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Three Part Question

In the [young women of child bearing age] is [Oral contraceptive pills usage] associated with [Pulmonary Hypertension in absence of pulmonary thromboembolism]?

Clinical Scenario

A 29-year-old white woman with no background history of cardio-pulmonary or rheumatic disease was admitted with rather abrupt onset of exert ional dyspnoea, dry cough and recurrent syncopal episodes in absence of chest pain or haemoptysis. Clinical examination revealed evidence of right heart failure. There was no clinical or echcardiographic evidence of valvular heart disease, cardiac constriction or restriction. A subsequent V-Q scan was reported to be low probability for pulmonary thrombo-embolism. Cardiac catheterization showed elevated pulmonary arterial pressure (measured 113/57 mm Hg) and normal pulmonary arterial wedge pressure (excluding left sided heart disease). Apparently the patient was commenced on oral contraceptive pills five years prior to the admission. One wonders if the sudden onset of primary pulmonary hypertension without any overt pulmonary thromboembolism, in a previously healthy woman with no positive family history could be associated with oral contraceptive pills.

Search Strategy

Medline database 1966 to week 3 July 2006 via OVID
The Cochrane library 2006, Issue 1
CinAHL: 1982 to week 3 July 2006
EMbase: 1980 to 2006 week 30
Medline: [oral contraceptive pills.mp OR exp oral contraceptive pills] AND [pulmonary hypertension.mp OR exp pulmonary hypertension] LIMIT to human and English language.
Cochrane: [oral contraceptive pills OR female steroid hormones OR oestrogen, progesterone] AND [pulmonary hypertension OR pulmonary vascular disease]
CinAHL: [oral contraceptive pills mp. OR exp oral contraceptive pills] AND [pulmonary hypertension mp. OR exp pulmonary hypertension]
Embase: [oral contraceptive pills mp. OR exp oral contraceptive pills] AND [pulmonary hypertension mp. OR exp pulmonary hypertension]

Search Outcome

Medline: 20 papers found of which 4 were relevant. Cochrane: 127 citations. None were relevant. CinAHL: No citations. Embase: 43 papers of which one was relevant but did not address the three-part question directly.
In addition, 2 interesting case reports found in the references of the relevant articles from Medline.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Oakley C, Sommerville J. 1968 London,United Kingdom	3 young women of child bearing age (2 with congenital septal defects of heart and 1 with PDA, all having left to right shunts)	Case series(Level 5)	Development of pulmonary hypertension with reversal of shunt (Eisenmenger's syndrome)	Rapid downhill course in the health of all 3 women with development of shunt reversal.	All women had predisposing factor for development of pulmonary hypertension. Small sample size. Long term follow up in 2 women did show no reversal on discontinuation of oral contraceptive pills.
			Development of raised pulmonary arterial pressure as measured by cardiac catherization.	Development of severe pulmonary hypertension in all 3 cases within 3 months to 2 years following inception of oral contraceptive pills.
			Death of patient as a result of pulmonary vascular compromise	1 of the 3 patients (33%) died within 2 years from the commencement of oral contraceptive pills. Autopsy findings were consistent with pulmonary vascular obstruction by intimal fibroelastosis and no thromboembolism
Irey et al 1973 Washington DC, USA	16 women of child bearing age group divided into 3 groups: 5 pregnant women(Age 21-31 years; avg 27 yrs), 4 postpartum (Age 18 –32 years; avg 25 yrs), 7 women taking oral contraceptive pills for a period of 6 wks – 5 yrs. (Age 22-44yrs; avg 30 yrs).	Case Control study (level 4)	Intimal vascular proliferation under the influence of exogenous (OC pills) or endogenous female steroid hormones, in various vascular beds including pulmonary, renal, cardiac, mesenteric, coronary etc	All 16 women developed intimal proliferation in at least one vessel bed	Not specific for pulmonary vascular bed and hypertension. Not specific for OC pills. Data incomplete regarding the long-term course and prognosis of the patients. No Statistical significance assessed.No Blinding. Small sample size
			proportion of women with pulmonary vascular lesion and development of pulmonary hypertension	5 out of 16 (31%) developed intimal proliferation in Pulmonary vascular bed.2 of the 7 (28%) women taking OC pills showed pulmonary vascular intimal lesions.
			Death of the patients due to various vascular lesions.	2 of 5 (40%) pregnant women died. 4of 4 (100%) postpartum women died. 3 of 7 (42%) women taking oral contraceptive pills died of which 2 (67%) had pulmonary vascular lesions.
Kleiger et al 1976 St. Louis	6 women of child bearing age group: (3 with predisposing factors and 3 with no known predisposing factors for development of pulmonary hypertension)	Case series (Level 5)	Raised pulmonary arterial pressure and pulmonary vascular resistance as measured by cardiac catherization, within 6 mnts to 5 yrs after commencement of OC pills without any evidence of pulmonary thrombo-embolism.	All 6 women (100%) developed raised pulmonary arterial pressure with signs and symptoms of pulmonary hypertension.	3 of the 6 women had predisposing factors for pulmonary hypertension. No data whether pulmonary hypertension regressed with cessation of OC pills. No follow up. Small sample size
			Death of the patient due to pulmonary vascular compromise	3 of 6 (50%) women died with the autopsy findings of right ventricular hypertrophy and intimal hyperplasia of pulmonary vascular bed, but no thromboembolism
Todd el at 1985 Belfast	22yr old women suffering from SLE	Case report (Level 5)	Pulmonary arterial pressure as measured on cardiac catherization	Pulmonary arterial pressure rose to 40/20 with acute and rapidly progressive signs and symptoms of pulmonary hypertension.	SLE could be a confounding factor. No reports whether OC pills were stopped. No long term follow up.
			V-P scan	VP scan was normal to exclude pulmonary emboli.
			ECG & ECHO	ECG & ECHO findings were consistent with right ventricular hypertrophy.Pulmonary hypertension developed in this patient if SLE in absence of chronic parenchymal lung disease or pulmonary emboli within 8 months of commencement of OC pills.
Miller et al 1987 Australia	16 year old white women having SLE on treatment with 20mg prednisone and 200mg hydrooxychloroquine(Clinically &serologically stable). Intervention: started OC pill (ethinyl oestradiol + levonorgestrone)	Case report (Level 5)	Pulmonary hypertension after starting OC pills	Raised pulmonary arterial pressure (59/22 mm of Hg) as evidenced on cardiac catheterization, within 7 months of commencement of OC pills	SLE could be a confounding factor. No autopsy findings mentioned
			Death of the patient due to pulmonary vascular compromise	Patient died after 6 months of diagnosis of pulmonary hypertension. Pulmonary hypertension occurred in this patient of SLE in absence of chronic interstitial lung disease or overt pulmonary emboli.
Townend et al 1992 England	24 year old healthy women taking OC pill for 1 year	Case report(Level 5)	Pulmonary hypertension due to pulmonary veno-occlusive disease	Patient developed raised pulmonary arterial pressure (65/30) as evidenced on Right cardiac catheterisation within 7 months of starting OC pills.	No control group. Single patient involved
			Death of patient due to pulmonary vascular compromise	On death of the patient, autopsy findings showed intimal cellular fibrosis of pulmonary veins. Walls of pulmonary arterial tree were thickened consistent with pulmonary hypertension.

Comment(s)

The available literature implies a weak causal association between oral contraceptive usage and pulmonary hypertension in absence of pulmonary thrombo-embolism based on poor quality level 4-5 evidence available from literature. It is well known that oestrogen is proven to cause intimal proliferation of vascular endothelial bed but is not very specific for pulmonary vasculature The histo-pathological findings on some of the cases are no different than that is expected for pulmonary arterial hypertension of any aetiology including idiopathic PAH. Due to the high prevalence of oral contraceptive usage in young women at childbearing age, a rare occurrence of pulmonary hypertension could be coincidental rather than casual. But what remains intriguing is whether OCP usage in patients with pre-existing risk pulmonary hypertension accelerates the natural course of the disease. A large multicentric, randomised clinical trial is desirable to answer this question effectively.

Clinical Bottom Line

There is a weak published evidence to relate casual association between use of oral contraceptives and development of pulmonary hypertension. Without, further study this association remains unclear.

References

1. Oakley C, Sommerville J. Oral contraceptive and progressive pulmonary vascular disease. Lancet 1 890-893, 1968
2. Irey N, Norris H Intimal vascular lesion associated with female reproductive steroids. Arch Pathol 96 227-234,1973
3. Kleiger RE, Boxer M, Ingham RE, et al : Pulmonary hypertension in patients using oral contraceptives: A report of six cases. Chest 69 143-147, 1976
4. GRG Todd et al Pulmonary hypertension, SLE and Oral contraceptive Annals of Rh disease 44(4) 266-7 1985 Apr
5. Miller et al Pulmonary hypertension, SLE and Oral contraceptive. Annals of Rh disease 46(2) 159-61 1987 Feb
6. Jonathan N. Townend, David H. Roberts, E. Lynn Jones and Michael K. Davies Fatal Pulmonary venoocclusive disease after oral contraceptive AH Journal 124(6) 1645-8, 1992 Dec