kontrasepsi and medical disease

8/6/2019 Kontrasepsi and Medical Disease

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The clinical content of preconception care:

women with chronic medical conditionsAnne L. Dunlop, MD, MPH; Brian W. Jack, MD; Joseph N. Bottalico, DO; Michael C. Lu, MD, MS, MPH;

Andra James, MD, MPH; Cynthia S. Shellhaas, MD, MPH; Lynne Haygood-Kane Hallstrom, DO, CNM, MS;

Benjamin D. Solomon, MD; W. Gregory Feero, MD, PhD; M. Kathryn Menard, MD, MPH; Mona R. Prasad, DO, MPH

Preconception care includes the de-tection and optimal control of spe-

cific medical conditions to optimizepregnancy-related outcomes for thewoman and her offspring. The increasedrate of pregnancy by women age 35 yearsand older has led to an increase in theproportion of women with chronic dis-eases upon conception.1 To inform re-productive decision making, women

with medical conditions should be pre-sented with information with regard tothe risk of pregnancy complications andmaternal morbidity and mortality givenpregnancy, disease prognosis irrespec-tive of pregnancy, whether there are con-flicts between maternal treatment andfetal well-being, the extent of risk thecondition or medications used to treatthe condition place on the fetus, optimal

timing of pregnancy (if desired), and the

woman’s ability to conceive at present

and in the future. Possible preconception

care strategies for women with medical

conditions might include optimizing dis-

ease control in preparation for pregnancy,

changing a potentially teratogenic treat-

ment regimen to one that is safer for the

fetus,andprovisionoffamilyplanningser-

vices to delay or avoid pregnancy.2

Experts consider that preconception

care should be provided in the context of

well-woman and/or chronic disease

care3-5 rather than as an isolated precon-

ception care visit by women who are

planning a pregnancy because most

components can be embedded in the

process of primary and preventive

care.6,7 Furthermore, the integrated ap-

proach recognizes that a large propor-

tion of women would be missed by pre-

From the Department of Family and Preventive Medicine, Emory University School of Medicine, Atlanta, GA (Dr Dunlop); Department of

Family Medicine, Boston University Medical Center, Boston, MA (Dr Jack); Division of Maternal-Fetal Medicine, Department of Obstetrics

and Gynecology, University of Medicine and Dentistry of New Jersey School of Osteopathic Medicine, Stratford, NJ (Dr Bottalico);

Department of Obstetrics and Gynecology and Community Health Sciences, University of California, Los Angeles, Schools of Public Medicine

and Public Health, Los Angeles, CA (Dr Lu); Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke

University Medical Center, Durham, NC (Dr James); Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The

Ohio State University College of Medicine (Drs Shellhaas and Prasad) and Bureau of Child and Family Health Services, State of Ohio (Dr

Shellhaas), Columbus, OH; Department of Obstetrics and Gynecology, Tulane University, New Orleans, LA (Dr Hallstrom); National

Human Genome Project Research Institute, National Institutes of Health, Bethesda, MD (Drs Solomon and Feero); and Department of

Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC (Dr Menard).

Received June 17, 2008; accepted Aug. 8, 2008.

Reprints: Anne Dunlop MD, MPH, Department of Family and Preventive Medicine, Emory University School of Medicine, 1256 Briarcliff Road, Building A, Suite 238, Atlanta, GA 30322. [email protected].

This work was supported in part by the National Human Genome Research Institute, National Institutes of Health.

Conflict of Interest: Anne L. Dunlop, MD, MPH; Brian W. Jack, MD; Michael C. Lu, MD, MS, MPH; Andra James, MD, MPH; Cynthia S. Shellhaas,MD, MPH; Lynne Haygood-Kane Hallstrom, DO, CNM, MS; Benjamin D. Solomon, MD; W. Gregory Feero, MD, PhD; and M. Kathryn Menard, MD,MPH have no conflict of interest including grants, honoraria, advisory board membership, or share holdings. Joseph N. Bottalico, DO, is a member of the CDC Select Panel on Preconception Care, a voluntary unpaid position in which he represents the American College of Osteopathic Ob-Gyn andthe American Osteopathic Assn (no known conflict). He is also an (appointed, unpaid) volunteer member of the NJ DHSS Diabetes Advisory Council,also without conflict. With the New Jersey Chapter of the March of Dimes, he is a member of the annual conference planning committee (no knownconflict) and has received one honorarium from the March of Dimes jointly with the Johnson and Johnson foundation (New Brunswick, NJ) for a grandrounds presentation on preconception care presented to the OB-Gyn Dept at UMDNJ-SOM in December 2007. He sits on the regional MCHconsortium’s BOD (Southern NJ Perinatal Cooperative) and chairs their Clinical/QA committee which also presents no known conflicts. Mona R.Prasad, DO, MPH is the recipient of a $25,000 service grant from the March of Dimes for the year 2008.

0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2008.08.031

This article reviews the medical conditions that are associated with adverse pregnancyoutcomes for women and their offspring. We also present the degree to which specificpreconception interventions and treatments can impact the effects of the condition onbirth outcomes. Because avoiding, delaying, or achieving optimal timing of a pregnancyis often an important component of the preconception care of women with medicalconditions, contraceptive considerations particular to the medical conditions are alsopresented.

Key words: chronic, medical condition, preconception

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S310 American Journal of Obstetrics& Gynecology Supplement to DECEMBER 2008

mailto:[email protected]





conception care strategies if suchstrategies were not systematically deliv-ered as part of women’s health care be-cause approximately half of pregnanciesareunintended,and even those who plantheirpregnanciesmightnotdosoincon-

junction with theirhealthcare providers.There are several medical conditionsfor which there is a link to adverse preg-nancy outcomes for women and theiroffspring as well as evidence that the ef-fect of the condition can have an impactby preconception care. These conditionswill be reviewed in this manuscript. Be-cause avoiding, delaying, or achievingoptimal timingof a pregnancy is often animportant component of the preconcep-tion care of women with medical condi-

tions, contraceptive considerations par-ticular to the medical conditions are alsopresented

Diabetes mellitus

Burdenof suffering

The National Ambulatory Medical CareSurvey 8 demonstrated that diabetes af-fects approximately 1.85 million (21 per1000) women in the United States aged18-44 years. In 2002, 9.3% of women of reproductive age had known diabetes.1

Whereas approximately 1% of pregnan-cies in the United States are complicatedby pregestational diabetes (predomi-nately type 2),9 gestational diabetes(GDM) occurs in approximately 7% of pregnancies, with rates varying from 1%to 14%.10 Given the high recurrence rateof GDM (30-84%) in subsequent preg-nancies,11,12 as well as the increased rateof subsequent type 2 diabetes and meta-bolic syndrome with a past history of GDM,13,14,15,16 attention to prediabetic

risk factors between pregnancies is rea-sonable, especially in those women whoare also obese.

The prevalence of risk factors for dia-betes mellitus is increasing in the UnitedStates. Based on 2005-2006US data fromthe National Health and Nutrition Ex-amination Survey (NHANES),17 30.5%of women aged 20-39 years were obese(body mass index [BMI] 30 kg/m2).The Healthy People 2010 objective of anobesity prevalence of less than 15% has

not been met for women (or men) of any age. An increased prevalence of obesity

in US adolescents has also been docu-mented and is associated with declininglevels of physical activity.18

The links between obesity, insulin re-sistance, and type 2 diabetes mellitus arewell known. An association between

obesity and elevated risk of GDM is alsoprobable. Data are not readily availablefor US reproductive-age females with re-gard to the prevalence of prediabetes;however, increasing overweight, obesity,and ethnicity trends suggest that a rise inprevalence may be occurring. Thesepopulation trends may also be contrib-uting to a rising prevalence of GDM.Obesity alone increases the risk of preg-nancy complications such as hyperten-sion, large babies, birth trauma, and ce-

sarean section. More recently, it has alsobeen found that the offspring of obeseand overweight women, independent of diabetes, have an increased risk of con-genital malformations and that obesity and diabetes contribute to birth defectssynergistically.19

Major congenital malformations areamong the leading causes of perinatalmortality in pregnancies complicated by pregestational (type 1 or type 2) diabetes.Whereas the risk of malformations in the

general population is 2-3%, reportedrates of malformations in pregnanciescomplicated by pregestational diabetesvary from 3% to 8% to 6-12%, and riskvaries directly with preconception andfirst-trimester glycemic control.20, 21 Therisk of spontaneous abortion is also re-lated to glycemic control in the first tri-mester.22 Although virtually any organsystem can be affected, the most charac-teristic congenital anomalies include sa-cral agenesis, complex cardiac defects,

spina bifida, and anencephaly. Thesemalformations occur during the criticalperiod of fetal organogenesis, approxi-mately 5-8 weeks after the last menstrualperiod.23,24

How detectable is the condition?

Screening tests for diabetes have beenwell validated and are widely utilized. Al-though recommended by the AmericanDiabetes Association and the AmericanCollege of Obstetricians and Gynecolo-

gists, the rate of post partum rescreeningafter GDM is suboptimal andreportedto

be less than 50% in 1 study. 25 Testing todetect prediabetes and type 2 diabetes inasymptomatic women should be consid-ered in adults who are overweight (BMI

25 kg/m2) orobese (BMI 30 kg/m2)and who have 1 or more additional risk

factors f or diabetes, including a history of GDM.26

How effective are the

current treatments?

Preconception control of diabetes re-duces the risk of congenital malforma-tions.27 Lifestyle modification withweight reduction and exercise has beenshown to reduce the risk of progressionfrom prediabetes to diabetes.28-30 Al-though oral antidiabetic agents are

widely prescribed for women with type 2diabetes and polycystic ovary syndrome,insulin is the preferred treatment forwomen who are planning a pregnancy.Because angiotensin-converting enzymeinhibitors, statins, and angiotensin re-ceptor blockers are also commonly pre-scribed for women with pregestationaldiabetes and because these drugs presentrisks in pregnancy, modification of drugtherapy in the preconception period isimportant.

Impact of preconception care

The National Ambulatory Medical CareSurvey 8 demonstrated that preconcep-tion diabetes control has the potential toreduce the risk of pregnancy loss andcongenital malformation for approxi-mately 113,000 births each year. Im-proved control of maternal glucose andantepartum fetal surveillance has led to asignificant reduction in the perinatalmortality rate in pregnancies compli-

cated by diabetes.

9,20,31

The increasedrate of congenital malformations in in-fants born to mothers with pregesta-tional diabetes is significantly reducedwhen women maintain good blood glu-cose control during the critical period of organogenesis. Several clinical studieshave demonstrated that diabetic womenwho seek medical care before pregnancy and who have good glycemic control atthe time of conception reduce their riskof having a fetus with major malforma-

tions to nearly that of the nondiabeticpopulation.27,32 Glycosylated hemoglo-

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Supplement to DECEMBER 2008 American Journal of Obstetrics& Gynecology S311



bin levels correlate directly with the fre-quency of congenital anomalies. Hemo-globin A1C levels should be as close tonormal as possible ( 7%) before con-ception is attempted.20,26,33

Contraception is important for

women who chose not to have a preg-nancy and for helping women achieveoptimal timing of pregnancy in relationto the optimal control of their condition.There is a theoretical concern that hor-monal contraceptives may increase insu-linresistance in womenwho are diabetic.In its Medical Eligibility Criteria forContraceptive Use, the World HealthOrganization(WHO) asserts that the ad-vantages of contraception—includinglow-dose combination contraceptives

(oral, injectable, vaginal ring, or skinpatch formulations) and all forms of progesterone-only contraceptives (oral,injectable, implantable formulationsoutweigh therisks of insulin resistance indiabetic women, except for those withvascular disease or diabetes for morethan 20 years.34 FDA labeling on theCooper T380A intrauterine device (FEIProducts, Tonawanda, NY) lists diabetesas a contraindication f or useduetocom-promised immunity;35 however, the

WHO lists the Copper T380A as a rec-ommended method for women with di-abetes, with a caution that a woman withdiabetes on insulin may be at higher riskof method failure.34

Recommendations

by other groups

The American Diabetes Association andthe American Collegeof Obstetricians andGynecologists have developed clinicalpractice guidelines for care before preg-

nancy for women with diabetes.

9,26,33

Recommendation. All women of re-productive age with diabetes should becounseled about the importance of dia-betes control before pregnancy. Impor-tant preconception counseling topicsinclude maximizing glucose control;self-monitoring of blood glucose; main-taining optimal weight; evaluation forvascular complications; modification of drug treatment if conception is plannedor likely; a regular exercise program; to-

bacco, alcohol, and substance abuse ces-sation; and social support to assist dur-

ing the pregnancy. In the months beforepregnancy, these women should demon-strate as near-normal glycosylated he-moglobin as possible for the purpose of decreasing the rate of congenital anom-alies and spontaneous abortion. Those

with suboptimal control of their diabetesshould be encouraged to use effectivebirth control. Strength of recommenda-

tion: A; quality of evidence: I.Testing to detect prediabetes and type 2

diabetes in asymptomatic women shouldbe considered in adults who are over-weight or obese (BMI 25 kg/m2) andwho have 1 or more additional risk factorsfor diabetes including a history of GDM.Strength of recommendation: B.

Women with GDM should be re-

screened 6-12 weeks postpartum.Strength of recommendation: E.

Thyroid disease

Burden of suffering

Thyroid disease is the second most com-mon endocrine disease that affectswomen of reproductive age.36 Hyperthy-roidism occursin approximately 0.2% of all pregnancies, with the most commoncause being Graves’ disease (95%).37 Theincidenceof maternal andneonatalmor-

bidity is significantly higher in patientswhose hyperthyroidism is not medically controlled.

The causes of maternal morbidity in-clude a higher incidence of preeclamp-sia, congestive heart failure, thyroid cri-sis, and placental abruption. The causesof neonatal morbidity include fetalgrowth restriction, low birthweight, pre-term birth, and stillbirth, as well as neo-natal immune-mediated hypo- or hy-perthyroidism. Maternal and fetal

outcome is directly related to the controlof hyperthyroidism.37 Women whosethyroid glands have been ablated forGraves’ disease might have circulatingthyroid-stimulating antibodies that caninduce thyrotoxicosis in their fetuses.38

Overt hypothyroidism, a low free thy-roxine level, and an elevated thyroidstimulating hormone (TSH) occurs inapproximately 2.5% of all pregnancies inthe United States.39,40 Subclinical hypo-thyroidism, a normal free thyroxine with

an elevated TSH, may be somewhatmore common, with a prevalence of

2-5% in pregnant women.39,41,42 Fur-thermore, a large cross-sectional study found that, among patients with hypo-thyroidism taking thyroid medication,only 60% were within the normal rangeof TSH.42

It is well established that overt hypothy-roidism, particularly during the first tri-mester, is associated with intellectual im-pairment of the offspring as well aspregnancy complicationsincluding hyper-tension and preeclampsia, placental ab-ruption, anemia, postpartum hemor-rhage, preterm birth, low birthweight, andfetal death.44,45 More recently studies haveshown that subclinical hypothyroidismduring pregnancy is also associated withimpaired psychomotor development of

offspring as well as an increased risk of poor pregnancy outcomes such as placen-tal abruption, preterm birth, low birth-weight, and stillbirth.40,43-48


current treatments?

Both hyper- and hypothyroidism arehighly treatable conditions, with the spe-cific treatment varying according to thediagnosis. Clinical practice guidelinesfor treating patients with hyper- and hy-

pothyroidism exist.

49


There is strong evidence that treatmentof thyroid conditions improves preg-nancy outcomes. Among women withhyperthyroidism in whom the diagnosisismadeearlyinpregnancyandforwhomtreatment is started promptly or who be-come pregnant while the thyrotoxicosisis under control, the prognoses formother and offspring are excellent in the

majority of studies.

37

Similarly, studieshave shown that women with hypothy-roidism in whom the diagnosis is madeearly in pregnancy and for whom re-placement is initiated or who have ade-quate replacement prior to pregnancydonot have an increased risk for perinatalmorbidity.50 No well-designed studieshave specifically evaluated the treatmentof thyroid disease before pregnancy,compared with that during pregnancy.

There are no special considerations

about contraceptive methods amongwomen with thyroid disease unless the

Supplement www.AJOG.org




thyroid disease is complicated by hyper-

tension.51 However, the most common

gynecoendocrine anomaly in women

with untreated hypothyroidism is

anovulation;52 therefore, conception

may be less frequent among women with

hypothyroidism.53

Recommendations

by other groups

Both the American College of Obstetri-

cians and Gynecologists and the American

Association of Clinical Endocrinologists

have developed preconception clinical

practice guidelines for pregnant women

with thyroid disease.36,38 For women with

hyperthyroidism who are pregnant, the

medication of choice is typically propyl-

thiouracil. Regarding preconception is-sues, the guidelines specify that it is advis-

able to achieve euthyroidism before

conception. Theideal formof treatment of

hyperthyroidism for women who wish to

become pregnant hasnot been defined but

depends on patient understanding of the

advantages and disadvantages of each and

patient and physician preference. Specifi-

cally, there is no evidence that radioactive

treatment given to themother before preg-

nancyhas anyadverseeffect onthefetus or

children later in life;however, it is custom-ary to avoid pregnancy for the first 6

months after radioactiveiodine treatment.

The guidelines recommend the testing

of thyroid function for women with a per-

sonal history of thyroid disease or symp-

toms of thyroid disease. Routine assess-

ment for the presence of subclinical

hypothyroidismis notrecommended. The

guidelines further specify that women be-

ingtreatedforhypothyroidismwillrequire

increased doses of thyroxine early and

throughout pregnancy to maintain ade-

quate levels; this is especially important

during the first trimester.36,38

Recommendation. Women of repro-

ductive age with thyroid disease should

be counseled about the risks of these

conditions on pregnancy-related out-

comes for the woman and offspring, and

the importance of achieving optimal re-

placement therapy prior to conception.

All women with symptoms of hypothy-

roidism should be screened for thyroiddisease, and if hypothyroid, they should

be adequately replaced. Strength of rec-

ommendation: A; qualityof evidence: II-1.

Phenylketonuria

Burden of suffering

Phenylketonuria (PKU) is a metabolic

disorder that results from an inheriteddeficiency of a liver enzyme known asphenylalanine hydroxylase. This enzymedeficiency leads to elevated levels of theamino acid phenylalanine in the bloodand other tissues. Elevated phenylala-nine levels result in mental retardation,microcephaly, delayed speech, seizures,eczema, behavior abnormalities, andother symptoms, if left untreated. Ap-proximately 1 of every 15,000 infants inthe United States is born with PKU.54

The offspring of mothers with PKU areat risk for a number of adverse outcomesassociated with high maternal phenylal-anine concentrations.

There is a strong relationship betweenincreasinglevels of phenylalanine and fe-tal abnormalities. Fetuses exposed tomaternal phenylalanine levels of 3-10mg/dL had a 24% chance of microceph-aly and congenital heart disease was notseen; in contrast, fetuses exposed to ma-ternal phenylalanine levels greater than

20 mg/dL had a 73% chance of micro-cephaly and a 12% chance of congenitalheart disease.54,55 Facial dysmorphisms,microcephaly, low birthweight, fetalgrowth restriction, developmental delay,and learning difficulties are also associ-ated with maternal phenylalanine lev-els.56,57 Unfortunately, few women withPKU achieve metabolic control prior toconception and maintain it during preg-nancy,54 and the difficulty of controllingblood phenylalanine levels as patients get

older is widely recognized.

58


All states perform newborn screening forPKU.54


current treatments?

Effective treatment for PKU involvesstrict metabolic control using a low-phe-nylalanine diet. The newborn screeningprogram for PKU has been remarkably

successful in that infants, when diag-nosed early in the newborn period and

treated to achieve good metabolic con-trol, have normal health and develop-ment and can likely expect a normal lifespan. However, metabolic control of PKUcan be difficult to achieve, and poorcontrol can result in significant decline

of mentaland behavioralperformance.

54


It has been demonstrated that the ad-verse outcomes associated with maternalPKUcan be preventedwhen mothers ad-here to a low phenylalanine diet beforeconception and continue it throughouttheir pregnancy.54,59-61

Recommendations

by other groups

The American College of Obstetricians

and Gynecologists and the National In-stitutes of Health have issued recom-mendations with regard to the screeningand management of PKU.54,59 They rec-ommend that phenylalanine levels below6 mg/dL be achieved at least 3 monthsbefore conception and that levels of 2-6mg/dL be maintained throughout thepregnancy.

Recommendation. Women of repro-ductive age with phenylketonuriashould be counseled about the impor-

tance of maintaining low phenylala-nine during their child-bearing yearsand should be encouraged to resume alow phenylalanine diet, particularly when they are planning to becomepregnant, to avoid adverse outcomesfor the offspring. Women who do notdesire a pregnancy should be encour-aged to use contraception. Strength of

recommendation: A; quality of evidence:

II-1.

Seizure disorders

Burdenof suffering

Seizure disorders affect approximately 1% of the general population.62 It hasbeen estimated that 3-5 per 1000 birthsare to women with seizure disorders,making them the most common seriousneurological complications during preg-nancy.63 Both the seizure disorder itself andthe medications used to treat the dis-order can have serious impacts on preg-nancy outcomes. Women with seizure

disorders are at increased risk for an in-crease in the frequencyof seizures during





pregnancy. During pregnancy, seizure

frequency increases in approximately

one third of women with seizure

disorders.64

There is an increased incidence of

congenital anomalies among offspring

born to women who experience sei-zures during pregnancy, whether they

are on treatment or not, and to those

who take anticonvulsant medications.

The risk of major malformations, mi-

nor anomalies, and dysmorphic fea-

turesis 2- to 3-foldhigher for infants of

mothers with epilepsy who receive

treatment with antiepileptic drugs,

compared with the risk for infants of

mothers without epilepsy.65

Other adverse pregnancy-related out-

comes associated with seizure disordersinclude spontaneous abortion, low

birthweight, diminished head circum-

ference, developmental disabilities, neo-

natal hemorrhagic disorder (caused by

anticonvulsant-induced vitamin K defi-

ciency), and perinatal death.66

Many anticonvulsants commonly used

to treat seizure disorders, including phe-

nytoin, carbamazepine, barbiturates, and

valproate have known teratogenicity in

humans,66 which can cause neural tube

defects, cleft lip and palate, cardiac anom-alies, facial abnormalities, and skeletal ab-

normalities. The risk of anomalies in-

creases significantly with higher-dose

therapy 67 and polytherapy,compared with

monotherapy.68 One mechanism of ter-

atogenicity may be anticonvulsant-related

reductions in folic acid, disturbances in fo-

lic acid-mediated biochemical processes,

or both.66


current treatments?

Currently available anticonvulsant

medications are effective in controlling

seizures among those with seizure

disorders.69


To date, no well-designed studies have

specifically addressed the role of specific

preconception strategies for the manage-

ment of seizures on pregnancy-related

outcomes for women with seizure disor-ders and their offspring. However, existing

randomized controlled trials and cohort

studiesclearlydocumenttheteratogenicity

of phenytoin, carbamazepine, barbitu-

rates, and valproate and the increased risk

of teratogenicity at higher doses and with

polytherapy.66-68

Preconception counseling and family planning are important in the care of

women of reproductive age who have sei-

zure disorders. Preconception counseling

can appropriately inform women of the

risks to their own health from pregnancy

and the risks of their condition on preg-

nancy-related outcomes. A thorough as-

sessment by a neurologist prior to preg-

nancy couldaddresswhetherthe woman is

an appropriate candidate for a withdrawal

of anticonvulsant therapy or for adjust-

ment of her medication regimen (with thegoalof achieving monotherapy, if possible,

and the lowest possible dosages to control

seizures). The principles that govern with-

drawal in women considering pregnancy

are the same as the principles for with-

drawal for the general population of pa-

tients with seizures.70 In general, with-

drawal can be considered in any woman

who has been seizure free for at least 2

years.70

Contraception is important forwomen who choose not to have a preg-

nancy and for helping women achieve

optimal timing of pregnancy in relation

to the optimal control of their condition.

There are considerations in choosing a

contraceptive method for women with

seizure disorders. Combined oral con-

traceptives do not exacerbate seizures;

however, the efficacy of oral contracep-

tives is impaired by concomitant use of

anticonvulsants that induce liver en-

zymes (eg, phenytoin, carbamazepine,barbiturates, topiramate, and tiagabine).

Specifically among women without sei-

zures, the failure rate of combined oral

contraceptives with high estrogen dose

( 50 m) is 0.7 per 100 woman-years,

whereas the rate increases to 3.1 per 100

woman-years in those receiving liver en-

zyme-inducing anticonvulsants. Failure

rates are higher for combined oral con-

traceptives with lower doses of estrogen

(

35m). Progestin-only methods alsohave a higher failure rate.66,71

Recommendations

by other groups

The American Academy of Neurology

has a published practice guideline for the

management of women with seizure dis-

orders,63 which specifies that women of

reproductive age with seizure disordersshould be placed on monotherapy at the

lowest dose whenever possible, and folic

acid supplementation should be insti-

tutedat 0.4 mgper day.If hormonal con-

traception is chosen by women taking an

enzyme-inducing anticonvulsant, the

risks of failure should be discussed and a

formulation that includes at least 50 m

of ethinyl estradiol should be used.

Women planning to become pregnant

should be evaluated for the possibility of

adjustment (or withdrawal) of their an-ticonvulsant medication and prepreg-

nancy counseling. If withdrawal is

planned, this should be completed at

least 6 months prior to conception.63

The American College of Obstetricians

and Gynecologists has an educational

bulletin addressing seizure disorders in

pregnancy, which specifies that to opti-

mize the neonatal outcome in a patient

requiring anticonvulsant therapy, using

a single drug at the lowest possible dose

to control seizures is preferable.65

Recommendation. Women of repro-

ductive age withseizure disordersshould

be counseled about the risks of increased

seizure frequency in pregnancy, the po-

tential effects of seizures and anticonvul-

sant medications on pregnancy out-

comes, and the need to plan their

pregnancies with a health care provider

well in advance of a planned concep-

tion. Those taking liver enzyme-induc-

ing anticonvulsants should be coun-

seled about the increased risk of

hormonal contraceptive failure.

Whenever possible, women of repro-

ductive age should be placed on anti-

convulsant monotherapy with the low-

est effective dose to control seizures.

Those who are planning a pregnancy

should be fully evaluated for consider-

ation of alteration or withdrawal of the

anticonvulsant regimen prior to concep-

tion and shouldinitiate folic acid supple-

mentation of 4 mg per day for at least 1month prior to conception and until the





end of the first trimester to prevent neu-ral tube defects. Strength of recommenda-

tion: A; quality of evidence: II-2.

Hypertension

Burdenof suffering

In 2002, a national survey estimated that3% of women of reproductive age hadchronic hypertension (HTN).1 In 2002,the hospital estimate for HTN prior topregnancy among 15-54 year old womenwas 28.9 per 1000 deliveries, a 2-fold in-crease from 12.3 in 1993.72

Pregnancies complicated by chronicHTN, especially if severe, may be associ-ated with worsening hypertension, pre-eclampsia and eclampsia, central nervoussystem hemorrhage, cardiac decompensa-

tion, and renal deterioration.

73,74

HTNduringpregnancy alsoposessubstantialfe-tal risks that include preterm birth, intra-uterine growth restriction, placental ab-ruption, andfetal demise.75 Superimposedpreeclampsia in women with hyperten-sion is associatedwith significantadverseperinatal outcomes.76 Pregnancy out-come is related to the degreeof hyperten-sion and the presence or absence of preeclampsia.77-79

How effective are thecurrent treatments?

The medical treatment of high bloodpressure is very effective in reducinglong-term, adverse cardiovascular out-comes and stroke as demonstrated inmany studies of the past 40 years.80

However, the data supporting improvedpregnancy-related outcomes amongwomen with HTN treated with antihy-pertensive medications are less compel-ling. A systematic review of management

of chronic hypertension during preg-nancy concluded that “the evidence baseregarding pharmacologic managementof chronic hypertension during preg-nancy is too small to either prove or dis-prove moderate to large benefits of anti-hypertensive therapy.”74

There is, to date, no scientific evidencethat antihypertensive therapy will im-prove perinatal outcomes for womenwith mild hypertension in pregnancy (140-179 mm Hg systolic or 90-109 mm

Hg diastolic blood pressure).

81-83

Specif-ically, multiple metaanalyses of random-

ized controlled trials show that the majormaternal outcomes improved by treat-ing mild to moderate hypertension in-clude decreased progression to severehypertension and decreased need forad-ditional antihypertensive therapy.84,85

There are, however, demonstrable bene-fits for pregnancy-related outcomesfrom antihypertensive therapy amongwomen with severe chronic hyperten-sion (systolic blood pressure 180 mmHg or diastolic blood pressure 110mm Hg).79

Methyldopa has been the most com-monly tested therapy, with 14 random-ized controlled trials demonstrating itsefficacy at reducing blood pressure andsafety during pregnancy.84 Metaanalyses

of beta-blocker trials show a borderlineincrease in small-for-gestational-age in-fants, with no related increase in perina-tal mortality as well as a decrease in theincidence of respiratory distress syn-drome.86 Among the beta-blockers,atenolol, especially when started early inpregnancy, has been associated with fetalgrowth restriction in several uncon-trolled studies and 1 small trial. Fromthese studies, however, the causal natureof the association remains unclear be-

cause of multiple agents being simulta-neously administeredand theinability toseparate effects of the mother’s underly-ing pathophysiology from effects of thedrug. Labetalol has been associated withfetal growth restriction in 3 randomizedtrials of hypertensive disorders otherthan chronic hypertension. Other beta-blockers, such as metoprolol, pindolol,and oxprenolol, have not been associ-ated with fetal growth retardation, butavailable data concerning these agents

are scarce.

87

Calcium channel blockers have mostly been evaluated for use late in pregnancy so their benefit-to-risk ratio remains un-clear, although they are generally re-garded as safe and effective.88 Diureticsare known to decrease the circulatingplasma volume, but a metaanalysis of 9randomized trials evaluating diureticsduring pregnancy did not find an in-creased risk of adverse fetal events nordida large cohort study.87 Angiotensin II

receptor blockers are contraindicated inpregnancy, having been linked to mis-

carriage, fetal death, fetal renal failure,and malformations.89-92


To date, no well-designed studies haveaddressed the effects of specific precon-

ception strategies for the management of HTN on pregnancy-related outcomesfor the woman and her offspring. How-ever, 3 trials synthesized in a recent re-view had evidence relevant to the pre-conception management of chronichypertension because they includedwomen 30-54 years of age. The data, in-volving 8565 women aged 30-54 yearswith mild to moderate HTN, show ap-proximately 250 (95% confidence inter-val, 158-1606) such women need to be

treated for 5 years to prevent a fatal ornonfatal cardiovascular event such asstroke. Women who are either youngerthan those involved in the trials or whoare treated for intervals shorter than 5 years can expect less clinical benefit fromantihypertensive therapy.87

Contraception is important for womenwho choose not to have a pregnancy andforhelpingwomenachieveoptimaltimingof pregnancy in relation to the optimalcontrol of their condition. Patients with

mild or well-controlled HTN (140-159/90-99) may be considered for low-dosecombination oral contraceptives or pro-gestin-only methods, particularly in theabsence of other risk factors such as smok-ing, diabetes, hyperlipidemia, or obesity.Combination pills are not recommendedinmoderatetosevereHTN(160/100) orif blood pressure cannot be monitored.93

The WHO lists the Copper T380A as a rec-ommended method of contraception forwomen with mild or moderate to severe

hypertension or if blood pressure can notbe monitored.

Recommendations

by other groups

Both the American College of Obstetri-cians and Gynecologists (ACOG) andthe National High Blood Pressure Edu-cation Program (NHBPEP) recommendthat the preconception care of womenwith hypertension should include coun-seling about the sizable (25%) risk of su-

perimposed preeclampsia and its associ-ated complications and that those with





hypertension of several years’ durationshould undergo a preconception assess-ment for ventricular hypertrophy, reti-nopathy, and renaldisease because targetorgan damage can progress duringpregnancy.

Both ACOG and the NHBPEP havestatements to address the treatment of high blood pressure during pregnancy.The ACOG practice bulletin states thereis no evidence that antihypertensivetreatment for mild to moderate hyper-tension improves maternal or fetal out-comes, even for women who are already receiving hypertension treatment. ACOGsuggests treatment may be stopped duringpregnancy or not initiated until bloodpressuresreach 150-160 mmHgsystolic or

100-110 mm Hg diastolic, unless themother has underlying renal or cardiovas-cular disease. Continuing previous antihy-pertensive medication is another option,although angiotensin-converting enzymeinhibitors and angiotensin receptor block-ers are contraindicated during preg-nancy.90 The NHBPEP recommends thesame guidelines as ACOG.91

Recommendation. Women of repro-ductive age with chronic hypertensionshould be counseled about the risks as-

sociated with hypertension during preg-nancy for both the woman and her off-spring and the possible need to changethe antihypertensive regimen when sheis planning a pregnancy. Those with hy-pertension for several years should be as-sessed for ventricular hypertrophy, reti-nopathy, and renal disease prior topregnancy. Angiotensin-converting en-zyme inhibitors and angiotensin-recep-tor blockers are contraindicated duringpregnancy; women who could become

pregnant while taking these medicationsshould be counseled about their adversefetal effects and should be offered con-traception if they are not planning apregnancy. Women who are planning apregnancy should discontinue thesemedications prior to pregnancy.Strength

of recommendation: A (because of medi-cations); quality of evidence: II-2.

Rheumatoid arthritis

Burdenof suffering

Rheumatoid arthritis (RA) is the mostcommon rheumatic disease that compli-

cates pregnancies. It affects 1-2% of theadult population with a female predom-inance.94 Fortunately, the disease remitsin approximately 70-80% of patientsduring pregnancy,95 probably because of the normal shift to a less inflammatory

state and human leukocyte antigen mis-match between the mother and fe-tus.96-98 However, 20-30% of patientswill continue to have activ e or worseningdisease during pregnancy.99

RA does not decrease fertility but may prolong time to conception.100,101 Mostreports do not show any increase in fetalmorbidity or losses among pregnantwomen with RA.102,103 However, activeRA may increase the risk of low birth-weight, and corticosteroid use may in-

crease the risk of fetal growth restrictionandpreterm prematurerupture of mem-branes.104 Approximately 90% of pa-tients flare in the postpartum period,usually within the first 3 months.105 Theflare may be caused by decreased proges-terone and cortisol, increased prolactin,and a return to Th1 predominance.106

Presently it is unclear whether breast-feeding might exacerbate postpartumflare.107

How effective are thecurrent treatments?

No treatment is curative for RA; how-ever, several therapies modify the diseaseor result in the control of symptoms as-sociated with RA. The safety of agentsused to treat RA during pregnancy wasrecently reviewed by Chamber et al.108

Based on available data, the teratogenicrisk of corticosteroids and nonsteroidalantiinflammatory drugs (NSAIDs) fol-lowing first-trimester exposure is mini-

mal. NSAIDs should be discontinued by 27 weeks’ gestation to avoid prematureclosure of the ductus arteriosus. The ac-tive metabolite of leflunomide under-goes extensive enterohepatic circulationand has a prolonged and unpredictablehalf-life; cholestyramine administrationmay enhance eliminationof leflunomidemetabolite before pregnancy.

Safety data on other disease-modifyingantirheumatic drugs are limited. NSAIDsare compatible with breast-feeding, al-

though there is potential risk of jaundiceand kernicterus. Corticosteroids may be

used, but breast-feeding should occur 4

hours after the last dosing. Hydroxychlo-

roquine and sulfasalazine should be used

cautiously, and azathioprine, cyclospor-

ine,cyclophosphamide,methotrexate,and

chlorambucil shouldbeavoided. There are

insufficient data regarding tumor necrosisfactor antagonists, anakinra, and ritux-

imab in relation to pregnancy or

lactation.109


No studies have investigated the effect of

preconception strategies on pregnancy-

related outcomes for women of repro-

ductive age with RA. Preconception

counseling and family planning are im-

portant in the care of the woman of re-

productive age with RA. Patients shouldbe advised of the natural history of the

disease during pregnancy and the likeli-

hood of flare during pregnancy. Also, pa-

tients should be counseled about the

extremely teratogenic effects of metho-

trexate and leflunomide and the need to

discontinue these medications prior to

pregnancy. Decisions regarding the con-

tinued use of other disease-modifying

antirheumatic drugs in patients plan-

ning a pregnancy should be made by

weighing potential benefits againstknown fetal risks. Women with RA who

are using these medications should be

offered suitable contraception. Male pa-

tients should be made aware of the ef-

fects methotrexate, leflunomide, sul-

fasalazine, and cyclophosphamide may

have on their fertility.

Contraception is important for women

with RA who donot desire to have a preg-

nancy.Hormonal contraceptionincluding

oral contraceptive pills may be used but

their long-term effects on RA remain un-

clear.110 Intrauterine devicesshouldnotbe

used bywomen with RA if they are oncor-

ticosteroids or other immunosuppressive

therapy. 93

Recommendations

by other groups

No practice recommendations or treat-

ment guidelines related to the treatment

of rheumatoid arthritis in pregnant

women or women planning a pregnancy are identified.





Recommendation. Women of repro-ductive age with RA should be advisedof the natural history of the disease dur-ing pregnancy and the probability of aflare after pregnancy. The most impor-tant task is to review the patient’s medi-

cation use. NSAIDs should be discontin-uedby 27 weeks’ gestation. Methotrexateand leflunomide are extremely terato-genic and should be discontinued inwomen planning a pregnancy. Men withRA should be informed of the possibleeffects of leflunomide, sulfasalazine, andcyclophosphamide on fertility. Strength

of recommendation: A; qualityof evidence:

III.

Systemic lupus

erythematosus (SLE)

Burdenof suffering

SLE is 1 of the most common autoim-mune disorders that affect women of re-productive age. In the United States, theprevalence of SLE is 14.6 to 50.8 cases per100,000 in the general population. Theincidence of SLE is much more commonamong females than males and amongAfrican Americans than whites, with aprevalence of SLE in female AfricanAmericans from 17.9 to 283 cases per

100,000.

111

Whether exacerbations of SLE aremore common during pregnancy re-mains controversial. However, it is gen-erally agreed that exacerbations duringpregnancy are common (57% of thosewith SLE).112 SLE increases the risk of spontaneous abortion, intrauterine fetaldeath, preeclampsia, and fetal growthre-striction, with the greatest risk being of preterm birth (25%). In addition, ap-proximately 10% of women with SLE

and anti-Ro antibodies will have a baby with neonatal lupus. Perinatal outcomesamong women with SLE depend on thestability of the disease. Prognoses forboth motherand child are best when SLEis quiescent for at least 6 months beforethe pregnancy and when the mother’sunderlying renal function is stable andnormal or near normal.112


SLE is diagnosed according to diagnostic

criteria defined by the American Collegeof Rheumatology, which involve the as-

sessment of physical examination fea-tures as well as laboratory parametersand should be considered amongwomen with recurrent spontaneousabortions.113


current treatments?

No treatment is curative for SLE; how-ever, several therapies are disease modi-fying or result in the control of symp-toms associated with SLE.

Randomized controlled trials demon-strate that maternal treatment with low-dose aspirin and subcutaneous heparinis as effective as low-dose aspirin andprednisone or low-dose aspirin alone inavoiding adverse fetalconsequences with

less frequent preeclampsia, prematurerupture of membranes, and pretermdelivery.114,115

Azathioprine and cyclophosphamideare the 2 most commonly used cytotoxicagents used in treating SLE. Cyclophos-phamide is teratogenic in humans andshould therefore be avoided duringpregnancy, and appropriate contracep-tion should be advised during the peri-ods of cyclophosphamide therapy.112,116

Azathioprine has not been associated

with congenital defects in humans; how-ever, the number of reported cases withadequate follow-up maynot be sufficientto detect a small increase in theserates.117-119 For patients in whom im-munosuppression is necessary to controldisease, azathioprine may be continuedthroughout pregnancy. Cyclosporin Adoes not seem to be associated with ter-atogenicity in human studies120,121 andmay be considered as an alternative toother cytotoxic agents for severe disease

in patients with SLE.Hydroxychloroquine is the most com-mon antimalarial drug used to treat SLE.Cohort studies rev eal that it is safe to useduring pregnancy.122-125 Because with-drawal of hydroxychloroquine is associ-ated with flares of SLE, it should not bestopped unnecessarily during pregnancy in patients with SLE.112


A number of studies demonstrate that ac-

tive SLE at the time of conception is asso-ciated with a higher risk of disease exacer-

bation during pregnancy and a higherrate of adverse pregnancy-related out-comes.126-129 Rates of exacerbation rangefrom7% to 33% in women who have beenin remission for at least 6 months to 61-67% in women who have active disease at

the time of conception. Flares and adversepregnancy outcomes are particularly ele-vated among those with lupus nephritisupon conception.127,129,130 The longer thepatient is in remission at the time of con-ception, the greater the chance the preg-nancy will be carried to term withoutcomplications.112

Contraception is important for womenwho choose not to have a pregnancy andforhelpingwomenachieveoptimaltimingof pregnancy in relation to the optimal

control of their condition. There are nu-merous considerations in choosing a con-traceptive method for women with SLE.Case reportsassociateestrogen-containingcontraceptives with exacerbation of SLE,131-134 but retrospective studies havefailed to find such an association.135-137

However, there is some evidence that therisk of thromboembolism related to com-binedoral contraceptives maybe higher inSLE patients, especially those with positiveantiphospholipid antibodies.138,139 Pro-

gestin-only contraceptives may be a goodchoice for patients with antiphospholipidantibodies or with risk factors for throm-boembolic disease (age 35 years old,obese, smoking, hypertension). Intrauter-ine contraceptive devices are associatedwith an increased risk of infection amongSLE patients, especially those who are onimmunosuppressive therapy.112

Recommendations

by other groups

Experts advise that in patients with SLEpregnancy is best undertaken during pe-riods of disease quiescence. In particular,nephritis, if present, should be in remis-sion for at least 6 months before concep-tion. Because of its teratogenicity, cyclo-phosphamide should be avoided inpregnancy. Furthermore, it is advisedthat all pregnancies complicated by SLEshould be considered high risk and man-aged with inv olvement of a high-riskperinatal team.112

Recommendation. Women of repro-ductive age with SLE should be coun-





seled about the risks associated with SLE

during pregnancy for both the woman

and her offspring, the importance of op-

timizing disease control prior to preg-

nancy, the possible need to change the

medication regimen close to conception

or early in pregnancy, and the impor-tance of specialized prenatal care once

pregnant. Those whose treatment regi-

men involves cyclophosphamide should

be advised of its teratogenic nature and,

whenever possible, should be changed to

a safer regimen prior to conception and

offered contraception if they are not

planning a pregnancy. Strength of recom-

mendation: B; quality of evidence: II-2.

Chronic renal disease

Burdenof suffering The incidence of moderate chronic renal

disease is estimated to be between 6 and

12 per 10,000, respectively.140 The diag-

nosis of renal disease before pregnancy is

approximately 0.03% in a population-

based study of pregnant women with

kidney disease.141 The potential impact

of chronic renal disease is dependent on

the degree of serum creatinine elevation,

defined as mild (0.9-1.4 mg/dL), moder-

ate (1.4-2.5 mg/dL), or severe ( 2.5mg/

dL), and the level of hypertension.142

Pregnant women with mild renal dis-

ease and normal blood pressure have a

greater than 90% chance of a successful

outcome and are unlikely to be affected

by the progression of renal disease.143

On the other hand, women with moder-

ate or severe renal disease before preg-

nancy are at risk for developing worsen-

ing renal function during pregnancy. In

1 study, for women with serum creati-

nine levels above 2.0 mg/dL at the begin-

ning of pregnancy, the progression to

end-stage renal disease was 23% within 6

months after delivery.144

Maternal morbidity associated with

moderate to severe chronic renal disease

commonly includes the development of

preeclampsia, anemia, chronic hyperten-

sion, and cesarean delivery. Adverse preg-

nancy outcomes associated with maternal

renal disease include preterm delivery, fe-

tal growth restriction, and increased fetal

loss and stillbirth.

141,144-149

In fact, mostpregnancies with moderate to severe renal

insuf ficiency will result in a pretermbirth.150

When hypertension is present at con-ception (defined as mean arterial pres-sure 105 mm Hg), there is a 10-foldincrease in fetal loss at comparable se-

rum creatinine levels, compared withwomen who are spontaneously or thera-peutically normotensive.151 Addition-ally, proteinuria is associated with poorpregnancy outcomes and long-term pro-gression of renal disease.152

A separate issue from the effect of re-nal disease on pregnancy is the possibleeffect on the fetus of drugs used to treatrenal disease. Angiotensin-convertingenzyme inhibitors and/or angiotensin IIreceptor blockers, which are commonly

used among renal patients, are knownteratogens (discussed more fully in Hy-

pertension section).


current treatments?

The impact of current treatment varies,depending on specific diagnosis. Man-agement guidelines for pregnant womenwith chronic renal disease are basedsolely on retrospective and observationalseries and opinions.142


To date, no well-designed studies havespecifically addressed the role of specificpreconception strategiesfor the manage-ment of patients with renal disease.However, cohort studies document thatthe higher the serum creatinine, protein-uria, andblood pressure prior to concep-tion, the greater the risk of disease pro-gression during pregnancy and adversepregnancy outcomes.143,144,151,152

Preconception counseling and family planning are important in the care of women of reproductive age with renaldisease. Preconception counseling canappropriately inform women of the risksto their own health from pregnancy andthe risks of their condition and medica-tions that may be used to treat the con-dition on pregnancy-related outcomesas well as the need for blood pressurecontrol prior to and throughout thepregnancy to lessen risks.

Contraception is important for womenwho choose not to have a pregnancy or in

helping women achieve optimal timing of pregnancy in relation to control of theircondition. Absolute contraindications tooral contraceptive pills relevant to womenwith chronickidney disease include signif-icant cardiovascular disease, history of ve-

nous thromboembolism, smokers olderthan 35 years,andimpaired liver function.Systemic lupus erythematosus, hypertri-glyceridemia, hypertension, and diabetesmellitus arerelative contraindications,andlower-dose oral contraceptive pills may bereasonable. Progestin-only pills can beconsidered for patients who cannot takeestrogen. 93

Recommendations

by other groups

There were none identified.Recommendation. Women of repro-ductive age with renal disease should becounseled about the likelihood of pro-gression of renal disease during preg-nancy and irrespective of pregnancy; theincreased risk of adverse pregnancy out-comes for the woman and offspring; andthe importance of achievement or main-tenance of normal blood pressure priorto conception. Angiotensin-convertingenzyme inhibitors and angiotensin-re-

ceptor blockers are contraindicated dur-ing pregnancy; women who could be-come pregnant while taking thesemedications should be counseled abouttheir adverse fetal effects and should beoffered contraception if they are notplanning a pregnancy. Women who areplanning a pregnancy should discon-tinue these medications prior to preg-nancy in favor of a safer regimen when-ever possible. Women who do not desirepregnancy should be offered an appro-

priate method of contraception. Strengthof recommendation: B; quality of evidence:

II-2.

Cardiovascular disease

Burdenof suffering

Approximately 3% of women 18-44 years of age have cardiac disease, and ap-proximately 1% of pregnancies are com-plicated by cardiac disease.1 Congenitalheart disease in pregnancyis increasingly common as more affected women are

surviving into reproductive age.

153

Forwomen with cardiac disease, however,





Recommendation. Women of repro-ductive age with cardiac disease shouldbe counseled about the risks pregnancy presents to their health, as well as therisks of the cardiac condition and any medications needed to treat the condi-

tion (eg, warfarin), on pregnancy-re-lated outcomes. Those who are consid-ering or planning a pregnancy should becounseled to achieve optimum controlof the condition prior to conception andshould be offered a suitable contracep-tive method to achieve optimum timingof the pregnancy. Those whose treat-ment regimen involves warfarin shouldbe counseled about its teratogenicnatureand, whenever possible, should bechanged to a less teratogenic anticoagu-

lant prior to conception. Those with acongenital cardiac condition should beoffered preconception genetic counsel-ing. Those who do not desire a preg-nancy should be offered a suitable formof contraception. Strength of recommen-

dation: B; quality of evidence: II-3.

Thrombophilia

Burdenof suffering

Thrombophilias (disorders that predis-pose to spontaneous, inappropriate ve-

nous clotting events) can be inherited oracquired. The prevalence of the variousthrombophilias vary substantially withethnicity, and numerous studies have yielded varying estimates of the preva-lence of thrombophilias in pregnancy.The most common inherited disordersduring pregnancy are mutations in fac-tor V Leiden, prothrombin gene, andmethylenetetrahydrofolate reductase.Whites have a higher rate of geneticthrombophilias than other racial

groups.

173

The factor V Leiden mutationmaybepresentinasmanyas1in20Cau-casian individuals, but it is very uncom-mon in Asian populations. Antiphos-pholipid antibody syndrome is the mostcommonly acquired thrombophilia of pregnanc y and is more common inblacks.174

Several studies demonstrate an associ-ation between thrombophilias and ad-verse pregnancy outcomes. Maternal ef-fects of thrombophilias include an

increased risk of venous thromboembo-lism (including deep vein thrombosis,

pulmonary embolism, and cerebral veinthrombosis), arterial thrombosis (pe-ripheral and cerebral), and severe pre-eclampsia. Placental and fetal effects in-clude thrombosis and infarcts, placentalabruption, recurrent miscarriage, fetal

growth restriction, fetal stroke, anddeath.175-179


The presence of a thrombophilia in anindividual may be suspected in the pres-ence of a personal or family history of venous thrombotic events, a history of recurrent early or late pregnancy loss, se-vere preeclampsia, severe intrauterinegrowth restriction, or placental abrup-tion/insufficiency. The sensitivity and

specificity of family history as a tool fordetecting the thrombophilias in the pre-natal setting is largely unknown and very likely variesamong populations. Labora-tory testing for specific thrombophiliasis widely available and both sensitiveand specific if properly ordered andinterpreted.

A thrombophilia work-up may in-clude testing for the following condi-tions: factor V Leiden, prothrombinG20210A mutation, antithrombin III

deficiency, hyperhomocystinemia, pro-tein C deficiency, protein S deficiency,and the presence of lupus anticoagu-lants.175-186 Although genetic testing forfactor V Leiden and prothrombinG20210A can be offered and interpretedat any time, antithrombin III assays areaffected by anticoagulation and acutethrombosis, and protein C and protein Sassays are affected by acute thrombosis,pregnancy, oral contraceptives, and war-farin.176 Because of the complexity and

variety of tests available for thrombo-philia, primary care providers may wishto work with a genetics health profes-sional and/or a hematologist when con-fronted with this clinical scenario.


current treatments?

There are no randomized trials evaluatingthromboprophylaxis for prevention of re-current adverse pregnancy outcomes inwomenwithpreviousseverepreeclampsia,

fetal growth restriction, or abruptio pla-centa in association with thrombophilias.

Therefore, any recommendation to treat

such women with low-molecular-weight

heparin with or without low-dose aspirin

in subsequent pregnancies should remain

empiric and/or prescribed after appropri-

ate counseling of the patients regarding

risks and benefits.173

Although treatment is controversial,

current American College of Obstetri-

cians and Gynecologists guidelines (level

C: based primarily on consensus and

expert opinion) recommend offering

treatment in pregnancy for women with

homozygotic factor V Leiden and pro-

thrombin G20210A mutations, anti-

thrombin III deficiency, and compound

heterozygous factor V Leiden/pro-

thrombin G20210A mutations.175 Addi-

tionally, treatment is recommended forwomen with protein C or protein S defi-

ciency as well as for women who are fac-

tor V Leiden or prothrombin G20210A

mutation heterozygotes. Treatment of

women with hyperhomocystinemia or

methylenetetrahydrofolate reductase

mutations is not well established;

whereas folic acid supplementation in

women with hyperhomocystinemia is

safe, treatment is not necessarily

efficacious.176,177,180-184


No studies have specifically evaluated the

effect of treatment of thrombophilias

prior to conception. However, because

untreated thrombophilias are associated

with adverse maternal and fetal conse-

quences and it is well established that

warfarin, commonly used to control

blood clotting, is teratogenic, precon-

ception counseling and family planning

are important considerations for women

with thrombophilias.

Preconception counseling can appro-

priately inform women of the risks to

their own health from pregnancy andthe

risks of their condition, and any medica-

tions used to treat their condition, on

pregnancy-related outcomes. Precon-

ception care may allow women to opti-

mize control of their condition prior to

pregnancy and allow women to transi-

tion to a medication regimen that is safer

for the fetus. For patients with heritabledisorders, genetic counseling prior to





pregnancy may help identify the risk tothe offspring.

Contraception is important for womenwho choose not to have a pregnancy andforhelpingwomen achieveoptimaltimingof pregnancy in relation to control of their

condition. Because estrogens promote hy-percoagulable states, combination oralcontraceptive pills are contraindicatedamong women with thrombophilias.There are no contraindications to proges-tin-only methods, intrauterine devices, orbarrier methods.93

Recommendations

by other groups

The American College of Obstetriciansand Gynecologists has a practice bulletin

addressing thrombophilias in preg-nancy,187 although this bulletin does notspecifically address preconception con-cerns related to thrombophilia. TheAmerican Heart Association and theAmerican College of Cardiology have a joint guideline for warfarin therapy forpregnant patients that recognizes 3 op-tions:162 (1) use heparin or LMWHthroughout pregnancy; (2) use warfarinthroughout pregnancy and change toheparin or LMWH at 38 weeks’gestation

with planned labor induction at approx-imately 40 weeks; or (3) use heparin orLMWH in the first trimester, switchingto warfarin in the second trimester, con-tinuing it until approximately 38 weeks’gestation and then changing to heparinor LMWH at 38 weeks with planned la-bor induction at approximately 40weeks.

Recommendation. Providers may con-sider screening women of reproductiveage for a personal or family history of

venous thrombotic events or recurrentor severe adverse pregnancy outcomes.Womenwith a personal or family history suggestive of thrombophilia may then beoffered counseling and testing forthrombophilias. Screening for thrombo-philias with laboratory testing in routinecare is not recommended. Women of re-productive age with a known geneticthrombophilia should be offered pre-conception genetic counseling to ad-dress the risk of the condition to the off-

spring. Strength of recommendation: C;quality of evidence: III.

Women of reproductive age with athrombophilia whose treatment regi-men involves warfarin should be coun-seled about its teratogenic nature and,whenever possible, should be changed toa less teratogenic anticoagulant prior to

conception. Strength of recommendation:B; quality of evidence: II-3.

Asthma

Burden of suffering

Asthma affects up to 8.2% of pregnantwomen and 9.4% of women of repro-ductive age in the United States.188 Forapproximately 30% of women withasthma, the severity of the disease wors-ens during pregnancy. Women who aremost likely to experience worsening of

their asthma during pregnancy are thosewith severe or poorly controlled asthmaprior to pregnancy.189 Subsequent preg-nancies tend to follow a course similar tothe first pregnancy with respect to statusof asthma severity.190

Asthma that is not adequately con-trolled duringpregnancy canresult in se-rious complications for both the motherand the fetus. Maternal complicationsinclude preeclampsia, hypertension, andhyperemesis gravidarum.191 Fetal com-

plications include increased stillbirthand infant death, neonatal hypoxia, in-trauterine growth retardation, prema-ture birth, and low birthweight.191,192

Women whose asthma is adequately controlled during pregnancy have peri-natal outcomes similar to those of non-asthmatic women.193-195 Studies and ob-servations of pregnant women withasthma demonstrate that the risks of un-controlled asthma appear to be greaterthan the risks of necessary asthma

medications.Studies of pregnant women demon-strate that most inhaled asthma medica-tions are safe for patients to use whilepregnant. In fact, inhaled corticosteroidsare the prophylactic treatment of choicefor pregnant women with mild, moder-ate, or severe persistent asthma, accord-ing to the National Asthma Educationand Prev ention Program Expert Panel(NAEPP).196 Specifically, existing obser-vational cohort data do not associate an

increased risk of preeclampsia, total con-genital malformations, preterm birth, or

low-birthweight infants with maternalexposure to inhaled beta agonists, cro-molyn, inhaled corticosteroids, or oraltheophylline. Maternal use of oral corti-costeroids, however, has been associatedwith reduced birthweight, an increased

risk of preeclampsia, and an increasedrisk of oral clefts (first-trimester use).197

Nevertheless, although some increasedrisks may be associated with the gesta-tional use of oral corticosteroids, theserisks are probably still less than the po-tential risks to the mother and the fetusof severe uncontrolled asthma.


current treatments?

There is general agreement that it is safer

for pregnant women with asthma to betreated with asthma medications than tohave asthma symptoms or exacerbationsand reduced lung function that may po-tentiall y impair oxygenation of the fe-tus.198 Short-acting beta agonists inducebronchodilation and are the initial res-cue therapy in pregnant and nonpreg-nant asthmatics. Although this class of medications has a pregnancy category Crating, the human data for albuterol,metaproterenol, and terbutaline are re-

assuring. Anticholinergics (category B),in addition to bronchodilators, are usu-ally added to short-acting beta agonistsfor additional rescue therapy.

Oral corticosteroids (category C) areused for asthma exacerbations that donot respond to initial rescue therapies.Unfortunately, the use of oral corticoste-roids during the first trimester of preg-nancy is associated with a 3- to 6-foldincreasedrisk of oralcleftsandlowbirth-weight in infants199 as well as an in-

creased risk of maternal preeclampsia.

200

However, when indicated for manage-ment of severe asthma, these risks of therapy are much less than the risks of uncontrolled severe asthma that can in-clude maternal and/or fetal death.

To both avoid uncontrolled asthma inthe mother and minimize the possibleneed for oral corticosteroids, preventivetherapy with controller medications isparamount. The choice of controllertherapy may differ in the pregnant vs

nonpregnant asthmatic. The first ther-apy currently recommended by the





American College of Allergy, Asthma,and Immunology (ACAAI)-AmericanCollege of Obstetricians and Gynecolo-gists 2000 position paper is still cro-molyn or nedocromil (category B) be-cause of reassuring animal and human

data for use during pregnancy. Unfortu-nately, these are most efficacious in mildasthmatics, and further therapy is usu-ally warranted.

Inhaled corticosteroids are the most ef-fective prophylactic therapy for asthma,and both beclomethasone and budes-onide have reassuring human data dur-ing pregnancy. In fact, the Food andDrug Administration changed budes-onide from pregnancy category C to B(all other inhaled corticosteroids are C).

The ACAAI-ACOG 2000 position paperrecommends the addition of salmeterol(a long-acting beta agonist) only in pa-tients notcontrolled by a maximum doseof inhaled corticosteroids. Leukotrienemodifiers (montelukast and zafirlukast,both category B) have been used inasthma therapy. However, no humandata are available, and as a systemic med-ication, it should be used in pregnancy only if it was effective for the patientprior to pregnancy. Animal data for the

leukotriene modifiers are reassuring.Theophylline (category C) has reassur-ing human data and may be consideredin patients not controlled by inhaledcorticosteroids.


There are no published studies that spe-cifically evaluate the impact of precon-ception asthma care on pregnancy-re-lated outcomes for the woman and fetus.However, research demonstrates that

womenwith severeasthma prior to preg-nancy are more likely to worsen duringpregnancy, reinforcing the importanceof adequate asthma control prior to con-ception.189 Subsequent pregnancies tendto follow a course similar to the firstpregnancy in any given patient,190 sug-gesting the potential for interconceptioncare focused on achieving asthma con-trol between pregnancies.

A single published study has evaluatedhealth care outcomes for pregnant

women with asthma who were and werenotusing an inhaled corticosteroid med-

ication prior to the pregnancy. Thisstudy found that patients using an in-haled corticosteroid before pregnancy experienced a decrease in the rate of asthma-related physician and emer-gency department visits during the preg-

nancy, whereas the patients not using aninhaled corticosteroid before pregnancy experienced no change in these mea-sures. Those patients using an inhaledcorticosteroid before pregnancy did nothave an increase in adverse pregnancy outcomes relativ e to the group that wasnot using them.201 Inhaled corticoste-roids are recommended in the 2004 NA-EPP asthma and pregnancy guidelines asthe prophylactic treatment of choice forpregnant women with persistent

asthma.

196

The preferred agent in theseguidelines is budesonide because this isthe only inhaled corticosteroid withFood and Drug Administration category rating B, based on accumulated evidencefrom the Swedish Medical Birth Registry indicating that budesonide treatment isnot associated with an increased risk of congenital malformations202 or with anincreased risk of preterm delivery, still-birth, or low birthweight.203

Morbidity during pregnancy because

of smoking may be independent of andadditive to morbidity because of asthma.Furthermore, maternal smoking may beassociated with increased risk for wheez-ing and development of asthma in herchild.

Recommendations

by other groups

No organizations or professional associ-ations have published guidelines or rec-ommendations for the delivery of spe-

cific preconception care to women withasthma. However, the National AsthmaEducation and Prevention Program(NAEPP) has developed a clinical prac-tice guideline for management of asthmaduring pregnancy, which recommendsthat asthma be treated aggressively inwomen who are pregnant.196 Inhaledcorticosteroids are recommended in the2004 NAEPP asthma and pregnancy guidelines as the prophylactic treatmentof choice for pregnant women with per-

sistent asthma.

196

The preferred agent inthese guidelines is budesonide because

this is the only inhaled corticosteroidwith Food and Drug Administration cat-egory ratingB, based on accumulated ev-idence from the Swedish Medical BirthRegistry indicating that budesonidetreatment is not associated with an in-

creased risk of congenital malforma-tions202 or with an increased risk of preterm deliv ery, stillbirth, or lowbirthweight.203

Recommendation. Women of repro-ductive age with asthma should be coun-seled about thepotential fortheir asthmacontrol to worsen with pregnancy andthe importance of achievingasthma con-trol prior to a pregnancy through appro-priate medical management and avoid-ance of triggers. Women with asthma

who are planning to become pregnant orwho could become pregnant should betreated with pharmacologic step therapy for their chronic asthma based on theACAAI-ACOG recommendations forthe Pharmacologic Step Therapy of Chronic Asthma During Pregnancy.Those with poor control of their asthmashould be encouraged to use effectivebirth control until symptom control isachieved. Strength of recommendation: B;quality of evidence: II-3.

Conclusion

All women of reproductive age present-ing to the primary care setting are con-sidered candidates for preconceptioncare.3,5 In addition to general precon-ception health promotion, health careprovidersfor womenof reproductiveagewith chronic medical conditions shouldalso address with the woman her risk of pregnancy complications and maternalmorbidity and mortality given: preg-

nancy, disease prognosis irrespective of pregnancy, whether there are conflictsbetween maternal treatment and fetalwell-being, the extent of risk the condi-tion or medications used to treat thecondition place on the fetus, optimaltiming of pregnancy (if desired), and thewoman’s ability to conceive at presentand in the future. Because avoiding, de-laying, or achieving optimal timing of apregnancy is often an important compo-nent of thepreconception care of women

with medical conditions, health careproviders should explicitly address re-





productive planning and contraceptive

considerations for women of reproduc-

tive age with chronic medical conditions.

Because a high proportion of pregnan-

cies is unintended, andeven women with

intended pregnancies do not typically

plan their pregnancies with a health careprovider, providers must be proactive in

systematically addressing reproductive

planning and preconception health care

interventions with their patients to en-

sure that those with chronic medical

conditions have the necessary knowl-

edge to inform their decisions and ac-

tions around family planning and

reproduction. f

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