Assisted reproduction and multiple pregnancies

Multiple pregnancies resulting from assisted reproductive manoeuvres are often blamed for the rising preterm delivery rates in developed countries. Indeed, a multiple pregnancy is deemed to be the most significant risk of in-vitro fertilisation.

Transferring two or more embryos at the day 2 single-cleavage stage results in higher pregnancy rates per cycle, but also more multiple pregnancies. It now appears that transferring a single embryo at a later stage of in-vitro development (day 5) might lead to higher implantation rates, together with lowered multiple pregnancy rates, especially in women with a good prognosis. The philosophy is that by selecting women who are likely to have successful outcomes (because at least four eight-cell embryos of quality are achieved) and allowing for the development of their embryos to the blastocyst stage prior to implantation of single embryos, better clinical pregnancy rates could be achieved.

Whether such a policy in a large assisted conception unit would be feasible and give superior results is not known. To test the hypothesis, Khalaf et al (BJOG 2008;115:385-90) changed their guidelines and recorded their results for 18 months before and after the implementation of the new protocols. Despite only a selected group of patients fulfilling the criteria for single blastocyst transfer, they improved their clinical pregnancy rates from 27% to 32% while reducing their multiple pregnancy rates from 32% to 17%.


It is therefore feasible to use selective single embryo transfers in a busy IVF unit without sacrificing overall pregnancy rates and at the same time reducing twin and higher order multiple pregnancy risks. The policy had the extra spin-off of having more supernumerary embryos for cryopreservation and later use.

A Canadian study has found that singleton preterm babies and multiple birth babies have similar outcomes at the same gestational age, except for multiples having a greater predisposition to respiratory distress (Qui et al Obstet Gynecol 2008;111:365-71).

The extra costs of multiple pregnancies are considerable. As Wood points out (BJOG 2008;115:416) a twin pregnancy costs £1826 more than a low-risk singleton in antenatal and intrapartum care but other expenses have to be added in such as neonatal intensive care which could add another £3500 plus further infant in-patient care at £4800. These figures do not take into account other costs should complications arise like postnatal depression, a handicapped survivor never mind the emotional and societal costs of the stresses of ongoing care. A proper audit is indeed sobering.

Elective delivery of twins can safely include a vaginal option according to Schmitz et al who describe their experience in a French tertiary referral unit (Obstet Gynecol 2008;111:695-703). With an active intervention policy aimed at facilitating the delivery of the second twin about 5 minutes after the first, they had morbidity and mortality rates similar to those delivered by caesarean section.

New JASS out

Much is being published on preventative measures.

The journals carry large, long-term studies which show that antenatal supplementation with broad-spectrum vitamin nutrients are superior to iron plus folate alone in reducing the incidence of how birth-weight in developing countries.

Bolstering nutrition in early childhood also has long-term benefits in terms of greater earning capacity in adulthood. Breastfeeding and basic hygiene are cheap and effective interventions (Lancet 2008;371 Haddinott et al 411-6, Bhutto et al 417-40, Vaidya et al 492-9, Bryce et al 510-26, Ruel et al 588-95, Morris et al 608-21).

Later in life smoking is the most common preventable cause of death. It killed 100 million people last century and is predicted to kill 1 billion this century. Half of all smokers will die prematurely, with men's lives being shortened by 6 years and women's by 8 years (NEJM 2008:doi:10.1056) (Britton & Edmunds pp 441-5).

If you doubted the link between obesity and cancer, the article by Renehan et al (Lancet 2008;371:569-75 will convince you of the association.

Meanwhile JASS this month is dominated by twins and embolic phenomena. It's fascinating what turns up serendipitously!

Latest JASS

The messages from this month's summaries are hugely important from the international perspective.

Modern research in the epidemiological field would have been unthinkable last century because the long-term data would not have been available and the resources to capture it unaffordable. Massive financial and human investment in nutritional studies, plus the technology to interpret the information, are leading to global conclusions.

The macro- and micro-nutrition of mothers and children up to two years of age are clearly shown to determine long-term outcomes, while longitudinal studies of oral contraceptive (OC) use forty years ago are now affecting old women's health.

Concepts such as disability-adjusted life-years (DALYs) and intra-uterine settings are just the start as mega- and meta-analysis drive our views to include new confounding variables in our assessments in Obstetrics and Gynaecology. The positive news about OCs must surely eventually lead to their wider and easier availability which will breach so many existing hindrances to women's health.

Pfizer and Medical Journal Referees

Pfizer tries to make journal reveal referees

HRT and breast cancer

The role of hormonal replacement therapy is controversial in the development of breast cancer. What does seem clear is that combined estrogen with progesterone taken orally either continually or sequentially does raise the risk by a quarter to a third if taken over a decade. Looking more closely into this group of women, it appears that C-19 progestins have a lower risk than C-21 progestins and the mechanism of action may be the potentiation of the proliferative effect of estrogens in breast tissue.

In contrast, taking estrogens alone or the delivery of estrogens with progesterone transdermally does not increase the risk of breast cancer (Opatrny et al BJOG 2008;115:169-75). The authors carried out a large observational case-control study on UK women with a mean age of 61 years that takes into account the hormone therapy women took at all stages of their post-menopausal lives as the Women's Health Initiative (WHI) study caused many to swap preparations. This new data confirms the estrogen-only arm of findings of the WHI study which showed no increased risk of breast cancer.

It is interesting that transdermal preparations were not associated with increased risk either. They provide constant low hormone levels in the blood which avoids hepatic protein synthesis which does occur with the oral route, causing peaks and troughs from one dose to the next. Transdermal estrogens alone or with progesterone did not raise the risk of breast cancer.

Tibolone is a selective tissue estrogen activity regulator which has estrogenic activity on the vagina and bone without similar effects on breast and endometrial tissue. The study summarised here showed that women using tibolone alone were not at increased risk of breast cancer but the numbers were small.

Information continues to become available showing that selected prescriptions of replacement hormones should be tailored to each woman's requirements in terms of the type of medication, the dosage, the route of administration and the duration of use if unwanted side-effects are to be avoided.

Urban legends

The end-of-year BMJ is a light-hearted issue which allows us to raise our eyes above the temperature charts and dwell on the funny side of our profession. Vreeman & Carroll (BMJ 2007;335:1288-9) bust a few medical myths that we may have wondered about:

Drink 8 glasses of water a day - not necessary. There is far more fluid in our food than we realise and our thirst signals when more is needed.

We use 10% of our brains - no areas of our brains are inactive for long despite many functions being localised.

Hair and fingernails grow after death - untrue but skin retraction from desiccation can give that appearance.

Reading in dim light ruins your eyes - poor lighting may make restaurant menus difficult to read but by next morning your eyes will be fine.

Shaving makes hair grow faster - shaving your chin or your legs removes the dead part of the hair and does not encourage growth.

Mobile phones are dangerous in hospitals - no serious consequences of mobile (cellular) phone use in hospitals have been reported and certainly no deaths.
Conversely, the use of mobile phones reduces errors from delays in communication.

Eating turkey makes you drowsy - turkey contains no specific sedatives but usually forms part of a large meal, redirecting blood flow from the brain to the abdomen, causing drowsiness.

OCs and cervical cancer

Overall oral contraceptives are not associated with an increased risk of cancer. Since they prevent pregnancy and thus the risk of maternal mortality, it is far safer for a woman to take OCs than not take them.

But within these broad statements are detailed changes of risk of various conditions which have been studied to confirm or refute the role of combined estrogen and progesterone medication in their aetiology. One such condition is cervical cancer and OCs have long been linked to its increased risk, with some suggesting their carcinogenic role (Sasieni Lancet 2007;370:1591-2).

Despite the causative nature of HPV in cervical cancer, by no means all such infections lead to malignancy, so the quest is now to find what causes some HPV infections to end up as precancerous or invasive cancer while others regress harmlessly.

Given that recurrent HPV infections are part of the process, contraceptive use has been scrutinised to see if barrier methods reduce risk or hormonal methods increase the risk of recurrent infection. Data have now been published for combined OC use which give consistent results from all around the world by the International Collaboration of Epidemiological Studies of Cervical Cancer - Lancet 2007;370:1609-21. They have shown that using OCs for 5 to 10 years doubles the risk, but this diminishes soon after stopping their use and is negligible after a decade.

The authors point out the absolute risks remain very small and the other factors such as screening, smoking and other infections - especially those associated with altered immunity - are more important in the long-term. So, for women taking OCs in their twenties and thirties in developed countries, the additional risk from OCs of eventually developing cervical cancer is very small - something of the order of 0.002% and, for a woman in sub-Saharan Africa, this rises to 0.4%.

In perspective, OCs and other hormones do fit into the complex pathology of cervical cancer but their aetiological role is minor - in the extreme.