Contribution of medico-administrative databases to health vigilance: example of post-oocyte retrieval infections.

STUDY QUESTION: Can we monitor post-oocyte retrieval infections in the French national health data system to complement the French ART vigilance system? SUMMARY ANSWER: Medico-administrative databases provide a more comprehensive view of post-oocyte retrieval infections and can be used to detect abnormal increases in frequency and outlier ART centers as a complementary tool to the ART vigilance system. WHAT IS KNOWN ALREADY: The various studies of ART complications are reassuring, showing relatively low overall complication rates. Nonetheless, the European Union has set up a vigilance system to monitor these complications. However, this system is not an exhaustive source of information and does not provide a complete overview of post-ART complications. STUDY DESIGN, SIZE, DURATION: The study population was identified from the comprehensive French national hospital discharge database. It included women under 46 years of age undergoing an oocyte retrieval in 2019, classified into three population subgroups according to the indication of oocyte retrieval: infertility (IF) , fertility preservation (FP), and oocyte donation (OD) . The study population included 52 098 women who had undergone 65 948 oocyte retrievals in 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospital stays and delivery of antibiotics within 31 days after oocyte retrieval were analyzed. Women and infections were characterized according to various characteristics (age, comorbidities, indication of oocyte retrieval, type of hospital stay, length of hospital stay, type of antibiotherapy, etc.). Multivariate analysis was performed to determine the relation between the occurrence of infection and women's characteristics, and results are expressed as odds ratios (ORs) and 95% CI. A funnel plot and a box plot were used to compare the infection rate per center with the national average and to detect outliers. MAIN RESULTS AND THE ROLE OF CHANCE: Infections in the month following the oocyte retrieval represented 6.9% of the procedures in 2019 (n = 4522). Of these infections, 112 were hospitalized (0.2% of oocyte retrievals), and 4410 were non-hospitalized (6.7% of oocyte retrievals). The hospitalized infections were essentially gynecological infections (40.9%) and urinary tract infections (23.5%). In 87.9% of non-hospitalized infections, a single antibiotic therapy was prescribed. Mixed-effect model analysis showed that the risk of infection was significantly higher in women under 30 years of age, in the FP population, in supplementary universal health coverage (CMU-C) beneficiaries, and women with endometriosis. Funnel plot and box plot analysis showed that three ART centers have an infection rate significantly higher than the national average. In the three centers that stand out from all the others, the objective is to return to these centers to understand the possible reasons for this observed rate and to implement corrective measures. LIMITATIONS, REASONS FOR CAUTION: Despite all its advantages, the French national health data system presents some limitations, such as the risk of inappropriate coding. Another limitation of this study is that we cannot confirm an attributable relation between the infection and the ART procedure, even if the delay of 31 days after oocyte retrieval is consistent with the occurrence of a post-retrieval complication. In addition, antibiotics may be prescribed as a 'precautionary' measure in certain situations (women with a susceptibility to infection, complicated procedures), or as antibiotic prophylaxis for embryo transfer. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limits in identifying post-ART infections in medico-administrative databases, this approach is a promising way to complement the ART vigilance reporting system. This concept developed for infections will also be generalized to other complications with regular feedback to professionals. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was sought for the study. The study was supported by the Agence de la biomédecine, France. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Overview of hospitalizations in women undergoing oocyte retrieval for ART in the French national health data system.

STUDY QUESTION: What is the incidence rate of complications in women undergoing ART procedures compared to the period prior to their first oocyte retrieval? SUMMARY ANSWER: The study shows a significant increase in the post-ART incidence rate of some complications but a low overall rate of occurrence relative to the total number of oocyte retrievals. WHAT IS KNOWN ALREADY: ART, widely used in Europe, accounts for 3.3% of births in France. The various studies of ART complications are fairly reassuring, showing relatively low overall complication rates but only few studies have used exhaustive national registers. STUDY DESIGN, SIZE, DURATION: The cohort for this study was identified from the comprehensive French national hospital-discharge database and includes women under 50 years with a first oocyte retrieval (T0) in 2012-2017, classified in three population subgroups according to the indication for oocyte retrieval: infertility (IF), oocyte donation (OD), and fertility preservation (FP). This study includes 156 916 women whose first oocyte retrieval occurred in 2012-2017 and 542 775 hospitalizations in 2010-2019 (excluding first retrieval). PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospitalizations for complications or others events (oocyte retrieval, delivery, pregnancy loss, and death in the hospital) during the 2 years before (control period) and after their first oocyte retrieval (post-oocyte retrieval period) were compared and expressed per 10 000 person-months (pm). MAIN RESULTS AND THE ROLE OF CHANCE: In the IF subgroup, incidence rates were significantly higher after (vs before) retrieval for hospitalized ovarian hyperstimulation syndrome (OHSS) (162 vs 6/10 000 pm), adnexal torsion (14 vs 3), venous thrombosis (8 vs 1), arterial thrombosis (3 vs 1), trauma (2 vs 1), and significantly lower for infections (61 vs 87). The higher incidences of OHSS, adnexal torsion and venous thrombosis could only partially be explained by the occurrence of pregnancy.In the FP subgroup, incidence increased significantly after (vs before) retrieval for hospitalized OHSS (55 vs 0), venous thrombosis (59 vs 4), and infections (176 vs 56). For the OD subgroup, hospitalized OHSS (116 vs 0) and bleeding (24 vs 0) were significantly higher after (vs before) retrieval. LIMITATIONS, REASONS FOR CAUTION: The French national health data system, despite all its advantages, present some limitations such as the risk of coding errors. The unavailability of some personal information and the absence of consideration of risk factors prevented us from adjusting the risk. Finally, only complications resulting in hospitalization were analyzed which probably leads to their underestimation. WIDER IMPLICATIONS OF THE FINDINGS: The use of medico-administrative bases will be a valuable tool in public health and will furnish a better overview of the complications. Further studies are needed to complete this analysis. Adding information on drugs would help to better define T0 and less severe complications. STUDY FUNDING/COMPETING INTEREST(S): N/A. TRIAL REGISTRATION NUMBER: N/A.

Urogenital infections in reproductive medicine.

Urogenital infections with Chlamydia trachomatis belong to the most prevalent sexually-transmitted bacterial diseases. In women, they can cause chronic salpingitis with subsequent tubal infertility and ectopic pregnancies. In men, C. trachomatis can cause urethritis, prostatitis and epididymitis. Urogenital infections can be symptomatic or asymptomatic. Symptomatic urogenital infections might impair male fertility. In vitro, C. trachomatis affects sperm motility and viability. However, there is no clear evidence that asymptomatic urogenital infections have an adverse effect on male fertility. Because C. trachomatis can be sexually transmitted and lead to female infertility, it is also of significance in male infertility work-up. Because of their high sensitivity, nucleic acid amplification tests should be used to examine first-void urine specimens. Both partners should be treated. The role of Ureaplasma urealyticum in reproductive medicine has been discussed controversially. There is no evidence that U. urealyticum has a significant impact on female or male infertility.

Hepatic effects of Cimicifuga racemosa extract in vivo and in vitro.

Extracts of Cimicifuga racemosa are used frequently for menopausal complaints. Cimicifuga is well tolerated but can occasionally cause liver injury. To assess hepatotoxicity of cimicifuga in more detail, ethanolic C. racemosa extract was administered orally to rats, and liver sections were analyzed by electron microscopy. Tests for cytotoxicity, mitochondrial toxicity and apoptosis/necrosis were performed using HepG2 cells. Mitochondrial toxicity was studied using isolated rat liver mitochondria. Microvesicular steatosis was found in rats treated with > 1,000 mg/kg [DOSAGE ERROR CORRECTED] body weight cimicifuga extract. In vitro, cytotoxicity was apparent at concentrations > or =75 microg/mL, and mitochondrial beta-oxidation was impaired at concentrations > or =10 microg/mL. The mitochondrial membrane potential was decreased at concentrations > or =100 microg/mL, and oxidative phosphorylation was impaired at concenq trations > or =300 microg/mL. The mechanism of cell death was predominantly apoptosis. C. racemosa exerts toxicity in vivo and in vitro, eventually resulting in apoptotic cell death. The results are compatible with idiosyncratic hepatotoxicity as observed in patients treated with cimicifuga extracts.

The role of heat shock proteins in reproduction.

Heat shock proteins (HSP) were first identified in cells after exposure to elevated temperature. Subsequently HSP have been identified as a critical component of a very complex and highly conserved cellular defence mechanism to preserve cell survival under adverse environmental conditions. HSP are preferentially expressed in response to an array of insults, including hyperthermia, free oxygen radicals, heavy metals, ethanol, amino acid analogues, inflammation and infection. HSP interact with intracellular polypeptides and prevent their denaturation or incorrect assembly. In addition HSP are also involved in several processes essential for cellular function under physiological conditions. HSP production is enhanced during in-vitro embryo culture and they are among the first proteins produced during mammalian embryo growth. The spontaneous expression of HSP as an essential part of embryo development is well documented and the presence or absence of HSP influences various aspects of reproduction in many species. Finally, HSP are immunodominant antigens of numerous microbial pathogens, e.g. Chlamydia trachomatis, which have been recognized as the main cause of tubal infertility. Many couples with fertility problems have had a previous genital tract infection, have become sensitized to microbial HSP, and a prolonged and asymptomatic infection may trigger immunity to microbial HSP epitopes that are also expressed in man. Antibodies to both bacterial and human HSP are present at high titres in sera and hydrosalpinx fluid of many patients undergoing in-vitro fertilization (IVF). In a mouse in-vitro embryo culture model, these antibodies impaired the mouse embryo development at unique developmental stages. Recent studies indicate an association between a previous infection, immunity to HSP and reproductive failure.

Heat shock protein expression during gametogenesis and embryogenesis.

When cells are subjected to various stress factors, they increase the production of a group of proteins called heat shock proteins (hsp). Heat shock proteins are highly conserved proteins present in organisms ranging from bacteria to man. Heat shock proteins enable cells to survive adverse environmental conditions by preventing protein denaturation. Thus the physiological and pathological potential of hsps is enormous and has been studied widely over the past two decades. The presence or absence of hsps influences almost every aspect of reproduction. They are among the first proteins produced during mammalian embryo development. In this report, the production of hsps in gametogenesis and early embryo development is described. It has been suggested that prolonged and asymptomatic infections trigger immunity to microbial hsp epitopes that are also expressed in man. This may be relevant for human reproduction, since many couples with fertility problems have had a previous genital tract infection. Antibodies to bacterial and human hsps are present at high titers in sera of many patients undergoing in vitro fertilization. In a mouse embryo culture model, these antibodies impaired the mouse embryo development at unique developmental stages. The gross morphology of these embryos resembled cells undergoing apoptosis. The TUNEL (terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling) staining pattern, which is a common marker of apoptosis, revealed that embryos cultured in the presence of hsp antibodies stained TUNEL-positive more often than unexposed embryos. These data extend preexisting findings showing the detrimental effect of immune sensitization to hsps on embryo development.

Presence of the major outer-membrane protein of Chlamydia trachomatis in patients with chronic salpingitis and salpingitis isthmica nodosa with tubal occlusion.

OBJECTIVE: To determine the presence of the major outer-membrane protein of Chlamydia trachomatis in fallopian tube tissue specimens of infertile women with chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion. DESIGN: Prospective controlled study. SETTING: Department of Obstetrics and Gynecology, University of Bochum, Herne, Germany. PATIENT(S): Fifty-six consecutive infertile women with histologically documented chronic salpingitis and/or salpingitis isthmica nodosa and bilateral tubal occlusions were evaluated. They were compared with 28 fertile women. INTERVENTION(S): Fallopian tube tissue specimens were taken during reconstructive infertility surgery, including cesarean section and tubal ligation. MAIN OUTCOME MEASURE(S): Detection of the major outer-membrane protein of C. trachomatis in fallopian tube tissue specimens by a direct fluorescent antibody test. RESULT(S): The major outer-membrane protein of C. trachomatis was found in fallopian tube tissue specimens in 11 of 56 infertile patients (20%) with chronic salpingitis and/or salpingitis isthmica nodosa. The median titer of IgG serum antibodies to Chlamydia was significantly higher in women with the major outer-membrane protein of C. trachomatis than in patients without this antigen. In comparison, the major outer-membrane protein of C. trachomatis was not found in any of the fallopian tube tissue specimens of the control group. CONCLUSION(S): The presence of the major outer-membrane protein of C. trachomatis is associated with chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion.

Humoral immune response to the chlamydial heat shock proteins hsp60 and hsp70 in Chlamydia-associated chronic salpingitis with tubal occlusion.

The aim of this study was to evaluate the prevalence of serum immunoglobulin (Ig)G and IgA antibodies to recombinant chlamydial 60 kDa heat shock protein (C-hsp60) and to assess the prevalence of serum IgG antibodies to recombinant chlamydial 70 kDa heat shock protein (C-hsp70) in Chlamydia-associated chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion. Infertile patients (n =34) with Chlamydia-associated, histologically documented chronic salpingitis and/or salpingitis isthmica nodosa and bilateral tubal occlusions (group I) were compared with infertile patients (n = 19) without tubal occlusions (group II). The prevalence of chlamydial antigen in endocervical, urethral and urine samples was low in both groups. The median chlamydial serum IgG and IgA antibody titres were significantly higher in group I than in group II (P < 0.0001 and P = 0.0002 respectively). Serum IgG antibodies to C-hsp60 and C-hsp70 were detected in 24 out of 34 patients (71%) in group I compared with 10 out of 19 (53%) and nine out of 19 (47%) patients in group II (not significantly different). There was a significant difference (P = 0.035) between the prevalences of serum IgA antibodies to C-hsp60 in groups I (seven out of 34 patients; 21%) and II (none of the 19 patients). The association between the presence of serum IgA antibodies to C-hsp60 and Chlamydia-associated chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion underlies the significance of chlamydial 60 kDa heat shock protein in the pathogenesis of tubal infertility.

[Chlamydia infections in gynecology and obstetrics]. / Chlamydieninfektionen in Gynäkologie und Geburtshilfe.

Urogenital infections with Chlamydia trachomatis belong to the most prevalent sexual transmitted diseases worldwide. In women, Chlamydia trachomatis can cause an infection of the cervix, the urethra, the endometrium and the Fallopian tubes. As potential sequelae, tubal infertility and ectopic pregnancies are associated with urogenital infections caused by this pathogen. An infection of the cervix in pregnancy can lead to neonatal and maternal complications. Therefore, by April 1st, 1995 a cervical swab for Chlamydia trachomatis has been included in the German antenatal care guide lines. The significance of these infections in health care is in contrast to its often hardly symptomatic or asymptomatic course. New diagnostic methods facilitate the detection of the pathogen and allow a specific antibiotic therapy. The aim of this review is a presentation of the clinical significance, diagnosis and therapy of urogenital infections with Chlamydia trachomatis in obstetrics and gynaecology to contribute to the prevention of potentially severe sequelae.

Chlamydial immunoglobulin IgG and IgA antibodies in serum and semen are not associated with the presence of Chlamydia trachomatis DNA or rRNA in semen from male partners of infertile couples.

The role of Chlamydia (C.) trachomatis in male infertility is controversial. The objective of this study was to determine the prevalence of asymptomatic C. trachomatis infections in male partners of infertile couples, and to compare this result with the presence of chlamydial antibodies in serum and semen. C.trachomatis was detected in five of 50 semen specimens (10%) by either polymerase chain reaction for C. trachomatis DNA or direct DNA probing for C. trachomatis rRNA. There was no association between the detection of C. trachomatis in semen and the presence of chlamydial antibodies in serum or semen. Chlamydial serum antibodies were neither associated with antiserum serum antibodies nor with pathological standard semen parameters. These results indicate that the assessment of chlamydial immunoglobulin IgG and IgA antibodies in serum or semen is of limited use in male infertility work-up, in contrast to its significance in female tubal infertility. The presence of C. trachomatis in semen emphasizes the potential risk of transmission during artificial insemination and other assisted reproductive techniques, and underlines the importance of sensitive direct detection methods in this group of patients.

[Is there a correlation between tubal occlusions in chronic salpingitis and urogenital chlamydia infections?]. / Gibt es einen Zusammenhang zwischen Tubenverschlüssen bei chronischer Salpingitis und urogenitalen Chlamydieninfektionen?

A prospective study was performed to analyse the relationship between urogenital infections caused by Chlamydia trachomatis and occlusions of the fallopian tubes with histologically confirmed chronic salpingitis and salpingitis isthmica nodosa. 110 infertile patients were tested for C. trachomatis infection. 23 patients with tubal occlusions and histologically confirmed chronic salpingitis (group 1) and eight patients with salpingitis isthmica nodosa (group 2) were compared to 13 patients with tubal occlusions after tuboligation (group 3), and to 66 patients with patent fallopian tubes as demonstrated by laparoscopy or hysterosalpingography (group 4). The prevalence of infections of the endocervix or urethra and the presence of Chlamydia in urine was low in all four groups. However, in groups 1 and 2, the median Chlamydia IgG and IgA serum antibody titres were significantly higher (p < or = 0.0002) than in groups 3 and 4. This result illustrates the association between urogenital infections with Chlamydia and tubal occlusions with histologically documented chronic salpingitis and salpingitis isthmica nodosa.

Embryonic losses after in vitro fertilization and embryo transfer.

Early loss of embryos is a major problem after in vitro fertilization (IVF) and embryo transfer (ET). Because implantation of the embryo is a precondition for an increasing serum beta-hCG level, the embryonic development cannot be evaluated during the pre- and peri-implantation period. Early pregnancy factor (EPF) is a marker of the development of the embryo before and during implantation. Therefore serum samples of 82 patients were screened for EPF and beta-hCG after IVF/ET. 63% (52/82) of all patients were positive for EPF, 21% (17/82) showed elevated serum beta-hCG levels. Clinical pregnancies occurred in 12 patients (15%) resulting in nine deliveries. After difficult ET EPF turned negative more frequently in the peri-implantation period compared to transfers without problems. Emphasis should be directed towards optimizing the placement of the embryos and towards minimizing the trauma of the uterus.

[Acute fatty liver of pregnancy]. / Akute Schwangerschaftsfettleber.

Liver diseases in pregnancy can occur as a complication of gestation or independently. Acute fatty liver of pregnancy is a rare disease of unknown etiology specifically associated to gestation. The frequency is increased in the first pregnancy, in the last trimester and in multiple pregnancies. Because of the high maternal and perinatal mortality early diagnosis is necessary for prompt termination of pregnancy. This case report is intended to facilitate the differentiation between acute fatty liver of pregnancy and other liver diseases in pregnancy. The differential diagnoses include preeclampsia, HELLP syndrome, intrahepatic cholestasis of pregnancy and acute viral hepatitis.

[Rate of early abortion after in vitro fertilization and embryo transfer]. / Frühstabortrate nach In-vitro-Fertilisation und Embryotransfer.

The high rate of implantation failures in infertile patients after in vitro fertilization must be regarded as the major problem of the kind of treatment. Usually, no information on the development of the embryo can be obtained for the time between embryo replacement and rising beta-hCG levels. Own studies on the early pregnancy factor (EPF) showed a positive reaction few hours following the contact of a fertilized oocyte with the endometrial surface. Therefore, we used the EPF as a marker for the viability of the embryo in 82 patients after in vitro fertilization and embryo transfer. Within two days after embryo transfer the EPF was positive in 52 (63%) patients and negative in 30 (37%) patients. In these women the embryos may have been lost during handling or may have discontinued further development. Between day 3 and day 12 after transfer the EPF turned to negative values in 35 patients--especially between day 6 and 10. These cases must be regarded as true implantation failures. After day 12 following embryo transfer, rising beta-hCG levels could be measured in 17 women (21%), but only in 12 patients (15%) could a growing embryonic sac be detected by ultrasound. From these figures, we may conclude, that about half of the embryos are lost already during the step of embryo transfer and the other half during implantation. Therefore, more attention should be given to the handling of the embryos to increase the pregnancy rate after in vitro fertilization.

[Glassy cell carcinoma of the cervix]. / "Glassy cell carcinoma" der Zervix.

Glassy cell carcinoma of the cervix is a rare carcinoma with rapid progression and early metastasis. The aggressive course of a glassy cell carcinoma of the cervix in Stage Ib (FIGO) of a 24-year-old woman could neither be markedly influenced by radical hysterectomy, nor by chemotherapy and radiation. The patient died ten months after diagnosis.

The effect of endometriomas on in vitro fertilization outcome.

To determine the effect of ovarian endometriomas on in vitro fertilization (IVF) outcome, two groups of patients were studied. Group I consisted of seven patients with ovarian endometriomas and severe pelvic adhesions treated for a total of 12 cycles. Group II patients consisted of eight patients with hydrosalpinges and comparable pelvic adhesions treated for a total of 27 cycles. There were no differences in the number of days required for stimulation or in the serum estradiol levels attained between the two groups. Group I patients were noted to have significantly fewer preovulatory follicles (1.42 vs 3.33, P less than 0.005), cycles with fertilization (28 vs 84%, P less than 0.005), and embryos transferred (0.78 vs 2.56, P = 0.01) than Group II patients. Three pregnancies occurred in Group II, while there were no conceptions among Group I patients. This study suggests that the presence of an ovarian endometrioma(s) has an adverse effect on IVF outcome and suggests that patients with ovarian endometriomas should have them removed prior to undergoing IVF.