Judith A.F. Huirne

Gonadotropin-releasing-hormone-receptor antagonists

The present invention relates to Gonadotropin Releasing Hormone (“GnRH”) (also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.Pulsatile gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH) and thus controls the hormonal and reproductive function of the gonads. Blockade of GnRH effects may be wanted for a variety of reasons-eg, to prevent untimely luteinisation during assisted reproduction or in the treatment of sex-hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. Only recently have GnRH-receptor antagonists, that immediately block GnRHs effects, been developed for clinical use with acceptable pharmacokinetic, safety, and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All current indications for GnRH-agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma, and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence so far has been in assisted reproduction and prostate cancer.

Prevalence, potential risk factors for development and symptoms related to the presence of uterine niches following Cesarean section: systematic review

To review systematically the medical literature reporting on the prevalence of a niche at the site of a Cesarean section (CS) scar using various diagnostic methods, on potential risk factors for the development of a niche and on niche‐related gynecological symptoms in non‐pregnant women.

Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome

BACKGROUND Approximately 15-20% of all clinically confirmed pregnancies end in a miscarriage. Intrauterine adhesions (IUAs) are a possible complication after miscarriage, but their prevalence and the contribution of possible risk factors have not been elucidated yet. In addition, the long-term reproductive outcome in relation to IUAs has to be elucidated. METHODS We systematically searched the literature for studies that prospectively assessed the prevalence and extent of IUAs in women who suffered a miscarriage. To be included, women diagnosed with a current miscarriage had to be systematically evaluated within 12 months by hysteroscopy after either spontaneous expulsion or medical or surgical treatment. Studies that included women with a history of recurrent miscarriage only or that evaluated the IUAs after elective abortion or beyond 12 months after the last miscarriage were not included. Subsequently, long-term reproductive outcomes after expectant (conservative), medical or surgical management were assessed in women with and without post-miscarriage IUAs. RESULTS We included 10 prospective studies reporting on 912 women with hysteroscopic evaluation within 12 months of miscarriage and 8 prospective studies, including 1770 women, reporting long-term reproductive outcome. IUAs were detected in 183 women, resulting in a pooled prevalence of 19.1% [95% confidence interval (CI): 12.8-27.5%]. The extent of IUAs was reported in 124 women (67.8%) and was mild, moderate and severe respectively in 58.1, 28.2 and 13.7% of cases. Relative to women with one miscarriage, women with two or three or more miscarriages showed an increased risk of IUAs by a pooled OR of 1.41 and 2.1, respectively. The number of dilatation and curettage (D&C) procedures seemed to be the main driver behind these associations. A total of 150 congenital and acquired intrauterine abnormalities were encountered in 675 women, resulting in a pooled prevalence of 22.4% (95% CI: 16.3-29.9%). Similar reproductive outcomes were reported subsequent to conservative, medical or surgical management for miscarriage, although the numbers of studies and of included women were limited. No studies reported long-term reproductive outcomes following post-miscarriage IUAs. CONCLUSIONS IUAs are frequently encountered, in one in five women after miscarriage. In more than half of these, the severity and extent of the adhesions was mild, with unknown clinical relevance. Recurrent miscarriages and D&C procedures were identified as risk factors for adhesion formation. Congenital and acquired intrauterine abnormalities such as polyps or fibroids were frequently identified. There were no studies reporting on the link between IUAs and long-term reproductive outcome after miscarriage, while similar pregnancy outcomes were reported subsequent to conservative, medical or surgical management. Although this review does not allow strong clinical conclusions on treatment management, it signals an important clinical problem. Treatment strategies are proposed to minimize the number of D&C in an attempt to reduce IUAs.

Ultrasound evaluation of the Cesarean scar: relation between a niche and postmenstrual spotting

To evaluate the relationship between a niche and abnormal uterine bleeding, and to develop a sonographic classification of niches and evaluate its relationship to abnormal uterine bleeding.

Contemporary Pharmacological Manipulation in Assisted Reproduction

Follicle-stimulating hormone (FSH) treatment to induce follicular development in anovulating women and multiple follicular development for assisted conception has been incorporated in almost all reproductive treatment cycles in the form of either urinary, purified urinary or recombinant preparations. Besides improved tolerance and theoretically lower chances of infection by prions, the latter may be more effective in terms of clinical pregnancy rates, FSH requirement and cost effectiveness. The low-dose, step-up protocol to induce monofollicular development, which is applied worldwide, has to compete with the equally effective but health economically beneficial step-down protocol. The long protocol using recombinant FSH 150 IU/day is advocated when using gonadotropin-releasing hormone (GnRH) agonists in in vitro fertilisation (IVF) or intracytoplasmatic sperm injection treatment. However, the current paradigmatic hyperstimulation came under scrutiny after the introduction of the GnRH antagonists, which allow milder and more convenient approaches with acceptable cancellation and pregnancy rates but lower requirements for FSH. Risk of ovarian hyperstimulation syndrome (OHSS) can be further eliminated if recombinant luteinising hormone (rLH) or GnRH agonists are used to trigger oocyte maturation and ovulation; the latter require pituitary responsiveness and are therefore excluded in agonist protocols.FSH and LH are both required for appropriate folliculo- and steroidogenesis. In hypogonadotropic women, the addition of LH (human menopausal gonadotropin, human chorionic gonadotropin or rLH) is therefore obligate to achieve appropriate follicular growth and pregnancy. The role of LH in ovulation induction is still a matter of debate, although in GnRH agonistic protocols there seems to be a ’‘therapeutic window’; levels that are too high or too low have detrimental effects on IVF outcome.To broaden the pharmaceutical armoury, recent efforts have been directed towards the development of novel GnRH antagonists and FSH preparations with optimal pharmacokinetic, pharmacodynamic and safety profiles. Alternative strategies with fewer adverse effects and higher benefit/cost ratios are under development. However, before the GnRH agonist is abandoned for the antagonist as standard therapy, the cause of the observed possible lower pregnancy rates with the latter need to be clarified. In addition, prospective studies investigating possible direct effects of GnRH analogues, optimal dose-finding studies and treatment regimens under different conditions, with or without pharmacological coadministration and for different indications, should be performed to optimise the efficacy and tailor treatment strategies to individual needs.

Standardized approach for imaging and measuring Cesarean section scars using ultrasonography

Incomplete healing of the scar is a recognized sequel of Cesarean section (CS) and may be associated with complications in later pregnancies. These complications can include scar pregnancy, a morbidly adherent placenta, scar dehiscence or rupture. To date there is uncertainty relating to the factors that lead to poor scar healing and how to recognize it. In recent years, there has been an increase in studies using ultrasound that describe scars as deficient, or poorly, incompletely or inadequately healed with few data to associate the morphology of the scar with the functional integrity of the lower segment of the uterus. There have been multiple attempts to describe CS scars using ultrasonography. Different terminology, methods and results have been reported, yet there is still no consensus regarding the prevalence, clinical significance or most appropriate method to describe the appearances of these scars. Developing a test that can predict the likelihood of women having problems associated with a CS scar is becoming increasingly important. On the other hand, understanding whether the ultrasound appearances of the scar can tell us anything about its integrity is not well supported by the research evidence. In this article we present an overview of ultrasound‐based definitions and methods used to describe CS scars. We also present information relating to the performance of alternative techniques used to evaluate CS scars. Having examined the current evidence we suggest a standardized approach to describe CS scars using ultrasound so that future studies can be meaningfully compared. Copyright

Long‐term complications of caesarean section. The niche in the scar: a prospective cohort study on niche prevalence and its relation to abnormal uterine bleeding

To study the prevalence of niches in the caesarean scar in a random population, and the relationship with postmenstrual spotting and urinary incontinence.

Effectiveness of Abdominal Cerclage Placed via Laparotomy or Laparoscopy: Systematic Review

Preterm delivery remains a primary cause of neonatal morbidity and mortality. One cause of preterm birth is cervical incompetence. In women with a shortened or absent cervix or in those in whom previous vaginal cerclage failed, abdominal cerclage may be recommended. We performed a systematic literature search of PubMed, EMBASE, and the Cochrane database. Thirty-one eligible studies were selected. Six studies (135 patients) reported on the laparoscopic approach, and 26 (1116 patients) on the abdominal approach. Delivery of a viable infant at 34 weeks of gestation or more varied from 78.5% (laparoscopic) to 84.8% (abdominal). Second-trimester fetal loss occurred in 8.1% (laparoscopic) vs 7.8% (abdominal), with no reported third-trimester losses (laparoscopic) vs 1.2% (abdominal). We conclude that abdominal cerclage is associated with excellent results as treatment of cervical incompetence, with high fetal survival rates and minimal complications during surgery and pregnancy. Further studies are needed to differentiate which method is superior.

Therapeutic Options of Caesarean Scar Pregnancy: Case Series and Literature Review

We describe our experience with the treatment of 4 caesarean scar pregnancies and provide an overview of current literature. Four women diagnosed with a caesarean scar pregnancy in our hospital between 1996 and 2007 were treated with local or systemic methotrexate and had a steady decline of the serum β‐hCG level. The uterus was preserved in all women and 3 of them had an uneventful subsequent pregnancy and delivery. We suggest that transcervical needle aspiration of amniotic fluid followed by intra‐amniotic injection of methotrexate should be the treatment of choice, followed by surgical treatment only if methotrexate fails.

Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis

STUDY QUESTION Could dilatation and curettage (D&C), used in the treatment of miscarriage and termination of pregnancy, increase the risk of subsequent preterm birth? SUMMARY ANSWER A history of curettage in women is associated with an increased risk of preterm birth in a subsequent pregnancy compared with women without such history. WHAT IS KNOWN ALREADY D&C is one of the most frequently performed procedures in obstetrics and gynaecology. Apart from the acknowledged but relatively rare adverse effects, such as cervical tears, bleeding, infection, perforation of the uterus, bowel or bladder, or Asherman syndrome, D&C has been suggested to also lead to an increased risk of preterm birth in the subsequent pregnancy. STUDY DESIGN, SIZE, DURATION In the absence of randomized data, we conducted a systematic review and meta-analysis of cohort and case-control studies. PARTICIPANTS/MATERIALS, SETTING, METHODS We searched OVID MEDLINE and OVID EMBASE form inception until 21 May 2014. We selected cohort and case-control studies comparing subsequent preterm birth in women who had a D&C for first trimester miscarriage or termination of pregnancy and a control group of women without a history of D&C. MAIN RESULTS AND THE ROLE OF CHANCE We included 21 studies reporting on 1 853 017 women. In women with a history of D&C compared with those with no such history, the odds ratio (OR) for preterm birth <37 weeks was 1.29 (95% CI 1.17; 1.42), while for very preterm birth the ORs were 1.69 (95% CI 1.20; 2.38) for <32 weeks and 1.68 (95% CI 1.47; 1.92) for <28 weeks. The risk remained increased when the control group was limited to women with a medically managed miscarriage or induced abortion (OR 1.19, 95% CI 1.10; 1.28). For women with a history of multiple D&Cs compared with those with no D&C, the OR for preterm birth (<37 weeks) was 1.74 (95% CI 1.10; 2.76). For spontaneous preterm birth, the OR was 1.44 (95% CI 1.22; 1.69) for a history of D&C compared with no such history. LIMITATIONS, REASONS FOR CAUTION There were no randomized controlled trials comparing women with and without a history of D&C and subsequent preterm birth. As a consequence, confounding may be present since the included studies were either cohort or case-control studies, not all of which corrected the results for possible confounding factors. WIDER IMPLICATIONS OF THE FINDINGS This meta-analysis shows that D&C is associated with an increased risk of subsequent preterm birth. The increased risk in association with multiple D&Cs indicates a causal relationship. Despite the fact that confounding cannot be excluded, these data warrant caution in the use of D&C for miscarriage and termination of pregnancy, the more so since less invasive options are available. STUDY FUNDING/COMPETING INTERESTS This study was funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97-12066.