NEUROLOGY OF PREGNANCY AND THE PUERPERIUM

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CHAPTER 112 NEUROLOGY OF PREGNANCY AND THE PUERPERIUM

Steven Feske, Autumn Klein

The hormonal changes of pregnancy mediate a multitude of physiological effects that promote successful gestation and birth and influence disease states. These physiological changes interact with many common neurological disorders. In addition, neurological injury and dysfunction constitute the most threatening aspect of preeclampsia-eclampsia, a condition unique to pregnancy. Here, we first review those aspects of the physiology of pregnancy that influence neurological disease and discuss selected important neurological disorders, focusing on their clinical recognition and available therapies.

PHYSIOLOGY OF PREGNANCY

Hormonal Changes

Human chorionic gonadotropin (HCG) is a glycoprotein composed of two subunits designated α and β. α-HCG, produced by cytotrophoblasts, structurally resembles follicle-stimulating hormone, leutinizing hormone, and thyroid-stimulating hormone, whereas β-HCG, made by syncitiotrophoblasts, has a unique structure, making it the earliest characteristic clinical marker of pregnancy. β-HCG can be detected in the maternal serum or urine within days after implantation. The serum level of β-HCG doubles about every 2 to 3 days and can be followed as a marker of the health of the placenta and the pregnancy. Lower than expected levels of β-HCG, as seen in ectopic pregnancies and spontaneous abortions, indicate failure of proper placental development. Higher than expected levels of β-HCG suggest multiple gestations or trophoblastic disease, such as choriocarcinoma or hydatiform mole. HCG stimulates production of progesterone from the corpus luteum, supporting the placenta during the early stages of pregnancy. It acts as an immunosuppressant and, because of its resemblance to thyroid-stimulating hormone, has some thyrotropic activity. β-HCG production peaks at 10 to 12 weeks of gestation, falls to 10% of peak at about 16 weeks, remains stable until 22 weeks, and then slightly increases to term.

α-Fetoprotein is a glycoprotein produced in the yolk sac and fetal liver. It may act as a fetal osmoregulator and an immunomodulator. It enters the fetal urine and is released into amniotic fluid. Because it is highly concentrated in the fetal central nervous system, elevation of its level in the maternal blood or in the amniotic fluid may indicate fetal central nervous system disease, such as a neural tube defect, or multiple gestations. A decrease in its level may suggest Down syndrome. In conjunction with β-HCG and estriol, its serum level is used in a “triple screen” to determine the overall health and development of the fetus and placenta.

The three estrogens that are essential for the maintenance and growth of the fetus and the placenta are estradiol, estrone, and estriol. These hormones increase most dramatically in the first 16 weeks of pregnancy and then continue to increase at a slower rate until term. Estrogens, primarily estriol, increase uterine blood flow and are believed to be the trigger for parturition. Estrogens enhance myometrial irritability and contractility. They play a role in the preparation of the breast for lactation and of the cervix for labor and delivery. Through actions on the fetal pituitary, they may play a role in triggering the onset of labor. Estrogens increase neuronal excitability and lower the seizure threshold. This effect occurs through several mechanisms that inhibit the inhibitory action of γ-aminobutyric acid (GABA), including negative allosteric modulation of GABA transmission by binding to the GABA receptor, transcription regulation causing decreased synthesis of messenger RNA encoding the GABA precursor GABA-amino-decarboxylase, and decreased synthesis of GABA receptor subunits.¹ Estrogens also have immunomodulatory effects (see Immune Changes).

Progesterone and 17α-hydroxyprogesterone are the two progestational steroid hormones most important in pregnancy. Progesterones act in many ways in opposition to estrogens. They relax myometrial musculature and decrease uterine irritability. They maintain the endometrium supporting the developing fetus, and they decrease uterine blood flow. Progesterones have immunosuppressive effects locally at the site of implantation, allowing placentation to occur without immunological rejection (see Immune Changes). The pathway for fetal steroid production is fed completely by progesterone. Near delivery, progesterone inhibits initiation of uterine contractions by stabilizing cell membranes and preventing prostaglandin formation. In contrast to estrogens, progesterones have an anticonvulsant effect, through positive allosteric modulation of GABA.¹

After delivery, the levels of all estrogens, progesterones, α-fetoprotein, and β-HCG return to normal within about 6 to 8 weeks. Normal ovulatory cycles return in approximately 10 weeks in a nonlactating woman and in about 17 weeks in a lactating woman. Normal menses returns in 12 weeks in women who are not breastfeeding. In lactating women, the timing of return is more variable. Return of menses does not always signal return of ovulation. Figure 112-1 summarizes some of the major hormonal changes of pregnancy and the puerperium.

Figure 112-1 Major hormonal changes during pregnancy and the puerperium.

Fluid, Hemodynamic, Cardiovascular, and Endothelial Changes

Pregnancy is a chronic state of hypervolemia. From placentation until 10 weeks of gestation, the aldosterone levels and renin activity increase, and the hypothalamic “osmostat” is reset to a lower threshold, resulting in renal retention of sodium and water and slight decrease in serum osmolality. The volume of total body water then remains stable until 1 or 2 weeks after delivery, at which time volume begins its gradual return to normal. At term, total body water is increased by almost 50% above the prepregnancy state. Plasma volume increases from 6 to 8 weeks of gestation and peaks at 32 weeks. The increase in plasma volume is far greater than the increase in red blood cell volume, leading to a physiological dilutional anemia of pregnancy. After delivery, plasma volume is lost at a faster rate than red blood cell volume as the hematocrit increases to that of the nonpregnancy state.

Albumin production is increased during pregnancy under the influence of estrogen. Therefore, overall total protein increases, but serum albumin concentration decreases as a result of the greater plasma volume. After delivery, albumin production and concentration return to normal within 3 weeks. Attention to albumin levels is very important in dosing and monitoring drugs that are highly protein bound.

Cardiac output, stroke volume, and heart rate increase 30% to 50% during pregnancy as a result of the increasing circulatory demands of the fetus and placenta and of the chronic hypervolemia of the pregnant mother. Half of this change occurs in the first 8 weeks of pregnancy. These measures of cardiac function then reach a peak at 25 to 30 weeks and remain stable until delivery. During labor and delivery, cardiac output increases to 50% above prepregnancy levels in the context of pain and apprehension. It increases another 20% to 30% within the 10 to 30 minutes after delivery. The increasing fluid mobilization after delivery maintains this high cardiac output for about 2 days. Cardiac output gradually decreases to about 25% above prepregnancy levels within 2 weeks after delivery and then normalizes in 6 to 12 weeks.

Blood pressure is decreased during pregnancy as a result of a decrease in systemic vascular resistance. Decreases in blood pressure, more so in diastolic than in systolic pressure, are first noted in the seventh week of pregnancy. The blood pressure reaches its nadir at 24 to 32 weeks and then increases progressively to prepregnancy levels at term. Venous compliance increases throughout pregnancy, leading to decreased blood flow, increased stasis, and a dampened ability to react to orthostatic changes. The mechanisms underlying the decrease in systemic vascular resistance have not been well established, but it is presumed that the effects of prostaglandins, progesterone, and nitric oxide lead to vasodilation via both arterial and venous relaxation. There is also evidence that pregnant women are refractory to the hypertensive effects of angiotensin II. Women with preeclampsia-eclampsia do not show this decreased response to angiotensin II, and it has been hypothesized that this dysregulation plays a primary role in the pathogenesis of this disorder. Figure 112-2 summarizes the hemodynamic changes of pregnancy and the puerperium.

Figure 112-2 Hemodynamic changes during pregnancy and the puerperium.

Changes in Coagulability

Several effects converge to make pregnancy a state of hypercoagulability. Compression of the inferior vena cava, the aorta, and the arteries and veins that supply and drain the gravid uterus causes vascular injury. Muscular relaxation and decreased venous compliance allow venous pooling and congestion. Levels of clotting factors, coagulation inhibitors, and other blood constituents that mediate clot formation and lysis are changed during pregnancy, leading to an increase in hypercoagulability close to term. These effects may be augmented by the acute phase response to acute blood loss and iron deficiency anemia immediately after delivery and for several weeks postpartum. This response includes elevation of fibrinogen.

Levels of the procoagulant factors I, VII, VIII, IX, X, XII, and XIII increase throughout pregnancy, while there is little or no increase in levels of factors II, V, and XI. These changes are probably mediated by estrogen. Increases in factor levels are most pronounced during the third trimester.

In contrast to the elevation of procoagulant factors, the levels of some coagulation inhibitors fall during pregnancy, contributing to an overall state of hypercoagulability. The coagulation inhibitor antithrombin III is significantly decreased, with the lowest levels in the third trimester.² Total and free levels of protein S are significantly decreased during the first and second trimesters. Although levels of protein C are largely unchanged, by the third trimester almost one third of women have functional activated protein C resistance.³

A study demonstrated that compared with pregnant controls, at all stages of gestation, protein C and activated protein C levels are lower in pregnant women with hypertension or a history of miscarriages.⁴ It has been postulated that these effects on protein C levels may contribute to the pathogenesis of preeclampsia-eclampsia.

Coexisting with the hypercoagulability caused by changes in the levels and function of clotting proteins, there is a low level of disseminated intravascular coagulation during pregnancy. By term, the erythrocyte sedimentation rate increases to 50 to 60 Westergren units, and there is an increase in platelet activation and in the levels of fibrinogen and fibrin degradation products. Platelets are also consumed in the uteroplacental unit near term, creating a benign thrombocytopenia of pregnancy with platelet counts decreasing to 80,000 to 150,000/µL. Near term, fibrin polymerization is faster leading to faster clot formation, and there is a significant decrease in fibrinolysis due to placental activator inhibitors 1 and 2.

Coagulation factors, coagulation inhibitors, platelets, and the regulation of fibrinolysis return to prepregnancy levels within a few weeks after delivery, with the exception of levels of protein S, antithrombin III, and von Willebrand factor. von Willebrand factor initially increases after delivery, while protein S and antithrombin III decrease even further.² By 8 weeks, almost all factors have normalized.

Immune Changes

Once the blastocyst contacts the uterine wall, the developing placenta acts to create an antigenically neutral barrier between the mother and the developing fetus. Controversy continues over whether there is systemic or localized immunosuppression that allows development of the fetus to proceed uninterrupted. The syncytiotrophoblasts, which make up the placenta closest to the mother, lack identifying major histocompatibility complex class I molecules, creating functional immunological blindness to the developing fetus. In addition, the synciotiotrophoblasts elaborate humoral factors, such as transforming growth factor β-2, that contribute to the immunosuppressed state by inhibiting cytotoxic T cells and natural killer cells. Progesterone has local immunosuppressive effects, inhibits T lymphocytes, and is found in higher concentrations in trophoblastic tissues. Estrogen decreases T cell proliferation and T helper cells. T helper type 1 (Th1) and T helper type 2 (Th2) cytokines are balanced during pregnancy. Th1 cytokines make interleukin 2, interferon α, and lymphotoxin, all of which promote cell-mediated immunity. Th2 cytokines make interleukins 4, 5, 6, and 10, which play roles in antibody-mediated and allergic responses. Overall, it is believed that pregnancy favors a state dominated by Th2 over Th1.

CLINICAL TOPICS

Migraine

After puberty, migraine affects women three times more often than men and occurs in almost 20% of women across their lifetime. Headache during pregnancy is usually the result of a benign condition, most commonly migraine, but pregnancy predisposes women to several disorders that must be considered in the diagnostic evaluation. In addition, pregnant women are, of course, subject to the many uncommon disorders that may present with headache. Table 112-1 lists some common causes of headache during pregnancy and the puerperium.

TABLE 112-1 Some Causes of Headache Related to Pregnancy and Puerperium

Epidemiology

Several studies have looked at the pattern of migraine in pregnancy with consistent findings. The effect of pregnancy does not parallel that of oral contraceptive agents. In a case-control study of 100 women with migraine with aura and 200 age-matched controls, whereas oral contraceptives worsened headaches in 25% of women, pregnancy lessened migraine in 77%.⁵ In a prospective study of 49 women, migraine frequency decreased by about 50% in the first trimester, with 10.6% of patients experiencing complete remittance.⁶ In the second trimester, 87% of women reported a decrease in migraine frequency with 53% remission, and in the third trimester, 87% of women reported a decrease in migraine frequency with 79% remission. Migraine returned in 4% of women by day 2 postpartum, 34% by 1 week, and 36% by 1 month. Women who breastfed had a lower rate of early headache recurrence after delivery. Women with menstrual migraine, defined strictly⁷ as headache that occurs on the first day of menses, have the greatest improvement in headaches during pregnancy. Pregnancy appears to affect the pattern of migraine with and without aura differently. In a self-reporting study comparing 88 women with migraine with aura and 180 women with migraine without aura, women with aura were more likely to have premenstrual syndrome and headaches exacerbated by oral contraceptive agents, and they were more likely to get relief from headaches during pregnancy.⁸ Women with migraine without aura had more menstrual migraine.

Pathophysiology

There is little precise information about the etiology and triggers of headaches during pregnancy. Although it has always been postulated that a change in the estrogen levels plays a role in the pattern of migraines in pregnancy, experimental studies have not made this relationship clear. It has been shown that estradiol leads to a decrease in excitatory neurotransmitters such as dopamine and norepinephrine and an increase in inhibitory neurotransmitters such as serotonin, GABA, and endorphins.⁹ Estradiol increases during the course of pregnancy. This increase is physiologically advantageous in preparation for the pain of childbirth, and it may underlie the lessening of headaches through the course of pregnancy.

Evaluation

The decision to perform neuroimaging at any time during pregnancy must be based on a weighing of the risks to the unborn fetus and benefits to the mother. If computed tomography scanning is done, it should be done with proper shielding to minimize radiation exposure. Computed tomography contrast dye poses a risk of fetal hypothyroidism and should be avoided. Noncontrast magnetic resonance imaging is very sensitive and safe. Gadolinium crosses the placenta, and its effects on the fetus are unknown, so it should be avoided. Lumbar puncture has no adverse effect on pregnancy, and pregnancy should not limit its use to test for hemorrhage, infection, or intracranial hypertension when the clinical situation warrants it.

Treatment

Counseling about preventive interventions and safe medications is important in all women with headaches. The importance of nonpharmacological interventions, such as regular sleep and meals, avoidance of dehydration, avoidance of known headache triggers, regular exercise, meditation, and biofeedback, should be stressed as the first line of treatment during pregnancy. In some studies, these interventions have been shown to be as efficacious as medications.¹⁰ However, in many women with significant migraine, help from medications will be desirable.

The choice of medications for migraines in pregnant women is dictated mainly by the potential for adverse side effects. Acute medications are given at the start of a headache to ameliorate or abort the headache pain. In most cases, women are motivated to minimize medication use during pregnancy, and intermittent dosing of safe agents provides adequate relief. If medication is needed for acute pain, acetaminophen should be the first-line of treatment. Combinations of acetaminophen with caffeine and butalbital may also be safely used, if they are not taken so frequently that they promote the transformed migraine of caffeine dependence or excessive barbiturate intake. If these agents are ineffective, then opiates and antiemetics are third-line agents. Opiates (category B) should not be used more than a few times a week, because if used to excess they can cause constipation and dependence in the mother and withdrawal in the baby at the time of birth. The antiemetics metoclopromide and prochloperazine (category B) can be as effective as analgesics in alleviating acute migraine symptoms.

Potent inhibitors of prostaglandin synthesis and strong vasoconstrictors should be avoided in pregnancy. Aspirin in analgesic doses should be avoided. Aspirin interferes with implantation during conception, it increases the risk of bleeding throughout pregnancy, and it promotes premature closure of the ductus arteriosus in late pregnancy. Nonsteroidal anti-inflammatory agents should be avoided. They also may prevent implantation, and they promote early closure of the ductus arteriosus. Although some authors recommend them as acceptable during the first and second trimesters, other choices are preferred. There have been some reports of cleft palate associated with codeine use in the first trimester, and although a causal link is not well supported, it is best to avoid it during pregnancy. Ergots should be strictly avoided due to their potent vasoconstricting effects and long half-lives. Serotonin agonists, “triptan” agents, should be avoided in pregnancy based on their potent vasoconstrictive effects and the lack of sufficiently powered data to argue for their safety. Registry data offer no clear evidence of an increased rate of congenital malformations in women who have taken these agents during pregnancy, but these data are not controlled and numbers of patients are too small to draw clear conclusions. A Danish study found an increased rate of preterm delivery and lower birth weight among users of sumatriptan.¹¹ A Swedish registry study found only statistically insignificant trends of preterm delivery and low birth weight and no increase in the rate of congenital malformations.¹²

If headaches occur too frequently or they are too intense, prophylactic medications may be used to prevent them. The degree and frequency of headaches that represent a personal threshold for tolerance vary, and many women prefer to tolerate pain in order to avoid regular medication while they are pregnant. The physician should consider teratogenesis as well as long-term behavioral side effects when prescribing prophylactic medications for daily use. Because major fetal organs and facial structures have formed by the tenth week, if one can temporize until this time, teratogenic toxicity is of much less concern. β-Blockers, calcium channel blockers, and tricyclic agents have all been safely used for headache prophylaxis during pregnancy, although they all have potential harmful effects. β-Blockers may cause fetal growth retardation, and near term they may cause fetal hypoglycemia, bradycardia, respiratory depression, and hyperbilirubinemia. Calcium channel blockers may cause uterine relaxation prolonging labor and fetal cardiac depression if used near term. Tricyclic agents may cause fetal anomalies, neonatal withdrawal, and neonatal urinary retention if given near term. Serotonin reuptake inhibitors may cause jitteriness in newborns. To avoid adverse effects in the newborn, it is best to discontinue these drugs near term.

Valproic acid and carbamazepine can cause neural tube and other major fetal malformations, and they should not be used for headache prevention during pregnancy.¹³^–¹⁵ Gabapentin is contraindicated given its effects on bony development and overall growth in laboratory animal studies. Experience with newer antiepileptic agents is limited, and they, too, are best avoided as migraine prophylactic agents.

Commonly used supplements that are regarded as benign should be reconsidered in pregnancy. Magnesium can be an effective preventive medication for some women, but it may delay the onset and progression of labor. Riboflavin is regarded as relatively safe in pregnancy.

A short course of corticosteroids can be used safely in mid to late pregnancy to break a persistent headache without undue exposure to the fetus. Prednisone is the preferred choice, because it crosses the placenta less than other corticosteroid preparations.

Migraines that might have been relieved by late pregnancy tend to return after delivery, and treatment during breastfeeding warrants special considerations. The American Association of Pediatrics recommends nonsteroidal anti-inflammatory agents as generally safe for breastfeeding. Highly lipophilic medications, such as sumatriptan, cross readily into breast milk. For women taken sumatriptan, a safe recommendation is to pump breast milk 6 hours after an oral dose and 4 hours after an injected dose. Caution should be used with β-blockers, because they may cause newborn bradycardia or heart block.

Cerebrovascular Issues

Epidemiology

There have been no well-designed, long-term prospective studies evaluating the incidence of stroke in pregnancy and the puerperium. Comparisons of available retrospective data are limited because authors have defined the patient groups differently, sometimes including all or only late pregnancy, all or part of the postpartum period, or including or excluding women with spontaneous or therapeutic abortions, and they have defined stroke differently, including or excluding venous sinus thrombosis, subarachnoid hemorrhage, and transient ischemic attack. Estimates of incidence of stroke in pregnancy range from a low of 4.3 to a high of 210 cases per 100,000. In recent years, several retrospective studies have examined stroke in pregnancy shedding some new light on its epidemiology. These studies agree with older ones that there is an increased risk of stroke in pregnancy and the puerperium compared with the nonpregnant state and that the distribution between ischemic and hemorrhagic stroke is roughly equal. In public hospitals in the Ile de France studied from 1989 to 1992, there were 4.3 ischemic strokes per 100,000 women and 4.6 hemorrhagic strokes per 100,000 women.¹⁶ This study included only 2 postpartum weeks, and it excluded cerebral venous sinus thrombosis, subarachnoid hemorrhage, and transient ischemic attacks from the definition of stroke. A population-based retrospective study of hospitals in the Baltimore-Washington, DC, area from 1988 through 1991 was able to compare the rate of stroke in pregnant and nonpregnant women aged 15 to 44 years to assess the risk attributable to pregnancy. This study found 11 cerebral infarctions and 9 intracerebral hemorrhages per 100,000 deliveries. There was no increased risk of ischemic stroke during pregnancy (relative risk [RR], 0.7) and only a small trend of increase in the risk of intracerebral hemorrhage (RR, 2.5; confidence interval, 1.0 to 6.4) but a significantly increased risk of stroke of both types in the 6 weeks postpartum (ischemic stroke RR, 8.7; confidence interval, 4.6 to 16.7; hemorrhagic stroke RR, 28.3; confidence interval, 13.0 to 61.4).¹⁷

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