17. DES-exposed women

Diethylstilbestrol (DES) is a synthetic oestrogen, transplacental carcinogen and an endocrine disrupting compound.^[1] It was prescribed from the 1940s until the early 1970s, predominantly to pregnant women in the first trimester, to prevent miscarriages by stimulating the synthesis of oestrogen and progesterone in the placenta.^[1] It has been estimated that 15,000 Australian women used the drug during pregnancy.^[2] DES is no longer registered for human use in Australia.

The first study to provide conclusive evidence of an association between in utero exposure to DES and clear cell adenocarcinoma (CCA) was reported in 1970 by Herbst and Scully, who found vaginal CCA in seven women aged 15–22 years.^[3] Subsequent studies have consistently confirmed this finding, and the most recent review of human carcinogens by the International Agency for Research on Cancer (2012) states that there is substantial evidence indicating that women exposed in utero to DES have a markedly increased risk of clear cell carcinoma of the vagina and cervix.^[1]

Vaginal adenosis is a known precursor of CCA that affects between 34–88% of DES-exposed women and less than 4% of unexposed women.^[1]

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Systematic review evidence

A systematic review was conducted to identify studies that evaluated the safety and effectiveness of screening women who were exposed to DES in utero and their daughters, using screening strategies other than those recommended for the general population, compared with those recommended for the general population. The search strategy and inclusion and exclusion criteria used are described in detail in the Technical report. No relevant randomised controlled trials or paired diagnostic performance studies were found.

General literature review evidence

In the absence of any direct evidence from the systematic review, three separate general reviews of the literature were performed to ascertain:

1. whether clear cell carcinomas are HPV positive
2. the risks of cervical and vaginal squamous cell carcinomas overall or high-grade cervical intraepithelial neoplasia (CIN) or high-grade vaginal intraepithelial neoplasia (VAIN) in women exposed to DES in utero, compared with women who were not exposed to DES
3. the risks of cervical and vaginal carcinomas or dysplasia in daughters of women who were exposed to DES in utero, compared with daughters of women who were not exposed.

Clear cell carcinomas

Nineteen studies were identified that tested for the presence of HPV DNA in samples of clear cell carcinoma of the cervix or vagina. Overall, about a third of 158 samples of clear cell carcinoma of the cervix were found to be HPV positive. The findings are summarised in the Technical report.

Squamous cell carcinomas in women exposed in utero

A Dutch study reported no excess risk for combined cervical and vaginal squamous cell carcinoma in a cohort of over 12,000 women exposed to DES in utero (standard incidence ratio 0.64; 95%CI 0.31–1.17].^[4] In this study, women were recruited in 1992 and were followed prospectively until 2008.

In another analysis, data was combined from three studies initiated in the 1970s with long-term follow-up on 4653 women exposed to DES and 1927 unexposed controls. The cumulative risk of CIN2/CIN2+ in women exposed to DES in utero was 6.9% versus 3.4% in women who were not exposed to DES (hazard ratio 2.28; 95%CI 1.59–3.27).^[5]

Squamous cell carcinomas in daughters of women exposed in utero

A recent study reported data, confirmed from medical notes, from 463 daughters of women exposed to DES in utero and 330 unexposed women. No significant increased risk of cervical dysplasia was found in the daughters:^[6]

• relative risk (RR) of any cervical lesion 1.45 (95%CI: 0.69–3.05)
• RR of moderate/severe cervical lesions 0.93 (95%CI: 0.29–2.94).

Consensus-based recommendation

REC17.1: Screening in DES-exposed women Women exposed to DES in utero should be offered an annual co-test and colposcopic examination of both the cervix and vagina indefinitely.

Consensus-based recommendation*

REC17.2: Colposcopy referral for abnormalities in DES-exposed women Women exposed to DES in utero who have a screen-detected abnormality should be managed by an experienced colposcopist.

Practice point

REC17.3: Daughters of women exposed to DES These women should be screened in accordance with the NCSP policy (5-yearly HPV testing). Evidence of an adverse effect on the daughters of women exposed to DES in utero has not been found. However, if these women have concerns, testing similar to that recommended for their DES-exposed mothers could be considered on an individual basis. Self-collection for HPV testing is not recommended.

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On the basis of the evidence summarised above, we have proposed that HPV testing be added to the previous recommendations for annual cytological testing as part of screening offered to women exposed to DES in utero. The addition of HPV testing is expected to increase the detection of CCA in DES-exposed women. It is important, however, that clinicians are aware that not all CCA are HPV positive and that co-testing with cytology is necessary for early detection.

There is very little evidence available on the risk of cervical cancer or CIN in the daughters of women exposed in utero to DES. Due to the lack of evidence, the possibility that the risk of cancer in the daughters of women exposed in utero to DES is different to the risk in the general female population cannot be excluded, but is considered unlikely. If requested, annual co testing (HPV and LBC) can be offered by clinicians to these women to provide reassurance.

See Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed National Cervical Screening Program (NCSP).

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Clinical practice

These recommendations are consistent with present clinical practice.

Frequent follow-up of this cohort of women will enable the timely observation and early treatment of any DES-associated changes.

Resourcing

No material changes to costs are anticipated.

Barriers to implementation

There are no barriers to implementation.

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Unresolved issues

There remains uncertainty as to whether daughters of women who were exposed to DES in utero experience a higher risk of clear cell carcinoma of the vagina or of other cervical or vaginal neoplasms than women without this maternal history.

Future research priorities

Where it is possible to do so, efforts should be made to follow-up additional cohorts of daughters of women who were exposed to DES in utero to ascertain whether or not they have a greater risk of cervical or vaginal neoplasms than women in the same populations without this maternal history.

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