Document Type : Review Article
Authors
1 Department of Cardiovascular, Bushehr University of Medical Sciences, Bushehr, Iran;Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehr
2 Department of Obstetrics and Gynecology, Iran University of Medical Sciences, Tehran, Iran
Abstract
Keywords
Hypertensive disorders (HDs) are the most prevalent
medical problem during pregnancy. It is estimated that
HDs involve up to 6-8% of all pregnancies (
In a recent retrospective study done in Ethiopia, Seyom
et al. (
Zibaeenezhad et al. (
Infertility is also a common condition and physicians
are deeply concerned about it, because it involves a couple,
rather than a single individual. It is defined as inability
of a couple to conceive after one year of regular intercourse
without using any form of contraception (
The prevalence of infertility is markedly high in Eastern
Europe, North Africa, Oceania and sub Saharan Africa
(
Once the pathologic basis of infertility is recognized,
therapy is directed toward curing reversible causes and
modifying irreversible etiologies. Therapeutic interventions
for both male and female infertility includes drug
therapy (
We searched PubMed and Google search engines for incidence of hypertension and also history of infertility in pregnant women. We also checked the internet for causes of female infertility and their association with hypertension, all kinds of treatments and medications that are applied for female infertility and the chance and the mechanisms by which they changing blood pressure (BP). Then we quested for general considerations, treatment modalities and follow-up in pregnant cases with HDs, with or without a history of infertility.
Physiological blood pressure changes during pregnancy
Normotensive women usually experience about 5 to 10
mmHg fall in their BP starting from the first trimester
which may be continued up to the third trimester; after
that, BP is restored to its preconception level (
Hypertension is generally labeled when systolic BP is
≥140 mmHg and/or diastolic BP is ≥90 mmHg, according
to the mean of at least two measurements, checked using
the same arm with at least fifteen minutes intervals, in
clinic or in hospital (
Grading of severity of hypertension and the need for antihypertensive treatment
Grade of hypertension | Blood pressure levels (mm Hg) | Treat | Grade of treatment |
---|---|---|---|
Mild | Diastolic: 90-99 | No* | Not applicable* |
Systolic: 140-149 | |||
Moderate | Diastolic: 100-109 | Yes | <150 systolic* |
Systolic: 150-159 | <100 diastolic* | ||
Severe hypertension | Diastolic: ≥110 | Yes | <150 systolic* |
Systolic: ≥160 | <100 diastolic* | ||
*; Except for women with chronic hypertension with end-organ damage who should be treated even if blood pressure is mild and the goal is to normalizing their blood pressure. Modified from: hypertension in pregnancy: the NICE guidelines (
HDs are classified into four major groups according
to working group of National Institutes of Health (NIH)
report on high BP in pregnancy (
It has also been mentioned that gestational hypertension
usually resolves within up to 12 weeks post-partum however
this is not applicable for cases with chronic hypertension
(
Risk factors for chronic hypertension are: early middle
age or about age 45, black race, using tobacco, too much
salt (sodium) in diet, too little potassium, calcium or vitamin
D in diet, drinking too much alcohol, high levels
of stress, being overweight or obese, little or no exercise,
history of high BP in the family (
Risk factors for preeclampsia include: prior history of
preeclampsia, family history of preeclampsia, intervals of
more than 10 years between pregnancies, nulliparity, pre-
existing medical conditions like antiphospholipid syndrome,
type 1 or 2 diabetes mellitus, chronic kidney disease, chronic
hypertension, chronic autoimmune diseases like systemic
lupus erythematous (SLE), mother age more than 40 years,
BMI >35 kg/m2, multiple pregnancy, high BP in the first visit,
gestational trophoblastic disease, fetal triploidy (
Thus, infertility by itself is neither a major risk factor for HDs during pregnancy nor a major risk factor for preeclampsia.
Higher rates of HDs in women who underwent infertility
treatment might be due to higher age and/or increased
risk of multiple pregnancies. Also, pathologic basis of infertility
like polycystic ovaries and endometriosis, must
be considered as a cause of or in correlation with hypertension.
In these conditions, hypertension may simply occur
due to associated obesity or insulin resistance, androgen
excess, sympathetic nerve over activity and chronic
use of oral contraceptives
(
Furthermore, chronic hypertension can cause poor egg quality; also, many hypertensive women suffer from obesity which is mostly a result of excessive estrogen production which can lead to infertility. Antihypertensive medications like angiotensin receptor inhibitors (ARBs) and calcium channel blockers typically affect male fertility rather than female ones.
The most common medications which are used for
treatment of female infertility are clomiphene, metformin,
aromatase inhibitors like letrozole, human chorionic
gonadotropins (hCG) like menotropin, dopamine
agonists like bromocriptine and gonadotropin-releasing
hormone (GnRH) agonists like leuprolide which is used
in GnRH protocol and consists of progesterone and estradiol.
Among these, letrozole, leuprolide and estradiol
can induce hypertension with a prevalence rate of 5-8%
(
It is well known that estrogen-containing medications
can induce hypertension in premenopausal women, but
the mechanisms are not fully understood. Supraphysiologic
concentrations of estrogen and its effect on increment
of angiotensinogen and insulin-like growth factor
I production by liver, increased sympathetic activity and
increased expression of angiotensin subtype 1 (AT1) receptor
in the kidneys, are the possible mechanisms (
In recently published meta-analysis, it was shown that
metformin decreases BP specially systolic type, particularly
in nondiabetic cases (
Farland et al. (
We could not find any correlation between risk of hypertension and hCG administration after adjustment by higher chance of multiple pregnancy and other prevalent factors.
In a meta- analytic study which was done in Germany,
oocyte donation was also reported as a risk factor for
HDs in pregnancy and this effect was possibly mediated
through immunological processes and ovarian dysfunction
(
In 1994, Sealey et al. (
In a retrospective observational cohort, Hernández-Díaz
et al. (
Alternatively, in a prospective cohort study, Farland
et al. (
Meanwhile, Toshimitsu et al. (
So, it seems that we should be concerned about hypertension in all pregnancies particularly in women underwent infertility treatments.
BP measurement should be performed in all routine prenatal
visits and more frequently in high risk patients. According
to the last version of guideline of prenatal care,
pregnant women should be visited every 4 weeks up to
week 28, every 2 weeks thereafter until week 36 and then
weekly up to time of delivery (
Low salt diet is not advised, and consumption of calcium
or magnesium supplements, fish oil derivatives, vitamins,
antioxidants and garlic are also ineffective. No data
supports using heparin and nitric oxide (
In the first half of pregnancy, selected patients with pre-
existing hypertension may need to discontinue their antihypertensive
medications due to physiological drop in BP
during this period, however, close monitoring is mandatory.
New-onset hypertension during pregnancy is an indication
for assessing proteinuria for early diagnosis of preeclampsia and should be repeated weekly. Fetal growth should be
regularly monitored by ultrasonography (
Most of the patients with pre-existing hypertension
have mild-to-moderate increment in BP, thus physicians
are not much worried about cardiovascular complications
in this group. There are still scanty evidence about clinical
benefits of administration of drugs to subjects with mild
hypertension during pregnancy (
Last European Society of Hypertension/ European Society of Cardiology (ESH/ESC) guidelines approved a systolic BP of 140 mmHg or a diastolic BP of 90 mmHg as the thresholds for antihypertensive treatment in pregnant women with one of the following criteria: gestational hypertension (with or without proteinuria), pre-existing hypertension superimposed by gestational hypertension, symptomatic hypertension and subclinical hypertension associated with end-organ damage.
The ESH/ESC thresholds are a systolic BP of 150
mmHg and a diastolic BP of 95 mmHg in any other conditions
(
Unfortunately, none of the antihypertensive agents
could significantly reduce perinatal mortality (
Recommendations for the management of hypertension
Recommendations | Class of recommendation | Level of evidence |
---|---|---|
Non-pharmacological management for pregnant women with systolic BP of 140-150 mmHg or diastolic BP of 90-99 mmHg is recommended. | I | C |
In women with gestational hypertension or pre-existing hypertension superimposed by gestational hypertension or with hypertension and subclinical organ damage or symptoms at any time during pregnancy, initiation of drug treatment is recommended at a BP of 140/90 mmHg. In any other circumstances, initiation of drug treatment is recommended if SBP ≥150 mmHg or DBP ≥95 mmHg. | I | C |
Systolic BP ≥170 mmHg or diastolic BP ≥110 mmHg in a pregnant woman is an emergency, and hospitalization is recommended. | I | C |
Induction of delivery is recommended in gestational hypertension with proteinuria with adverse conditions such as visual disturbances, coagulation abnormalities, or fetal distress | I | C |
In preeclampsia associated with pulmonary edema, nitroglycerine given as an intravenous infusion, is recommended. | I | C |
In severe hypertension, drug treatment with intravenous labetalol or oral methyldopa or nifedipine is recommended. | I | C |
Women with pre-existing hypertension should be considered to continue their current medication except for ACE inhibitors, ARBs, and direct renin inhibitors under close BP-monitoring | IIa | C |
From: ESC Guidelines on the management of cardiovascular diseases during pregnancy (
BP; Blood pressure, SBP; Systolic blood pressure, DBP; Diastolic blood pressure, ACE; Angiotensin converting enzyme, and ARB; Angiotensin receptor blocker.
Oral antihypertensive drugs commonly used in pregnancy
Drug | Indication | FDA category | Initial dose | Maximum dose | Potential side effects |
---|---|---|---|---|---|
Methyldopa | Often used as first line | B | 125-250 mg BD | 500 mg QID | Lethargy |
Labetalol | Often used as first line | C | 100 mg BD | 200-400 mg QID | Exacerbation of asthma |
Nifedipine (immediate release) | Second line or alternative first line | C | 10-20 mg BD | 40 mg BD | Concern for synergy with magnesium sulfate for neuromuscular depression |
Modified from: Queensland Clinical Guideline: Hypertensive disorders of pregnancy (23) and Chronic Hypertension in Pregnancy (16). Category B; Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women, Category C; Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks, BD; Twice a day, and QID; Four times a day.
Severe hypertension is defined as BP ≥160/110 mmHg
or systolic BP ≥170 mmHg and diastolic BP ≥110
mmHg. It is a medical emergency which requires hospital
admission, rapid management and monitoring every
10 to 20 minutes depending on management strategy. In
a systematic review of cases with very high BP, published
from Cochrane library in 2013, 15 different antihypertensive
medications in 35 trials were compared
and the results showed that less persistent hypertension
was seen with calcium channel blockers than with hydralazine
and they also had less side effects compared to
labetalol (
Management of severe hypertension during pregnancy
Type of medication | Strategy |
---|---|
Hydralazine (IV) | 5 mg IV bolus, then 10 mg every 20-30 minutes to a maximum of 25 mg, repeat in several hours as necessary |
Labetalol (IV) | 20 mg IV bolus over 2 minutes, then 40 mg 10 minutes later, 80 mg every 10 minutes for two additional doses to a maximum of 220 mg |
Nifedipine (oral) (controversial) | 10 mg po, repeat every 20 minutes to a maximum of 30 mg |
Sodium nitroprusside (rarely used, usually when others fail) | 0.25 μg/kg/minutes to a maximum of 5 μg/kg/minutes IV infusion Fetal cyanide poisoning may occur if used for more than 4 hours |
Modified from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Committee Opinion No. 623. American College of Obstetricians and Gynecologists (
As a general agreement, diastolic BP should be kept
above 80 mmHg (
Uncontrolled severe hypertension is the most common
maternal reason for preterm childbirth. There are no definite
data for time of termination of pregnancy in patients
with chronic hypertension specially when BP is well controlled.
Delivery at term is suggested for cases with gestational
hypertension. Patients with milder forms of preeclampsia
can be observed up to gestational week 37 (
Rout of delivery should be determined as obstetric indication,
so vaginal delivery is the first choice (
Although all antihypertensive medications are secreted
in milk at very low levels, breast feeding is safe in hypertensive
mothers. Lower dosages of captopril and enalapril
are harmless. No adverse effect following administration
of calcium channel blockers has been seen, although there
are some controversies about nifedipine. Some references
also recommend not to use amlodipine. Diuretics are best
avoided as they potentially decrease milk production.
Beta blockers other than atenolol can be used safely (
Methyldopa should not be used in this period due to
some reports about the risk of post-natal depression (
BP commonly rises immediately over the first 5 days after
delivery (18.5% in a recent report) (
Women with a history of HDs during pregnancy, particularly when associated with early-onset pre-eclampsia,
premature labor before 32 weeks of gestation, stillbirth,
or IUGR are at high risk for developing cardiovascular
complications such as hypertension, stroke and ischemic
heart disease in later life. So, lifestyle modifications and
close screening for sign and symptoms of cardiovascular
diseases and also early detection of other risk factors are
highly suggested in these groups. Notably, risk of subsequent
hypertension or prehypertension in previously normotensive
women with a history of HDs in pregnancy, is
higher than others regardless of coincidence with gestational
diabetes, even during the first year postpartum (
In a subsequent pregnancy, mothers who experienced
hypertension in their first pregnancy are at greater risk
specially if it was early onset or associated with HELLP
syndrome. Although some other predictors like pre-pregnancy
plasma volume have been suggested for risk assessment
(
HDs of pregnancy are highly prevalent, so do infertility treatments. It seems that elevated BP is somehow more common in women who received infertility treatments. Since hypertension is associated with many short and also long-term comorbidities and even perinatal mortality, this group of patients should be particularly screened, treated and followed up for high BP, although the hypertension treatment is not markedly different from those given to fertile mothers.