2/14/05njm

Q. What preventive therapy is recommended for patients at high risk for
pre-eclampsia?

A. Low dose aspirin is recommended for selected high risk patients.
Calcium is less certain.

**[Low dose aspirin]{.underline}**

Low dose aspirin therapy is indicated if the patient has had:

(Level I recommendation\*)

-prior severe pre-eclampsia

-chronic hypertension

-pre existing diabetes

-significant renal disease

Treatment should begin at 12 to 14 weeks of gestation. Early therapy is
probably important since the pathophysiologic features of preeclampsia
develop at this time, weeks before clinical disease is apparent. Some
observers recommend discontinuing aspirin five days before expected
delivery to diminish the risk of bleeding during delivery; however, no
adverse maternal or fetal effects related to aspirin have been proven.
The safety of aspirin use in the second and third trimesters is
well-established.

Low-dose aspirin (60 to 150 mg per day) was chosen in an attempt to
diminish platelet thromboxane synthesis while maintaining vascular wall
prostacyclin synthesis. 81 mg aspirin tablets are widely available and
well tolerated.

**[Calcium]{.underline}**

As with
[aspirin](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/21595&drug=true),
there does not appear to be any benefit to routine calcium
supplementation for healthy, nulliparous women. There may be a benefit
for preeclampsia prevention in high-risk populations, but further study
is required since current information is based upon small numbers of
women and diverse study populations.

Please note many AI/AN populations are known to have low calcium values
and calcium has been shown to be helpful patients with a low calcium
intake. In the Alaska Native population lactose intolerance is not
uncommon. Reports have suggested that almost 90% of Alaska Native women
had low calcium intakes compared to a NHANES II control data, and
calcium supplementation appears to be beneficial for women at high risk
of gestational hypertension and in communities with low dietary calcium
intake.

Hence, other AI/AN providers should consult local dietary staff for the
lactose intolerance and calcium data in their area. If there is a known
low calcium intake, then there may be an advantage to recommending
increasing calcium in the diet, or calcium supplementation until further
national data is available.

**References**

Coomarasamy A, et al  Aspirin for Prevention of Preeclampsia in Women
with Historical Risk Factors: A Systematic Review. Obstet Gynecol June
2003, Volume 101, Number 6: 1319 -- 1332 (Level I)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12798543&dopt=Abstract>

Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems
(Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester,
UK: John Wiley & Sons, Ltd.

<http://www.ihs.gov/generalweb/webapps/sitelink/site.asp?link=http://www.cochranelibrary.com/enter/>

Hypertension in Pregnancy Guidelines, ANMC

<http://www.ihs.gov/NonMedicalPrograms/nc4/Documents/HYPERT12004.doc>

UpToDate: Prevention of preeclampsia

<http://www.uptodateonline.com/application/topic.asp?file=pregcomp/5540&type=A&selectedTitle=2~48>

Diagnosis and management of preeclampsia and eclampsia. ACOG Practice
Bulletin No. 33. American College of Obstetricians and Gynecologists.
Obstet Gynecol 2002;99:159-167 (Level III)

[\<http://www.acog.com/publications/educational_bulletins/pb033.htm\>]{.underline}

Chronic Hypertension in Pregnancy. ACOG Practice Bulletin No. 29.
American College of Obstetricians and Gynecologists. Obstet Gynecol
2001; 98:177-185 (Level III)

[\<http://www.acog.com/publications/educational_bulletins/pb029.htm\>]{.underline}

Aspirin for Prevention of Preeclampsia in Women with Historical Risk
Factors: A Systematic Review.

Coomarasamy A, et al Obstet Gynecol June 2003, Volume 101, Number 6:
1319 -- 1332 (Level I)

[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12798543&dopt=Abstract]{.underline}

*Management of Chronic Hypertension During Pregnancy*. Summary, Evidence
Report/Technology Assessment: Number 14. AHRQ Publication No. 00-E010,
August 2000. Agency for Healthcare Research and Quality, Rockville, MD.
(Level III)
[\<http://www.ahrq.gov/clinic/epcsums/pregsum.htm\>]{.underline}

[Screening for Preeclampsia Guide to Clinical Preventive
Services]{.underline}

Second Edition (1996) US Preventive Service Task Force. (Level III)

[\<http://www.ahrq.gov/clinic/2ndcps/preeclam.pdf\>]{.underline}

Etiology and pathogenesis of preeclampsia: Current concepts. Dekker GA,
Sibai BM. Am J Obstet Gynecol 1998; 179:1359-75. (Level III)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9822529&dopt=Abstract>

Primary, secondary, and tertiary prevention of preeclampsia. Dekker GA,
Sibai BM. Lancet 2001; 357:209-215. (Level III)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11213110&dopt=Abstract>

Report of the National High Blood Pressure Education Program Working
Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;
183:S1-S22. (Level III)

[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10920346&dopt=Abstract]{.underline}

[Obstetrics: Normal and Problem Pregnancies]{.underline}. Hypertension,
Chapter 28. Gabbe SG, Neibyl JR, Simpson JL (Eds.) 4th Edition.
Churchill Livingstone, New York, 2002. Pages 945-1004. (Level III)

[Williams Obstetrics]{.underline}. Hypertensive Disorders in Pregnancy,
21st Edition. Cunningham GF, et al (Eds.) Section 7, No. 24, pp.
567-618. McGraw-Hill, 2001. (Level III)

Chobanian AV, et al. The Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure *JAMA.* 2003;289:2560-2571. (Level III)

<http://jama.ama-assn.org/cgi/content/full/289/19/2560>

Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems
(Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester,
UK: John Wiley & Sons, Ltd.

<http://www.ihs.gov/generalweb/webapps/sitelink/site.asp?link=http://www.cochranelibrary.com/enter/>

Special thanks to Betsy Nobmann, PhD, Nutrition, former IHS Area
Nutrition Director for information on calcium intake in Alaska Native
women.

**\*Summary and recommendations** --- Major questions remain as to which
subgroups of women are most likely to benefit from low-dose
[aspirin](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/21595&drug=true)
therapy, when treatment should be started (first or second trimester),
and the optimum dose to inhibit placental synthase and also allow the
antiinflammatory effects of aspirin
\[[24](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=24&title=24)\].
At present, there is no easily identifiable group of pregnant women that
will predictably derive a clinically significant benefit from low-dose
aspirin therapy
\[[25](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=25&title=25)\].
For moderate and high risk women, 59 to 167 patients would have to be
treated to prevent one case of preeclampsia; 44 to 200 would have to be
treated to prevent one preterm birth, and 125 to over 10,000 would have
to be treated to prevent one perinatal death
\[[26](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=26&title=26)\].

The American College of Obstetricians and Gynecologists practice
bulletin does not recommend
[aspirin](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/21595&drug=true)
therapy for women at low-risk for development of preeclampsia ([show
table
1](http://www.uptodateonline.com/application/image.asp?file=obst_pix/risk_f36.gif))
\[[27](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=27&title=27)\].
However, no conclusions were reached about moderate to high risk women.

Many perinatologists recommend use of low dose
[aspirin](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/21595&drug=true)
in women at moderate to high risk of developing preeclampsia. Treatment
should begin at 12 to 14 weeks of gestation
\[[28](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=28&title=28)\].
Early therapy is probably important since the pathophysiologic features
of preeclampsia develop at this time, weeks before clinical disease is
apparent. Some observers recommend discontinuing aspirin five days
before expected delivery to diminish the risk of bleeding during
delivery
\[[5,8](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=5~8&title=5,8)\];
however, no adverse maternal or fetal effects related to aspirin have
been proven. The safety of aspirin use in the second and third
trimesters is well-established
\[[9,16,29](http://www.uptodateonline.com/application/abstract.asp?TR=pregcomp/5540&viewAbs=9~16~29&title=9,16,29)\].

**UpToDate: Prevention of preeclampsia**

<http://www.uptodateonline.com/application/topic.asp?file=pregcomp/5540&type=A&selectedTitle=2~48>

**\*ACOG Summary of Recommendations**

[**Preeclampsia**]{.underline}

***The following recommendations are based on good and consistent
scientific evidence (Level A):***

>  Magnesium sulfate should be used for the prevention and treatment of
> seizures in women with severe preeclampsia or eclampsia.
>
>  If analgesia/anesthesia is required, regional or neuraxial
> analgesia/anesthesia should be used because it is efficacious and safe
> for intrapartum management of women with severe preeclampsia in the
> absence of coagulopathy.
>
>  Low-dose aspirin has not been shown to prevent preeclampsia in women
> at low risk and, therefore, is not recommended.
>
>  Daily calcium supplementation has not been shown to prevent
> preeclampsia and, therefore, is not recommended.

***The following recommendations are based on limited or inconsistent
scientific evidence (Level B):***

 The management of a woman with severe preeclampsia remote from term is
best

accomplished in a tertiary care setting or in consultation with an
obstetrician-gynecologist

with training, experience, and demonstrated competence in the management
of high-risk

pregnancies, such as a maternal-fetal medicine subspecialist.

>  Practitioners should be aware that although various laboratory tests
> may be useful in the management of women with preeclampsia, to date
> there is no reliable predictive test for preeclampsia.
>
>  Invasive hemodynamic monitoring should be considered in preeclamptic
> women with severe cardiac disease, renal disease, refractory
> hypertension, pulmonary edema, or unexplained oliguria.

***The following recommendations are based primarily on consensus and
expert opinion (Level C):***

 Women should be considered as having severe preeclampsia if they have
blood pressure

levels of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher
on two occasions

at least 6 hours apart while the patient is on bed rest, proteinuria of
5 g or higher in a 24-

hour urine specimen or 3+ or greater on two random urine samples
collected at least 4

hours apart, oliguria of less than 500 mL in 24 hours, cerebral or
visual disturbances,

pulmonary edema or cyanosis, epigastric or right upper-quadrant pain,
elevated liver

enzymes, thrombocytopenia, or fetal growth restriction.

>  Expectant management should be considered for women remote from term
> who have mild preeclampsia.
>
>  Antihypertensive therapy (with either hydralazine or labetalol)
> should be used for treatment of diastolic blood pressure levels of
> 105-110 mm Hg or higher.

**[Chronic Hypertension in pregnancy]{.underline}**

***The following recommendation is based on good and consistent
scientific evidence (Level A):***

>  Angiotensin-converting enzyme inhibitors are contraindicated during
> pregnancy and are associated with fetal and neonatal renal failure and
> death.
>
>  Aspirin therapy should be considered in women with historical risk
> factors to decrease superimposed preeclampsia, e.g., preexisting
> diabetes, chronic hypertension, previous severe preeclampsia, and
> renal disease.

***The following recommendations are based on limited or inconsistent
scientific evidence (Level B):***

>  Antihypertensive therapy should be used for pregnant women with
> severe hypertension for maternal benefit.
>
>  Methyldopa and labetalol are appropriate first-line antihypertensive
> therapies.
>
>  Treatment of women with uncomplicated mild chronic hypertension is
> not beneficial because it does not improve perinatal outcome.

 The beta-blocker atenolol may be associated with growth restriction
and is not

recommended for use in pregnancy.

***The following recommendations are based primarily on consensus and
expert opinion (Level C):***

>  Women with chronic hypertension should be evaluated for potentially
> reversible etiologies, preferably prior to pregnancy.
>
>  Women with long-standing hypertension should be evaluated for
> end-organ disease, including cardiomegaly, renal insufficiency, and
> retinopathy, preferably prior to pregnancy.
>
>  When chronic hypertension is complicated by IUGR or preeclampsia,
> fetal surveillance is warranted.