How should I treat acute agitation in pregnancy?

FOCUS OF THE EMERGENCY EVALUATION

Agitation is defined as the physical manifestation of internal distress, due to an underlying medical condition such as delirium or to a psychiatric condition such as acute intoxication or withdrawal, psychosis, mania, or personality disorder.⁴

For the agitated pregnant woman who is not belligerent at presentation, triage should start with a basic assessment of airways, breathing, and circulation, as well as vital signs and glucose level.⁵ A thorough medical history and a description of events leading to the presentation, obtained from the patient or the patient’s family or friends, are vital for narrowing the diagnosis and deciding treatment.

The initial evaluation should include consideration of delirium, trauma, intracranial hemorrhage, coagulopathy, thrombocytopenia, amniotic and venous thromboembolism, hypoxia and hypercapnia, and signs and symptoms of intoxication or withdrawal from substances such as alcohol, cocaine, phencyclidine, methamphetamine, and substituted cathinones (“bath salts”). From 20 weeks of gestation to 6 weeks postpartum, eclampsia should also be considered in the differential diagnosis.¹ Ruling out these conditions is important since the management of each differs vastly from the protocol for agitation secondary to psychosis, mania, or delirium.

NEW SYSTEM TO DETERMINE RISK DURING PREGNANCY, LACTATION

The US Food and Drug Administration (FDA) has discontinued its pregnancy category labeling system that used the letters A, B, C, D, and X to convey reproductive and lactation safety. The new system, established under the FDA Pregnancy and Lactation Labeling Rule,⁶ provides descriptive, up-to-date explanations of risk, as well as previously absent context regarding baseline risk for major malformations in the general population to help with informed decision-making.⁷ This allows the healthcare provider to interpret the risk for an individual patient.

FIRST-GENERATION ANTIPSYCHOTICS SAFE, EFFECTIVE IN PREGNANCY

Reproductive safety of first-generation (ie, typical) neuroleptics such as haloperidol is supported by extensive data accumulated over the past 50 years.^2,3,8 No significant teratogenic effect has been documented with this drug class,⁷ although a 1996 meta-analysis found a small increase in the relative risk of congenital malformations in offspring exposed to low-potency antipsychotics compared with those exposed to high-potency antipsychotics.²

In general, mid- and high-potency antipsychotics (eg, haloperidol, perphenazine) are often recommended because they are less likely to have associated sedative or hypotensive effects than low-potency antipsychotics (eg, chlorpromazine, perphenazine), which may be a significant consideration for a pregnant patient.^2,8

There is a theoretical risk of neonatal extrapyramidal symptoms with exposure to first-generation antipsychotics in the third trimester, but the data to support this are from sparse case reports and small observational cohorts.⁹

NEWER ANTIPSYCHOTICS ALSO SAFE IN PREGNANCY

Newer antipsychotics such as the second-generation antipsychotics, available since the mid-1990s, are increasingly used as primary or adjunctive therapy across a wide range of psychiatric disorders.¹⁰ Recent data from large, prospective cohort studies investigating reproductive safety of these agents are reassuring, with no specific patterns of organ malformation.^11,12

DIPHENHYDRAMINE

Recent studies of antihistamines such as diphenhydramine have not reported any risk of major malformations with first-trimester exposure to antihistamines.^13,14 Dose-dependent anticholinergic adverse effects of antihistamines can induce or exacerbate delirium and agitation, although these effects are classically seen in elderly, nonpregnant patients.¹⁵ Thus, given the paucity of adverse effects and the low risk, diphenhydramine is considered safe to use in pregnancy.¹³

BENZODIAZEPINES

Benzodiazepines are not contraindicated for the treatment of acute agitation in pregnancy.¹⁶ Reproductive safety data from meta-analyses and large population-based cohort studies have found no evidence of increased risk of major malformations in neonates born to mothers on prescription benzodiazepines in the first trimester.^17,18 While third-trimester exposure to benzodiazepines has been associated with “floppy-baby” syndrome and neonatal withdrawal syndrome,¹⁶ these are more likely to occur in women on long-term prescription benzodiazepine therapy. No study has yet assessed the risk of these outcomes with a 1-time acute exposure in the emergency department; however, the risk is likely minimal given the aforementioned data observed in women on long-term prescription benzodiazepine therapy.

STEPWISE MANAGEMENT OF AGITATION IN PREGNANCY

If untreated, agitation in pregnancy is independently associated with outcomes that include premature delivery, low birth weight, growth retardation, postnatal death, and spontaneous abortion.¹ The risk of these outcomes greatly outweighs any potential risk from psychotropic medications during pregnancy.

Nevertheless, intervention should progress in a stepwise manner, starting with the least restrictive and progressing toward more restrictive interventions, including pharmacotherapy, use of a seclusion room, and physical restraints (Figure 1).^4,19

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Figure 1

A stepwise approach to acute agitation in pregnancy.

Before medications are considered, attempts should be made to engage with and “deescalate” the patient in a safe, nonstimulating environment.¹⁹ If this approach is not effective, the patient should be offered oral medications to help with her agitation. However, if the patient’s behavior continues to escalate, presenting a danger to herself or staff, the use of emergency medications is clearly indicated. Providers should succinctly inform the patient of the need for immediate intervention.

If the patient has had a good response in the past to one of these medications or is currently taking one as needed, the same medication should be offered. If the patient has never been treated for agitation, it is important to consider the presenting symptoms, differential diagnosis, and the route and rapidity of administration of medication. If the patient has experienced a fall or other trauma, confirming a viable fetal heart rate between 10 to 22 weeks of gestation with Doppler ultrasonography and obstetric consultation should be considered.

DRUG THERAPY RECOMMENDATIONS

Mild to moderate agitation in pregnancy should be managed conservatively with diphenhydramine. Other options include a benzodiazepine, particularly lorazepam, if alcohol withdrawal is suspected. A second-generation antipsychotic such as olanzapine in a rapidly dissolving form or ziprasidone is another option if a rapid response is required.²⁰ Table 1 provides a summary of pharmacotherapy recommendations.

Severe agitation may require a combination of agents. A commonly used, safe regimen—colloquially called the “B52 bomb”—is haloperidol 5 mg, lorazepam 2 mg, and diphenhydramine 25 to 50 mg for prophylaxis of dystonia.²⁰

The patient’s response should be monitored closely, as dosing may require modification as a result of pregnancy-related changes in drug distribution, metabolism, and clearance.²¹

Although no study to our knowledge has as sessed risk associated with 1-time exposure to any of these classes of medications in pregnant women, the aforementioned data on long-term exposure provide reassurance that single exposure in emergency departments likely has little or no effect for the developing fetus.

PHYSICAL RESTRAINTS FOR AGITATION IN PREGNANCY

Physical restraints along with emergency medications (ie, chemical restraint) may be indicated when the patient poses a danger to herself or others. In some cases, both types of restraint may be required, whether in the emergency room or an inpatient setting.

However, during the second and third trimesters, physical restraints such as 4-point restraints may predispose the patient to inferior vena cava compression syndrome and compromise placental blood flow.⁴ Therefore, pregnant patients after 20 weeks of gestation should be positioned in the left lateral decubitus position, with the right hip positioned 10 to 12 cm off the bed with pillows or blankets. And when restraints are used in pregnant patients, frequent checking of vital signs and physical assessment is needed to mitigate risks.⁴