T. Al-Shawaf

Prevention and treatment of ovarian hyperstimulation syndrome

The ovarian hyperstimulation syndrome (OHSS) is a potentially fatal condition with a pathophysiology that is not clearly understood. A shift in fluid from the extravascular space occurs, thought to be induced by cytokines and/or vascular endothelial growth factor. Human chorionic gonadotrophin (hCG), exogenous or endogenous, seems to be the triggering mechanism, resulting in early and late development of the syndrome, respectively. The management of the syndrome is mainly symptomatic. Preventive strategies are being developed and constantly refined. Women at increased risk of OHSS need to be on the lowest possible dose of gonadotrophin with the aim of reducing the granulosa/luteal cell mass. Ultrasound and serum oestradiol (E2) measurements are, at present, the main methods used to identify and monitor those at risk during controlled ovarian hyperstimulation (COH). Withholding gonadotrophin stimulation (coasting), but continuing down-regulation, when a large number of follicles (greater than 20) and a rising serum oestradiol level are seen, is the most widely favoured and used preventive measure and the most cost effective. Management is symptomatic and aimed at achieving fluid balance, restoring plasma volume and improving renal function. This may be combined with an early resort to ascitic fluid aspiration, which will improve the feeling of wellbeing and may remove those agents responsible for the syndrome. Heparin, to prevent the risk of thromboembolism as a result of haemoconcentration, is important.

Relevance of basal serum FSH to IVF outcome varies with patient age

Live birth rate (LBR), age and basal serum FSH values were analysed in 1589 women undergoing their first cycle of IVF. Four age groups (<30, 30-34, 35-38, 39-45 years) and three FSH groups (<5, 5-9.9, > or =10 IU/l) were established. Logistic regression analysis was used to determine the effect of age and FSH on live birth. A model to predict the probability of a live birth suggests that an additional 10 years of age reduces the odds for live birth (OR = 0.66, 95% CI 0.48-0.91); an increase of FSH by 5 IU/l reduces the probability of live birth (OR = 0.75, 95% CI 0.61-0.92); women > or =39 years have an additional reduction in probability of live birth (OR = 0.58, 95% CI 0.61-0.92). Analysis by age and FSH categories showed that pregnancy rate (PR) did not change significantly with rising FSH for women <35 years old. In cycles started with serum FSH <5 IU/l, increasing age did not effect PR and LBR. Cycles started with serum FSH > or =10 IU/l had a PR and LBR of 23.6 and 16.9% respectively. The clinical relevance of elevated FSH varies according to age; younger women with elevated FSH and older women with low FSH still have an acceptable LBR.

Assisted conception following radical trachelectomy

BACKGROUNDnRadical trachelectomy (RT) has been established as a valuable fertility-preserving treatment in women with early stage cervical cancer. A number of these women will require assisted conception which may bring certain challenges to those managing treatment. An awareness of those challenges is essential to maximize outcome in terms of live birth rates.nnnMETHODSnAll women who had undergone assisted conception following RT were assessed with respect to treatment management and pregnancy outcome.nnnRESULTSnPregnancy rates were good, with nine pregnancies in seven women treated. Difficulties in treatment were essentially related to isthmic stenosis. There was a clear need for trial embryo transfer (ET) prior to treatment and dilatation of the isthmus where necessary. The premature delivery rate was high (75% at <37 weeks), highlighting the importance of single ET to avoid multiple pregnancy.nnnCONCLUSIONSnAssisted conception following RT is associated with a good pregnancy rate, although there is a high miscarriage and premature delivery rate. Treatment outcome should be maximized by careful patient preparation in terms of assessing the need for isthmic dilatation, and ET should be performed by an experienced operator.

The correlation between basal serum follicle-stimulating hormone levels before embryo cryopreservation and the clinical outcome of frozen embryo transfers

OBJECTIVEnTo evaluate the correlation between basal serum FSH level before the fresh IVF/intracytoplasmic sperm injection (ICSI) cycle and the clinical outcome of the subsequent frozen embryo replacement cycles.nnnDESIGNnRetrospective observational study.nnnSETTINGnUniversity tertiary referral center, London, United Kingdom.nnnPATIENT(S)nFive hundred four consecutive frozen embryo transfer (FET) cycles where serum FSH levels were obtained, on days 1-4 of the cycle before the fresh IVF +/- ICSI cycles.nnnINTERVENTION(S)nFrozen-thawed embryo transfer.nnnMAIN OUTCOME MEASURE(S)nClinical pregnancy (CP) and live birth (LB).nnnRESULT(S)nBasal serum FSH in 127 women (25.2%) who had a CP was significantly lower compared with that in women who did not have a CP. Multivariate regression analysis showed significant correlation between basal serum FSH levels and clinical pregnancy and a low significance to LB, but there was no statistical significant differences between women who had a CP and those who did not with regard to age, treatment protocol (natural or hormone treatment cycle), or the freeze-thaw interval. The LB rate was higher in natural cycles (n = 71; 21.2%) than in hormone treatment cycles (n = 28; 16.7%). Conceiving in the fresh cycle had a positive influence on the FET outcome.nnnCONCLUSION(S)nBasal serum FSH level before fresh IVF/ICSI cycle is inversely correlated to a CP outcome in FET cycles. A trend was present between FSH levels and LB, but this failed to reach statistical significance.

Safety of Drugs Used in Assisted Reproduction Techniques

Infertility may affect one in six couples; however, the development of the assisted reproduction technique (ART) created the opportunity for a large proportion of the infertile population to bear children. Pharmacological agents are routinely used in ART, and new ones are introduced regularly, with the aim of retrieving multiple oocytes to increase the prospect of pregnancy. The combinations of drugs that are used have specific adverse effects, but it is mostly the combined action of more than one agent that causes the greatest concern. The matter is complicated by the suspicion that some techniques in ART, for example intracytoplasmic sperm injection for severe male infertility problems (including azoospermia), may also contribute to the increase in adverse effects, especially congenital malformation. Gonadotropin releasing hormone (GnRH) agonists are widely used in controlled ovarian hyperstimulation. It may give rise to a short period of estradiol withdrawal symptoms and it may also lead to luteal phase deficiency. Similarly GnRHa antagonists, which have been recently introduced to control ovarian hyperstimulation, can lead to luteal phase deficiency and may cause some local injection site reactions. The more pure form of gonadotropin leads to less local injection site reactions and their main adverse effects are associated with the consequences of multiple ovulations. It has been proposed that gonadotropins may be a factor in the increasing risk of ovarian cancer and possibly breast cancer, but this has not been substantiated. Prion infection is another potential hazard, although no cases have been reported. Ovarian hyperstimulation syndrome is a well recognised complication of controlled ovarian hyperstimulation in ART. It is usually a result of recruitment of a large number of ovarian follicles. Efforts to minimise the incidence of this syndrome and its severity are now well developed. Congenital malformations are another possible adverse effect of fertility drugs, but it is more probable that the increase in congenital abnormality that is reported in ART is because of the population studied, i.e. patients already at high risk of congenital malformation, rather than the fertility drugs used or the technique employed. High order multiple pregnancy and its sequela is a well established complication of controlled ovarian hyperstimulation. This could be a result of multiple ovulations or more than one embryo replacement. Reducing the number of embryos transferred can reduce this more serious adverse effect for expectant mothers and for children conceived from ART.

Can the fall in serum FSH during coasting in IVF/ICSI predict clinical outcomes?

This retrospective cohort study determined whether the total falls in serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection could predict clinical outcomes. Ninety-nine cycles, with gonadotrophin-releasing hormone-agonist down-regulation where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of severe ovarian hyperstimulation syndrome, were consecutively included. The primary clinical outcome was live-birth rate (LBR); other outcomes measured were number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates. LBR for FSH fall>10 IU/l compared with 5-10 and<5 IU/l were 45.4% versus 22.0% and 25.0%, respectively. Mean serum FSH fall was similar with and without live birth (8.4 ± 6.2 versus 7.3 ± 5.0 IU/l) as were mean oestradiol and FSH concentrations on HCG administration, oestradiol fall, percentage fall in FSH/oestradiol and duration of coasting. None of the variables efficiently predicted live birth on regression analysis. The AUC of FSH fall was 0.53 at 11.0 IU/l. Basal FSH, starting and total gonadotrophin dose and duration of coasting were positively correlated with FSH fall. A potentially clinically important association between live birth and FSH fall during coasting was apparent, which requires further evaluation. The purpose of this retrospective cohort study was to determine whether the magnitude of fall in the serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection cycles could predict the clinical outcomes. Gonadotrophin-releasing hormone-agonist down-regulated cycles (n=99), where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of ovarian hyperstimulation, were consecutively included. Live birth was the primary clinical outcome measured; number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates were the other outcomes examined. Live-birth rate tended to be high when FSH fall was >10 IU/l, compared with 5-10 IU/l and <5 IU/l, although not statistically significantly. Mean serum FSH fall were similar in live-birth and no-live-birth cycles (8.4 ± 6.2 versus 7.3 ± 5.0) as were mean oestradiol and FSH concentrations on hCG administration, oestradiol fall, percentage fall in FSH and oestradiol and duration of coasting. None of the variables efficiently predicted live birth. The area under the curve of FSH fall was 0.53. FSH fall of <11.0 IU/l was found to be more likely to predict negative outcome (specificity 84.72%) than predicting positive outcome when FSH fall was >11 IU/l (sensitivity 34.48%). Womens basal FSH, starting and total gonadotrophin dose of ovarian stimulation and duration of coasting had direct positive correlation with the magnitude of FSH fall. A potentially clinically important rise in live birth in association with greater FSH fall during coasting was apparent, which requires further evaluation.

Controlled ovarian hyperstimulation for low responders in in vitro fertilization/intracytoplasmic sperm injection: a low-dose flare protocol

In this retrospective study of 652 anticipated low response women, the overall clinical outcomes (live birth rate and clinical pregnancy rate [PR]) of low-dose flare (LDF) protocol appeared lower than those of conventional down-regulation (DR) (LDF: 15.1% vs. DR: 20.6% and LDF: 10.3% vs. DR: 17.4%, respectively). The findings that LDF protocol improved the clinical outcome in older women, or when LDF followed an unsuccessful IVF/intracytoplasmic sperm injection (ICSI) cycle with DR (LDF: 19.4% vs. DR: 9.76% and LDF: 13.9% vs. DR: 4.2% respectively), need further evaluation through randomized trials.

Re: Ovarian hyperstimulation syndrome (OHSS)

industry. 3. When reviewing evidence, it is important to be sure that what we view as reinforcing our beliefs is not simply confirmation bias. The Hannah example is interesting because the reaction of the academic community to those data seemed to work to remove the woman’s choice for vaginal breech birth but we would question whether that was in the best interest of women? It could be that if service users had been involved in the interpretation of the results, that a wide range of opinions might have become evident. Academic judgments can also be at odds with clinicians in practice. After a debate at the RCOG in 2002, just one member of the audience of 200 clinicians put their hand up to support the conclusions of the Hannah breech trial. Perhaps, we need to consider more sophisticated means of synthesising evidence into guidance? 4. Yes, we do see a difference between research evidence and best practice for the patient though we might phrase it slightly differently. Good research provides information that helps define interventions that can be offered to women, but we need to be cautious as to who makes that interpretation, ensuring that service users are involved. We also hold that whilst healthcare workers are bound by the spirit of co-created guidance, those seeking healthcare are not. When advising an individual woman, we need to use our expertise to take account of her individual circumstance, but we must also use our wisdom to allow her the freedom to line up her needs, wishes and beliefs alongside the guidance for herself. Put another way, national recommendations guide a doctor or midwife on how to advise a woman, but they do not tell the woman what to do. Put in a slightly heartless way – clinicians advise, patients decide. It might be that an individual woman does view a 1 in 300 risk to her singleton term breech baby as being high, but then again, she might not.

Many NHS centres offering self funded in vitro fertilisation are poor performers

Yet again vulnerable couples are targeted by NHS managers promoting “self funded” in vitro fertilisation (IVF). IVF is considered an easy option to boost NHS finances because serious complications are rare, so it falls below the radar of those monitoring quality of care based on mortality only.nnLike primary care trusts before them, many clinical commissioning groups are ignoring the National …

Letters and emails

Dear Sir It was good to read about positive developments related to HIV in pregnancy. However, many HIV infections go undiagnosed. Under these circumstances, labour management remains important in preventing vertical transmission, while it is a minor factor combined with highly active antiretroviral therapy (HAART). Similarly, labour management has had little influence in preventing rhesus sensitisation since anti-D became widely available: how many drain the placenta in the third stage if the mother is or could be rhesus negative? A 1995 paper discusses how to prevent vertical HIV transmission (one of the worst outcomes):