{"paper_id":"41a7cbd7-bd75-4754-9a00-520e1463c71e","body_text":"Hypertensive disorders (HDs) are the most prevalent \nmedical problem during pregnancy. It is estimated that \nHDs involve up to 6-8% of all pregnancies ( 1 ). HDs account \nfor about 25% of all pre-birth hospital admissions \n( 2 ). It has been well-documented that hypertension plays \nan important role in development of atherosclerosis consequently \nleading to nonfatal or fatal myocardial infarction \nand cerebrovascular accidents. It has also been shown that \nhypertension is the main cause of perinatal and maternal \nmorbidity and mortality including intrauterine growth retardation \n(IUGR), Hemolysis, Elevated Liver enzymes, \nand Low Platelet count (HELLP) Syndrome, renal impairment, \npremature labor, neonatal intensive-care-unit \nadmission, caesarean section, placental abruption, perinatal \ndeath and maternal convulsion ( 3 - 5 ).\nIn a recent retrospective study done in Ethiopia, Seyom \net al. ( 6 ) reported rate of dead fetus, low birth weight and \nlow APGAR score, abortion, preterm delivery and HELLP \nsyndrome as 10.2, 30.5, 18.5, 10.7, 31.4 and 12.4%, respectively \nin 55,860 pregnant women with HDs.\nZibaeenezhad et al. ( 7 ) found a prevalence of 2.32% for \nHDs in pregnant women in south of Iran including a prevalence \nof 2.13% for chronic hypertension. Moreover, Khosravi \net al. ( 8 ) reported a prevalence of 9.8% for HDs among \npregnant women who were admitted to a tertiary center in \nTehran for delivery. So, the disease is also prevalent in Iran.\nInfertility is also a common condition and physicians \nare deeply concerned about it, because it involves a couple, \nrather than a single individual. It is defined as inability \nof a couple to conceive after one year of regular intercourse \nwithout using any form of contraception ( 9 ).\nThe prevalence of infertility is markedly high in Eastern \nEurope, North Africa, Oceania and sub Saharan Africa \n( 10 ). The main causes of infertility include male factors, \ndecreased ovarian reserve, ovulatory factors, tubal \nfactors, uterine factors, pelvic factors, and unexplained \nreasons ( 11 ).\nOnce the pathologic basis of infertility is recognized, \ntherapy is directed toward curing reversible causes and \nmodifying irreversible etiologies. Therapeutic interventions \nfor both male and female infertility includes drug \ntherapy ( 12 ) and surgery ( 13 ), with or without procedures \nlike intra uterine insemination (IUI) or in vitro fertilization \n(IVF) ( 14 ,  15 ).\nWe searched PubMed and Google search engines for \nincidence of hypertension and also history of infertility in \npregnant women. We also checked the internet for causes \nof female infertility and their association with hypertension, \nall kinds of treatments and medications that are applied \nfor female infertility and the chance and the mechanisms \nby which they changing blood pressure (BP). Then \nwe quested for general considerations, treatment modalities \nand follow-up in pregnant cases with HDs, with or \nwithout a history of infertility.\nPhysiological blood pressure changes during pregnancy \nNormotensive women usually experience about 5 to 10 \nmmHg fall in their BP starting from the first trimester \nwhich may be continued up to the third trimester; after \nthat, BP is restored to its preconception level ( 16 ). This \nis due to marked vasodilation which can overcome the \nincrement of blood volume in this period. This phenomenon \ncan also induce normal BP in cases with mild chronic \nhypertension which results in reduction in dose or discontinuation \nof antihypertensive medications or even masking \npreviously undiagnosed cases.\nHypertension is generally labeled when systolic BP is\n≥140 mmHg and/or diastolic BP is ≥90 mmHg, according \nto the mean of at least two measurements, checked using \nthe same arm with at least fifteen minutes intervals, in \nclinic or in hospital ( 17 ).\nAlthough the definition of HDs \nis somewhat different in some references and defined only \nwhen diastolic BP is greater than 90 mmHg on two sessions \nwith more than 4 hours interval or when a single \ndiastolic BP >110 mmHg was recorded ( 18 ). BP should \nbe measured in the sitting position while the arm is at the \nlevel of the heart, using a cuff of appropriate size. Mild \nhypertension is defined as a diastolic BP of 90-99 mmHg \nand/ or a systolic BP of 140-149 mmHg. Severe hypertension \nis defined as a systolic BP of ≥160 mmHg or a \ndiastolic BP of ≥110 mmHg. Obviously, moderate hypertension \nranges between mild and moderate values ( Table 1 ) ( 17 ,  19 ,  20 ).\nGrading of severity of hypertension and the need for antihypertensive treatment\n*; 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 ( 20 ).\nHDs are classified into four major groups according \nto working group of National Institutes of Health (NIH) \nreport on high BP in pregnancy ( 3 ): i. Chronic or pre-\nexisting hypertension diagnosed either before pregnancy \nor earlier than 20 gestational weeks, ii. Preeclampsia-\neclampsia. Preeclampsia described as the presence of \nhypertension, along with new-onset of significant proteinuria \nof >0.3 g/24 hours. However, there are some \nother definitions in other references which are more precise \nand complete, iii. Preeclampsia superimposed on \nchronic hypertension, and iv. Gestational hypertension \nis defined as a hypertension beginning at later than 20 \ngestational weeks and can persist for up to 42 days post-\npartum.\nIt has also been mentioned that gestational hypertension \nusually resolves within up to 12 weeks post-partum however \nthis is not applicable for cases with chronic hypertension \n( 21 ).\nRisk factors for chronic hypertension are: early middle \nage or about age 45, black race, using tobacco, too much \nsalt (sodium) in diet, too little potassium, calcium or vitamin \nD in diet, drinking too much alcohol, high levels \nof stress, being overweight or obese, little or no exercise, \nhistory of high BP in the family ( 22 ). Certain chronic conditions \nalso may increase the risk of high BP, such as kidney \ndisease, diabetes and sleep apnea.\nRisk factors for preeclampsia include: prior history of \npreeclampsia, family history of preeclampsia, intervals of \nmore than 10 years between pregnancies, nulliparity, pre-\nexisting medical conditions like antiphospholipid syndrome, \ntype 1 or 2 diabetes mellitus, chronic kidney disease, chronic \nhypertension, chronic autoimmune diseases like systemic \nlupus erythematous (SLE), mother age more than 40 years, \nBMI >35 kg/m2, multiple pregnancy, high BP in the first visit, \ngestational trophoblastic disease, fetal triploidy ( 23 ,  24 ).\nThus, infertility by itself is neither a major risk factor \nfor HDs during pregnancy nor a major risk factor for \npreeclampsia.\nHigher rates of HDs in women who underwent infertility \ntreatment might be due to higher age and/or increased \nrisk of multiple pregnancies. Also, pathologic basis of infertility \nlike polycystic ovaries and endometriosis, must \nbe considered as a cause of or in correlation with hypertension. \nIn these conditions, hypertension may simply occur \ndue to associated obesity or insulin resistance, androgen \nexcess, sympathetic nerve over activity and chronic \nuse of oral contraceptives\n( 25 ,  26 ).\nFurthermore, chronic hypertension can cause poor egg \nquality; also, many hypertensive women suffer from obesity \nwhich is mostly a result of excessive estrogen production \nwhich can lead to infertility. Antihypertensive \nmedications like angiotensin receptor inhibitors (ARBs) \nand calcium channel blockers typically affect male fertility \nrather than female ones.\nThe most common medications which are used for \ntreatment of female infertility are clomiphene, metformin, \naromatase inhibitors like letrozole, human chorionic \ngonadotropins (hCG) like menotropin, dopamine \nagonists like bromocriptine and gonadotropin-releasing \nhormone (GnRH) agonists like leuprolide which is used \nin GnRH protocol and consists of progesterone and estradiol. \nAmong these, letrozole, leuprolide and estradiol \ncan induce hypertension with a prevalence rate of 5-8% \n( 27 - 29 ),\n8% ( 30 ) and 3-7%\n( 31 ), respectively. Although \nbromocriptine usually causes vasodilatation and specially \nedema thereafter, there are some case reports on bromocriptine-\ninduced hypertension ( 32 ).\nIt is well known that estrogen-containing medications \ncan induce hypertension in premenopausal women, but \nthe mechanisms are not fully understood. Supraphysiologic \nconcentrations of estrogen and its effect on increment \nof angiotensinogen and insulin-like growth factor \nI production by liver, increased sympathetic activity and \nincreased expression of angiotensin subtype 1 (AT1) receptor \nin the kidneys, are the possible mechanisms ( 33 ).\nIn recently published meta-analysis, it was shown that \nmetformin decreases BP specially systolic type, particularly \nin nondiabetic cases ( 34 ).\nFarland et al. ( 35 ) reported relative risk of hypertension \nin infertile women receiving different kinds of treatments, \nas follows: clomiphene: relative risk (RR)=0.97, \nconfidence interval (CI): 0.90-1.04; gonadotropin alone: \nRR=0.97, CI: 0.87-1.08, IUI: RR=0.86, CI: 0.71-1.03, \nIVF: RR=0.86, CI: 0.73-1.01.\nWe could not find any correlation between risk of hypertension \nand hCG administration after adjustment by \nhigher chance of multiple pregnancy and other prevalent \nfactors.\nIn a meta- analytic study which was done in Germany, \noocyte donation was also reported as a risk factor for \nHDs in pregnancy and this effect was possibly mediated \nthrough immunological processes and ovarian dysfunction \n( 36 ).\nIn 1994, Sealey et al. ( 37 ) revealed that renin and urinary \naldosterone excretion had 5-fold increases during \nthe luteal phase (day 7) in patients who underwent ovarian \nstimulation. Alternatively, Tollan et al. ( 38 ) showed a \nstatistically significant decrement in both systolic and diastolic \nBP during ovarian stimulation for IVF, most probably \ndue to decreased level of adrenalin.\nIn a retrospective observational cohort, Hernández-Díaz \net al. ( 39 ) interviewed 5151 women within six months of \ndelivery and stated that the incidence of gestational hypertension \nwas significantly greater in women with a history \nof infertility who were treated for this problem (15.8%) \nthan among those infertile cases who did not receive such \nmanagements (8.9%). Results were the same for patients \nwith preeclampsia and also after adjustment for age, twin \npregnancy, parity and body mass index. There were some \ncases without a history of infertility treatments who mentioned \nsome difficulties in fertility in past or untreated \nsub-fertility in the present pregnancy. Surprisingly, these \nwomen were not at increased risk of hypertension and this \nfinding demonstrates the direct role of infertility treatment \nin induction of hypertension. All kinds of infertility treatment \napproaches or drugs were associated with a similar \nincreased risk, although not unexpectedly, treatments \nwith the greatest chance of multiple gestations, were associated \nwith higher risk of HDs.\nAlternatively, in a prospective cohort study, Farland \net al. ( 35 ) included 116,430 women and followed them \nfor 20 years to assess the risk of development of hypertension \nin later life. Among them, 12,183 received \nsome kinds of infertility treatment. During follow-up, \napproximately 20,066 women were diagnosed with hypertension. \nThe authors emphasized that only infertility \ndue to tubal causes was accompanied by greater risk of \nhypertension as these cases had 15% greater risk of hypertension \nthan women without a history of infertility. \nBut among other causes of infertility, no clear relation \nwas detected between receiving fertility treatment and \nsubsequent hypertension.\nMeanwhile, Toshimitsu et al. ( 40 ) showed that the incidence \nof HDs was significantly higher in infertile couples \nwith IVF/intracytoplasmic sperm injection conception \nthan the spontaneous conception group in both the \nwomen aged ≥40 years (20.5 vs. 7.9%) and those aged \n30-34 years (14.3 vs. 2.6%). However, gestational diabetes \nmellitus, premature birth, or low birth weight were not \ndifferent between these two groups.\nSo, it seems that we should be concerned about hypertension \nin all pregnancies particularly in women underwent \ninfertility treatments.\nBP measurement should be performed in all routine prenatal \nvisits and more frequently in high risk patients. According \nto the last version of guideline of prenatal care, \npregnant women should be visited every 4 weeks up to \nweek 28, every 2 weeks thereafter until week 36 and then \nweekly up to time of delivery ( 41 ). If HDs were diagnosed, \nthen BP should be checked weekly in milder forms \nand no association with preeclampsia, or twice and four \ntimes a week in moderate and severe forms, respectively \n( 24 ).\nLow salt diet is not advised, and consumption of calcium \nor magnesium supplements, fish oil derivatives, vitamins, \nantioxidants and garlic are also ineffective. No data \nsupports using heparin and nitric oxide ( 18 ,  42 ). Weight \nreduction is not recommended. Moderate activity is suggested \nfor patients with well-controlled chronic hypertension \nand it seems that there is no increase in incidence of \npreeclampsia in this group. If preeclampsia occurs, some \nphysical activity restrictions may be required although it \ndoes not change maternal or fetal outcome ( 43 ). Bedtime \nlow-dose aspirin (75-100 mg/day) should be started and \ncontinued until delivery to prevent preeclampsia although \nit has neutral effect on perinatal and maternal morbidity \n( 17 ,  44 ). No evidence supports administration of dipyridamole \n( 18 ).\nIn the first half of pregnancy, selected patients with pre-\nexisting hypertension may need to discontinue their antihypertensive \nmedications due to physiological drop in BP \nduring this period, however, close monitoring is mandatory. \nNew-onset hypertension during pregnancy is an indication \nfor assessing proteinuria for early diagnosis of preeclampsia and should be repeated weekly. Fetal growth should be \nregularly monitored by ultrasonography ( 24 ).\nMost of the patients with pre-existing hypertension \nhave mild-to-moderate increment in BP, thus physicians \nare not much worried about cardiovascular complications \nin this group. There are still scanty evidence about clinical \nbenefits of administration of drugs to subjects with mild \nhypertension during pregnancy ( Table 1 ) ( 45 ). Sometimes \nthese patients should be hospitalized for at least a short \nperiod of time for confirmation of diagnosis and risk stratification \nspecially for ruling out or ruling in preeclampsia \nfor which the only effective treatment is termination of \npregnancy.\nLast European Society of Hypertension/ European Society \nof Cardiology (ESH/ESC) guidelines approved a \nsystolic BP of 140 mmHg or a diastolic BP of 90 mmHg \nas the thresholds for antihypertensive treatment in pregnant \nwomen with one of the following criteria: gestational \nhypertension (with or without proteinuria), pre-existing \nhypertension superimposed by gestational hypertension, \nsymptomatic hypertension and subclinical hypertension \nassociated with end-organ damage.\nThe ESH/ESC thresholds are a systolic BP of 150 \nmmHg and a diastolic BP of 95 mmHg in any other conditions \n( Table 2 ) ( 43 ,  46 ).\nUnfortunately, none of the antihypertensive agents \ncould significantly reduce perinatal mortality ( 45 ). \nContinuation of current medication except for angiotensin-\nconverting enzyme (ACE) inhibitors, ARBs, \nand direct renin inhibitors may be the best strategy in \ncases with pre-existing hypertension. Drug of choice is \na-Methyldopa and labetalol shows comparable efficacy. \nCalcium channel blockers like nifedipine are drugs \nof second choice ( 17 ,  47 ). Dosages are stated in Table 3. Generally, diuretics should be avoided in all kinds \nof HDs as they may theoretically decrease placental \nblood flow ( 46 ); however, thiazides are mentioned as \nthe second line therapy in some references ( 43 ,  48 ) as \ntheir teratogenicity or adverse effects have not been extensively \nstudied ( 45 ). Mineralocorticoid receptor antagonists \nshould never be prescribed ( 43 ). Nowadays, \nhydralazine is used only in hypertensive urgencies in \nintravenous form, although its chronic oral use showed \nno adverse effect. Prazosin and atenolol are no more \nrecommended during pregnancy ( 17 ).\nRecommendations for the management of hypertension\nFrom: ESC Guidelines on the management of cardiovascular diseases during pregnancy ( 46 ).\nBP; Blood pressure, SBP; Systolic blood pressure, DBP; Diastolic blood pressure, ACE; Angiotensin converting enzyme, and ARB; Angiotensin receptor blocker.\nOral antihypertensive drugs commonly used in pregnancy\nModified 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.\nSevere hypertension is defined as BP ≥160/110 mmHg\nor systolic BP ≥170 mmHg and diastolic BP ≥110 \nmmHg. It is a medical emergency which requires hospital \nadmission, rapid management and monitoring every \n10 to 20 minutes depending on management strategy. In \na systematic review of cases with very high BP, published \nfrom Cochrane library in 2013, 15 different antihypertensive \nmedications in 35 trials were compared \nand the results showed that less persistent hypertension \nwas seen with calcium channel blockers than with hydralazine \nand they also had less side effects compared to \nlabetalol ( 50 ). The most popular plan is to start treatment \nwith intravenous labetalol or oral nifedipine as soon as \npossible ( Table 4 ) ( 49 ). Intravenous hydralazine is not \nthe first choice according to some references ( 46 ) while \nthere are references suggesting it as medication of first \nchoice ( 48 ,  49 ). The optimal drug in hypertensive crises \ncan be sodium nitroprusside. Intravenous magnesium \nsulfate is the preferable drug only for management of \nseizures and/or preventing eclampsia in selective cases \nof severe preeclampsia ( 46 ). If recurrent seizures occurred, \nalternative anticonvulsants like benzodiazepines, \nsuch as lorazepam and diazepam, phenytoin (Dilantin), \nand levetiracetam can be started ( 51 ).\nManagement of severe hypertension during pregnancy\nModified 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 ( 48 ,  49 ).\nAs a general agreement, diastolic BP should be kept \nabove 80 mmHg ( 19 ). The American College of Obstetrics \nand Gynecology (ACOG) recommended to maintain \nBP between 120/80 and 160/105 mm Hg in pregnant \nwomen with HDs with no complications ( 52 ). Clinical \npractice guidelines of the Society of Obstetricians and \nGynecologists of Canada emphasize that systolic BP \nof 130-155 mmHg and diastolic BP of 80-105 mmHg \nshould be achieved in patients without any comorbidities \nand systolic BP of 130-139 mmHg and diastolic pressure \nof 80-89 mmHg are the goal BPs in cases with comorbidities \nlike diabetes mellitus ( 53 ). According to a recent \nsystematic review of patients with non -severe hypertension, \ntarget BP is variable and obviously dependent on the \ntype of HDs in pregnancy and presence or absence of co-\nmorbidities ( 1 ). So, if any form of end-organ dysfunction \nlike left ventricular hypertrophy, chronic kidney disease \nand hypertensive retinopathy exists, the target BP would \nbe 140/90 mmHg ( 5 ,  17 ,  20 ). In cases with no end-organ \ndamages, target BP would be different. Accordingly in \nany form of HDs, the target is BP of 150/80-100 mmHg \n( 5 ,  20 ), 130-159/80-105 mmHg ( 17 ), or, 160/110 mmHg, \nin patients with chronic hypertension, it would be120-\n159/80-104 mmHg and at last in women with gestational \nhypertension or non-severe preeclampsia, the goal of BP \nis defined as 160/110 mmHg ( 54 ).\nUncontrolled severe hypertension is the most common \nmaternal reason for preterm childbirth. There are no definite \ndata for time of termination of pregnancy in patients \nwith chronic hypertension specially when BP is well controlled. \nDelivery at term is suggested for cases with gestational \nhypertension. Patients with milder forms of preeclampsia \ncan be observed up to gestational week 37 ( 17 ). \nAlthough the amount of proteinuria is not an important \nfactor ( 43 ), severe preeclampsia and eclampsia necessitate \nurgent termination of pregnancy. Some cases with \nsevere preeclampsia at low gestational age, can be closely \nobserved for up to 34 weeks of pregnancy for better prognosis \nfor child ( 23 ). In a recent study, adverse perinatal \noutcome of postponing delivery to later than 39 weeks \nof gestation ( 55 ) was shown; probably the best time for \ndelivery in gestational hypertension is between weeks 38 \nand 39 ( 56 ).\nRout of delivery should be determined as obstetric indication, \nso vaginal delivery is the first choice ( 43 ). If vaginal \ndelivery is planned, then active managing of the third \nstage of labor with oxytocin is recommended ( 17 ).\nAlthough all antihypertensive medications are secreted \nin milk at very low levels, breast feeding is safe in hypertensive \nmothers. Lower dosages of captopril and enalapril \nare harmless. No adverse effect following administration \nof calcium channel blockers has been seen, although there \nare some controversies about nifedipine. Some references \nalso recommend not to use amlodipine. Diuretics are best \navoided as they potentially decrease milk production. \nBeta blockers other than atenolol can be used safely ( 16 , \n 17 ,  23 ,  24 ,  43 ).\nMethyldopa should not be used in this period due to \nsome reports about the risk of post-natal depression ( 23 ), \nso must be discontinued within 2 days postpartum if has \nbeen prescribed during pregnancy ( 19 ,  24 ).\nBP commonly rises immediately over the first 5 days after \ndelivery (18.5% in a recent report) ( 57 ). Patients with \nHDs during pregnancy may become normotensive after \nlabor but then becomes hypertensive in the first week.\nWomen with a history of HDs during pregnancy, particularly when associated with early-onset pre-eclampsia, \npremature labor before 32 weeks of gestation, stillbirth, \nor IUGR are at high risk for developing cardiovascular \ncomplications such as hypertension, stroke and ischemic \nheart disease in later life. So, lifestyle modifications and \nclose screening for sign and symptoms of cardiovascular \ndiseases and also early detection of other risk factors are \nhighly suggested in these groups. Notably, risk of subsequent \nhypertension or prehypertension in previously normotensive \nwomen with a history of HDs in pregnancy, is \nhigher than others regardless of coincidence with gestational \ndiabetes, even during the first year postpartum ( 58 ).\nIn a subsequent pregnancy, mothers who experienced \nhypertension in their first pregnancy are at greater risk \nspecially if it was early onset or associated with HELLP \nsyndrome. Although some other predictors like pre-pregnancy \nplasma volume have been suggested for risk assessment \n( 59 ), they are not clinically relevant ( 60 ).\n\nHDs of pregnancy are highly prevalent, so do infertility \ntreatments. It seems that elevated BP is somehow more \ncommon in women who received infertility treatments. \nSince hypertension is associated with many short and also \nlong-term comorbidities and even perinatal mortality, this \ngroup of patients should be particularly screened, treated \nand followed up for high BP, although the hypertension \ntreatment is not markedly different from those given to \nfertile mothers.","source_license":"CC-BY-4.0","license_restricted":false}