Research

Fertility levels below replacement: a worldwide trend

When each woman has 2.1 children, the population stabilises. Any more and the population grows, any less and it falls. Over the last few decades, fears of the “population explosion” led to some frightening predictions of the inability of world resources to cope. So perhaps it is surprising to learn that the rate of growth of population is slowing and in some countries has reached what is considered by some demographers to be a precariously low level.

Amongst the more developed countries, the United States is the only one with a total fertility rate (TFR) near replacement level, at just under 2.1. All others have lower rates, which are currently falling to unsustainable lowest-low fertility rates, arbitrarily defined as equal to or below 1.3. Until recently, such fertility rates were only found for short, temporary periods, but they have become common over the last 15 years in Spain, Greece, Italy, Germany, most of Eastern Europe and Japan. Socio-economic factors are the most important elements in these changes. High, chronic youth unemployment, job instability and increasing university enrolment all correlate with delaying first births and having fewer children. Whether this trend will be reversed if these factors change when the new cohort of children become adults remains to be seen.¹

However, even in the developing world, the TFR is falling, from 6.0 in the 1960s to 2.9 today in countries such as Brazil and China,² and the full impact of AIDS is yet to occur. The most recent UN Population Report estimates that 75% of developing countries will have below-replacement fertility rates by 2050. The world population is still rising and will continue to do so over the next 50 years, but at a reduced rate from previous estimates. Taking into account current trends, the UN has revised total world population estimates for 2050 from 9.3 billion to 8.9 billion. About half of the drop is accounted for by the estimated impact of AIDS. Nevertheless, in 2050 the population in the least developed regions of the world will still be rising, albeit at a slower rate than previously.³

The low TFR in the developed world combined with a falling TFR in the developing world will lead to major demographic changes. Estimates for Europe in 2050 show a uniform age distribution among those under 50, i.e. the same number of 0–4 year olds as 35–39 year olds, an increase in those over age 50, and millions living well into their 90s. In comparison, North Africa and West Asia are expected to maintain populations where the majority of the population is under 30. The total population is expected to increase as individuals live longer, although this prediction may be considerably affected by AIDS.⁴ Developing countries will therefore have an excess of working-age people with relatively few dependants, whilst developed countries will have an ageing population that requires support. The effects of demographic changes of this magnitude are difficult to predict, but it has been argued that they will alter the needs of those in the developed world, and the relationship between North and South.

Some governments are taking these changes and their long-term effects very seriously. In France, where the TFR is currently 1.8, the prime minister has just announced a package of measures to support parents, including a bonus of €800 to each baby born after 1 January 2004.⁵

1.	Kohler H-P, Billari FC, Ortego JA. The emergence of lowest-low fertility in Europe during the 1990s. Population and Development Review 2002;28(4);641–80.
2.	Wattenberg BJ. It will be a smaller world after all. New York Times. 8 March 2003.
3.	World Health Organization. World Population Prospects: the 2002 revision. At: 〈www.un.org/esa/population/unpop.htm〉.
4.	Demeny P. Population policy dilemmas in Europe at the dawn of the twenty-first century. Population and Development Review 2003;29(1):1–28.
5.	Dorozynski A. France offers a €800 reward for each new baby. BMJ 2003;326:1002.

Low-cost screening for cervical cancer?

The lack of cervical cancer screening can lead to a high burden of cervical cancer in resource-poor settings. Decision-makers intending to introduce screening need to consider both the effectiveness in saving lives and the costs and benefits of alternative screening strategies. A simulation model, using conditions in Thailand as a basis, compared visual inspection of the cervix after applying acetic acid (VIA), human papilloma virus testing, Pap smear and combinations of these tests, in terms of the discounted costs per year of life saved. Although all models indicated women's lives were saved when appropriate follow-up occurred, the costs varied considerably. VIA was the least expensive option.¹ Another Thai study showed that VIA followed by immediate cryotherapy was safe, acceptable and feasible for detecting and treating cervical cancer.² There are also a number of studies being carried out in the developing world using instruments which magnify the cells inspected by VIA, but it is not yet clear whether such instruments will increase the sensitivity and specificity of VIA.³ Furthermore, there are not yet any data showing whether VIA screening programmes actually reduce the incidence or mortality of cervical cancer.

Critics of the VIA approach cite the low specificity of VIA, which may lead to serious over-treatment; poor knowledge of the effect of the presence of STIs or genital schistosomiasis on VIA; and a lack of comparison with other screening methods in terms of sensitivity, specificity, proven cost-effectiveness and reduction in mortality.⁴ Proponents of VIA point to the value of a method where only a single patient visit is required; the success of the Thailand study in establishing safety and feasibility; the fact that unnecessary treatment is not dangerous to the patient; and modelling and other studies which suggest that VIA is cost-effective, at least in settings where STI prevalence is low.⁵ A vaccine against human papillomavirus may prove to be a more viable alternative for the prevention of cervical cancer, but research is still in the early stages of development.

1.	Mandelblatt JS, Lawrence WF, Gaffikin L, et al. Costs and benefits of different strategies to screen for cervical cancer in less-developed countries. Journal of National Cancer Institute 2002;94:1469–83.
2.	RTOG/JHPIEGO Safety, acceptability and feasibility of a single-visit approach to cervical cancer prevention in rural Thailand: a demonstration project. Lancet 2003;361:814–20.
3.	Winkler JL, Tsu VD, Bishop A, et al. Confirmation of cervical neoplasia using a hand-held, lighted magnification device. International Journal of Gynecology and Obstetrics 2003;81:35–40.
4.	Walraven G. Prevention of cervical cancer in resource-poor settings [Letter]. Lancet 2003;361:2160.
5.	Prevention of cervical cancer in resource-poor settings [Authors' reply]. Lancet 2003;361:2160.

Human papillomavirus screening to prevent cervical cancer in women over 30 and HIV-positive women

There are over 60 types of human papillomavirus (HPV) that can infect women. Of these, 18 are currently known to be strongly associated with cervical cancer, and some of these are believed to be causative agents. This might suggest that screening for HPV would be a useful addition to cervical cancer screening services. However, HPV infection is very common in young, sexually active women. Most of this infection is transient, self-resolving and clinically non-significant, though it may produce temporary changes in cervical cells. Only about 10% of women become persistently infected with HPV, and it is this group that has a substantial risk of developing high-grade, pre-cancerous lesions or cervical cancer. Thus, although being negative for HPV suggests that a woman is at low risk for cervical cancer, being positive for HPV is not in itself an indicator of high risk. HPV testing can be valuable but needs to be used appropriately to avoid women assuming they are at high risk for cancer when this may not be the case. The American Cancer Society recommends that HPV testing is carried out at intervals of at least three years in women over 30, as one way to avoid alarming and overtreating large numbers of probably transiently infected women in their 20s. Providing advice to HPV-positive women that reduces anxiety and at the same time impresses on them the importance of proper follow-up will be a difficult task.¹

Evidence of increased risk of cervical cell abnormalities and cervical cancer in HIV-positive women has been available for ten years from studies in the USA, Europe and Africa. In an ongoing multi-centre study, a subgroup of 89 HIV-positive and 52 HIV-negative women were followed for a mean of 14 months to analyse factors predicting persistence and clearance of HPV and cervical abnormalities. The results indicated that HIV-positive women, even those on highly active antiretroviral therapy, demonstrated a more aggressive clinical course of cervical HPV infections and abnormalities, which failed to resolve more frequently than in HIV-negative women. The authors recommend Pap smear and HPV screening for high-risk HPV types to provide additional prognostic information in the management of cervical lesions in women with HIV infection.²

Thus, the addition of HPV screening to cytological testing can be considered an important addition to increasing detection rates of pre-cancerous lesions and cervical cancer.

1.	Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical cancer screening. New England Journal of Medicine 2003;348(6):489–90.
2.	Branca M, Garbuglia AR, Benedetto A, et al. Factors predicting the persistence of genital human papillomavirus infections and Pap smear abnormality in HIV-positive and HIV-negative women during prospective follow up. International Journal of STD & AIDS 2003;14(June):417–25.

New blood test improves antenatal screening for Down's syndrome

The definitive antenatal screening tests for Down's syndrome are amniocentesis or chorionic villus sampling (CVS). However, as these procedures may in a small number of cases cause spontaneous abortion, it is important that they are only used when the risk of abnormalities in the fetus is high. A number of indicators can be used in assessing that risk; maternal age is a key determinant along with ultrasound, fetal biometric measurements and three maternal serum factors—alphafetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE3). The relative value of each of these as predictors may vary according to the timing of the test, but in general the more combinations used, the better the chance of detecting true abnormalities and reducing false positives. So, for example, if using maternal age alone is compared with using maternal age plus AFP/HCG/uE3, the detection rate increases from about 49% to 78% and the false-positive rate drops from about 13% to 8%. Now, two recent studies suggest that a fourth serum measurement, inhibin-A, should be added to second-trimester tests, increasing the detection rate to about 81% and decreasing the false positive rate to 7%. It is therefore becoming policy not to use maternal age alone as a sufficient basis for offering amniocentesis or CVS. Incorporation of serum and ultrasound screening is becoming routine practice instead.^1–3

1.	Benn P. Improved antenatal screening for Down's syndrome [Commentary]. Lancet 2003;361(9360):794.
2.	Benn PA, Fang M, Egan JF, et al. Incorporation of inhibin-A in second-trimester screening for Down syndrome. Obstetrics and Gynecology 2003;101(3):451–54.
3.	Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening for Down's syndrome with the quadruple test. Lancet 2003;361(9360):835–36.

Mifepristone shrinks uterine fibroids

Uterine fibroids account for 30% of all hysterectomies in the USA and research is seeking to find non-surgical treatments for this condition. In a recent study, researchers showed that doses of mifepristone as low as 5 mg daily for six months can reduce uterine size, used as a measure of reduction in fibroid size, by up to 50%. This effect was correlated with significant declines in the severity of pelvic pain, pelvic pressure, bladder pressure, urinary frequency and lower back pain in patients with uterine fibroids, although there was an increase in the prevalence and severity of hot flushes. The next stage in this research will be to investigate whether even lower doses of mifepristone are effective, whether the fibroids will re-grow after therapy is stopped, and whether longer-term administration of mifepristone is safe.¹

1.	Eisinger SH, Meldrum S, Fiscella K et al. Low-dose mifepristone for uterine leiomyomata. Obstetrics and Gynecology 2003;101(2):243–50.