When experts disagree
By Dr Peter Moodie, College Clinical Advisor
22 June 2023
Recently there have been two coroners’ reports concerning young women who died in 2021 as a result of pulmonary emoboli (PE). Both were taking combined oral contraceptives (COCs) and were found to have an undiagnosed factor V Leiden (FVL) mutation.
Relative and absolute risk of DVT and PE
Statistics regarding the risks of Deep Vein Thrombosis (DVT) and PE vary according to the source, and the data is often presented in a confusing way. The consensus, however, seems to be:
- 5% of Caucasian women have an FVL mutation which increases the risk of DVT.
- Otherwise healthy women taking COCs increase their risk of DVT by a factor of 4-6.
- Women with FVL and taking COCs increase their risk by at least a factor of 20.
- Pregnant women increase their risk of a DVT by a factor of 60.
- If a woman develops a DVT she has about a 1% chance of developing a serious or fatal PE.
- The frequency of women who are not on COCs developing a DVT is 4/10,000 woman years.
The risk of developing a DVT while on COCs, even if they have an FVL mutation, is therefore very small and is outweighed by the risk of a DVT while pregnant.
The consensus view is that there was no need to routinely test women wanting to go on COCs for FVL.
Case 1: Susan aged 29
Susan (not her real name) had been on the pill trade named Ginet for four years before her death. Ginet has a higher dose of oestrogen and contains a 3rd generation progesterone. The coroner did not record any information about who prescribed the COC for her, or the medical management of her prescriptions. There was no mention of other risk factors, including obesity or smoking. The fact, however, that she was on Ginet may suggest that she had polycystic ovary syndrome.
On the day of her death at about 1pm she texted a friend and her father to say that she felt unwell with back and leg pain. She did not respond to any texts, and her flatmate found her dead in her room at 4.30 pm. A post-mortem showed a large thrombus in her pulmonary artery, and blood tests showed that she had an FVL mutation.
The coroner has emphasised that a careful history needs to be taken for anyone starting COCs and the risk of DVT/PE needs to be highlighted to these patients.
Case 2: Mary aged 17
Mary (not her real name) had been taking a 2nd generation COC for some months. A blood test taken in the 24 hours before her death showed that she had a factor V Leiden (FVL) mutation. She was otherwise a fit 17-year-old non-smoker (although she had taken up vaping) with a normal BMI, who had been given fast track acceptance to Law school for 2022 and had competed at a national level in swimming.
Mary collapsed while out walking with her father. Despite resuscitation she remained deeply unconscious and died the next morning from a pulmonary embolus that had caused irreversible global cerebral anoxia. A blood test taken a few hours before her death showed that she had an FVL mutation.
The coroner focused on the last year of her life and whether her death could have been prevented. He asked for expert opinions from a specialist general practitioner (SGP), a haematologist who was also qualified as an obstetric physician (HOP), Medsafe’s New Zealand Pharmacovigilance Centre (CARM) committee and the Immunisation Advisory Centre.
The history was:
- Sometime early in 2021, Mary had started on a COC which she obtained from a friend who had been prescribed it by a school nurse and it was then passed on to Mary (the friend did not go to the same school as Mary).
- In June, Mary developed a sore throat, a rash and fleeting joint pains, and she was admitted to hospital with a provisional diagnosis of rheumatic fever. She was fully investigated with an ECG, chest X-ray, bloods and subsequently an echo cardiogram. The final diagnosis was that she had had a viral illness with an exanthem. She did not disclose that she was taking the COC.
- In July, Mary attended a medical clinic (not her normal doctor) and explained that she had been on Levlen COC for the previous 4 months and that she wanted to continue with this. She apparently answered “no” to all questions regarding risk, and the coroner noted that the information sheet for Levlen clearly spelt out the risks, including the risk of FVL (which Mary did not know that she had).
- In August, Mary received her first Covid immunisation and there were no reported adverse effects.
- On 6 September, Mary had a phone consultation, followed by a face-to-face consultation during which she described both a nighttime and exercise-induced wheeze when she went running. Mary surmised that the wheeziness could be attributed to her leaving open containers of acrylic paint in her bedroom (she had recently taken up painting) and since closing the containers she thought her symptoms were improving.
Her doctor carried out a thorough examination and specifically noting that there was no respiratory distress and no wheeze on auscultation. He agreed with the probable cause and offered a beta agonist inhaler, but Mary did not think that was necessary. The Doctor said that he gave “safety netting” advice to come back if symptoms persisted.
- On 9 September 2021, Mary collapsed and died the next day.
With this background the coroner asked for expert opinions on the case.
Possible association with Covid immunisation
Both CARM and the Immunisation Advisory Centre advised that there was no real indication that VTE was caused by the Covid immunisation.
The haematologist explained that reputable bodies (ROCG and the CDC) had advised against screening for FVL in both the general population and in women taking COCs. The basic logic behind this was that the risks of not going on COCs were outweighed by the VTE risks of pregnancy. Finally, she highlighted that there is emerging evidence of an increased risk of VTE for vapers. The HOP, however, was critical of the fact that the doctor who first prescribed the COC for Mary did not document the fact that he had specifically warned her of the risks of VTE. She also criticised the second doctor for not recording the patient’s respiratory rate. She felt that if he had done that, it would have alerted him to the possibility of a VTE and they should have then done a D-Dimer to exclude this.
General practice expert opinion
The specialist general practitioner (SGP) disagreed with the haematologist and considered that the doctor who first prescribed COCs to Mary did so in a manner entirely consistent with good medical practice.
The SGP also disagreed with the haematologist as to the management of the wheeziness that Mary reported. The attending doctor had noted that the patient was not breathless, and she felt this was an adequate alternative to measuring her respiratory rate. She further noted that Mary’s presentation in September was far from typical of a VTE.
So, who was right and what are learnings?
Warning of risks
It goes without saying that all women starting COCs must be warned about the risks associated with taking these medications. The HDC and the coroners are expecting these warnings to be documented. This is part of a worrying trend where various disciplinary bodies, including the HDC, are beginning to read case notes as if they were legal documents, where an omission of a recording or an explanation to a patient is regarded as evidence that there was a lack of care.
As competent clinicians we should:
- Be aware that this is occurring, and the habit is worrisome.
- Not condone incomplete case notes.
- Be clear on what is a competent case note and its purpose.
- Work to define the need for case notes with MCNZ.
Should all women on COCs with wheeze/shortness of breath have a D-Dimer?
Firstly, there is the matter of pre-test probability. If you are a haematologist specialising in thrombophilia, the likelihood of your patients having VTE is quite high. Contrariwise, the chances of this happening in primary care are vanishingly small and doing a D-Dimer on every patient who presents with increasing shortness of breath or wheeziness is not feasible. This does not, however, mean that we should not consider VTE as a differential diagnosis. Specialists in one field should be wary of criticising other specialties in the way they manage illnesses.
At the end of the day, two young women died tragically. The role of the coroner is to establish cause of death but not to apportion blame. In this case, the coroner was careful to give equal opportunity for both sides to be aired.
Take home points
- Routine testing for FVL mutation is not generally recommended when commencing a patient on COC. However, a thorough discussion of the risks of DVT and a screen for history of clotting disorder in family history is needed.
- VTE should be considered in the differentials for women on the COC presenting with increased shortness of breath/wheeze.