrate for the first time in trisomy 21 pathology, how abnormal endogenous hCG signaling impairs human placental development.

Re-evaluation of the indication for and limitation of laparoscopic salpingotomy for tubal pregnancy

Objective We investigated the outcome of laparoscopic salpingotomy for tubal pregnancy by follow-up hysterosalpingography (HSG) or second-look laparoscopy (SLL) and reexamined the indication for and limitation of this conservative surgery. Study design From April 1991 to December 2003, we treated 181 cases of tubal pregnancy using laparoscopic salpingotomy. The tubal patency was assessed by either HSG or SLL performed at 3 months post-surgery. The patients with a successful initial operation and confirmed ipsilateral patent tubes at follow-up were classified as truly successful cases (group I). Even after successful operation, if the treated tubes were found to be occluded, they were considered as unsuccessful cases. Therefore, those cases that were unsuccessful at initial surgery as well as at follow-up were categorized as group II. Results One hundred and thirty-four cases (74%) were successfully treated by salpingotomy at initial laparoscopy and 85 of them (63.4%) were found to be truly successful at follow-up (group I). The remaining 47 cases (26.0%) were unsuccessful at initial surgery and 18 (13.4%) cases at follow-up (group II). Thirty-one other patients refused to accept a tubal patency test or were not examined for personal reasons or were lost to follow-up. No difference in surgical outcome was observed between these two groups of patients with regard to gestational age, intra-operative hemorrhage, size or anatomic location of the pregnancy mass, and pre-operative adhesions of the fallopian tube. However, pre-operative serum levels of hCG were significantly higher in group II than in group I. In addition, the unsuccessful cases were more frequently associated with positive fetal heart beat (FHB), tubal rupture, and pre-operative serum levels of hCG of more than 10,000 IU/l ( p < 0.05, χ 2 test). The log-rank test indicated a higher pregnancy success rate in group I ( p < 0.05) than in group II in those who desired future pregnancy. Conclusion Laparoscopic salpingotomy may be practised as conservative surgery for proximal ectopic pregnancy, and gestational mass size is not as important and is not a relative contraindication for conservative laparoscopic surgery, as previously reported. Low pre-operative HCG levels, absence of FHB, absence of tubal rupture initially or minimal rupture may be considered suitable parameters for successful surgery and for achieving future pregnancy.

Quantification of urinary chorionic gonadotropin in spontaneous abortion of pre-clinically recognized pregnancy: Method development and analytical validation

Determination of environmental impacts on reproductive health and specifically on the incidence of early spontaneous abortion requires accurate estimates of the latter. This negative reproductive outcome can be detected by the pattern of elevation and decline of human chorionic gonadotropin (hCG) levels near and shortly beyond the expected time of implantation, requiring daily biomonitoring of hCG levels during the relevant period of the menstrual cycle. Prospective pregnancy studies to assess effects of potentially toxic exposures on human reproductive outcomes can involve up to three menstrual cycles and a huge number of samples in each, for the quantification of the inherently very low hCG levels usually can be determined only in serum. The invasive nature of blood collection, the number of samples needed for the development of prospective studies, and the lack of quantitative methods for the determination of low hCG levels in urine point to the need for collecting urine rather than blood and make it imperative to develop suitable quantitative methods for biomonitoring of very low levels of hCG in urine. This paper describes the development and validation procedures of an automated solid-phase two-site chemiluminescent immunometric assay for the quantification of urinary hCG in early pregnancy and early pregnancy loss. For the validation, both undiluted and diluted urine and control samples have been prepared. From the results, it can be concluded that the assay has a calibration range that extends to 5000 mIU/ml, with a detection limit of approximately 1.2 mIU/ml, practically identical to that found by the IMMULITE 2000 manufacturer's validation study. The intra- and inter-assay precision ranges up to a maximum of around 7%, meaning that the practical limit for functional sensitivity can be established as low as 10%. This means that the immunoassay from DPC ® can identify, with relatively high confidence, non-pregnant women and the typical “rise and fall” pattern of early pregnancy loss through analysis of urine samples. Results also lead to the conclusion that there is a very good agreement between expected and observed urinary hCG levels indicative of good immunoassay accuracy for the studied range of hCG concentrations. In terms of analyte stability, it can be concluded that urinary hCG is stable under the expected conditions required for ongoing investigations that include temperatures of 2–8 °C for up to 48 h and temperatures of around −20 °C for longer periods that can extend to over 3 months.

Placental Alkaline Phosphatase (PLAP) Staining and Human Chorionic Gonadotropin (hCG) Production in Cultures of Fresh and Cryopreserved Cytotrophoblasts Isolated by CD9/MHC Class I/MHC Class II Immunoelimination

We have further characterized villous trophoblasts isolated by trypsinization and purified by elimination of CD9/MHC class I/MHC class II expressing cells. The cells isolated were >99.99% cytotrophoblasts by criteria of cytokeratin (positive) and vimentin (negative) expression. Purified cells directly after isolation (fresh) were compared with cryopreserved and thawed cells (frozen) for production of human chorionic gonadotropin (hCG) and expression of placental alkaline phosphate (PLAP) after 4 h of culture. We found that fresh cells may adhere slightly more strongly than frozen cells, contained approximately 8-fold more PLAP-positive cells (indicating syncytial fragments) after adherence but neither preparation would secrete hCG until day 4 of culture. We conclude that the cells isolated by cell elimination were cytotrophoblasts with only a small number of PLAP (<0.2% of the fresh population plated) positive cells and that both populations shared the property of very low hCG production until cultured past day 4. We speculate that cells isolated by other methods (accompanying paper) may be contaminated by even more syncytial fragments, detectable by PLAP staining and by production of hCG in the first 48 h of culture.

Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results

Objectives. A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future. Methods. The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test. Results. Among these 170 patients, the average persistent hCG result was 102 ± 152 mIU/ml, with a range of 6.1–900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma ( n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present. Conclusion. Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.

Gestational trophoblastic diseases: 3. Human chorionic gonadotropin-free β-subunit, a reliable marker of placental site trophoblastic tumors

Objectives. Placental site trophoblastic tumor (PSTT) commonly presents with low and variable concentration of hCG immunoreactivity in serum which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease (quiescent GTD). Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low hCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. We investigate the usefulness of hCG-free β-subunit to make this discrimination. Methods. Data collected on cases referred to the USA hCG Reference Service for consultation served as a basis for this retrospective analysis. There were 13 cases with histology proven PSTT and 12 with nontrophoblastic malignancy. hCG-free β-subunit was measured by immunoassay and reported as a proportion of total hCG (hCG-free β-subunit(%)). hCG-free β-subunit(%) results were determined for all histologically proven cases of PSTT and for the nontrophoblastic malignancies. Comparisons of hCG-free β-subunit(%) were made and compared with those of the 82 choriocarcinoma/GTN cases and 69 quiescent GTD cases. The accuracy of hCG-free β-subunit(%) to discriminate these malignancies was analyzed by investigating the areas under receiver-operating characteristics curve ± standard error. Results. hCG-free β-subunit(%) was the predominant hCG form in cases of PSTT (mean ± standard deviation, 60 ± 19%) and nontrophoblastic malignancies (91 ± 11%), thus discriminating these diagnoses from choriocarcinoma/GTN (9.3 ± 9.2%) and from quiescent GTD (5.4 ± 7.8%). The cutoff of >35% free β-subunit is proposed. At this cutoff, 100% detection at 0% false-positive is achieved. The accuracy of hCG-free β-subunit(%) for this discrimination is 100 ± 0%. At a proposed cutoff of >80%, the free β-subunit test will also distinguish PSTT from nontrophoblastic malignancy, with 77% detection at 23% false-positive or an accuracy of 92 ± 3.2%. Conclusion. Measurement of the proportion hCG-free β-subunit(%) was found to be useful in the diagnosis of PSTT using proposed cutoff values of >35% and >80%. While this finding needs to be confirmed by larger studies, it would be reasonable to measure hCG-free β-subunit(%) whenever the diagnosis of PSTT is considered.

Association Between Low Day 16 hCG and Miscarriage After Proven Cardiac Activity

To investigate an association between low human chorionic gonadotrophin (hCG) levels at the end of the first week of implantation and later clinical miscarriage occurring after ultrasound confirmation of a live pregnancy. This was an observational retrospective study of 1,054 women who underwent in vitro fertilization and achieved an ultrasound-confirmed live singleton pregnancy with cardiac activity. The incidence of miscarriage diagnosed at 8-19 weeks +6 days of gestation was estimated in these 3 subgroups according to their hCG concentrations at day 16 after conception: less than the 25th, 25th-75th, and more than the 75th percentiles. The overall incidence of miscarriage was 11.1% (117/1,054), and the median gestational age at diagnosis was 10 weeks and 4 days. The median (95% confidence interval) day 16 hCG level in the miscarriage group was 182 mIU/mL (157-211), significantly lower than the median level in those who had an ongoing pregnancy (223 mIU/mL [213-233], P < .003). There was an increasing risk of miscarriage associated with decreased hCG levels (8.0% at > 75th percentile; 9.9% at 25th-75th percentiles; 16.7% at < 25th percentile; P = .003). Low hCG levels in very early pregnancy are associated with an increased risk of miscarriage occurring after the clinical recognition of pregnancy. The mechanisms underlying late first-trimester and second-trimester miscarriages may have begun as early as the first week of implantation. III.

Isolation of hCG and its Characterization by Radioimmunoassay, Enzyme‐Immunoassay, and Radio‐Receptor Assay

The nature of human chorionic gonadotropin (hCG) molecules present during early pregnancy of Indian women is poorly understood. Therefore, a study has been undertaken to isolate hCG and characterize different forms of hCG from urine. The hCG molecules from urine of pregnant women (45–75 days post LMP) were adsorbed onto kaolin, eluted with ammonium hydroxide, and precipitated using acetone and then lyophilized. The lyophilized extract was subjected to Sephadex G‐100 chromatography followed by ion‐exchange fractionation. Three major fractions of protein (i.e., Peaks I, II, and III) associated with carbohydrate activity were obtained. Peaks II and III eventually resolved into a single peak I following repeated ion exchange chromatography, which suggested the presence of aggregates of molecules. Further purification on an affinity column resolved all three peak fractions into one unadsorbed and two adsorbed (A and B) fractions. These adsorbed fractions were characterized by radioreceptor assay (RRA), radioimmunoassay (RIA), and enzyme linked immunosorbent assay (ELISA). The activity was standardized against WHO reference preparation 75/589. Peaks I (A and B) were found to have maximum at about 75% of immunologically potent hCG, followed by peaks II (40%) and III (5%). The molecular sizes of peaks I, II, and III on a Sephadex G‐200 column corresponded to 27,500D, 66,000D, and 84,000D, respectively. Relative mobilities of all adsorbed fractions in sodium dodecyl sulphate‐polyacrylamide gel electrophoresis (SDS‐PAGE) showed the presence of hCG‐α (mol. wt. 19,539D) and hCG‐β (28,870D) subunits. The presence of both subunits of hCG were also revealed by Western blot analysis. For the first time, we report the low molecular weight hCG molecule, of 27,500D by size exclusion chromatography, which has immunological and biological activity as measured by RIA, ELISA, and RRA.

“Un-Coasting” Is a Safe and Effective Method to Complete Ovarian Folliculogenesis in Very High Responders

To describe the use of downregulation followed by recombinant-FSH (rec-FSH) plus low dose HCG followed by low-dose hCG monotherapy for the last 2 days of stimulation in 13 high responding patients undergoing in vitro fertilization (IVF) who were at risk of both cancellation and ovarian hyperstimulation (OHSS).

Urinary Human Chorionic Gonadotropin (hCG), Intramuscular or Subcutaneously Administered, Yields higher hCG Serum and Follicular Levels Than Recombinant hCG in Egg Donors

Benefits of easy and improved local tolerance of subcutaneous recombinant HCG (rhCG) administration has been widely reported. To evaluate and compare the efficacy and safety of 250 microg of recombinant hCG with 10,000 UI of urinary hCG (uhCG) in egg donors administered subcutaneously or intramuscularly. Prospective, randomized, double blind clinical trial. Sixty egg donors from November 2003 to June 2004 who underwent a controlled ovarian hyperstimulation (COH) in our clinic were included. Using a random number table, egg donors were randomized into one of three treatment arms. COH was followed by 10,000 IU uhCG injection, given intramuscularly (i.m.) (n=20) or subcutaneously (s.c.) (n=20), or 250 microg rhCG by s.c route (n=20). Only egg donors with body mass index below 32 and between 18 to 35 years old were accepted. There were no statistically significant differences in age or body mass index (BMI) among donors receiving uhCG or rhCG sc-im. Mean days of stimulation, total dose of gonadotrophins were similar in all groups. Mean number of oocytes retrieved per treatment group were similar as well as mean numbers of metaphase II oocytes retrieved. There were no differences between mean numbers of zygotes obtained in both groups. No patients with no oocytes retrieved were found. Implantation rate and pregnancy rate were similar in recipients. Serum oestradiol and progesterone levels were similar in all groups on day of oocyte retrieval and 5 days after hCG injection, as well as progesterone levels in follicular fluid. Statistically significant differences were found in hCG serum and follicular fluid levels between groups (* p < 0.01). No adverse events were registered by any patient receiving hCG by either injection method. Tabled 1 Recombinant and urinary hCG subcutaneously administered are effective and well tolerated in the induction of final follicular maturation and luteinization in egg donors. This investigation suggests that clinical use of uhCG by sc. is suitable for egg donors and could enhance the fulfilment. In addition, lower hCG serum and follicular levels were obtained with rhCG group and that could be considered in high responders with increased risk of ovarian hyperstimulation syndrome.

Low serum HCG concentrations following the ovulatory dose of HCG are not associated with reduced IVF success rates

Background and Significance: Human chorionic gonadotropin (hCG) is routinely used to induce oocyte maturation. However, high serum concentration of hCG may increase risk of ovarian hyperstimulation syndrome (OHSS). The minimum effective dose of hCG has yet to be determined.

Low serum HCG concentrations following the ovulatory dose of HCG are not associated with reduced IVF success rates

Background and Significance: Human chorionic gonadotropin (hCG) is routinely used to induce oocyte maturation. However, high serum concentration of hCG may increase risk of ovarian hyperstimulation syndrome (OHSS). The minimum effective dose of hCG has yet to be determined.

Serum hCG levels 12 days after embryo transfer is predictive of pregnancy outcome

Objective: To determine the predictive value of serum hCG concentrations measured on the twelfth day after embryo transfer (D12) as a marker to distinguish between viable and non-viable pregnancies.Design: Two thousand four hundred six women who had fresh embryo transfers between January 2000 and December 2002 were studied retrospectively. Patients who had serum hCG concentrations higher than 5IU/l on D12 post embryo transfer were stratified and evaluated.Materials and Methods: All women underwent GnRH agonist suppression and controlled ovarian stimulation with gonadotropin administration. Transvaginal follicle aspiration was performed 36 hr after hCG administration and embryo transfers performed on the third post retrieval day. On day 12 following embryo transfer, serum hCG level of each patient was determined by a fluoroimmunometric assay system. Serum hCG values for viable and non-viable pregnancies were compared by Student’s t test.Results: The median hCG concentration was 161.00 IU/l for viable autologous singleton pregnancies. The median hCG concentration in viable multiple pregnancies was 200% higher than in singleton pregnancies with a median value of 321.42 IU/l. Patients with singleton pregnancies that resulted spontaneous abortion (sab) had lower median hCG levels (126.98 IU/l, p<0.01) than viable singleton pregnancies. Multiple pregnancies which resulted in an sab had a median hCG concentration of 196.54 IU/l which was also significantly lower compared to serum hCG concentrations in live multiple birth/ongoing pregnancies. Patients identified as having a biochemical pregnancy were found to have median hCG levels of 36.15 IU/l. Patients with ectopic pregnancies were also associated with low hCG values with the median concentration of 42.56 IU/l.Conclusion: Serum hCG concentration on day 12 following embryo transfer may be a useful prognostic tool in counseling patients regarding pregnancy outcome. Objective: To determine the predictive value of serum hCG concentrations measured on the twelfth day after embryo transfer (D12) as a marker to distinguish between viable and non-viable pregnancies. Design: Two thousand four hundred six women who had fresh embryo transfers between January 2000 and December 2002 were studied retrospectively. Patients who had serum hCG concentrations higher than 5IU/l on D12 post embryo transfer were stratified and evaluated. Materials and Methods: All women underwent GnRH agonist suppression and controlled ovarian stimulation with gonadotropin administration. Transvaginal follicle aspiration was performed 36 hr after hCG administration and embryo transfers performed on the third post retrieval day. On day 12 following embryo transfer, serum hCG level of each patient was determined by a fluoroimmunometric assay system. Serum hCG values for viable and non-viable pregnancies were compared by Student’s t test. Results: The median hCG concentration was 161.00 IU/l for viable autologous singleton pregnancies. The median hCG concentration in viable multiple pregnancies was 200% higher than in singleton pregnancies with a median value of 321.42 IU/l. Patients with singleton pregnancies that resulted spontaneous abortion (sab) had lower median hCG levels (126.98 IU/l, p<0.01) than viable singleton pregnancies. Multiple pregnancies which resulted in an sab had a median hCG concentration of 196.54 IU/l which was also significantly lower compared to serum hCG concentrations in live multiple birth/ongoing pregnancies. Patients identified as having a biochemical pregnancy were found to have median hCG levels of 36.15 IU/l. Patients with ectopic pregnancies were also associated with low hCG values with the median concentration of 42.56 IU/l. Conclusion: Serum hCG concentration on day 12 following embryo transfer may be a useful prognostic tool in counseling patients regarding pregnancy outcome.

Morbid obesity adversely impacts outcomes with IVF

Objective: Obesity, defined as a BMI greater than 30, is a growing epidemic in our nation. Obesity is well known to increase the risk of medical disorders such as diabetes and hypertension. This study was designed to evaluate the impact of obesity and morbid obesity (BMI >35) on outcome with IVF. Design: A retrospective analysis of non-donor, IVF patients, less than age 40, undergoing IVF or IVF/ICSI from March 1st, 2000 to March 31st, 2003. Materials and Methods: Patients underwent Antagon(r) (Organon) or Cetrotide(r) (Serono) antagonist protocols, Lupron(r) (TAP) agonist protocols, or flare protocols prior to controlled ovarian hyper-stimulation with Follistim(r) (Organon) or Gonal-F(r) (Serono). Oocyte retrieval occurred 36–39 hours post Human Chorionic Gonadotropin (hCG) administration. Insemination was performed 38–42 hours post hCG using a two hour co-incubation of sperm with oocytes or sperm injection. Fertilization was evaluated 18–20 hours after insemination. Fertilized oocytes were placed into fresh micro-drops of sequential media (G1.2, G1.3) and cultured in groups of two under oil to Day 3. Multi-cell embryos were moved to new micro-drops of sequential media (CCM, G2.2, G2.3, Vitrolife) under oil for culture to Day 5 or Day 6 and subsequent blastocyst embryo transfer. Abdominal ultrasound (5 MHz) was utilized to assist intrauterine placement of the embryo transfer catheter (Wallace, Cook). Results: There was no significant difference in the mean age of the patients in the four groups (range: 33.1 to 33.7 years). Nor was there a difference in the number of patients undergoing ICSI versus IVF. Total gonadotropin consumption was likewise similar between the groups, ranging from 37.4 to 41 amps. There was a trend towards a lower peak estradiol level in the >35 BMI group; however, this was not statistically significant. The fertilization rate was similar between all groups (62.6 to 67.3%). The average number of embryos transferred was similar in all groups (1.9 to 2.0). The ongoing pregnancy rate and implantation rate was significantly lower (Fisher Exact) in the >35 BMI group compared to <25 and 25–29.9 BMI groups. Tabled 1† P < 0.05 vs. BMI >35‡ P < 0.01 vs. BMI >35P < 0.001 vs. BMI >35 † P < 0.05 vs. BMI >35 ‡ P < 0.01 vs. BMI >35 P < 0.001 vs. BMI >35 Conclusion: Patients undergoing IVF or IVF/ICSI with a BMI > 35, have a significantly decreased implantation rate and ongoing pregnancy rate in comparison to obese (BMI 30 -34.9), overweight (BMI 25–25.9) or normal weight (BMI < 25) patients. There was a trend towards decreasing implantation rate with overweight (BMI 25–29.9) and obese patients but this was not statistically significant. Possible etiologies for this decrease in pregnancy rate may include: greater volume of distribution resulting in lower serum levels of FSH/decreased stimulation of the ovaries, lower hCG levels for oocyte maturation prior to retrieval or possible endometrial effects. Counseling patients regarding the impact of weight loss prior to an IVF cycle should become a routine part of the physician/patient discussion.

Very low alpha-fetoprotein in Down syndrome maternal serum screening.

To establish the frequency of very low maternal serum AFP and to differentiate congenital AFP deficiency from those diseases known to be associated with low AFP. AFP values below 2 microg/L and borderline values up to 3 microg/L were retrospectively analysed in 839 773 singleton pregnancies included in a programme for routine screening of trisomy 21 maternal serum markers. Serum AFP was undetectable (< or =2 microg/L) in 8 cases, giving a frequency of 1/105 000. The calculated risk of Down syndrome was > or =1/250 in 5 cases. Fetal karyotype was normal. Seven of these pregnancies went to term (39-41 weeks) uneventfully, and birth weight was normal (3050-4110 g). In the 8th case, fetal death occurred at 35 weeks due to severe maternal diabetes. AFP levels between 2.1 and 3.0 microg/L were noted in 7 other cases. The calculated risk of Down syndrome was > or =1/250 in 5 cases, and fetal karyotype was normal. Pregnancies went to term in 4 cases (33-41 weeks), and birth weight was normal (3000-3380 g). In 3 cases, low hCG (<0.6 MoM) was associated with low AFP, and fetal death occurred at 15 to 16 weeks. Once technical errors have been excluded (repeat assay in a second run, calcium assayed to exclude the interference of EDTA for fluorimetric methods, dilution to exclude interfering antibodies, running on an alternative analyser, checking a second sample), very low second-trimester maternal serum AFP should prompt ultrasound examination in order to check fetal viability. Congenital AFP deficiency, an extremely rare disorder (1/100 000), should be suspected. It has no consequences for fetal and infant development, and parents should be reassured.

Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease

Objective: This study was undertaken to evaluate the significance of persistent low-level human chorionic gonadotropin (hCG) titers (usually <50 IU/L) in the absence of clinical evidence of pregnancy or gestational trophoblastic disease. Study Design: The USA hCG Reference Service consulted on 114 cases with persistent low levels of hCG; 51 had false-positive hCG results. The remaining 63 cases had real hCG results and are presented here. Results: Antecedent gestational events included hydatidiform mole (27), pregnancy (35), and gestational trophoblastic neoplasm (1). Forty of the 63 (64%) cases received therapy, including chemotherapy (38), hysterectomy (2), or both (10). Despite treatment, in all cases, low hCG titers persisted. After 1 to 4.5 years of low titers, four women had a sudden rapid increase in hCG levels, and malignant disease was confirmed or clearly suggested (gestational trophoblastic neoplasm [3] and placental site trophoblastic tumor [1]). Invasive trophoblast antigen (ITA) is a marker of invasive cytotrophoblast cells. ITA was measured in 38 of the cases with persistent low hCG, in all cases ITA accounted for less than 25% of the hCG concentration. It was also determined in the 4 cases indicated with malignant disease, accounting for more than 80% of the hCG. Conclusion: The presence of persistent low-level hCG titers defines a subset of women with preinvasive or quiescent gestational trophoblastic disease. ITA effectively detected the presence or absence of invasive cells in these cases. The recommended management of the quiescent disease is close surveillance without therapy until malignant disease detected. (Am J Obstet Gynecol 2003;188:1254-9.)

Low maternal serum concentrations of human chorionic gonadotropin as part of the triple test screening: a follow-up study

Objective: To determine whether low maternal serum concentrations of human chorionic gonadotropin (hCG) were associated with poor pregnancy outcome. Methods: Between 1999 and 2000, 20 880 women underwent triple test screening in our hospital. The levels of hCG were detected by fluorescent immunoassay. Low hCG levels (≤ 0.20 MoM in our center) were considered to be a marker for increased risk for trisomy 18 or adverse pregnancy outcome. Each patient completed a questionnaire regarding fetal karyotype, complications of pregnancy and pregnancy outcome. Results: Low maternal serum concentrations of hCG were detected in 119 pregnancies (0.57%). Of these, 19 (16%) were found to be missed abortions. The distribution of the remaining 100 cases was as follows: 72% had an isolated low hCG level, 24% had a low hCG level and a combination of hCG + α-fetoprotein < 0.80 MoM, and 4% had a low hCG level and a combination of hCG + unconjugated estriol < 0.80 MoM. No trisomy 18 or other chromosomal abnormalities were detected in our patient population. However, there were perinatal complications. Conclusion: Based on our screened population, a combination of multiple analytes seemed to be a better marker than an isolated finding of low maternal serum concentrations of hCG with regards to abnormal fetal karyotype, specifically trisomy 18, although it did determine a high-risk group in terms of complications of pregnancy.