Caring For Two in The ICU Pharmacologic Management of Pregnancy-Related Complications

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Received: 12 December 2022 Revised: 11 May 2023 Accepted: 11 May 2023
DOI: 10.1002/phar.2837
REVIEW
Caring for two in the ICU: Pharmacologic management of

pregnancy-related complications
Mojdeh S. Heavner1 | Michaelia D. Cucci2 | Brooke Barlow3 |

Carolyn Magee Bell4 | Claire C. Eng5 | Grace Erdman6 | Matthew Li7 |
Susan E. Smith8 | Mohammed Aldhaeefi9 | Melissa L. Thompson Bastin10,11 |
W. Anthony Hawkins8,12 | Christina Rose13 | Allison Lankford14
1
University of Maryland School of
Pharmacy, Baltimore, Maryland, USA Abstract
2
Cleveland Clinic Akron General, Akron, Maternal mortality continues to be an issue globally despite advances in technology
Ohio, USA
3
and pharmacotherapy. Pregnancy can lead to complications that necessitate immedi-
Memorial Hermann Woodlands Medical
Center, Texas, USA ate action to prevent severe morbidity and mortality. Patients may need escalation
4
Medical University of South Carolina, to the ICU setting for close monitoring and administration of advanced therapies not
Charleston, South Carolina, USA
5
available elsewhere. Obstetric emergencies are rare but high-stakes events that re-
Memorial Hermann Sugar Land Hospital,
Sugar Land, Texas, USA quire clinicians to have prompt identification and management. The purpose of this
6
University of Maryland Medical Center, review is to describe complications of pregnancy and provide a focused resource
Baltimore, Maryland, USA
of pharmacotherapy considerations that clinicians may encounter. For each disease
7
Westchester Medical Center, Valhalla,
New York, USA
state, the epidemiology, pathophysiology, and management are summarized. Brief
8
University of Georgia College of descriptions of non-pharmacological (e.g., cesarean or vaginal delivery of the baby)
Pharmacy, Athens, Georgia, USA interventions are provided. Mainstays of pharmacotherapy highlighted include ox-
9
Clinical and Administrative Pharmacy
ytocin for obstetric hemorrhage, methotrexate for ectopic pregnancy, magnesium
Sciences, College of Pharmacy, Howard
University, Washington, DC, United States and antihypertensive agents for preeclampsia and eclampsia, eculizumab for atypi-
10
University of Kentucky HealthCare, cal hemolytic uremic syndrome, corticosteroids, and immunosuppressive agents for
Lexington, Kentucky, USA
11 thrombotic thrombocytopenic purpura, diuretics, metoprolol, and anticoagulation for
University of Kentucky College of
Pharmacy, Lexington, Kentucky, USA peripartum cardiomyopathy, and pulmonary vasodilators for amniotic fluid embolism.
12
Medical College of Georgia at Augusta
University, Albany, Georgia, USA KEYWORDS
13
Temple University School of Pharmacy, critical care, drug therapy, obstetric, pregnancy, pregnancy complications
Philadelphia, Pennsylvania, USA
14
University of Maryland School of
Medicine, Baltimore, Maryland, USA
Correspondence
Allison Lankford, Department of
Obstetrics, Gynecology and Reproductive
Sciences, University of Maryland School
of Medicine Ringgold, 655 West Baltimore
Street, Baltimore, MD 21201-1544, USA.
Email: allison.lankford@som.umaryland.
edu
Pharmacotherapy. 2023;00:1–16. wileyonlinelibrary.com/journal/phar |

© 2023 Pharmacotherapy Publications, Inc. 1
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2 HEAVNER et al.
1 | I NTRO D U C TI O N It is characterized by the trimester when it occurs, anatomical loca-

tion, and underlying pathology. Etiologies of vaginal bleeding include
Maternal mortality is a long-standing public health crisis but has been placenta previa, placenta accreta spectrum disorders, placental
slowly improving globally. However, the United States (US) continues abruption, uterine rupture, and vasa previa.
to see a rise in maternal mortality ratio (number of maternal deaths
per 100,000 live births) in contrast to what is observed in other indus-
trialized countries.1 Primary reasons for pregnant patients requiring 2.1.1 | Placenta previa
admission to an intensive care unit (ICU) include preeclampsia and ec-
lampsia, hemorrhage, cardiovascular conditions, and sepsis.2 In 2020, Placenta previa is a condition in which the placenta covers the inter-
a World Health Organization global survey on maternal and newborn nal cervical os (opening) and is a major risk factor for hemorrhage.
health indicated that ICU utilization was associated with a significant The classic presentation of placenta previa is painless vaginal bleed-
reduction in the odds of maternal death and severe maternal morbid- ing during the second or third trimester. Management of asymp-
ity (SMM) among obstetric patients with severe conditions.3 tomatic placenta previa includes planned cesarean delivery of the
An obstetric emergency is defined as a condition that necessi- fetus at 35 or 36 weeks. Earlier delivery before 34 weeks gestation
tates immediate action to prevent SMM or mortality. These patients may be required in cases with bleeding or presence of other placen-
may require ICU admission for increased monitoring and more ad- tal complications.10
vanced therapies. However, providers may not possess specialized
obstetrics training in this setting. Similarly, the pharmacy profession
has historically maintained limited involvement in obstetric pharma- 2.1.2 | Placenta accreta spectrum disorders
cotherapy despite evidence indicating that pharmacist involvement
can result in significant improvement of perinatal pregnancy-related Placenta accreta spectrum (PAS) disorders occur when either a por-
4,5
outcomes. While obstetric emergencies are considered to be rare tion of or the entire placenta invades the uterine wall and becomes
and high-stakes, pharmacists and other clinicians should be pre- inseparable.11 Risk factors for placenta accreta include history of
pared to provide the same high-quality care as routine encounters. uterine surgery, specifically previous cesarean deliveries, and pla-
The purpose of this review was to describe obstetric emergencies centa previa.12 Management involves appropriate multidisciplinary
clinicians may encounter in the ICU and serve as a pharmacotherapy preparation, anticipation for aggressive resuscitation, and plan for
resource for these specialized cases. prompt hysterectomy.13 Administration of blood products should be
Obstetric emergencies described in this review include hem- protocolized and administered in a fixed ratio consisting of packed
orrhage and associated etiologies, hypertensive emergencies, red blood cells (PRBC), fresh frozen plasma (FFP), and platelets.
microangiopathies, peripartum cardiomyopathy, amniotic fluid Cryoprecipitate should be considered in patients with a fibrinogen
embolism, and acute fatty liver of pregnancy. For each section, level < 150 mg/dL or when disseminated intravascular coagulation
the epidemiology, pathophysiology, and management are high- (DIC) is suspected.
lighted. Management includes a brief overview of surgical and non-
pharmacological standards of care, followed by an emphasis on
pharmacological options and considerations. Figure 1 visually high- 2.1.3 | Placental abruption
lights the pregnancy-related complications covered in this review
and Figure 2 provides a context of the maternal-fetal anatomy re- Placental abruption is a complete or partial premature separation
ferred to throughout. Table 1 is a summary of key pharmacotherapy of the placenta from the decidua before delivery of the fetus and
considerations for each obstetric emergency. occurs in approximately 1% of pregnancies. It is a significant cause
of obstetric hemorrhage, DIC, and fetal compromise secondary to
the loss of placental surface area for maternal-fetal exchange of
2 | O B S TE TR I C H E M O R R H AG E nutrients and oxygen. Risk factors for placental abruption include
advanced maternal age, multiparity, hypertensive disorders of preg-
Maternal hemorrhage (antepartum and postpartum) can occur in up nancy, preterm pre-labor rupture of membranes, cocaine or tobacco
to 32% of pregnancies, accounting for 11.4% of pregnancy-related use, and trauma.14 Definitive management of placental abruption is
deaths in the US and remains the leading cause for obstetric-related either vaginal or cesarean delivery of the infant and placenta, de-
ICU admissions.6–8 pending on the degree of maternal and fetal compromise.15
2.1 | Antepartum hemorrhage 2.1.4 | Uterine rupture
Antepartum hemorrhage complicates up to 25% of pregnancies.9 It Uterine rupture is a uterine wall defect characterized by spontane-
refers to vaginal bleeding that occurs anytime throughout pregnancy. ous tearing of the uterus that may result in the fetus being expelled
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HEAVNER et al. 3
F I G U R E 1 Obstetric emergencies: critical care management.11–105 Figure created with Biorender.com.
into the peritoneal cavity. The leading risk factor is a history of prior 2.2 | Postpartum hemorrhage
uterine surgery. Additional risk factors include Ehlers–Danlos syn-
drome and other connective tissue disorders, prolonged exposure Postpartum hemorrhage (PPH) is the most common cause of maternal
to high-dose oxytocin or prostaglandin, blunt abdominal trauma, mortality worldwide. The incidence of PPH is approximately 3% in the
and multiparity.16 Management for uterine rupture involves surgi- US.13 To achieve hemostasis following delivery of the placenta, en-
cal interventions; primary uterine repair, if possible, with some cases dogenous oxytocin, and prostaglandins stimulate uterine muscle con-
necessitating hysterectomy.17 tractions, resulting in compression of uterine vessels and subsequent
decrease in blood flow.20 The American College of Obstetricians and
Gynecologists (ACOG) defines PPH as a cumulative blood loss greater
2.1.5 | Vasa previa than or equal to 1 L following vaginal or cesarean delivery accompanied
by signs and symptoms of hypovolemia within 24 h after birth. It may
Vasa previa is a rare condition (1/2500 deliveries) characterized by also occur up to 6 weeks after delivery.13 The most common cause of
exposed fetal vessels that are not protected in Whartons jelly tra- PPH is uterine atony. Additional causes include perineal and cervical
versing the amniotic membranes and covering the internal cervical lacerations, retained products of conception, coagulopathy, and PAS.
os. These fetal vessels are extremely fragile; rupture is associated Uterine atony refers to the inadequate contraction of myometrial cells
18,19
with high fetal morbidity and mortality. Management of vasa in response to endogenous uterotonic agents. Risk factors include pro-
previa includes hospitalization between 30 and 34 weeks gestation longed use of oxytocin, high parity, polyhydramnios, multiple gesta-
to ensure immediate cesarean delivery in case of fetal membrane tions, and chorioamnionitis.13,21 Prevention of uterine atony includes
14
rupture. active management of the third stage of labor via administration of
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4 HEAVNER et al.
F I G U R E 2 Anatomy of a fetus in utero

and the female reproductive system.108,109
(A) Fetus in utero. (B) Female reproductive
system. Anticoagulation is recommended
for LVEF < 30% and acute heart failure
exacerbations; it is continued for
6–8 weeks postpartum.
oxytocin. Additional maneuvers to improve uterine tone include uter- and prostaglandins (misoprostol and carboprost) should be con-
ine massage and compression, alternative uterotonics (methylergono- sidered.22 Choice of the second- and or third-line agent is guided
vine, carboprost, misoprostol) and placement of a uterine tamponade by medication- and patient-specific factors and can include com-
device in high-risk patients.21 binations of options. In massive hemorrhage, it is recommended to
Treatment for uterine atony should follow standard resuscitative activate massive transfusion protocols and be prepared to use he-
measures such as obtaining large-bore intravenous (IV) access and mostatic resuscitation methods through a 1:1:1 ratio of PRBCs, FFP,
administration of blood products, crystalloids, colloids, and vaso- and platelets.
pressors. Due to normal physiologic changes in pregnancy including Obstetric trauma that occurs during childbirth includes peri-
increased blood volume and cardiac output, clinical signs of deterio- neal, vaginal, and cervical lacerations and should be suspected in all
ration such as tachycardia may not be present until collapse is immi- patients with vaginal bleeding despite having a contracted uterus.
nent. If bleeding persists after oxytocin, prompt initiation of second Management of genital tract lacerations involves surgical explora-
line uterotonic agents including ergot alkaloids (methylergonovine), tion and repair.13
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HEAVNER et al. 5
TA B L E 1 Pharmacotherapy management of pregnancy-related obstetric complications.11–105
Pregnancy/lactation
Disease state Medication Dosing Monitoring parameters Therapeutic goal considerations
Obstetric hemorrhage Oxytocin IV: 10 units over 11 min Uterine tone, uterine Hemostasis
IM: 10 units rupture, tachycardia
CI 10–4 0 units/h, titrated to hypotension, myocardial
sustain uterine contraction ischemia
Methylergonovine IM: 0.2 mg every 2–4 h Hypertension, headaches, Hemostasis Reports of seizures,
PO: 0.2 mg every 6–8 h myocardial infarction vomiting, and diarrhea
in infants (not a
contraindication for
treatment)
Misoprostol Every 2 h (every 6 h if ADR) Pyrexia, shivering Hemostasis

PO: 600 mcg–1000 mcg
SL: 800 mcg
Buccal: 400 mcg
PR: 1000 mcg
Carboprost 0.25 mg IM every 15–3 0 min Bronchospasm, diarrhea, Hemostasis

(max total 2 mg) vomiting
Tranexamic acid 1 g IV over 10 min. If bleeding Thrombotic events Hemostasis

persists after 30 min or
stopped and restarted
within 24 h of first dose, 2nd
dose 1 g IV over 10 min
Human fibrinogen Varies based on fibrinogen level Fibrinogen level, thrombotic Fibrinogen >300 mg/dL
concentrate 2–8 g IV infusion (every 2 g events
increases fibrinogen by
50 mg/dL)
Ectopic pregnancy Methotrexate 1-dose: 50 mg/m2 for β-hCG β-hCG levels, β-hCG levels to decrease Avoid breastfeeding for at
levels <3600 mIU/mL). May ultrasonography, fetal ≥15%; surgical least 1 week after final
repeat a 2nd or 3rd dose cardiac activity outside management may be methotrexate dose
of 50 mg/m2) if β-hCG level of the uterus, vital signs necessary
decreases <15% on days 4–6
Preeclampsia/eclampsia Fluid administration Not recommended Pulmonary edema Often ineffective due to
hemoconcentration
and fluid contraction
Magnesium (for severe IV (preferred): Mg sulfate LD Deep tendon reflexes (Mg Therapeutic range: High body mass index >35
features; seizure 4–6 g over 20 to 30 min, ≥9 mg/dL), respiratory 4.8–9.6 mg/dL and larger volume of
prevention) followed by a CI of 1–2 g/h depression (Mg ≥12 mg/ (4–8 mEq/L) distribution in the
IM: LD 10 g (5 g doses in each dL), UOP, Mg levels antepartum period
buttock), followed by 5 g every 2–4 h may require higher
every 4 h. Decrease dose to doses and longer
1 g/h for mild renal failure infusions to achieve
or oliguria (<30 mL UOP therapeutic range
for >4 h) which complicates
dosing
Hydralazine IV (acute): 5–10 mg IV every Blood Pressure (if above SBP <160 mmHg DBP Neonatal
20–4 0 min threshold after 20– <110 mmHg thrombocytopenia and
30 mg cumulative, bleeding secondary to
alternative agents maternal ingestion of
should be used) hydralazine have been
Heart rate-may cause reflex reported
tachycardia (if exceeds
100 bpm, alternative
agents should be used)
Labetalol IV (acute): 10–20 mg. Initial dose Blood pressure, heart rate SBP <160 mmHg DBP Monitor fetal growth
should not exceed 20 mg. (hold if <60 bpm) <110 mmHg After delivery, monitor
Repeat in incremental doses Avoid parenteral labetalol newborn for 48 h
of 20–8 0 mg over 2 min with active‡ asthma, for bradycardia,
every 10 min (maximum heart disease, or hypoglycemia, and
single dose: 80 mg, maximum congestive heart failure; respiratory depression
daily dose 300 mg) use with caution with
CI: LD 20 mg over 2 min followed history of asthma
by 1–2 mg/min titrated to
response
PO (chronic): 200 mg every
12 h and titrated up to
800 mg every 8 h (maximum
2400 mg/day)
(Continues)
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6 HEAVNER et al.
TA B L E 1 (Continued)
Pregnancy/lactation
Nifedipine PO (acute): 10–20 mg (can be Blood pressure SBP <160 mmHg DBP An increase in perinatal
repeated in 20 min) every Heart rate-may cause reflex <110 mmHg asphyxia, cesarean
2–6 h; maximum daily dose tachycardia delivery, prematurity,
is 180 mg Immediate-release and intrauterine
Oral (chronic): 30–120 mg ER formulation should growth retardation
every 24 h generally be reserved have been reported
for control of severe, following maternal use
acutely elevated blood
pressures in hospitalized
patients. Should be
avoided in tachycardia
Atypical hemolytic Eculizumab (for aHUS) IV: 900 mg weekly for 4 weeks Platelet, hemoglobin, For unvaccinated patients,
uremic syndrome for induction, then 1200 mg LDH, renal function, vaccinate as soon
(aHUS) at week 5, followed by infections (including as possible, 2 weeks
1200 mg every 2 weeks. meningococcal) of meningococcal
Supplemental doses after prophylaxis will
plasma exchange be needed after
vaccination
Thrombotic Methylprednisolone IV: 1 mg/kg daily tapered over ADAMTS13 > 20%,

thrombocytopenic 2–3 months platelet count,
purpura (TTP) prevent hemolysis
Azathioprine PO: 50 mg oral titrated up to Platelets, CBC, total ADAMTS13 > 20%, Monitoring infant blood
(ADAMTS13 < 20% 2 mg/kg daily bilirubin, LFTs, lipase, platelet count, cell count 10–15 days
and + anti- renal function, infection, prevent hemolysis after breastfeeding
ADAMTS13 nausea is initiated or in
antibody) infants with frequent
infections
Tacrolimus No established dosing regimen. Serum tacrolimus levels, ADAMTS13 > 20%,

(ADAMTS13 < 20% Adjust dose based on renal function, platelet count,
and + anti- tacrolimus levels electrolytes prevent hemolysis
ADAMTS13
antibody)
Cyclosporine No established dosing regimen. Serum cyclosporine ADAMTS13 > 20%,

(ADAMTS13 < 20% Adjust dose based on levels, renal function, platelet count,
and + anti- cyclosporine levels electrolytes prevent hemolysis
ADAMTS13
antibody)
Peripartum Bromocriptine PO: 2.5–5 mg once daily for Vital signs (blood pressure, Role is controversial. May suppress lactation and
cardiomyopathy 1–8 weeks postpartum heart rate), prolactin Recommended by breastfeeding should
levels, serum glucose European guidelines, be avoided
but not the American
Heart Association
guidelines
Diuretics (furosemide) PO: 20–4 0 mg once or twice Urine output, potassium, Decreased signs of May suppress lactation
daily, titrate to effect and as magnesium, serum fluid overload (i.e.,
tolerated creatinine, volume shortness of breath,
status, BNP lower extremity
edema)
Hydralazine PO: 25–50 mg 3–4 times daily, up Vital signs (blood pressure, Avoid hypotension, which Compatible with lactation
to 300 mg TDD heart rate) may cause placental
hypoperfusion (2nd
trimester –systemic
vasodilation peaks)
Beta-blockers PO: 12.5–25 mg once daily, up to Vital signs (blood pressure, Avoid hypotension, which Preferred beta-blocker in
(metoprolol 200 mg TDD heart rate) may cause placental lactation
succinate) hypoperfusion (2nd
trimester –systemic
vasodilation peaks)
Digoxin PO/IV: 0.125–0.25 mg once daily Serum digoxin concentration, Digoxin 0.5–0.9 ng/mL Insignificant amounts
heart rate, serum Consider for symptomatic found in breastmilk;
creatinine, potassium HFrEF despite goal- digoxin crosses the
directed medical placenta and there
therapy or those may be changes in
with concomitant pharmacokinetics
supraventricular during pregnancy
arrhythmias
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HEAVNER et al. 7
TA B L E 1 (Continued)
Pregnancy/lactation
Anticoagulation SQ: enoxaparin 1 mg/kg every Serum creatinine, complete Prevention of venous Do not cross the placenta
[unfractionated 12 h; dalteparin 100 units/ blood count, signs, and thromboembolism and are compatible
heparin (UFH) or low kg every 12 h; UFH infusion, symptoms of bleeding Consider for LVEF <30%, with lactation
molecular weight titrated for aPTT 1.5–2 .5x Consider anti-f actor Xa until 6–8 weeks
heparin (LMWH)] baseline levels, but not routinely postpartum
recommended Consider for LVEF<35%
with bromocriptine
use
Amniotic fluid embolism Fluid/blood Blood transfusion products Vital signs (blood pressure, serum fibrinogen of
administration preferred; Crystalloids no heart rate), volume 150–200 mg/dL,
more than 500 mL status thromboelastography
Vasopressors Vital signs (blood pressure, Mean arterial

(norepinephrine, heart rate), volume pressure ≥ 65 mmHg
vasopressin) status, echocardiogram
Inotropes (dobutamine, Dobutamine is

milrinone) hypothesized
to be safe for
breastfeeding in the
setting of its poor
oral bioavailability
and short half-life of
approximately 2 min
Pulmonary vasodilators Pulse oximetry Sildenafil is known to cross

(inhaled nitric oxide, the placenta as well as
inhaled/ systemic into the breastmilk
epoprostenol,
sildenafil)
Abbreviations: ADR, adverse drug reaction; aPTT, activated partial thromboplastin time; bpm, beats per minute; CBC, complete blood count; DBP,
diastolic blood pressure; ER, extended release; h, hour; HFrEF, heart failure reduced ejection fraction; IM, intramuscular; IV, intravenous; LD, loading
dose; LDH, lactate dehydrogenase; LFT, liver function test; LVEF, left ventricular ejection fraction; Mg, magnesium; min, minutes; PO, oral; PR, rectal;
SBP, systolic blood pressure; SL, sublingual; SQ, subcutaneous; TDD, total daily dose; UOP, urine output; β-hCG, beta-human chorionic gonadotropin.
2.2.1 | Oxytocin onset of action, intramuscular (IM) oxytocin is considered an accept-

able alternative when IV access is unavailable.
Oxytocin is a polypeptide produced by the posterior pituitary gland
that induces myometrial contractions.13,23 Dose-dependent car-
diovascular effects include tachycardia, hypotension, myocardial 2.2.2 | Methylergonovine
ischemia, and coronary artery vasoconstriction. 24 Oxytocin under-
goes rapid hepatic metabolism and is eliminated via urine and biliary Methylergonovine is a semisynthetic ergot derivative that primar-
routes resulting in a half-life of less than 6 min. In a randomized con- ily acts on 5-HT2 receptors in smooth muscle to produce uterine
trolled trial of 143 patients undergoing cesarean delivery with one or contraction with minimal effects on systemic vasoconstriction. 22
more risk factors for uterine atony, no difference was demonstrated Methylergonovine is available in the IV, IM, and oral routes with an
in the need for additional uterotonic drugs or adverse effects with a onset of action of 1, 5, and 10 min, respectively. 27 Routine IV admin-
five international unit (IU) bolus of oxytocin over 30 s compared to istration is not recommended due to the potential for hypertensive
25
saline. Oxytocin is routinely administered just before or after pla- or cerebrovascular events. Methylergonovine is dosed at 0.2 mg IM
cental separation. The prophylactic dosing and duration of oxytocin or directly into the myometrium every 2–4 h as needed or 0.2 mg
vary and are often institution specific. Oxytocin 10–4 0 IU diluted in orally three to four times daily for up to 1 week if needed after the
500–1000 mL of 0.9% sodium chloride is often infused at 20 IU/h initial IM doses.13 Adverse effects include hypertension, headaches,
titrated to sustain uterine contraction and tone. A bolus of oxytocin and seizures, and are therefore contraindicated in patients with
before infusion initiation does not improve the need for additional hypertensive disorders of pregnancy. Because methylergonovine
uterotonic drugs compared to the infusion alone. 25 Receptor density is a substrate of CYP3A4 metabolism, potent inhibitors should be
in the myometrium progressively increases throughout pregnancy, avoided. 27 Although generally considered safe, recommendations
which may impact the patient's response to oxytocin. 26 In addition, for breastfeeding during methylergonovine therapy vary based on
the use of oxytocin for induction or prolonged exposure may lead reports of adverse effects experienced by infants such as vomit-
to oxytocin receptor desensitization and tachyphylaxis. 22 Although ing, diarrhea, and seizures. 27 Methylergonovine is the second-line
IV administration is preferable due to its favorable absorption and uterotonic agent after oxytocin. If pharmacotherapies fail to achieve
|
8 HEAVNER et al.
adequate uterine tone or hemostasis, several uterine tamponade reported in breast-fed babies following maternal use of TXA in the
techniques are utilized. In refractory cases, a hysterectomy can be WOMAN trial.36 Routine use of human fibrinogen concentrate for
13
performed for definitive treatment. PPH remains controversial but can be considered when rapid treat-
ment is warranted or if cryoprecipitate is not rapidly available, since
fibrinogen concentrate does not require thawing. In a randomized
2.2.3 | Misoprostol trial of 437 patients with persistent PPH, 3 g of human fibrinogen
concentrate did not reduce blood loss, transfusion requirements,
Misoprostol is an analog of prostaglandin E1 that increases uter- or the need for postpartum anemia but did prevent plasma fibrino-
ine tone. Misoprostol is available in oral, buccal, sublingual, vaginal, gen loss.39 Due to evidence of excessive microthrombi leading to
and rectal routes with the oral and sublingual routes yielding the multiorgan failure, recombinant Factor VII should be considered as
fastest onset of approximately 30 min. 28 Misoprostol is given as a last resort where hemorrhage cannot be stopped despite massive
600–1000 mcg (routinely rectally) every 4–6 h with a maximum of transfusion and surgical interventions.37 Viscoelastic testing such as
13
1600 mcg in 24 h. Adverse effects include pyrexia and shivering, thromboelastography is a supportive tool to characterize coagulopa-
29
commonly seen at higher dosages. The overall safety profile and thy and guide provider management.15
convenient storage requirements are both advantages of misopros-
tol, but appropriate precautions should be considered during prepa-
ration and handling due to its classification as a hazardous drug.30 2.3 | Ectopic pregnancy
Misoprostol can be considered as an alternative second-line agent
when methylergonovine is contraindicated or as an adjunctive in re- Rupture of an ectopic pregnancy can also lead to life-t hreatening
fractory hemorrhage. hemorrhage. Ectopic pregnancy occurs when a fertilized ovum im-
plants outside the uterus. The estimated prevalence in the US is
2%. Risk factors include age > 35 years, history of smoking, pelvic
2.2.4 | Carboprost inflammatory disease, and previous ectopic pregnancy.40 Ectopic
pregnancy should be considered in women early in pregnancy pre-
Carboprost is an analog of prostaglandin F2α that increases intra- senting with lower abdominal pain or vaginal bleeding. Diagnostic
cellular free calcium concentrations and augments uterine con- workup includes monitoring by ultrasonography and serial quan-
traction.31 Concentrations peak 20 min after IM injection with titative beta-human chorionic gonadotropin (β-h CG). Surgical
an estimated half-life of 2 h.32 Carboprost is given as 250 mcg IM management consisting of either salpingostomy or salpingectomy
doses every 15–30 min with a maximum total dose of 2 mg. Adverse should be considered in the following scenarios: hemodynamic in-
effects include bronchospasm and diarrhea. It should be used stability, β-h CG level is greater than 5000 mIU/mL, fetal cardiac
with caution in hypoxemia or patients with a history of asthma.33 activity outside of the uterus, medical contraindications to metho-
Carboprost is less effective than methylergonovine.34 It is therefore trexate or social factors precluding frequent laboratory monitor-
reserved as a third-line agent only in patients with contraindications ing.41 Methotrexate is the mainstay for medical management of
to methylergonovine. 22 ectopic pregnancy.
2.2.5 | Hemostatic agents and blood products 2.3.1 | Methotrexate
Cryoprecipitate is gaining utility over FFP in the setting of obstet- Methotrexate is a folate antagonist that inhibits DNA synthesis,
ric hemorrhage to target a serum fibrinogen of 150–300 mg/dL thereby halting cell proliferation of ectopic pregnancy and allows
and minimize the risk of volume overload.35 Tranexamic acid (TXA) for reabsorption into the body. Methotrexate should not be used
is an antifibrinolytic that has been evaluated for use in traumatic in women with symptoms suggesting hemorrhagic complications.42
injury and PPH. In the WOMAN trial, administration of 1 g of IV It should be used with caution and in some cases is contraindicated
TXA was associated with reduced mortality and similar incidence in patients with renal or hepatic dysfunction, active peptic ulcer dis-
of adverse events in patients with obstetric hemorrhage compared ease, alcohol use disorder, or hematologic diseases.41 A fetal heart-
to placebo.36 Similar to the trauma literature, earlier use of TXA beat or visible gestational sac are risk factors for methotrexate failure
within 3 h of birth in PPH is considered to be superior to delayed and may necessitate surgery. Methotrexate is a known teratogen,
treatment.36 Some data suggest higher doses of 2 g may improve so effective contraception is recommended for at least 3–6 months
maternal outcomes.37,38 Contraindications to TXA include a his- and breastfeeding should be avoided at least 1 week after the
tory of venous thromboembolism or a history of seizures as TXA final methotrexate dose.41,42 Several regimens of IM methotrexate
can lower the seizure threshold. While TXA has not demonstrated have been evaluated. In general, a single-dose protocol of 50 mg/
teratogenic effects from animal studies, it is known to cross the m2 should be utilized when β-hCG levels are less than 3600 mIU/
placenta and into the breastmilk. No thromboembolic events were mL and the two-dose regimen should be utilized for higher β-hCG
|
HEAVNER et al. 9
levels.43 The decision to administer repeat doses of methotrexate or for four doses) should be administered for fetal lung maturation
proceed with surgical management is guided by serial β-hCG levels if delivery is indicated at <34 weeks gestation.49 All women with
checked every 4–7 days. Repeat methotrexate doses are adminis- gestational hypertension or preeclampsia without severe features
tered if the β-hCG levels do not decrease by at least 15% by day four. should be monitored throughout labor for progression to severe
Pharmacists should be vigilant in assessing the dosing of methotrex- disease, with treatment escalated as needed.46
ate as it is a high-alert medication prone to medication error. Dosing Treatment goals for preeclampsia are two-fold: (1) prevention
errors with methotrexate have been associated with life-threatening of seizures and (2) control hypertension to a goal of <140/90 mm
toxicities.44 Hg. Controlling hypertension in preeclampsia is important to pre-
vent maternal complications such as congestive heart failure, myo-
cardial ischemia, acute kidney injury, stroke, and fetal complications
3 | H Y PE RTE N S I V E E M E RG E N C I E S O F including placental abruption. Antihypertensive treatment should
PR EG N A N C Y be started as soon as possible for acute onset severe hypertension
(SBP of ≥160 and/or DBP ≥110 for longer than 15 min). The three
3.1 | Preeclampsia agents most commonly used are hydralazine, labetalol, and nifedip-
ine. A large Cochrane systematic review of 35 trials with 3573 preg-
Worldwide, hypertensive disorders of pregnancy are one of the nant women with severe hypertension during pregnancy showed no
leading causes of maternal and perinatal mortality, occurring in difference in safety or efficacy among hydralazine, labetalol, or cal-
45
2%–8% of pregnancies globally. Preeclampsia is defined as hy- cium channel blockers.50 Parenteral agents may be needed for acute
pertension that occurs at >20 weeks gestation with or without blood pressure control with severe features. Oral medications may
proteinuria. Hypertension is defined as a systolic blood pressure be preferred if expectant management is pursued. The most com-
(SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 on two mon oral medication utilized is labetalol, initiated at 200 mg every
occasions at least 4 h apart or a single instance of SBP ≥160 mmHg 12 h and titrated to 800 mg every 8 h.46
or DBP ≥110 mmHg in a woman with previously normal blood
pressure. Proteinuria is defined as ≥300 mg per 24-h urine collec-
tion, protein/creatinine ratio ≥0.3 mg/dL, or dipstick reading of 2+ 3.1.1 | Magnesium sulfate
(if quantitative methods are unavailable). Although hypertension
and proteinuria are the classic criteria for diagnosis of preeclamp- To prevent seizures, magnesium sulfate is administered for preec-
sia, it can occur without proteinuria if one or more severe features lampsia with severe features, but there is no consensus on using
are present, including: thrombocytopenia (platelets <100,000/ magnesium to prevent seizures in the absence of severe features. A
mm3), renal insufficiency (serum creatinine >1.1 mg/dL or 2x base- systematic review that compared IV magnesium sulfate to placebo in
line), impaired liver function (liver function tests >2x upper limit preeclamptic patients showed a reduced risk of eclampsia, reduced
of normal), pulmonary edema, new-onset headache unresponsive risk of placental abruption, and a non-statistically significant reduc-
to medication and not accounted for by alternative diagnoses.46 tion in maternal mortality.46,51 Magnesium sulfate is more effective
Headache is often a presenting feature due to intense vasospasm for seizure prevention than phenytoin, diazepam, or nimodipine.51–53
secondary to imbalances in vasodilatory (e.g., prostacyclins and Magnesium is thought to cause cerebral vasodilation, therefore, re-
nitric oxide) and vasoconstriction mediators (e.g., thromboxane ducing cerebral ischemia caused by vasospasms that occur in preec-
A2 and endothelins). The decision to deliver or continue expect- lampsia. It may also decrease cerebral edema and have anticonvulsant
ant management (i.e., watchful waiting) for preeclampsia should properties.54 The optimal dose of magnesium for preeclampsia-
only be considered after comprehensively evaluating maternal and related seizures has not been established. The preferred regimen
fetal risks. In women with preeclampsia without severe features, in the US is magnesium sulfate loading dose of 4–6 g IV over 20–
observation is recommended with a preterm fetus (<37 weeks ges- 30 min and a continuous infusion of 1–2 g/h. If a cesarean section is
tational age). At >37 weeks gestation, delivery is recommended. required, the infusion should start before surgery and continue for
When preeclampsia with severe features occurs <34 weeks gesta- 24 h after delivery. If IV access cannot be obtained, IM magnesium
tion, expectant management may be considered if maternal and sulfate 10 g loading dose, divided into 5 g doses in each buttock, fol-
fetal conditions are stable and a > 34 weeks delivery is preferred. lowed by 5 g every 4 h can be administered. To reduce pain, the dose
Two randomized controlled trials of preterm preeclampsia with se- can be mixed with 2% lidocaine.46 Therapeutic serum magnesium
vere features evaluating delivery versus expectant management target range is thought to be 4.8–9.6 mg/dL (4–8 mEq/L).55,56 High
demonstrated that expectant management is associated with body mass index (BMI) >35 kg/m2 and changes in volume of distribu-
higher gestational age at delivery and improved neonatal out- tion antepartum may necessitate higher doses and longer infusions
47,48
comes. If pursued, delivery is recommended at any point that to achieve therapeutic range.57 Adverse effects of magnesium can
maternal or fetal condition deteriorates. Antenatal corticoster- be seen at supratherapeutic levels and are more frequent with IM
oid therapy with betamethasone (two 12-mg doses given IM 24 h administration. Magnesium-induced vasodilation can cause facial
apart) or dexamethasone (four 6-mg doses given IM 12 h every flushing and hypotension, especially at initiation and up-titrations of
|
10 HEAVNER et al.
continuous infusions. Loss of deep tendon reflexes can also occur administering an additional magnesium sulfate bolus of 2–4 g IV over
at a serum magnesium level of 9 mg/dL (7 mEq/L). Magnesium acts 5 min.63 If a patient has refractory seizures, defined as seizures last-
as a smooth muscle relaxant resulting in respiratory depression at ing 20 min after magnesium bolus or more than two recurrences, an-
serum concentrations above 12 mg/dL (10 mEq/L) and cardiac arrest tiepileptics such as phenytoin may be used.64
at 30 mg/dL (25 mEq/L). Deep tendon reflexes and respiratory status
should be monitored. Magnesium sulfate is excreted in the urine;
therefore, urine output (UOP) should be followed, and adjustments 3.3 | HELLP syndrome
to dosing made accordingly. For patients with mild renal failure or
oliguria (<30 mL UOP for >4 h) the continuous infusion should be The triad of Hemolysis, Elevated Liver enzymes, and Low Platelets
46
decreased to 1 g/h. Loading doses should remain 4–6 g because (HELLP) syndrome is associated with increased maternal morbidity
lower loads have been associated with subtherapeutic levels for up and mortality.48 Laboratory definition of HELLP syndrome includes
58
to 4 h. The infusion should be stopped if serum magnesium lev- lactate dehydrogenase (LDH) >600 IU/L, aspartate aminotransferase
els exceed 9.6 mg/dL (8 mEq/L), with follow-up levels every 2 h. The (AST) >2x upper limit of normal, and platelets <100,000/mm3.48 Low
infusion can be resumed when magnesium levels reach <8.4 mg/dL platelets occur due to increased platelet aggregation, activation, and
(7 mEq/L). If respiratory failure occurs, intubation may be required. consumption.65 AST is the dominant transaminase released due to per-
Calcium gluconate 10% solution, 10 mL IV over 3 min should be ad- iportal necrosis. Elevated LDH is due to hepatic dysfunction and hemol-
ministered, and loop diuretics can be given to accelerate renal elimi- ysis from the destruction of red blood cells. HELLP syndrome typically
46
nation of magnesium. Although the term preeclampsia suggests a occurs in the third trimester but can also be seen postpartum.46 The
natural progression to eclampsia if not treated, seizures only occur in main presenting features are right upper quadrant pain and generalized
1.9% of patients with preeclampsia and 3.2% of patients with severe malaise in 90% and nausea and vomiting in 50% of cases.66,67 Although
59
preeclampsia. hypertension and proteinuria are typically present, both may be ab-
sent in up to 15% of cases.60 HELLP syndrome often causes sudden
maternal and fetal decompensation. Many experts agree that deliv-
3.2 | Eclampsia ery should occur regardless of gestational age. Frequent monitoring
of liver enzymes, liver function tests, LDH, and platelets should occur
Eclampsia is defined by new-onset, tonic–clonic, focal, or multifocal during and after delivery. Supportive care should be employed, as pa-
seizures during pregnancy in a patient without a history of seizures. tients with HELLP syndrome are at risk for renal failure, pulmonary
It can occur before, during, or after labor. Although eclampsia is rare, edema, and acute respiratory distress syndrome.46
it is a significant cause of maternal death due to severe maternal Anti-inflammatory effects of corticosteroids have been theo-
46
hypoxia, anoxic brain injury, trauma, or aspiration pneumonia. rized to aid in the management of HELLP syndrome. However, there
Some patients may experience short- or long-term neurologic defi- is insufficient evidence to support their use. A Cochrane review of
cits from eclampsia such as memory loss or cognitive impairment.60 11 randomized controlled trials including 550 women comparing
Many women do not exhibit classical signs of preeclampsia prior to corticosteroids to placebo showed no difference in maternal death,
seizure. In a United Kingdom study, there was no prior documenta- SMM, or perinatal or infant death. The only observed treatment ef-
tion of hypertension or proteinuria in 38% of eclamptic seizures.61 fect was an increase in platelet count.68
Women who develop preeclampsia and eclampsia with headache,
altered consciousness, or visual abnormalities are at risk for poste-
rior reversible encephalopathy syndrome (PRES). 4 | TH RO M B OTI C M I C ROA N G I O PATH Y
For women with eclampsia, supportive measures should be em- O F PR EG N A N C Y
ployed such as placement in lateral decubitus position, prevention
of aspiration, oxygen administration, and monitoring vital signs. Pregnancy and postpartum are high-risk periods for the development
Eclamptic seizures can cause an increase in uterine contractility and of thrombotic microangiopathy (TMA). TMA is characterized by en-
fetal heart rate decelerations. Delivery should only occur after ma- dothelial cell injury that preferentially affects the brain, kidneys, and
ternal hemodynamic stabilization. Maternal resuscitation typically heart. It typically presents with thrombocytopenia, hemolytic ane-
normalizes fetal tracing. Timely delivery is important, and mode of mia, and organ dysfunction including encephalopathy, acute kidney
delivery will depend on gestational age, fetal status, and cervical injury, and cardiac ischemia. TMA in pregnancy is diagnosed based
examination. Magnesium sulfate at doses discussed previously for on a platelet count <100,000/mm3, hemoglobin <10 g/dL, LDH
preeclampsia remains the agent of choice to prevent recurrent sei- >1.5x the upper limit of normal, undetectable serum haptoglobin,
zures in eclampsia and is associated with less maternal and neonatal negative direct erythrocyte antiglobulin test, and either the pres-
52,62
morbidity than other agents. Benzodiazepines may be used for ence of schistocytes on a peripheral blood smear or TMA features in
agitated patients to aid in placement of IV access, laboratory collec- kidney or another organ biopsy. The two main forms of TMA include
tion, and foley catheter placement, but should be used with caution thrombotic thrombocytopenic purpura (TTP) and complement-
as they may increase risk of aspiration. If convulsions recur, consider mediated atypical hemolytic uremic syndrome (aHUS).69
|
HEAVNER et al. 11
Pregnancy-associated TTP is due to a severe deficiency in in patients with high-risk features. If ADAMTS13 < 20% and anti-
ADAMTS13, a metalloproteinase that cleaves von Willebrand fac- ADAMTS13 antibody are detected, additional immunosuppressive
tor (VWF), and accounts for 10%–30% of all adult cases.70 TTP is agents may be needed to control antibody production. In pregnancy,
a rare complication of pregnancy and is estimated to occur in 1 in immunosuppressive agents include azathioprine, calcineurin inhib-
17,000 to 1 in 200,000 pregnancies.71,72 ADAMTS13 is known to itors, and rituximab. Azathioprine and calcineurin inhibitors (cyclo-
decrease steadily by 50% from the second trimester until delivery in sporine and tacrolimus) do cross the placenta, but most investigators
normal pregnancy due to increased release of VWF. In preeclamp- consider these agents relatively safe in pregnancy.80,81 Data for rit-
sia, eclampsia, HELLP syndrome, and pregnancy-associated aHUS, uximab use are limited and other agents are preferred. Rituximab is
ADAMTS13 activity is decreased to 20%–4 0% but is still detectable, known to cross the placenta and can cause fetal harm such as pre-
but in pregnancy-associated TTP is defined as severe deficiency in mature births and infant hematologic abnormalities, congenital mal-
ADAMTS13 < 20%. This occurs most commonly in the second and formations, and infections.82 However, safe use of rituximab in TTP
73,74
third trimesters. TMA is a diagnosis of exclusion; alternative, during pregnancy has been reported.83
more common diagnoses with features of TMA, such as preeclamp- In patients with a history of immune-mediated TTP, the risk of
sia, HELLP syndrome, and acute fatty liver of pregnancy (AFLP), relapse during pregnancy remains unknown but depends on the
should be ruled out and an ADAMTS13 level drawn prior to plasma ADAMTS13 activity at the beginning of pregnancy. Therapies re-
exchange and administration of blood products should be obtained main the same as for pregnancy-associated TTP: steroids, plasma
to rule in or out pregnancy-associated TTP. exchange, and other immunosuppression as needed.69 Medication
A multidisciplinary approach including hematologists, intensiv- doses should be increased after 20 weeks gestational age to account
ists, nephrologists, pharmacists, and maternal fetal medicine spe- for increases in volume of distribution. Hereditary TTP is unlikely
cialists is critical for improved perinatal outcomes in patients with to be first diagnosed during pregnancy and is typically treated
thrombotic microangiopathies. Following maternal stabilization, de- with plasma exchange alone. For patients with a history of hered-
livery may be considered depending on the gestational age at time itary TTP, risk of relapse during pregnancy is 100%. Prophylactic
of diagnosis. Plasma exchange should be initiated early (<24 h) in plasma exchange, 10–15 mL/kg every 10–21 days, is recommended
the following scenarios: atypical presentation of preeclampsia, ec- immediately after pregnancy diagnosis or at 10 weeks and contin-
lampsia, HELLP syndrome in addition to life-threatening neurologic ued throughout pregnancy and postpartum. Goals of treatment are
symptoms (seizures, altered consciousness, coma), profound throm- to raise ADAMTS13 > 20%, normalize platelet count, and prevent
bocytopenia (platelets <30,000/mm3) or less commonly cardiac hemolysis.69
signs (elevated troponin levels on systematic screening, electrocar- Pregnancy-associated aHUS is estimated to be responsible
diographic abnormalities, altered cardiac function) until ADAMTS13 for 16% of all aHUS cases in women aged 18–45.84 Pregnancy-
results are known. Outside of those criteria, plasma exchange can be associated HUS presents most commonly in the postpartum period
considered if there is no improvement in thrombocytopenia, hemo- but may occur in any trimester. If further evaluation of thrombotic
lysis, or serum creatinine does not decrease by at least 25% within microangiopathy leads to a diagnosis of aHUS, plasma exchange
24–72 h of monitoring. Plasma exchange should be started to treat should be stopped, and the patient should start anti-C5 treatment
a potential TTP while work up is ongoing. If anti-ADAMTS13 anti- with eculizumab.84
bodies are present or in rare cases of catastrophic antiphospholipid
syndrome, plasma exchange should continue.
The treatment of pregnancy-associated TTP can depend on co- 4.1 | Eculizumab
presenting diagnosis, if it is immune-mediated or hereditary, or if the
patient has a history of TTP and then becomes pregnant. Treatment Eculizumab is a humanized monoclonal antibody that prevents
of pregnancy-associated TTP leads to a response rate similar to that cleavage of the C5 molecule, blocking activation of the terminal
of all TTP of about 80%–90%.71,75,76 When TTP occurs concomi- pathway and the formation of the membrane attack complex (C5b-
tantly with preeclampsia or HELLP, maternal mortality increases up 9). No randomized controlled trials have evaluated anti-C5 treat-
to 44%.77 However, the diagnosis for TTP in pregnancy has likely ment in pregnancy-associated HUS. Eculizumab has been used in
improved with the increased use and availability of ADAMTS13 and pregnant patients with paroxysmal nocturnal hemoglobinuria and
therefore mortality rates may have also improved. Preeclampsia, aHUS, and despite being detectable in 1/3 of cord samples, the
eclampsia, or HELLP syndrome improve with delivery; however, potential maternal benefit far outweighs the fetal risk. In one re-
with associated TTP, delivery should only occur after failed plasma port of 35 patients, 90% of pregnant patients achieved renal and
exchange or if fetal compromise is present.69 Platelet transfusion hematologic resolution with eculizumab.69 In another report of 22
should be avoided if possible due to concerns for thrombosis and patients, 10 patients received eculizumab due to lack or response
78,79
worsening neurological symptoms. TTP during pregnancy is to plasma exchange and 9 of these patients achieved hematological
treated with plasma exchange and glucocorticoids. A typical gluco- and renal remission.84 Of patients who did not receive eculizumab,
corticoid regimen may include prednisone 1 mg/kg daily or methyl- 50% developed ESRD compared to 0 of 10 who received eculizumab
prednisolone 1000 mg for 3 days followed by prednisone 1 mg/kg after 2 years.84 Eculizumab for aHUS is dosed 900 mg weekly for
|
12 HEAVNER et al.
4 weeks for induction and 1200 mg at week 5 followed by 1200 mg anticoagulation due to high risk of thromboembolic events.97
every 2 weeks.85 Supplemental doses are recommended after Diuretics (preferentially furosemide) should be considered to man-
plasma exchange. Due to higher volume of distribution, increased age volume status.97 Beta-blockers should be used if tolerated based
C5 synthesis in pregnancy, and possible urinary loss in cases with on hemodynamics, with a preference for beta-1 selective agents
proteinuria, a higher dose or increased frequency of eculizumab may such as metoprolol. Hydralazine may also be considered, if needed
69,86
be required. Monitoring of the degree of terminal complement for vasodilator effect.98 While digoxin may be considered, it may be
blockade may be required. The duration of treatment also remains associated with low birth weight.98 Anticoagulation is recommended
unclear and should be individualized. The presence of complement in the setting of low EF <30% and acute heart failure exacerbations
abnormalities carries a risk of relapse after eculizumab discontinua- and continued up to 6–8 weeks postpartum.97 Unfractionated or low
tion.87,88 Eculizumab increases the risk of meningococcal infections, molecular weight heparin are preferred because they do not cross
therefore, meningococcal vaccine should be administered 2 weeks the placenta and are considered safe in lactation.98
before administration, or as soon as possible. In unvaccinated pa- Clinical practice guidelines recommend against the use of several
tients, administer meningococcal vaccine as soon as possible and agents because of the risk for fetal harm.97 Agents to avoid while
provide at least 2 weeks of antibacterial prophylaxis.85 If vaccination pregnant in PPCM include angiotensin-converting enzyme inhib-
is not possible, prophylaxis with penicillin V potassium 250 mg orally itors (ACEi) and angiotensin receptor blockers (ARBs) due to the
every 12 h is typically recommended for the duration of eculizumab association with second- and third-trimester teratogenicity.99 ACEi
89
therapy. In a pregnant patient with penicillin allergy, azithromycin may be reinitiated during the postpartum period with enalapril or
90
can be considered as an alternative for prophylaxis. Lastly, patients captopril as the preferred agents.97 Other agents, including ivabra-
with a history of aHUS have about a 25% chance of relapse during dine, sodium-glucose cotransporter-2 inhibitors, vericiguat, and an-
pregnancy or postpartum.91 Prophylactic anti-C5 treatment is not giotensin receptor-neprilysin inhibitors should be avoided given the
recommended but should be given promptly if aHUS recurs during lack of data in pregnancy.97 Beta-blockers with limited data, includ-
pregnancy and was used pre-pregnancy.69 ing carvedilol and bisoprolol, should be avoided.92 Spironolactone
has been shown to cause reproductive tract abnormalities in both
male and female rats. The anticipated benefit from spironolactone
5 | PE R I PA RT U M C A R D I O M YO PATH Y in pregnancy should be weighed with possible risks to the fetus but
virilization has been observed in female fetuses when administered
Peripartum cardiomyopathy (PPCM) is characterized by left ven- during pregnancy.100 However, it can be started after delivery due
tricular dysfunction and heart failure and typically occurs in the late to minimal excretion into breast milk.92 Direct oral anticoagulants
third trimester and up to several months postpartum, with potential should be avoided due to lack of data in pregnancy and lactation.98
to progress to cardiogenic shock.92 The incidence in the US is 1 in Warfarin should be used with caution in the third trimester due to
1000–8 000 deliveries.93 Risk factors associated with PPCM include risk of fetal intracranial hemorrhage.98 It may be considered after
advanced maternal age, history of PPCM, African ancestry, multipar- delivery, with close monitoring of the INR.92
92
ity, twin gestation, hypertension, preeclampsia, and malnutrition.
Non-pharmacologic therapies include fluid and sodium restric-
tion and mechanical support. Mechanical support should be consid- 6 | A M N I OTI C FLU I D E M B O LI S M
ered for patients with severe left ventricular (LV) dysfunction. These
include intra-aortic balloon pumps (IABP), LV and biventricular assist Amniotic fluid embolism (AFE) is a rare yet serious condition that
devices, and extracorporeal membrane oxygenation (ECMO). If re- is characterized by sudden cardiovascular collapse and DIC.101,102
covery does not occur, cardiac assist devices can be used as a bridge While the incidence ranges from 2 to 7 occurrences in every 100,000
to transplantation.94 pregnancies, it carries a mortality reported to exceed 50% and is
Pharmacologic strategies include bromocriptine, diuretics, hy- a leading cause of maternal death in industrialized countries.101,102
dralazine, beta-blockers, digoxin, and anticoagulation. Bromocriptine The published incidence is likely an underestimate based on prob-
added to standard of care heart failure therapy is associated with a able underreporting of nonfatal cases.
higher rate of LV recovery and lower mortality as compared with Risk factors are inconsistently reported.37,103 AFE is primar-
95
standard of care alone. European heart failure guidelines suggest ily characterized as a severe anaphylactoid response manifesting
postpartum bromocriptine for uncomplicated cases of PPCM, pro- most commonly as cardiac arrest.104 The reaction is driven by the
longed treatment regimen for ejected fraction (EF) <25%, or car- introduction of amniotic fluid into maternal circulation, triggering
diogenic shock.96 The use of bromocriptine for the management exposure to fetal elements along with prostaglandins, bradykinins,
of PPCM is associated with the cessation of breastfeeding. While leukotrienes, both endothelin and plasminogen activators and their
the American Heart Association/American College of Cardiology/ respective inhibitors.35 An intense inflammatory response ensues,
Heart Failure Society of America guideline does not recommend generating pulmonary vasoconstriction and bronchoconstriction
for or against the use of bromocriptine, it is recommended that if that contribute to cardiovascular collapse in two distinct phases.
prescribed, it should be given with at least prophylactic-dosed The first phase contributes to right ventricular (RV) failure, where
|
HEAVNER et al. 13
the extreme initial increase in pulmonary pressure triggers a vaso- 7 | ACU TE FAT T Y LI V E R O F PR EG N A N C Y
spasm of pulmonary vasculature, resulting in ventilation and per-
fusion (V/Q) mismatch and severe pulmonary hypertension. This Acute fatty liver of pregnancy (AFLP) is characterized by microve-
progresses to RV dysfunction and enlargement, causing the intra- sicular fatty infiltration of the liver that leads to hepatic failure.107
ventricular septum to bow into the LV. The second phase is driven Pathogenesis is not entirely understood but there is a link between
by the obstruction of the LV caused by the bowed septum, impairing fetal Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) defi-
left-sided filling. This leads to a decreased cardiac output, and the ciency and AFLP.72 Preeclampsia concomitantly occurs in approxi-
resulting hypotension and hypoxemia result in sudden cardiovascu- mately half of women with AFLP. Non-pharmacological strategies
lar collapse.35 Inflammatory mediators can trigger coagulation and are the mainstay of management and include prompt delivery and
35
fibrinolytic pathways leading to DIC in 22%–83% of patients. AFE supportive care. If liver function does not rapidly improve after
can also elicit severe uterine atony, further exacerbating the risk of delivery, liver transplantation should be considered. Women with
hemorrhage in a patient that is already predisposed to clot risk based AFLP and their children should undergo genetic testing for LCHAD
on the physiologic changes of pregnancy.104 deficiency.107
Treatment for AFE is primarily supportive, with priority on provid-
ing high-quality cardiopulmonary resuscitation (CPR), airway support,
and correction of coagulopathy. Left lateral uterine displacement is ad- 8 | CO N C LU S I O N S
vised immediately to relieve aortocaval compression.37 In the setting
of maternal cardiac arrest, the Society for Maternal-Fetal Medicine Obstetric emergencies necessitating ICU admission require close
recommends that viable fetuses over 20 weeks be evacuated if re- monitoring and advanced therapeutic interventions to prevent
turn of spontaneous circulation (ROSC) is not achieved within 4 min SMM. Complications of pregnancy include hemorrhage, hyperten-
of cardiac arrest. Veno-arterial ECMO can be considered in cases that sive emergencies, microangiopathies, peripartum cardiomyopathy,
require prolonged CPR or exhibit severe RV dysfunction refractory to amniotic fluid embolism, and acute fatty liver of pregnancy. Optimal
medical management.37,102 Following airway securement, the patient management of these conditions requires prompt recognition and
can be resuscitated using fluids and vasopressors. Blood products management using both non-pharmacological and pharmacological
are recommended for volume resuscitation rather than crystalloids therapies. Risks and benefits to the fetus must be considered, with
or colloids to avoid fluid overload and support the already expanded knowledge of drug-related monitoring parameters for effectiveness
blood volume of the patient.105 When crystalloids are used, volume and toxicities of pharmacotherapy options.
increments should not exceed 500 mL to avoid dilution of clotting
factors in the setting of potential coagulopathy.37 Vasopressors such C O N FL I C T O F I N T E R E S T S TAT E M E N T
as norepinephrine and vasopressin are suggested for earlier consid- The authors declare no conflicts of interest.
eration, especially in the setting of severe RV dysfunction, to target a
mean arterial pressure of ≥65 mmHg.35 It is important to consider that DATA AVA I L A B I L I T Y S TAT E M E N T
the increased clearance exhibited in the second and third trimesters The data that support the findings of this study are available from
may require an increased dose of vasopressin. These agents will also the corresponding author upon reasonable request.
serve to maintain coronary perfusion pressure in the setting of hypo-
tension. The Society for Maternal-Fetal Medicine endorses the use of ORCID
transthoracic or transesophageal echocardiograms to determine the Mojdeh S. Heavner https://orcid.org/0000-0003-3007-7685
severity of RV failure. Depending on severity, ventricular output may Michaelia D. Cucci https://orcid.org/0000-0002-5823-7495
be improved using inotropes, such as epinephrine, dobutamine, and Brooke Barlow https://orcid.org/0000-0001-5118-7029
milrinone, to increase cardiac contractility and exert pulmonary vaso- Carolyn Magee Bell https://orcid.org/0000-0001-7024-9934
dilatory effects. Teratogenic effects have not been shown in animal Claire C. Eng https://orcid.org/0000-0001-5492-3802
studies, but there are limited data in pregnancy.37 Although inhaled Matthew Li https://orcid.org/0000-0003-1320-7134
nitric oxide, inhaled and systemic epoprostenol, and sildenafil have Susan E. Smith https://orcid.org/0000-0002-5171-8405
been successfully used to treat acute pulmonary vasoconstriction in W. Anthony Hawkins https://orcid.org/0000-0002-4083-7919
various cases, there is no formal recommendation supporting their
use to improve outcomes.37,104 Some experts caution the use of these REFERENCES
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doi:10.1007/s11936-019-0797-1

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Received: 12 December 2022 Revised: 11 May 2023 Accepted: 11 May 2023