Spontaneous loss of early pregnancy and risk of ischaemic heart disease in later life: retrospective cohort study
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7386.423 (Published 22 February 2003) Cite this as: BMJ 2003;326:423
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ABORTION
AND RISK OF NON-FATAL ACUTE MYOCARDIAL INFARCTION IN ITALY
EDITOR-A
Scottish record-linkage study found that a history of any spontaneous abortion
before the first live birth was associated with a 50% increase of ischaemic
heart disease risk, based on 261 events.1
No relation was found with induced abortion.
No information on major covariates, including smoking status, was
available.
Another
American case-control study, based on 50 cases, found an association between
coronary heart disease and miscarriage, with crude odds ratios (OR) of 2.9 and
3.8 respectively for 1-2 and 3-7 abortions.2
We
analyzed data of a
combined dataset from three case-control studies
on nonfatal acute myocardial infarction (AMI)
conducted in Italy.3,4
The first study, conducted in 1983-92, included 314 women with AMI and
733 female controls; the second, conducted in 1988-89, included 115 cases and
130 controls; the third, conducted in 1995-99, included 129 cases and 181
controls. Consequently the present
analysis included 558 women with a first episode of nonfatal AMI (median age 55
years, range 18-79), and 1,044 controls (median age 53 years, range 17-79) in
hospital for acute diseases unrelated
to smoking and other risk factors for AMI (22%
traumas, 34% non-traumatic orthopaedic disorders, 14% acute surgical conditions,
30% other miscellanea).
Participation was over 95%. Interviews
were conducted in hospital using similar questionnaires, including
information on age, socio-demographic factors, anthropometric variables,
smoking, alcohol, diet, medical history, history of AMI in relatives, menstrual
and reproductive factors, including age at first pregnancy and birth, and number
of spontaneous or induced abortions. The
multivariate OR and the corresponding 95% confidence intervals (CI) were derived
using unconditional multiple logistic regression models.5
No
relation with AMI risk was found neither for spontaneous (OR 1.0, 95% CI 0.6-1.5
for >1 abortion compared to none) nor induced abortions (OR 0.7, 95% CI
0.4-1.2) (Table). The OR and
95% CI did not change when analyses were limited to parae.
In women with an abortion before the first live birth the OR for >1
spontaneous abortion was 0.8 (95% CI 0.3-2.19) compared to none.
The crude OR for >1 spontaneous abortion was 1.1.
Although we found similar results for spontaneous and induced abortions,
we considered them separately, as the underlying biological mechanisms are
different, and duration of pregnancy may be longer for spontaneous than for
induced abortion (i.e. <13 weeks).
The apparent difference between our results and previous data1,2
may be at least partly explained in terms of confounding factors, which in our
study were allowed for.
REFERENCES
1.
Smith GCS, Pell JP, Walsh D.
Spontaneous loss of early pregnancy and risk of ischaemic heart disease
in later life: retrospective cohort study.
Br Med J 2003;326:423-4.
2.
Winkelstein W Jr.
Spontaneous
abortion and coronary heart disease. J
Clin Epidemiol 1995;48:500-1.
3.
La Vecchia C, Decarli A, Franceschi S, Gentile A, Negri E, Parazzini F.
Menstrual and reproductive factors and the risk of myocardial infarction
in women under fifty-five years of age. Am J Obstet Gynecol 1987;157:1108-12.
4.
Tavani A, Bertuzzi M, Gallus S , Negri E, La Vecchia C.
Diabetes
mellitus as a contributor to the risk of acute myocardial infarction.
J
Clin Epidemiol 2002;55:1082–7.
5.
Breslow NE,
Day NE. Statistical Methods in Cancer Research. Vol. I. The
Analysis of Case-control Studies. Lyon:
IARC Scientific Publications, 32, 1980.
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Table - |
Distribution of 558 women with acute myocardial |
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AMI |
|
Controls |
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OR (95% CI)a |
OR (95% CI)b |
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Spontaneous abortions |
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|
|
|
|
|
||
|
|
None |
406 |
|
794 |
|
1c |
1c |
|
|
|
1 |
99 |
|
156 |
|
1.2 (0.9-1.6) |
1.3 (0.9-1.7) |
|
|
|
>1 |
53 |
|
94 |
|
1.0 (0.7-1.5) |
1.0 (0.6-1.5) |
|
|
|
c2, trend |
|
|
|
|
0.37 (p=0.541) |
0.27 (p=0.602) |
|
|
Induced abortions |
|
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|
|
|
|
||
|
|
None |
506 |
|
938 |
|
1c |
1c |
|
|
|
1 |
26 |
|
50 |
|
1.1 (0.7-1.8) |
0.9 (0.5-1.5) |
|
|
|
>1 |
26 |
|
56 |
|
0.9 (0.5-1.4) |
0.7 (0.4-1.2) |
|
|
|
c2, trend |
|
|
|
|
0.14 (p=0.704) |
1.64 (p=0.201) |
|
|
|
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b Estimated from multiple |
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c |
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Competing interests:
None declared
Competing interests:
EDITOR - Smith and colleagues report an increased risk of ischaemic
heart disease in later life among women with spontaneous losses of early
pregnancy (1).The authors hypothesise that innate thrombotic disorders
underlie both the fetal loss as well as the coronary occlusion.
When considering an alternative biological explanation for the
observed association, the innate immune system immediately comes to mind.
Cytokines are key regulators of this system and we have previously shown
that production capacity of interleukin-10 is under tight genetic control,
with heritability estimates up to 75% (2). Similar to innate thrombotic
disorders, women with low interleukin 10 production are at a three-fold
increased risk to have consecutive spontaneous abortions (3). Reproductive
success is dependent on an appropriate immune response at the fetal-
maternal interface and low interleukin-10 production impairs implantation
and distorts development of the placenta. To complete the parallel,
individuals with low interleukin-10 production carry a high risk of
developing the metabolic syndrome and type 2 diabetes (4) as well as
stroke (5) and thus show to be susceptible of atherosclerotic disease in
older age.
Anton JM de Craen (1)
Frans M Helmerhorst (2)
Frederique M van Dunne (2)
Tom WJ Huizinga (3)
Rudi GJ Westendorp (1)
Department of General Internal Medicine (1), Gynaecology and
Reproductive Medicine (2), Rheumatology (3), Leiden University Medical
Centre, PO Box 9600, 2300 RC, Leiden, Netherlands.
References
1. Smith GCS, Pell JP, Walsh D. Spontaneous loss of early pregnancy and
risk of ischaemic heart disease in later life: retrospective cohort study.
BMJ 2002;326:423-24.
2. Westendorp RGJ, Langermans JA, Huizinga TWJ, et al. Genetic influence
on cytokine production and fatal meningococcal disease. Lancet
1997;349:170-73.
3. Westendorp RGJ, van Dunne FM, Kirkwoord TBL, Helmerhorst FM, Huizinga
TWJ. Optimizing human fertility and survival. Nat Med 2001;7:873.
4. van Exel E, Gussekloo J, de Craen AJM, Bootsma-van der Wiel A, Frölich
M, Westendorp RGJ. Inflammation and stroke. The Leiden 85-plus study.
Stroke 2002;33:1135-38.
5. van Exel E, Gussekloo J, de Craen AJM, Frölich M, Bootsma-van der Wiel
A, Westendorp RGJ. Low production capacity of interleukin-10 associates
with the metabolic syndrome and type 2 diabetes. Diabetes 2002;51:1088-92.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
Smith et al make the important observation that adverse events in
early life can be related to apparently disparate events later in life.
In the instance of spontaneous pregnancy loss and subsequent ischaemic
heart disease, Smith et al hypothesise a role for inherited and acquired
thrombophilias in the mother as a common aetilogical factor.
They adjusted for the potential confounding effects of maternal age
at the time of first birth, height, socioeconomic deprivation, essential
hypertension, and complications during the first pregnancy.
It appears that they were not able to adjust for maternal body weight
and thereby in conjunction with height, obesity. Maternal obesity has been
demonstrated to be strongly associated with pregnancy loss, at least in
sub-fertile women (1), and is an independent contributor to risk of
ischaemic heart disease. Obesity may therefore be operating as a
significant confounding factor in the association between pregnancy loss
and subsequent heart disease.
The influence of obesity may also explain in large part the results
of previous studies that have found an association between the total
number of pregnancies and maternal risk of IHD. High parity is associated
with adult weight gain (2). The confounding effect of obesity is also
consistent with the null effect of therapeutic abortion on risk of IHD, as
there is no particular reason for obesity to be strongly associated with
receiving a termination.
Hence, while the reported study had the strengths of prospective data
collection, it relied on data that were not collected for the purposes of
the present analysis and may not contain details of all relevant
confounding factors. While the observation of Smith et al is important,
and there may be multiple factors making a contribution including
inherited and acquired thrombophilias, we need further analysis on the
effects of obesity and additional studies linking reproduction, adult
weight gain and elevated disease risk (3).
1 Wang JX, Davies MJ, Norman RJ. Obesity increases the risk of
spontaneous abortion during infertility treatment. Obes Res. 2002
Jun;10(6):551-4.
2 Lahmann PH, Lissner L, Gullberg B, Berglund G. Sociodemographic
factors associated with long-term weight gain, current body fatness and
central adiposity in Swedish women. Int J Obes Relat Metab Disord. 2000
Jun;24(6):685-94.
3 Ball K, Brown W, Crawford D. Who does not gain weight? Prevalence
and predictors of weight maintenance in young women. Int J Obes Relat
Metab Disord. 2002 Dec;26(12):1570-8.
Competing interests:
None declared
Competing interests: No competing interests
The findings of an association between spontaneous abortion and
maternal risk of ischaemic heart disease (1) and that drinking coffee
during pregnancy is associated with an increased risk of stillbirth but
not with infant death (2) are consistent with the hypothesis that fetal
and infant wellness are dependent upon the adequacy of mitochondrial
oxidative phosphorylation (3). That some studies have shown that folate
supplements reduce the risk of neural tube defects and others have shown
that it does not (4) would also be consistent with this hypothesis if the
beneficial effects of the supplement were to be shown to be due to the
effects of the potent xanthine oxidase inhibitor contaminating commercial
preparations of folate rather than the folate per se (5). The findings are
also consistent with the hypothesis that an inadequacy of mitochondrial
oxidative phosphorylation is the principle cause of acute and chronic
organ dysfunctions and failures and nosocomial infections in adults (6-
12).
Occult cardiovascular, microvascular, or haemostatic dysfunction may
in themselves be the products of an impairment of mitochondrial oxidative
phosphorylation in the intima and/or media (10,11). It which case it is
likely to be an inadequacy of mitochondrial oxidative phosphoprylation
rather than vascular and haematologic diseases, as proposed (1), that
result in "pregnancy complications during reproductive years and in overt
cardiovascular disease in later life". As the occult cardiovascular,
microvascular, or haemostatic dysfunction may also impair oxygen delivery
to cells they may, however, be a secondary cause of an inadequacy of
oxidative phosphoprylation.
In future stusies all causes of an inadequacy of oxidative
phosphorylation need to be considered including the effects of food which
are not unlike the effects of phosphodiesterase inhibitors such as
caffiene (14,15). Both food and caffiene may cause a transient impairment
or transient increase in the severity of an impairment of mitochondrial
oxidative phosphorylation by increasing the demand for energy from ATP
hydrolysis beyond the capacity of cells to replenish ATP stores in a
timely manner. Excessive food intake and/or caffiene should, therefore,
increase the likelihood of developing an impairment of mitochondrial
oxidative phosphorylation especially in those with preexisting occlusive
vascular diseases.
There is a danger that in attributing adverse events, such as the
spontaneous loss of a pregnancy and ischaemic heart disease, to vascular
and haematologic disorders rather than to impaired mitochondrial oxidative
phosphorylation that detection of significant risk will be delayed and
accordingly management delayed, ineffective and/or even harmful.
1. Spontaneous loss of early pregnancy and risk of ischaemic heart
disease in later life: retrospective cohort study Gordon C S Smith, Jill P
Pell, and David Walsh BMJ 2003; 326: 423-424
2. Maternal consumption of coffee during pregnancy and stillbirth and
infant death in first year of life: prospective study Kirsten Wisborg,
Ulrik Kesmodel, Bodil Hammer Bech, Morten Hedegaard, and Tine Brink
Henriksen BMJ 2003; 326: 420
3. SIDS: identifying the real cause or causes Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7371/981#27589, 5 Dec 2002
4. Neural tube defects and periconceptional folic acid in England and
Wales: retrospective study • Commentary: Food should be fortified with
folic acid Rezan A Kadir, Caroline Sabin, Barry Whitlow, Ely Brockbank,
Demetrios Economides, Eva Alberman, and Joan M Noble
BMJ 1999; 319: 92-93
5. On the beneficial effects of contaminants in folate supplements
Richard G Fiddian-Green bmj.com/cgi/eletters/326/7381/131#28861, 17 Jan
2003
6. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003
7. Iatrogenic diseases with a common cause? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7370/913#26512, 25 Oct 2002
8. Madness, hyperhomocysteinemia, metabolic rate and body temperature
Richard G Fiddian-Green bmj.com/cgi/eletters/325/7378/1433#28469, 6 Jan
2003
9. Metformin, "lactic acidosis" and renal failure Richard G Fiddian-Green
bmj.com/cgi/eletters/326/7379/4#28486, 6 Jan 2003
10. Hypertension: product of mitochondrial dysfunction?
Richard G Fiddian-Green bmj.com/cgi/eletters/325/7370/917#26634, 31 Oct
2002
11. Unreversed ATP hydrolysis: the initiating endothelial event? Richard G
Fiddian-Green bmj.com/cgi/eletters/325/7369/887#26445, 22 Oct 2002
12. Hyperphosphataemia, hypophosphataemia and risk of organ dysfunctions
and failures Richard G Fiddian-Green
bmj.com/cgi/eletters/326/7385/382#29805, 20 Feb 2003
14. Determining the cause(s) of SIDS Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7371/1007#29622, 13 Feb 2003
15. Hypophosphataemia and the feeding of malnourished children Richard G
Fiddian-Green bmj.com/cgi/eletters/326/7381/146#29382, 3 Feb 2003
Competing interests:
None declared
Competing interests: No competing interests
Dear sir
It is interesting to read the article entitled 'Spontaneous loss of
early pregnancy and risk of ischaemic heart disease in later life:
retrospective cohort study' by Smith GC et al which has attracted so much
of media attention very recently.
It is essential to look into the underlying causes of miscarriages
(especially recurrent) in relation to acquired (anticardiolipin antibody,
lupus anticoagulant 1) and hereditary thrombophilia ( Factor V Leiden
G1691A 2, Prothrombin G20210A 3., Methylenetetrahydrofolate reductase 4,5
etc). This might reveal already known pathogenesis of this association and
looking from a different angle.
Definitely the other confounding factors e.g’ smoking, diabetes,
hyperlipidaemia, homocysteinaemia, weight, height, lifestyle (sedentary
habits) need critical evaluation.
References
1. Rai R S. Clifford K, Cohen H. Regan L. High prospective fetal loss rate
in untreated pregnancies of women with recurrent miscarriage and
antiphospholipid antibodies. Hum Reprod 1995; 10:3301-4.
2.Grandone E, Margaglione M, Colaizzo D, d’Addedda M, Cappucci G,
Vecchione G, Scianname N, Pavone G, Di Minno G. Factor V Leiden is
associated with repeated and recurrent unexplained fetal losses. Thromb
Haemost. 1997;77:822–824
3.Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait
G, Lessing JB. Increased frequency of genetic thrombophilia in women with
complications of pregnancy. N Engl J Med. 1999;340:9–13
4.Kluijtmans LNJ, Kastelein JJP, Lindemans J, Boers GHJ, Heil SG,
Bruschke AVG, Jukema JW, van den Heuvel L, Trijbels FJM, Boerma GJM,
Verheugt FWA, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate
reductase in coronary artery disease. Circulation. 1997;96 :2573–2577
5.Murphy RP, Donoghue C, Nallen RJ, D'Mello M, Regan C, Whitehead AS,
Fitzgerald DJ. Prospective evaluation of the risk conferred by factor V
Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms
in pregnancy. Arterioscler Thromb Vasc Biol 2000 ;20(1):266-70
Competing interests:
None declared
Competing interests: No competing interests
Sir,
In 1998 you published our letter pleading for medical journals to
adopt the terminology for early pregnancy loss which was recommended by
the Royal College of Obstetricians and Gynaecologists.(1) As we pointed
out in the letter, papers published in highly reputable journals using the
old insensitive nomenclature tend to legitimise its continued use.
It is unfortunate therefore in this issue of the journal there are
two inappropriate uses of abortion terminology. First in “This week in the
BMJ” spontaneous abortion is used in the comment about the coffee in
pregnancy paper, although the abortion term is not used in the paper
itself. Secondly in the paper on spontaneous loss in early pregnancy and
risk of ischaemic heart disease in later life,(2) the authors
unfortunately lapse into spontaneous abortion terminology in the comment
section.
The impact of terminology used in international journals on medical
students and trainee doctors cannot be over emphasized and we plead once
more for journal editors and authors to keep to the RCOG recommended
terminology.
Yours sincerely,
David J R Hutchon
Consultant Obstetrician and Gynaecologist
References
1. Hutchon DJR and Cooper S. Terminology for early pregnancy loss
must be changed. BMJ 1998 ;317(7165):1081
2. Smith GCS et al. Spontaneous loss of early pregnancy and risk of
ischaemic heart disease in later life:retrospective cohort study. BMJ
2003;326:423-4
Competing interests:
None declared
Competing interests: No competing interests
Dear sir
The article about spontaneous miscarriage and CAD is very interesting.
Framingham Heart Study and Rotterdam study showed in the past that
multiparity is associated with increased risk of ischemic heart
disese. Lipoprotein and cholesterol factors were thought to be the
contributing factors for this.
But with this retrospective study by Prof Gordon Smith et al
unveiled another possible aetiology of microvascular dysfunction as
probable contributor linking spontaneous miscarriage and coronary artery
disese. The age of the women and risk factors like smoking , diabetes,
hypertension, hypercholestrlemia should be included in the study to show
more light regarding this correlation.
This topic definitely needs more research.
References
1.Spontaneous loss of early pregnancy and risk of ischaemic heart disease
in later life: retrospective cohort study
Gordon C S Smith, Jill P Pell, and David Walsh
BMJ 2003; 326: 423-424
2 Humphries, K. H., Westendorp, I. C.D., Bots, M. L., Spinelli, J. J.,
Carere, R. G., Hofman, A., Witteman, J. C.M. (2001). Parity and Carotid
Artery Atherosclerosis in Elderly Women:J. Stroke.
3..Ness RB, Harris T, Cobb J, Flegal KM, Kelsey JL, Balanger A, et
al. Number of pregnancies and the subsequent risk of cardiovascular
disease. N Engl J Med 1993; 328:
Competing interests:
None declared
Competing interests: No competing interests
Cardiac disorders and fetal loss
Smith et al[1]may be right in claiming their study was the first to
report an association between spontaneous abortion and maternal risk of
subsequent ischaemic heart disease (IHD). However, some years ago we
unexpectedly found that women with heart disorders in general were
strongly over-represented in a series of recurrent miscarriage patients
[2]. Indeed, 2 out of 143 had rare cardiac conduction abnormalities [2].
IHD is likely to be present in early adulthood long before the disease is
manifested. It seems plausible that asymptomatic heart problems in the
mother may predispose to early fetal loss.
[1]Smith GCS, Pell JP, Walsh D. Spontaneous loss of early pregnancy
and risk of ischaemic heart disease in later life: retrospective cohort
study. BMJ 2003;326:423-4
[2] Kilpatrick DC, Liston WA. Characteristics of Scottish patients
presenting with recurrent miscarriage. J Obstet Gynaecol 1994;14:221-5
Competing interests:
None declared
Competing interests: No competing interests