Is IVF-served two different ways-more cost-effective than IUI with controlled ovarian hyperstimulation?

STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization (IVF) with conventional ovarian stimulation, single embryo transfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were €7187 for IVF-SET, €8206 for IVF-MNC and €5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences €2117; 95% CI: €1544-€2657 and €3136, 95% CI: €2519-€3754, respectively).The ICER for IVF-SET compared with IUI-COH was €43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months. WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development, (120620027) and a grant from Zorgverzekeraars Nederland, the Netherlands' association of health care insurers (09-003). TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.

Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation.

OBJECTIVES: To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. DESIGN: Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. SETTING: 17 centres in the Netherlands. PARTICIPANTS: Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. INTERVENTIONS: Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. MAIN OUTCOME MEASURES: The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality RESULTS: 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). CONCLUSIONS: In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates.Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.

Expression of cytokeratin 10, 13, and involucrin as prognostic factors in low stage squamous cell carcinoma of the uterine cervix.

BACKGROUND: The identification of pretreatment markers with predictive significance for the presence of lymph node metastases and treatment outcome in low stage cancer of the uterine cervix is clinically important. Because the presence of differentiation-related markers varies in this type of cancer, the authors investigated whether loss of these markers is related to a poor clinical course. METHODS: An indirect immunoperoxidase technique was applied to formalin fixed, paraffin embedded tissue sections of 80 patients with International Federation of Gynecology and Obstetrics Stage IB and IIA primary squamous cell cervical carcinomas for detection of expression of cytokeratin 10 and 13, and involucrin. Comparisons were made of the expression of each of these markers among 40 patients with regional node metastases and 40 age-matched patients with no lymph node metastases. Differences in the frequency of expression of these markers also were analyzed in relation to histopathologic characteristics, recurrence, and survival. RESULTS: Expression of cytokeratin 10, 13, and involucrin was found in 24, 64, and 53%, respectively, of all patients studied. The authors found no differences between patients with positive regional lymph nodes and those with negative lymph nodes. Expression of cytokeratin 13 and involucrin was associated with tumor grade (P = 0.01). No relationship was found between expression of the markers used and recurrence or survival in the entire group. Within the lymph node-positive group, however, the survival rate of patients with tumors with cytokeratin 13 expression was significantly higher than that of patients with tumors lacking cytokeratin 13 expression (P = 0.02). CONCLUSION: Expression of cytokeratin 10, 13, or involucrin in the primary tumor is of no predictive value with respect to the presence of regional lymph node metastases in low stage squamous cell cervical cancer. However, cytokeratin 13 expression appears to be of prognostic significance in patients with positive regional lymph nodes.

Differences in MHC and TAP-1 expression in cervical cancer lymph node metastases as compared with the primary tumours.

In previous studies we have shown down-regulation of class I major histocompatibility complex (MHC) expression in a significant proportion of primary cervical carcinomas, which was found to be strongly correlated with loss of expression of the transporter associated with antigen presentation (TAP). By contrast, class II MHC expression was frequently up-regulated on neoplastic keratinocytes in these malignancies. In order to investigate whether these changes are associated with biological behaviour of the tumours, 20 cervical carcinomas were analyzed for MHC (HLA-A, HLA-B/C, HLA-DR) and TAP-1 expression in the primary tumours and in lymph node metastases by immunohistochemistry. The results showed a significant increase in the prevalence of HLA-A and HLA-B/C down-regulation in metastasised neoplastic cells as compared with the primary tumour (P = 0.01). In all cases this was accompanied by loss of TAP-1 expression. Up-regulated HLA-DR expression was found exclusively in primary tumours and was absent in the corresponding metastases (P = 0.002). These data are consistent with the hypothesis that loss of TAP-1 and the consequent down-regulation of class I MHC expression provides a selective advantage for neoplastic cervical cells during metastasis. Furthermore, the lack of class II MHC expression in metastasised cells either reflects a different local lymphokine production or indicates that these cells may have escaped CD4+ cytotoxic T-lymphocyte (CTL)-mediated killing.

Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia.

A retrospective study of 227 patients presenting with abnormal cervical cytology was conducted to investigate the relationship between human papillomavirus (HPV) and progression of untreated cervical intraepithelial neoplasia (CIN) lesions. All patients had colposcopically directed biopsies for histologic diagnosis. The patients were followed cytologically and colposcopically for a mean of 19 months (range 6-42 months). Progression of a cervical lesion was defined as progression to a higher CIN grade confirmed histologically by directed biopsy. HPV DNA detection was done on material remaining from the cervical swabs by the general primer polymerase chain reaction (PCR) and type-specific PCR method, which made the detection of HPV types 6, 11, 16, 18, 31, 33 and not yet sequenced DNA types (X) possible. The presence of HPV DNA increased with the severity of the lesion (P < 0.001). In CIN III, a 100% HPV DNA prevalence was found, with HPV type 16 being the most prevalent type in 75%. Progression was significantly related to the presence of HPV DNA, in particular HPV type 16. The percentage of progressive disease was 21% in the case of HPV DNA positive lesions (n = 130) and 29% in the presence of HPV type 16, whereas HPV DNA negative lesions (n = 97) showed no progression. The detection of HPV DNA and HPV genotype can be used to identify patients with high-risk cervical lesions, since the presence of HPV DNA and genotype 16 in particular are closely related to CIN progression.

Psoas abscess related to spontaneous abortion, intra-uterine contraceptive device and curettage.

This case report presents a patient with a psoas abscess related to a dilatation and (aspiration) curettage for an incomplete abortion with an IUD. Psoas abscess is extremely rare in obstetrics and gynecology and a life threatening condition. It is important to recognize the clinical presentation. Psoas abscess should be suspected in patients presenting with fever, pain in the leg, thigh, or low back region. Whether antibiotic prophylaxis in abortion curettage may prevent this and other complications is discussed.

PIP: In the Netherlands a 34-year old pregnant women presented at the obstetrics and gynecology department of OLVG Hospital in Amsterdam with uterine bleeding. She was at 11 weeks gestation and had an IUD in situ. A vaginal ultrasound revealed that the pregnancy was intact so the physicians could not remove the IUD. She returned 12 days later because she was suffering from an incomplete spontaneous abortion. The physicians removed the IUD and performed an aspiration curettage. They did not administer antibiotics. 10 days after the operation the woman suffered worsening pain in the right thigh and leg and had difficulty walking, a fever, and general sickness. She was breathing very rapidly. Repeated vaginal ultrasounds revealed that she had retained the conceptus. The physicians prescribed respiratory support and antibiotics (claforan, gentamicin, and metronidazole). Blood culture indicated Staphylococcus aureus. Computer tomography revealed a retroperitoneal abscess at the level of the right iliopsoas muscle near the os ilium and the sacro-iliac joint. The physicians performed an extraperitoneal incision and drainage of the abscess and a repeat aspiration curettage. Staphylococcus aureus was isolated from all abscess samples, the conceptus, the cervix, the vagina, the urine, and the sputum. The physicians continued gentamicin and metronidazole treatment. They dismissed her after a complete recovery 16 days after the 2nd aspiration curettage. Possible complications of psoas abscess are sepsis, pulmonary embolism, hemorrhage, and bowel obstruction. Antibiotic prophylaxis in abortion curettage may prevent late sequelae, such as psoas abscess and pelvic inflammatory disease.

HPV DNA presence and HPV genotypes as prognostic factors in low-stage squamous cell cervical cancer.

Sixty-four patients with FIGO stages IB and IIA squamous cell carcinoma of the uterine cervix were studied to assess the prognostic potential of the presence of HPV DNA and HPV genotypes in the tumor, as detected by a general primer-mediated polymerase chain reaction followed by a type-specific PCR on paraffin-embedded tissue sections of the primary tumor. The prevalence of various HPV types in 32 patients with positive lymph nodes was compared to the prevalence found in 32 age-matched controls with negative lymph nodes. In both patient groups HPV DNA was found in all cases. The prevalence rates of HPV types 16, 18, and X in the positive and negative lymph node group were 78% versus 72%, 13% versus 9%, and 3% versus 16%, respectively. These differences were not statistically significant. HPV genotypes 6, 11, and 31 were not found. Differences in recurrence rate and 5-year survival rate between the patient groups with different tumor-containing HPV genotypes were not statistically significant. Nor was there any statistically significant relationship between HPV type and other well-known prognosticators. In conclusion, in our study a 100% HPV DNA prevalence was found in squamous cell cervical carcinomas. Neither the presence of HPV DNA nor the HPV genotype appeared to be related to either the presence of lymph node metastases at the time of initial treatment or to 5-year survival.

A review of prognostic factors in early-stage carcinoma of the cervix (FIGO I B and II A) and implications for treatment strategy.

Several prognostic factors in stages I B and II A cervical carcinoma have been widely studied to define groups of patients with a poor prognosis. Most of these factors are interrelated. The characteristics which should be regarded as main factors have not yet been defined, because the studies reported were based on mainly retrospective and non-randomized analysis. Reviewing the literature, lymph node metastasis, differentiation grade, tumor size, parametrial extension, lymph-blood vessel invasion and cervical invasion seem to be prognostically important factors, which suggests that the subdivision of patients according to the FIGO classification alone is inaccurate. It seems useful to define subgroups of patients according to tumor characteristics, determined after surgical treatment and accurate histologic examination of the surgical specimen. Patients with one or more of these tumor features need additional treatment to improve survival. The current treatment modalities, such as postoperative radiotherapy, have not been thoroughly evaluated, but doubt exists as to their efficacy. Data in the literature suggest that particularly patients with para-aortic or multiple pelvic lymph node metastasis (greater than 3) have already developed distant metastases at the time of primary treatment and therefore need adjuvant systemic therapy. Patients with tumors larger than 4 cm in diameter, differentiation grade III, lymph-blood vessel invasion or cervical invasion (of more than 70%) seem to have high recurrence rates at both pelvic and distant sites, indicating that there is also a need for better pelvic control.