Bipolar disorder in women - Preconception and prenatal maintenance pharmacotherapy.pdf

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Official reprint from UpToDate

www.uptodate.com2013 UpToDate

Author

Victoria Hendrick, MD

Section Editor

Paul Keck, MD

Deputy Editor

David Solomon, MD

Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.

Literature review current through:Oct 2013. | This topic last updated:Nov 16, 2013.

INTRODUCTION Euthymic bipolar patients often receive maintenance pharmacotherapy prior to conception and during

pregnancy [1,2]. Onset of bipolar disorder in women typically occurs during childbearing years [3], and most patients are at

risk for recurrent mood episodes [1].

This topic reviews preconception and prenatal maintenance pharmacotherapy for bipolar patients. Indications for

maintenance pharmacotherapy during pregnancy, the teratogenic risks of medications used for bipolar disorder,

preconception counseling and care for bipolar disorder, and the general maintenance treatment of bipolar disorder arediscussed separately.

DEFINITION OF BIPOLAR DISORDER Bipolar disorder is characterized by episodes of mania (table 1), hypomania

(table 2), and major depression (table 3) [4]. The subtypes of bipolar disorder include bipolar I and bipolar II . Patients with

bipolar I disorder experience manic episodes, and nearly always experience major depressive and hypomanic episodes.

Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode, and the absence of

manic episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately.(See "Bipolar disorder in adults: Clinical features"and "Bipolar disorder in adults: Assessment and diagnosis", section on

'Diagnosis'.)

MANAGEMENT

General principles Preconception and prenatal maintenance treatment for bipolar patients is usually provided by

perinatal or general psychiatrists in collaboration with obstetricians and primary care clinicians [ 5-8].

After considering medical advice about the risks of fetal exposure to medications and the risks of avoiding preconception and

prenatal maintenance pharmacotherapy, bipolar patients can choose to [ 9]:

For bipolar patients who plan to or do become pregnant, we suggest maintenance pharmacotherapy to prevent mood

episodes, based upon prospective observational studies that found untreated pregnant patients were at increased risk of

recurrent mood episodes [2,10], as well as our clinical experience and that of several authorities [ 1,11-14]. However, for

patients with a mild lifetime course of illness, it is reasonable to try to avoid pharmacotherapy during pregnancy. Indications

for preconception and prenatal maintenance pharmacotherapy, risks of avoiding maintenance pharmacotherapy, and specific

drugs suggested as preconception and prenatal maintenance treatment are discussed separately. (See "Bipolar disorder in

women: Indications for preconception and prenatal maintenance pharmacotherapy"and 'Risks of avoiding pharmacotherapy'

below and 'Specific drugs'below.)

In prescribing preconception and prenatal maintenance pharmacotherapy, clinicians should attempt to use [1,5,15]:

(See "Bipolar disorder in women: Indications for preconception and prenatal maintenance pharmacotherapy".)

(See "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy".)

(See "Bipolar disorder in women: Contraception and preconception assessment and counseling".)

(See "Bipolar disorder in adults: Maintenance treatment".)

Maintain existing pharmacotherapy throughout conception, the pregnancy, and birth

Switch medications before they try to conceive to avoid drugs with a greater risk of teratogenicityDiscontinue pharmacotherapy prior to conception and restart medications during the second or third trimester (when

organogenesis is completed).

Discontinue pharmacotherapy prior to conception and remain medication-free throughout conception, the pregnancy,

and delivery.

olar disorder in women: Preconception and prenatal maintenance p... http://www.uptodate.com/contents/bipolar-disorder-in-women-preconce...

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For euthymic bipolar patients who are receiving preconception or prenatal maintenance treatment with lamotrigine, a

second-generation antipsychotic, orlithium, we suggest continuing the same drug [15,16]. For patients who are currently

treated with valproateorcarbamazepine, we suggest switching treatment to avoid the teratogenic effects of these two

antiepileptics [11,17]. (See 'Switching from valproate or carbamazepine to less teratogenic drugs'below and "Risks

associated with epilepsy and pregnancy", section on 'Effect of antiepileptic drugs on the fetus'.)

Female bipolar patients who want to conceive and continue maintenance treatment with valproateorcarbamazepinecan

consider in vitro fertilization and use of a gestational carrier [8]. (See "Surrogate pregnancy".)

Medication doses generally need to be increased over the course of pregnancy, especially in the second and third

trimesters, to prevent decreases in serum concentrations [18-21]. This is because pregnancy causes physiologic changes

that alter pharmacokinetics (eg, increased extracellular fluid volume and body fat increase the volume of distribution,

increased activity of hepatic enzymes increases metabolism, and increased renal blood flow and glomerular filtration rate

increase renal elimination).

Recurrent bipolar mood episodes may occur despite preconception or prenatal maintenance pharmacotherapy because of

problems with adherence [9]. Suggestions for improving adherence are discussed separately. (See "Bipolar disorder in

adults: Maintenance treatment", section on 'Adherence'.)

Risk of adverse pregnancy and birth outcomes The risk of adverse pregnancy and birth outcomes in women with

bipolar disorder who receive pharmacotherapy and women with bipolar disorder who are not treated with pharmacotherapy

is discussed separately. (See "Bipolar disorder in women: Contraception and preconception assessment and counseling".)

Teratogenic and postnatal risks of pharmacotherapy Following the first trimester, the risk of teratogenesis decreases

and it is safer to prescribe drug combinations and higher doses. The teratogenic and postnatal risks of medications

commonly used to treat bipolar disorder are discussed separately. (See "Bipolar disorder in adults: Teratogenic and

postnatal risks of pharmacotherapy".)

Risks of avoiding pharmacotherapy For bipolar patients who are receiving preconception or prenatal maintenance

pharmacotherapy, discontinuing treatment includes the following risks [2,10,13,17,22]:

Switching from valproate or carbamazepine to less teratogenic drugs For bipolar patients who plan to become

pregnant, are treated with valproateorcarbamazepine, and are clinically stable (eg, euthymic for at least six months), we

suggest that clinicians attempt to switch maintenance treatment to other drugs [ 11,23]. Valproate and carbamazepine are

generally regarded as teratogens, primarily based upon observational studies of epilepsy patients [1,5,24,25]. In addition,

prenatal exposure to these medications is associated with developmental delay [26]. Specific drugs suggested as

preconception and prenatal maintenance treatment and the teratogenic effects of valproate and carbamazepine are

discussed separately. (See 'Specific drugs'below and "Risks associated with epilepsy and pregnancy", section on 'Fetal and

neonatal effects'.)

For bipolar patients who plan to become pregnant and decide to switch from valproateorcarbamazepineto a less

teratogenic drug, we suggest changing pharmacotherapy at least three to six months before patients try to conceive, to

assess the effectiveness of the new medication. Valproate or carbamazepine are tapered and discontinued over 15 to 30

days; this approach appears to be associated with a lower risk of recurrence than a faster taper [2]. The medication is

tapered by the same amount for each dose decrease. As an example, valproate 2000 mg per day is decreased by 250 to

500 mg per day, every three to seven days. At the same time, the new medication is started and titrated up.

Alternative medications may not work as well as valproateorcarbamazepine, and switching medications can precipitate a

Drugs with fewer known teratogenic effects

Monotherapy

Doses at the low end of the therapeutic range

It is not known if maintenance drugs that are discontinued provide the same level of prophylactic efficacy after they are

restarted.

Stopping treatment may increase the risk of recurrent mood episodes, particularly if medications are discontinued

abruptly (eg, in less than two weeks). (See "Bipolar disorder in women: Contraception and preconception assessment

and counseling", section on 'Relapse after discontinuing pharmacotherapy'.)

Treating recurrent episodes during pregnancy may be difficult and expose the fetus to more medications at higher

doses compared with pharmacologic maintenance of euthymia.

Postpartum mood episodes may occur more frequently in patients who are not treated with maintenance

pharmacotherapy during pregnancy.


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recurrence of bipolar mood symptoms [27]. Thus, it is reasonable to maintain valproate or carbamazepine for patients with a

history of poor outcomes using other medications, such as lamotrigine, quetiapine, risperidone, and lithium. Patients treated

with valproate or carbamazepine during pregnancy should also receive high doses of folic acid(eg, 4 to 5 mg per day),

although the efficacy of folate supplementation in reducing the risk of neural tube defects is not clear [ 28]. Managing

pregnant patients who receive valproate or carbamazepine is discussed separately in the context of epilepsy, including the

use of folic acid. (See "Management of epilepsy and pregnancy", section on 'Management during pregnancy and delivery'

and "Folic acid for prevention of neural tube defects", section on 'Anticonvulsant therapy'.)

For bipolar patients who are maintained on valproateorcarbamazepineand unexpectedly become pregnant, we suggest

switching medications. (See 'Unplanned pregnancies'below.)

Monitoring patients Bipolar patients receiving preconception or prenatal maintenance pharmacotherapy should be

regularly monitored for recurrence of manic and depressive symptoms as well as medication side effects. Particular

attention is given to suicidal ideation and to psychotic symptoms. Stable patients can be seen every one to two months. For

patients who remit from an acute mood episode and remain stable, monitoring can be tapered, with progressively longer

intervals between assessments. As an example, a patient who is seen every two weeks at the time of remission can be

seen every two weeks for one to three more visits, then every one to two months until parturition. More frequent visits

should be scheduled for patients who develop symptoms or side effects; monitoring acutely ill patients is discussed

separately. (See "Bipolar disorder in pregnant women: Treatment of mania and hypomania", section on 'Monitoring the

patient'.)

Adjunctive psychotherapy For bipolar patients who receive preconception or prenatal maintenance pharmacotherapy,

we suggest adjunctive psychoeducation or cognitive-behavioral therapy (CBT), based upon randomized trials that excluded

pregnant patients. Although no head-to-head trials have compared these psychotherapies, we generally choose

psychoeducation because there are more data supporting its use, it is easier to administer than CBT and thus usually more

available, and psychoeducation is generally an element of CBT. The evidence of efficacy for reducing recurrent mood

episodes with other psychotherapies, such as family therapy and interpersonal and social rhythm therapy, is not as strong.

(See "Bipolar disorder in adults: Maintenance treatment", section on 'Adjunctive psychotherapy'.)

SPECIFIC DRUGS There are no randomized trials in bipolar patients who plan to or do become pregnant to guide

preconception and prenatal maintenance pharmacotherapy; the benefits and risks of treatment are thus based upon

randomized trials that excluded pregnant patients [29-31], as well as observational studies, birth registries, and clinical

experience [18].

First line For euthymic, bipolar patients who plan to or do become pregnant, we suggest lamotrigineas first line

maintenance treatment [5], based upon randomized trials that excluded pregnant patients. There are more data supporting

the efficacy of lamotrigine for the general maintenance treatment of bipolar disorder compared with quetiapineand

risperidone. In addition, a prospective observational study of euthymic, pregnant bipolar patients found that relapse occurred

in significantly fewer patients who continued lamotrigine (N = 10) than patients who stopped pharmacotherapy (N = 16) (30

versus 100 percent) [10]. Further, the reproductive safety profile of lamotrigine is generally regarded as favorable [5,24,32],

and there is more experience using lamotrigine during pregnancy compared with quetiapine and risperidone. Although there

are more data supporting the efficacy oflithiumthan lamotrigine, the reproductive safety of lamotrigine is generally regarded

as comparable or superior to lithium.

Evidence for the efficacy oflamotrigine, quetiapine, risperidone, and lithiumfor delaying or preventing bipolar mood episodes

is discussed separately, as are the reproductive safety profile of these drugs, and the dose schedule, side effect profile, andpharmacology of lamotrigine. (See "Bipolar disorder in adults: Maintenance treatment", section on 'Pharmacotherapy'and

"Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy"and "Pharmacology of antiepileptic drugs",

section on 'Lamotrigine'.)

Resistant patients Maintenance treatment for bipolar disorder with lamotrigineis often not efficacious, based upon

randomized trials (which excluded pregnant patients) [29]. For resistant bipolar patients who do not respond to or tolerate

preconception or prenatal maintenance lamotrigine, we suggest quetiapineorrisperidone, based upon their efficacy and

adverse effects in randomized trials that excluded pregnant patients [30,33]. (Response is defined as psychopathology that

is considerably less than full criteria for a mood episode, eg, no more than two moderately or three mildly intense

symptoms.) No head-to-head trials have compared quetiapine and risperidone. The specific choice is thus based upon other

factors, including past response to medications, side effect profiles, comorbid general medical conditions, patient

preference, and cost.

Although there are more data supporting the maintenance efficacy oflithiumthan quetiapineorrisperidone, study findings

suggest that quetiapine and risperidone are not associated with an increased risk of major malformations [34-37], whereas

lithium is generally regarded as teratogenic [20,23,38]. In addition, the preference for treating pregnant bipolar patients with


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quetiapine or risperidone rather than lithium is consistent with practice guidelines from the United Kingdom National Institute

for Health and Clinical Excellence [9,39]. However, second generation antipsychotics may cause metabolic complications.

(See 'Metabolic complications'below.)

To switch drugs, lamotrigineis tapered and discontinued over one to two weeks while at the same time quetiapineor

risperidoneis started and titrated up. We generally taper lamotrigine by the same amount for each dose decrease. As an

example, lamotrigine 200 mg per day is decreased by 50 mg per day, every two to three days.

For resistant bipolar patients who do not respond to preconception or prenatal maintenance treatment with eitherquetiapine

orrisperidone, we suggest tapering and discontinuing the failed medication over one to two weeks while at the same timethe other drug is started and titrated up. The failed medication is generally tapered by the same amount for each dose

decrease.

The efficacy ofquetiapineand risperidonefor the general maintenance treatment of bipolar disorder is discussed separately,

as is the dose, side effect profile (table 4), pharmacology, and reproductive safety profile. (See "Bipolar disorder in adults:

Maintenance treatment"and "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania"

and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and

"Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy", section on 'Second-generation'.)

Metabolic complications Second-generation antipsychotics may cause hyperglycemia [40]. In pregnant women with

diabetes, hyperglycemia is associated with increased risks of spontaneous abortion, congenital malformations, and

macrosomia. (See "Pregnancy risks in women with type 1 and type 2 diabetes mellitus", section on 'Fetal and neonatalcomplications'.)

In addition, second-generation antipsychotics may cause obesity [40,41]. Obesity during pregnancy is associated with an

increased risk of multiple obstetric complications, including gestational diabetes mellitus and pre-eclampsia. (See "The

impact of obesity on female fertility and pregnancy".) Although many clinicians use second-generation antipsychotics during

pregnancy [42], some authorities avoid them due to concerns about excessive weight gain and gestational diabetes

[24,25,43].

Clinicians using second-generation antipsychotics in pregnant patients should manage potential metabolic complications by

monitoring [9,23,39]:

Patients are assessed at baseline and every one to three months during pregnancy [17,23]. In addition, a glucose tolerance

test is performed every four months. (See "Screening and diagnosis of diabetes mellitus during pregnancy".)

Refractory patients Based upon clinical experience, many bipolar patients do not respond to or tolerate sequential trials

of preconception or prenatal maintenance lamotrigine, quetiapine, and risperidone. For these refractory patients, we suggest

lithium[11,17]. (Response is defined as psychopathology that is considerably less than full criteria for a mood episode, eg,

no more than two moderately or three mildly intense symptoms.) Evidence for the efficacy of lithium includes the following:

Although lithiumis generally regarded as teratogenic due to increased risks of cardiac defects (eg, Ebsteins anomaly)

[20,23,38], many authorities consider the absolute risk small [1,5,24,25,44]. For pregnant patients using lithium, we suggest

prenatal screening for anomalies with high-resolution ultrasonography at 16 to 18 weeks gestation, and depending upon the

results, fetal echocardiography, which can aid decisions about pregnancy termination, referral for delivery at a hospital with

Weight gain

Blood pressure

Fasting serum glucose, cholesterol, and triglyceride concentrations. The normal reference range for cholesterol and

triglycerides is generally higher in pregnant women compared with nonpregnant individuals (table 5). (See "Normal

reference ranges for laboratory values in pregnancy".)

Randomized tr ials (that excluded pregnant patients) have demonstrated the benefit of maintenance treatment with

lithiumin bipolar disorder; these trials are discussed separately. (See "Bipolar disorder in adults: Maintenance

treatment", section on 'Lithium'.)

A prospective observational study found that relapse occurred in significantly fewer pregnant bipolar patients who

continued pharmacotherapy (N = 27, 85 percent received lithium) than patients who stopped pharmacotherapy (N =

62) (37 versus 86 percent) [2].

A prospective observational study found that relapse occurred in fewer pregnant bipolar patients who received

maintenance pharmacotherapy (N = 31, 97 percent received lithium) than patients who did not (N = 10) (19 versus 40

percent; statistical significance not tested) [15].


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the appropriate level of neonatal care, and postnatal interventions for congenital malformations [1,8,25]. The teratogenic

effects of lithium are discussed separately. (See "Bipolar disorder in adults: Teratogenic and postnatal risks of

pharmacotherapy", section on 'Lithium'.)

For pregnant patients treated with lithium, we suggest using the lowest amount necessary to achieve a therapeutic serum

concentration [20]. The total daily dose is often given in two to three divided doses (rather than a single daily dose) using

controlled release preparations, to avoid high peak serum levels [ 15,45,46]; however, it is not known whether this reduces

the risk of teratogenic effects [45]. Serum lithium concentrations are checked every two to four weeks during pregnancy,

until 36 weeks gestation, at which point levels should be checked weekly [7,21,23]. The dose schedule for lithium, use of

serum concentrations to establish the proper dose, and lithium toxicity are discussed separately. (See "Bipolar disorder in

adults and lithium: Pharmacology, administration, and side effects".)

Additional laboratory monitoring oflithiumincludes thyroid and renal function tests that are checked at baseline and repeated

every three months [23]. Normal reference ranges for laboratory tests often differ for gravid and nongravid patients ( table

5). (See "Normal reference ranges for laboratory values in pregnancy".)

Serum lithiumconcentrations generally decrease during pregnancy and the doses required to effectively prevent bipolar

mood episodes thus increase [1,19]. These changes are a consequence of increases in maternal glomerular filtration rate

and extracellular fluid volume and their impact upon pharmacokinetics. As an example, renal excretion of lithium may

increase 30 to 100 percent [20,21,46]. During the second and third trimesters, twice the prepregnancy dose of lithium may

be required to achieve therapeutic serum concentrations [45]. In addition, serum lithium concentrations can be altered by

concomitant medications and other clinical factors (eg, diarrhea). (See "Bipolar disorder in adults and lithium: Pharmacology,

administration, and side effects", section on 'Prescribing lithium'.)

Frequent urination, thirst, weight gain, and nausea are common during pregnancy and can be exacerbated by lithium. Side

effects of lithium are discussed separately. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and

side effects", section on 'Lithium side effects' .)

For pregnant patients treated with lithium, delivery should occur in facilities with the ability to resuscitate neonates, given the

risks of postnatal complications [23]. Postnatal toxicity and withdrawal secondary to lithium are discussed separately. (See

"Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy", section on 'Lithium'.)

We suggest withholding lithiumfor one to two days before a scheduled delivery or at the onset of labor, consistent with the

practice of many perinatal psychiatrists [7,21,47]. Although a brief reduction in serum lithium concentrations may possibly

precipitate a postpartum relapse, the risk seems small. In a prospective observational study of nine pregnant bipolar

patients treated with lithium in the third trimester, lithium was withheld for one to two days before a scheduled delivery or at

the onset of labor; maternal serum concentrations decreased from a mean of 0.8 mEq/L (0.8 mmol/L) to 0.5 mEq/L (0.5

mmol/L), and none of the patients became symptomatic [ 47].

For pregnant patients treated with lithium, adequate hydration must be maintained throughout labor, especially if the serum

level drawn at the time of delivery is high. During labor and delivery, vascular volume can decrease through loss of blood as

well as diaphoresis [19]. Intravenous fluids are typically used to prevent dehydration and lithium toxicity [7,17].

After delivery, lithiumis resumed when patients are medically stable (provided breastfeeding is not planned) at doses lower

than those used during the third trimester, because maternal glomerular filtration rates rapidly decrease to pregravid levels

[47,48]. Patients treated with lithium prior to conception are restarted on the prepregnancy dose. Patients not treated with

lithium prior to conception are usually started at a dose of 600 to 900 mg per day, which is then increased by 300 to 600 mgevery one to five days based upon response, tolerability, and body mass index. Serum concentrations are measured 24

hours after delivery and every three to five days until they stabilize at a therapeutic level. (See "Bipolar disorder in adults and

lithium: Pharmacology, administration, and side effects", section on 'Lithium dose and serum concentrations'.)

The newborn should be monitored for symptoms of lithiumtoxicity for up to 10 days after delivery [20,48], even if the

maternal serum lithium concentration at delivery is within normal limits. Signs of neonatal toxicity at the time of delivery

should prompt a cord serum level [23] and a neonatal electrocardiogram [20,48]. Neonatal lithium toxicity and withdrawal are

discussed separately. (See "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy", section on

'Lithium'.)

UNPLANNED PREGNANCIES Unintended pregnancies in bipolar patients are common and may precipitate mood

episodes. Two prospective observational studies of pregnant bipolar pat ients (N = 89 and 26) found that the pregnancy wasnot planned in 34 and 58 percent, and that unplanned pregnancy was associated with recurrent prenatal mood episodes

[2,10].

For euthymic bipolar patients who unintentionally become pregnant during maintenance treatment with lamotrigine, a second-

generation antipsychotic, or lithium, we suggest continuing the same drug [15,16].


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For bipolar patients who are maintained on valproateorcarbamazepineand unexpectedly become pregnant, we suggest

switching medications. We typically titrate up the new drug as rapidly as tolerated, and then taper and discontinue the

antiepileptic over the course of a few days. The antiepileptic is decreased the same amount for each dose reduction. As an

example, valproate 1500 mg per day is decreased by 500 mg every one to two days. The choice of a new drug is discussed

elsewhere in this topic, as is management of patients who decline switching medications. (See 'Specific drugs'above and

'Switching from valproate or carbamazepine to less teratogenic drugs'above.)

Bipolar patients who unexpectedly become pregnant may decide to discontinue maintenance pharmacotherapy. However,

stopping medications (particularly over a period of less than two weeks) may increase the risk of recurrent mood episodes.

(See "Bipolar disorder in women: Contraception and preconception assessment and counseling", section on 'Relapse after

discontinuing pharmacotherapy'.)

Determining the gestational age will inform the decision to use maintenance pharmacotherapy in bipolar patients with

unplanned pregnancies. The period of greatest risk for the teratogenic effects of medications is between the third and eighth

week of gestation (weeks of gestation are counted from the first day of the last menstrual period) (figure 1and figure 2).

Many unplanned pregnancies are discovered after this period of greatest r isk has passed [1,49]; thus, discontinuing or

switching treatment at this point often puts the mother at risk for relapse of a mood episode and provides minimal benefit to

the fetus [42].

FOLIC ACID SUPPLEMENTATION Folic acidis recommended for every woman planning to conceive a child and is

discussed separately. (See "Nutrition in pregnancy", section on 'Folic acid'and "Folic acid for prevention of neural tube

defects"and "Management of epilepsy and pregnancy", section on 'Folic acid supplementation'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond

the Basics. The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they

answer the four or five key questions a patient might have about a given condition. These articles are best for patients who

want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are

longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best

for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to

your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the

keyword(s) of interest.)

These educational materials can be used as part of psychoeducational psychotherapy. (See "Bipolar disorder in adults:

Maintenance treatment", section on 'Psychoeducation'.)

The National Institute of Mental Health also has educational material explaining the symptoms, course of illness, and

treatment of bipolar disorder in a booklet entitled "Bipolar Disorder," which is available online at the website

http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml or through a toll-free number,

866-615-6464. The web site also provides references, summaries of study results in language intended for the lay public,

and information about clinical trials currently recruiting patients.

More comprehensive information is provided in many books written for patients and family members, including The Bipolar

Disorder Survival Guide: What You and Your Family Need to Know, written by David J. Miklowitz, PhD (published by The

Guilford Press, 2002); An Unquiet Mind: A Memoir of Moods and Madness, written by Kay Jamison, PhD (published by

Random House, 1995); and Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by RM Post, MD, and GS

Leverich, LCSW (published by Norton Press, 2008).

The Depression and Bipolar Support Alliance (http://www.dbsalliance.orgor 800-826-3632) is a national organization that

educates members about bipolar disorder and how to cope with it. Other functions include increasing public awareness of

the illness and advocating for more research and services. The organization is administered and maintained by patients and

family members, and has local chapters.

The National Alliance on Mental Illness (http://www.nami.orgor 800-950-6264) is a similarly structured organization devoted

to education, support, and advocacy for patients with any mental illness. Bipolar disorder is one of their priorities.

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topics (See "Patient information: Bipolar disorder (The Basics)"and "Patient information: Reducing the costs of

medicines (The Basics)".)

Beyond the Basics topics (See "Patient information: Bipolar disorder (manic depression) (Beyond the Basics)"and

"Patient information: Reducing the costs of medicines (Beyond the Basics)".)


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Topic 16971 Version 5.0

Bipolar disorder is characterized by episodes of mania ( table 1), hypomania (table 2), and major depression (table 3).

(See 'Definition of bipolar disorder'above and "Bipolar disorder in adults: Assessment and diagnosis", section on

'Diagnosis'.)

Bipolar disorder is a highly recurrent illness. For bipolar patients who plan to or do become pregnant, we suggest

maintenance pharmacotherapy rather than no treatment (Grade 2C). However, for patients with a mild lifetime course

of illness, it is reasonable to try to avoid pharmacotherapy during pregnancy. (See 'General principles'above and

"Bipolar disorder in women: Indications for preconception and prenatal maintenance pharmacotherapy"and 'Risks of

avoiding pharmacotherapy'above.)

In prescribing preconception or prenatal maintenance pharmacotherapy for bipolar patients, clinicians should attempt to

use drugs with fewer known teratogenic effects, monotherapy, and doses at the low end of the therapeutic range.

Following the first trimester, the risk of teratogenesis decreases and it is safer to prescribe drug combinations and

higher doses. (See 'General principles'above.)

Valproateand carbamazepineare generally regarded as teratogens. For stable bipolar patients who plan to or do

become pregnant and are currently treated with valproate and carbamazepine, we suggest switching treatment to a

less teratogenic drug rather than maintaining valproate or carbamazepine (Grade 2C). However, it is reasonable to

maintain valproate or carbamazepine for patients with a history of poor outcomes using other medications. (See

'Switching from valproate or carbamazepine to less teratogenic drugs'above.)

For bipolar patients who plan to or do become pregnant, we suggest lamotrigineas first line maintenance treatmentrather than other medications (Grade 2C). (See 'First line'above.)

For patients who are unresponsive to or intolerant of lamotrigine, we suggest quetiapineorrisperidonerather than

other medications (Grade 2C). (See 'Resistant patients'above.)

For refractory patients who do not respond to sequential maintenance treatment trials with lamotrigine, quetiapine, and

risperidone, lithiumis a reasonable option. Although lithium is generally regarded as teratogenic due to increased risks

of cardiac defects, the absolute risk is considered low. (See 'Refractory patients'above.)

For bipolar patients with unplanned pregnancies, determining the gestational age will inform the decision to use

maintenance pharmacotherapy. The period of greatest r isk for the teratogenic effects of medications is between the

third and eighth week of gestation ( figure 1and figure 2). (See 'Unplanned pregnancies'above.)

Every woman planning to conceive a child should receive folic acid. (See "Nutrition in pregnancy", section on 'Folic acid'

and "Folic acid for prevention of neural tube defects"and "Management of epilepsy and pregnancy", section on 'Folic

acid supplementation'.)


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GRAPHICS

DSM-5 diagnostic criteria for manic episode

A.A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally

and persistently increased goal-directed activity or energy, lasting at least one week and present most of

the day, nearly every day (or any duration if hospitalization is necessary).

B.During the period of mood disturbance and increased energy or activity, three (or more) of the following

symptoms (four if the mood is only irritable) are present to a significant degree and represent a noticeablechange from usual behavior:

1) Inflated self-esteem or grandiosity.

2) Decreased need for sleep (eg, feels rested after only three hours of sleep).

3) More talkative than usual or pressure to keep talking.

4) Flight of ideas or subjective experience that thoughts are racing.

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli), as reported

or observed.

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation (ie, purposeless non-goal-directed activity).

7) Excessive involvement in activities that have a high potential for painful consequences (eg, engaging

in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

C.The mood disturbance is sufficiently severe to cause marked impairment in social or occupational

functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic

features.

D.The episode is not attributable to the physiological effects of a substance (eg, a drug of abuse, a

medication, other treatment) or to another medical condition.

NOTE:A full manic episode that emerges during antidepressant treatment (eg, medication,

electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect of that

treatment is sufficient evidence for a manic episode and, therefore, a bipolar I diagnosis.

NOTE:Criteria A through D constitute a manic episode. At least one lifetime manic episode is

required for the diagnosis of bipolar I disorder.Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association. All Rights Reserved.


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DSM-5 diagnostic criteria for hypomanic episode

A.A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally

and persistently increased activity or energy, lasting at least four consecutive days and present most of the

day, nearly every day.

B.During the period of mood disturbance and increased energy and activity, three (or more) of the

following symptoms (four if the mood is only irritable) have persisted, represent a noticeable change from

usual behavior, and have been present to a significant degree:

1) Inflated self-esteem or grandiosity.

2) Decreased need for sleep (eg, feels rested after only three hours of sleep).

3) More talkative than usual or pressure to keep talking.

4) Flight of ideas or subjective experience that thoughts are racing.

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli), as reported

or observed.

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation.

7) Excessive involvement in activities that have a high potential for painful consequences (eg, engaging

in unrestrained buying sprees, sexual indiscretions, or foolish business investments).

C.The episode is associated with an unequivocal change in functioning that is uncharacteristic of the

individual when not symptomatic.

D.The disturbance in mood and the change in functioning are observable by others.

E.The episode is not severe enough to cause marked impairment in social or occupational functioning or to

necessitate hospitalization. If there are psychotic features, the episode is, by definition, manic.

F.The episode is not attributable to the physiological effects of a substance (eg, a drug of abuse, a

medication, or other treatment).

NOTE:A full hypomanic episode that emerges during antidepressant treatment (eg, medication,

electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect of that

treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is indicated so that

one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant

use) are not taken as sufficient for a diagnosis of a hypomanic episode, nor necessarily indicative of a

bipolar diathesis.

NOTE:Criteria A through F constitute a hypomanic episode. Hypomanic episodes are common in

bipolar I disorder but are not required for the diagnosis of bipolar I disorder.Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association. All Rights Reserved.


23 02/12/2013 04:43


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DSM-5 diagnostic criteria for bipolar major depression

A.Five (or more) of the following symptoms have been present during the same two-week period and

represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or

(2) loss of interest or pleasure.

NOTE:Do not include symptoms that are clearly attributable to another medical condition.

1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels

sad, empty, hopeless) or observations made by others (eg, appears tearful). (NOTE: In children and

adolescents can be irritable mood.)

2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every

day (as indicated by either subjective account or observation)

3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5 percent of body

weight in a month), or decrease or increase in appetite nearly every day. (NOTE: In children, consider

failure to make expected weight gain.)

4) Insomnia or hypersomnia nearly every day

5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective

feelings of restlessness or being slowed down)

6) Fatigue or loss of energy nearly every day

7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every

day (not merely self-reproach or guilt about being sick)

8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their

subjective account or as observed by others)

9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan,

or a suicide attempt or a specific plan for committing suicide

B.The symptoms cause clinically significant distress or impairment in social, occupational, or other

important areas of functioning.

C.The episode is not attributable to the direct physiological effects of a substance or to another medical

condition.

NOTE:Criteria A through C represent a major depressive episode.

NOTE:Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a

serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss,

insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode.

Although such symptoms may be understandable or considered appropriate to the loss, the presence of a

major depressive episode in addition to the normal response to a significant loss should also be carefully

considered. This decision inevitably requires the exercise of clinical judgement based on the individual's

history and the cultural norms for the expression of distress in the context of loss.

D.The occurence of the major depressive episode is not better explained by schizoaffective disorder,

schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified

schizophrenia spectrum and other psychotic disorders.

Specify:

With anxious distress

With mixed features

With rapid cycling

With melancholic features

With atypical features

With psychotic features

With catatonia

With peripartum onset

With seasonal pattern

Adapted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright


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2013). American Psychiatric Association. All Rights Reserved.


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Selected adverse effects of antipsychotic medications for schizophrenia

Weight

gain/diabetes

mellitus

Hyper-

cholesterolemiaEPS/TD

Prolactin

elevationSedation

An

First generation agents

Chlorpromazine +++ +++ + ++ +++

Fluphenazine + + +++ +++ +

Haloperidol + + +++ +++ ++

Loxapine ++ ND ++ ++ ++

Perphenazine ++ ND ++ ++ ++

Pimozide + ND +++ ++ +

Thioridazine* ++ ND + +++ +++

Thiothixene ++ ND +++ ++ +

Trifluoperazine ++ ND +++ ++ +

Second generation agents

Aripiprazole + +

Asenapine + + ++ ++

Clozapine +++ +++ +++

Iloperidone ++ ++ + +

Lurasidone + + ++

Olanzapine +++ +++ + ++

Paliperidone ++ + ++ +++ +

Quetiapine ++ +++ ++

Risperidone ++ + ++ +++ +

Ziprasidone + + +

Adverse effects may be dose dependent.EPS: extrapyramidal symptoms; TD: tardive dyskinesia; ND: no data.* Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to text. Clozapine also causes granulocytopenia or agranulocytosis in approximately 1 percent of patients requiring regularblood cell count monitoring.Adapted from:

Treatment Guidelines from The Medical Letter, August 2010; Vol. 8 (96):61. www.medicalletter.org.1.

[1]


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Normal reference ranges in pregnant women

Nonpregnant

adult*

First

trimester

Second

trimester

Third

trimesterReferences

Hematology

Erythropoietin (U/L) 4-27 12-25 8-67 14-222 1-3

Ferritin (ng/mL) 10-150 6-130 2-230 0-116 1-8

Folate, red blood cell

(ng/mL)

150-450 137-589 94-828 109-663 6, 9, 10

Folate, serum (ng/mL) 5.4-18.0 2.6-15.0 0.8-24.0 1.4-20.7 1, 6, 9-13

Hemoglobin (g/dL) 12-15.8 11.6-13.9 9.7-14.8 9.5-15.0 2, 3, 6, 7, 13

Hematocrit (percent) 35.4-44.4 31.0-41.0 30.0-39.0 28.0-40.0 1, 2, 5, 6,

13-15

Iron, total binding

capacity (g/dL)

251-406 278-403 Not reported 359-609 7

Iron, serum (g/dL) 41-141 72-143 44-178 30-193 2, 7

Mean corpuscular

hemoglobin (pg/cell)

27-32 30-32 30-33 29-32 5

Mean corpuscular

volume (xm )

79-93 81-96 82-97 81-99 5, 6, 13, 14

Platelet (x10 /L) 165-415 174-391 155-409 146-429 5, 6, 14, 16, 17

Mean platelet volume

(m )

6.4-11.0 7.7-10.3 7.8-10.2 8.2-10.4 5

Red blood cell count

(x10 /mm )

4.00-5.20 3.42-4.55 2.81-4.49 2.71-4.43 5, 6, 13, 14

Red cell distribution

width (percent)


14/23

Factor VIII (percent) 50-150 90-210 97-312 143-353 17, 25

Factor IX (percent) 50-150 103-172 154-217 164-235 17

Factor XI (percent) 50-150 80-127 82-144 65-123 17

Factor XII (percent) 50-150 78-124 90-151 129-194 17

Fibrinogen (mg/dL) 211-496 244-510 291-538 301-696 5, 17, 20, 21,

23, 24, 87

Homocysteine (mol/L) 4.4-10.8 3.34-11 2.0-26.9 3.2-21.4 6, 9, 10-12

International

Normalized Ratio

0.9-1.04 0.86-1.08 0.83-1.02 0.80-1.09 19, 24

Partial thromboplastin

time, activated (sec)

26.3-39.4 23.0-38.9 22.9-38.1 22.6-35.0 5, 17, 19, 24

Plasminogen activator

inhibitor-1 (PAI-1)

antigen (pg/mL)

17.3 +/ 5.7 17.7 +/ 1.9 Not reported 66.4 +/ 4.9 87

Plasminogen activator

inhibitor-1 (PAI-1)

activity (arbitrary units)

9.3 +/ 1.9 9.0 +/ 0.8 Not reported 31.4 +/ 3.0 87

Prothrombin time (sec) 12.7-15.4 9.7-13.5 9.5-13.4 9.6-12.9 5, 17, 24

Protein C, functional

(percent)

70-130 78-121 83-133 67-135 19, 25, 26

Protein S, total

(percent)

70-140 39-105 27-101 33-101 17, 25, 26

Protein S, free (percent) 70-140 34-133 19-113 20-65 25, 26

Protein S, functional

activity (percent)

65-140 57-95 42-68 16-42 25

Tissue plasminogen

activator (ng/mL)

1.6-13 1.8-6.0 2.36-6.6 3.34-9.20 17, 19, 87

Tissue plasminogen

activator inhibitor-1

(ng/mL)

4-43 16-33 36-55 67-92 17

von Willebrand measurements

von Willebrand factor

antigen (percent)

75-125 62-318 90-247 84-422 20, 27, 28

ADAMTS-13, von

Willebrand cleaving

protease

40-170 40-160 22-135 38-105 20, 28

Blood chemical constituents

Alanine transaminase

(U/L)

7-41 3-30 2-33 2-25 4, 5, 8, 29

Albumin (g/dL) 4.1-5.3 3.1-5.1 2.6-4.5 2.3-4.2 29-32

Alkaline phosphatase

(U/L)

33-96 17-88 25-126 38-229 4, 5, 8, 29, 30

Alpha-1 antitrypsin

(mg/dL)

100-200 225-323 273-391 327-487 5

Amylase (U/L) 20-96 24-83 16-73 15-81 4, 5, 33, 34

Anion gap (mmol/L) 7-16 13-17 12-16 12-16 5

Aspartate transaminase

(U/L)

12-38 3-23 3-33 4-32 4, 5, 8, 29


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Bicarbonate (mmol/L) 22-30 20-24 20-24 20-24 5

Bilirubin, total (mg/dL) 0.3-1.3 0.1-0.4 0.1-0.8 0.1-1.1 4, 29

Bilirubin, unconjugated

(mg/dL)

0.2-0.9 0.1-0.5 0.1-0.4 0.1-0.5 5, 29

Bilirubin, conjugated

(mg/dL)

0.1-0.4 0-0.1 0-0.1 0-0.1 29

Bile acids (mol/L) 0.3-4.8 0-4.9 0-9.1 0-11.3 29, 35

CA-125 antigen (/mL) 7.2-27.0 2/2-268 12-25.1 16.8-43.8 88, 89, 90

Calcium, ionized

(mg/dL)

4.5-5.3 4.5-5.1 4.4-5.0 4.4-5.3 5, 31, 36, 37

Calcium, total (mg/dL) 8.7-10.2 8.8-10.6 8.2-9.0 8.2-9.7 4, 5, 30, 32,

36-38

Ceruloplasmin (mg/dL) 25-63 30-49 40-53 43-78 5, 39

Chloride (mEq/L) 102-109 101-105 97-109 97-109 4, 5, 40

Creatinine (mg/dL) 0.5-0.9 0.4-0.7 0.4-0.8 0.4-0.9 4, 5, 46

Gamma-glutamyltranspeptidase (U/L)

9-58 2-23 4-22 3-26 4, 5, 8, 29

Lactate dehydrogenase

(U/L)

115-221 78-433 80-447 82-524 4, 5, 32, 8

Lipase (U/L) 3-43 21-76 26-100 41-112 33

Magnesium (mg/dL) 1.5-2.3 1.6-2.2 1.5-2.2 1.1-2.2 4, 5, 30-32, 36,

38

Osmolality (mOsm/kg

H20)

275-295 275-280 276-289 278-280 38, 41

Phosphate (mg/dL) 2.5-4.3 3.1-4.6 2.5-4.6 2.8-4.6 4, 5, 30, 31, 42

Potassium (mEq/L) 3.5-5.0 3.6-5.0 3.3-5.0 3.3-5.1 4, 5, 15, 31,

32, 38, 40

Prealbumin (mg/dL) 17-34 15-27 20-27 14-23 5

Protein, total (g/dL) 6.7-8.6 6.2-7.6 5.7-6.9 5.6-6.7 5, 31, 32

Sodium (mEq/L) 136-146 133-148 129-148 130-148 4, 5, 15, 31,

32, 38, 41

Urea nitrogen (mg/dL) 7-20 7-12 3-13 3-11 4, 5, 40

Uric acid (mg/dL) 2.5-5.6 2.0-4.2 2.4-4.9 3.1-6.3 4, 5, 41

Metabolic and endocrine tests

Aldosterone (ng/dL) 2-9 6-104 9-104 15-101 43, 44, 45

Angiotensin converting

enzyme (U/L)

9-67 1-38 1-36 1-39 39, 46

Alpha-fetoprotein

(ng/mL)

0-8.5 Not reported 50-425 50-590 84, 86

Cortisol (g/dL) 0-25 7-19 10-42 12-50 5, 45

Hemoglobin A

(percent)

4-6 4-6 4-6 4-7 36, 47, 48

Parathyroid hormone

(pg/mL)

8-51 10-15 18-25 9-26 30

Parathyroid hormone-

related protein (pmol/L)


16/23

Renin, plasma activity

(ng/mL/h)

0.3-9.0 Not reported 7.5-54.0 5.9-58.8 40, 44

Thyroid-stimulating

hormone (IU/mL)

[American Thyroid

Association

recommendation]**

0.34-4.25 0.60-3.40 0.37-3.60 0.38-4.04 4, 5, 49

0.1-2.5 0.2-3.0 0.3-3.0 85

Thyroxine-binding

globulin (mg/dL)

1.3-3.0 1.8-3.2 2.8-4.0 2.6-4.2 5

Thyroxine, free (ng/dL) 0.8-1.7 0.8-1.2 0.6-1.0 0.5-0.8 5, 49

Thyroxine, total (g/dL) 5.4-11.7 6.5-10.1 7.5-10.3 6.3-9.7 5, 32

Triiodothyronine, free

(pg/mL)

2.4-4.2 4.1-4.4 4.0-4.2 Not reported 49

Triiodothyronine, total

(ng/dL)

77-135 97-149 117-169 123-162 5

Vitamins and minerals

Copper (g/dL) 70-140 112-199 165-221 130-240 50, 51, 5

Selenium (g/L) 63-160 116-146 75-145 71-133 5, 50

Vitamin A (retinol)

(g/dL)

20-100 32-47 35-44 29-42 5

Vitamin B12 (pg/mL) 279-966 118-438 130-656 99-526 6, 10

Vitamin C (ascorbic

acid) (mg/dL)

0.4-1.0 Not reported Not reported 0.9-1.3 52

Vitamin D,

1,25-dihydroxy (pg/mL)

25-45 20-65 72-160 60-119 30, 36

Vitamin D, 24,25-

dihydroxy (ng/mL)

0.5-5.0 1.2-1.8 1.1-1.5 0.7-0.9 53

Vitamin D, 25-hydroxy

(ng/mL)

14-80 18-27 10-22 10-18 30, 53

Vitamin E (-tocopherol)

(g/mL)

5-18 7-13 10-16 13-23 5

Zinc (g/dL) 75-120 57-88 51-80 50-77 5, 13, 50

Autoimmune and inflammatory mediators

C3 complement (mg/dL) 83-177 62-98 73-103 77-111 5

C4 complement (mg/dL) 16-47 18-36 18-34 22-32 5

C-reactive protein

(mg/L)

0.2-3.0 Not reported 0.4-20.3 0.4-8.1 54

Erythrocyte

sedimentation rate

(mm/h)

0-20 4-57 7-47 13-70 55

Immunoglobulin A

(mg/dL)

70-350 95-243 99-237 112-250 5

Immunoglobulin G

(mg/dL)

700-1700 981-1267 813-1131 678-990 5

Immunoglobulin M

(mg/dL)

50-300 78-232 74-218 85-269 5

Sex hormones


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Dehydroepiandrosterone

sulfate (mol/L)

1.3-6.8 2.0-16.5 0.9-7.8 0.8-6.5 56

Estradiol (pg/mL)


18/23

Left vent, fractional

shortening (percent)

35-36 35-37 3.5 35-36 69, 70

Left vent ejection

fraction (percent)

60-73 61-75 61-63 60-73 69, 70

Atrial natriuretic peptide

(pg/mL)

Not reported Not reported 28.1-70.1 Not reported 73

B-type natriuretic

peptide (pg/mL)


19/23

reactive fibrinolysis . References values are from Cerneca et al and Choi et al: Tissue plasminogen activator levels change with plasmafibrinogen concentrations during pregnancy . Reference values are from Mannuci et al: Changes in health and disease of the metalloprotease that cleaves vonWillebrand factor . Reference values are from Bacq Y et al: Liver function tests in normal pregnancy: a prospective study of 102pregnant women and 102 matched controls . Reference values are from the fi fteenth edition ofHarrison's Principles of Internal Medicine .** The American Thyroid Association recommends these TSH ranges if individual laboratories do not determine theirown trimester-specific reference ranges. Range is for premenopausal females and varies by menstrual cycle phase. Reference values are from Leiserowitz GS et al: Creatine kinase and its MB isoenzyme in the third trimester andthe peripartum period .Reference values are from Dunlop W: Serial changes in renal haemodynamics during normal humanpregnancy .References:

[19]

[17,19]

[28]

[29]

[85]

[74]

[79]


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20/23

Beguin Y, Lipscei G, Thourmsin H, et al: Blunted erythropoietin production and decreased erythropoiesis in earlypregnancy. Blood 78(1):89, 1991.

1.

Bianco I, Mastropietro F, D'Aseri C, et al: Serum levels of erythropoietin and soluble transferrin receptor duringpregnancy in non--thalassemic and -thalassemic women. Haematologica 85:902, 2000 [PMID: 10980626].

2.

Milman N, Graudal N, Nielsen OJ: Serum erythropoietin during normal pregnancy: Relationship to hemoglobinand iron status markers and impact of iron supplementation in a longitudinal, placebo-controlled study on 118women. Int J Hematol 66:159, 1997 [PMID: 9277046].

3.

Larsson A, Palm M, Hansson L-O, et al: Reference values for clinical chemistry tests during normal pregnancy.BJOG 115:874, 2008 [PMID: 18485166].

4.

Lockitch G: Handbook of Diagnostic Biochemistry and Hematology in Normal Pregnancy. Boca Raton, FL, CRCPress, 1993.

5.

Milman N, Bergholt T, Byg KE, et al: Reference intervals for haematological variables during normal pregnancyand postpartum in 434 healthy Danish women. Eur J Haematol 79:39, 2007 [PMID: 17598837].

6.

Romslo I, Haram K, Sagen N, et al: Iron requirement in normal pregnancy as assessed by serum ferritin, serumtransferring saturation and erythrocyte protoporphyrin determinations. Br J Obstet Gynaecol 90:101, 1983[PMID: 6824608].

7.

Van Buul EJA, Steegers EAP, Jongsma HW, et al: Haematological and biochemical profile of uncomplicatedpregnancy in nulliparous women; a longitudinal study. Neth J Med 46:73, 1995.

8.

Milman N, Byg KE, Hvas AM, et al: Erythrocyte folate, plasma folate and plasma homocysteine during normalpregnancy and postpartum: A longitudinal study comprising 404 Danish women. Eur J Haematol 76:200, 2006[PMID: 16412135].

9.

Walker MC, Smith GN, Perkins SL, et al: Changes in homocysteine levels during normal pregnancy. Am J ObstetGynecol 180:660, 1999 [PMID: 10076144].

10.

Lpez-Quesada E, Vilaseca MA, Lailla JM: Plasma total homocysteine in uncomplicated pregnancy and inpreeclampsia. Eur J Obstet Gynecol Reprod Biol 108:45, 2003 [PMID: 19899161].

11.

zerol E, zerol I, Gkdeniz R, et al: Effect of smoking on serum concentrations of total homocysteine, folate,vitamin B12, and nitric oxide in pregnancy: A preliminary study. Fetal Diagn Ther 19:145, 2004.

12.

Qvist I, Abdulla M, Jgerstad M, et al: Iron, zinc and folate status during pregnancy and two months afterdelivery. Acta Obstet Gynecol Scand 65:15, 1986 [PMID: 3716775].

13.

Balloch AJ, Cauchi MN: Reference ranges for haematology parameters in pregnancy derived from patientpopulations. Clin Lab Haemat 15:7, 1993 [PMID: 8472501].

14.

Singh HJ, Mohammad NH, Nila A: Serum calcium and parathormone during normal pregnancy in Malay women.J Matern Fetal Med 8:95, 1999 [PMID: 10338062].

15.

AzizKarim S, Khurshid M, Rizvi JH, et al: Platelets and leucocyte counts in pregnancy. J Pak Med Assoc 42:86,1992.

16.

Choi JW, Pai SH: Tissue plasminogen activator levels change with plasma fibrinogen concentrations duringpregnancy. Ann Hematol 81:611, 2002 [PMID: 12454697].

17.

Belo L, Santos-Silva A, Rocha S, et al: Fluctuations in C-reactive protein concentration and neutrophil activationduring normal human pregnancy. Eur J Obstet Gynecol Reprod Biol 123:46, 2005 [PMID: 16260340].

18.

Cerneca F, Ricci G, Simeone R, et al: Coagulation and fibrinolysis changes in normal pregnancy increased levelsof procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combinedwith a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 73:31, 1997 [PMID: 9175686].

19.

Lattuada A, Rossi E, Calzarossa C, et al: Mild to moderate reduction of a von Willebrand factor cleaving protease(ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 88(9):1029, 2003.

20.

Francalanci I, Comeglio P, Liotta AA, et al: D-Dimer concentrations during normal pregnancy, as measured byELISA. Thromb Res 78:399, 1995 [PMID: 7660356].

21.

Kline JA, Williams GW, Hernandez-Nino J: D-Dimer concentrations in normal pregnancy: New diagnosticthresholds are needed. Clin Chem 51:825, 2005 [PMID: 15764641].

22.

Morse M: Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonaryembolism and deep vein thrombosis. J Thromb Haemost 2:1202, 2004 [PMID: 15219216].

23.

Liu XH, Jiang YM, Shi H, et al: Prospective, sequential, longitudinal study of coagulation changes duringpregnancy in Chinese women. Int J Gynaecol Obstet 105(3):240, 2009.

24.

Lefkowitz JB, Clarke SH, Barbour LA: Comparison of protein S functional and antigenic assays in normalpregnancy. Am J Obstet Gynecol 175:657, 1996 [PMID: 8828430].

25.

Faught W, Garner P, Jones G, et al: Changes in protein C and protein S levels in normal pregnancy. Am J ObstetGynecol 172:147, 1995 [PMID: 7847526].

26.

Wickstrm K, Edelstam G, Lwbeer CH, et al: Reference intervals for plasma levels of fibronectin, von Willebrandfactor, free protein S and antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest 64:31, 2004[PMID: 13035697].

27.

Mannucci PM, Canciani MT, Forza I, et al: Changes in health and disease of the metalloprotease that cleaves von

Willebrand factor. Blood 98(9):2730, 2001.

28.

Bacq Y, Zarka O, Brchot JF, et al: Liver function tests in normal pregnancy: A prospective study of 102pregnant women and 102 matched controls. Hepatology 23:1030, 1996 [PMID: 8621129].

29.

Ardawi MSM, Nasrat HAN, BA'Aqueel HS: Calcium-regulating hormones and parathyroid hormone-relatedpeptide in normal human pregnancy and postpartum: A longitudinal study. Eur J Endocrinol 137:402, 1997[PMID: 9368509].

30.

Handwerker SM, Altura BT, Altura BM: Serum ionized magnesium and other electrolytes in the antenatal periodof human pregnancy. J Am Coll Nutr 15:36, 1996 [PMID: 8632112].

31.

Hytten FE, Lind T: Diagnostic Indices in Pregnancy. Summit, NJ, CIBA-GEIGY Corporation, 1975.32.Karsenti D, Bacq Y, Brchot JF, et al: Serum amylase and lipase activities in normal pregnancy: A prospectivecase-control study. Am J Gastroenterol 96:697, 2001 [PMID: 11280536].

33.

Strickland DM, Hauth JC, Widish J, et al: Amylase and isoamylase activities in serum of pregnant women.Obstet Gynecol 63:389, 1984 [PMID: 6199704].

34.

Carter J: Serum bile acids in normal pregnancy. BJOG 98:540, 1991 [PMID: 1873244].35.Mimouni F, Tsang RC, Hertzbert VS, et al: Parathyroid hormone and calcitriol changes in normal and insulin-dependent diabetic pregnancies. Obstet Gynecol 74:49, 1989 [PMID: 2733941].

36.

Pitkin RM, Gebhardt MP: Serum calcium concentrations in human pregnancy. Am J Obstet Gynecol 127:775,1977 [PMID: 848531].

37.

Shakhmatova EI, Osipova NA, Natochin YV: Changes in osmolality and blood serum ion concentrations inpregnancy. Hum Physiol 26:92, 2000.

38.

Louro MO, Cocho JA, Tutor JC: Assessment of copper status in pregnancy by means of determining the specificoxidase activity of ceruloplasmin. Clin Chim Acta 312:123, 2001 [PMID: 11580917].

39.

Dux S, Yaron A, Carmel A, et al: Renin, aldosterone, and serum-converting enzyme activity during normal and

40.


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Modified and reproduced with permission from: Abbassi-Ghanavati M, Greer LG. Reference Table of Normal LaboratoryValues in Uncomplicated Pregnancies. In: Cunningham FG, Leveno KJ, Bloom S, Hauth JC, Rouse DJ, Spong CY.Williams Obstetrics, 23rd Edition. New York: McGraw-Hill, 2010. Copyright 2010 The McGraw-Hill Companies, Inc.


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Periods of sensitivity during development

Reproduced with permission from: Unborn Patient: Prenatal Diagnosis and Treatment.Harrison, Golbus, Filly (eds). Philadelphia, Saunders, 1990. p. 44. Copyright 1990 Elsevier.


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The developing fetus

Reproduced with permission from: Moore, K. The developing human: Clinically orientedembryology, WB Saunders, Philadelphia 1982. Copyright 1982 Elsevier.


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