Antepartum period

This section examines specific alterations during pregnancy in ocular and otolaryngeal function, sleep, and the musculoskeletal system.

Sleep

Sleep patterns are altered during pregnancy and the postpartum period. Sleep quality and insomnia tend to be most prominent in the first and third trimesters.^{59,106,123,137,212,218} With advancing gestation total sleep hours progressively decrease.¹²³ Sleep time also decreases prior to labor onset with an increase in night awakenings reported beginning about 5 days prior to labor onset.¹⁷ Both hormonal and mechanical factors alter the pregnant woman’s sleep-wake patterns (Figure 15-1).^209,212 Sleep is divided into rapid eye movement (REM) and non–rapid eye movement (NREM) or deep sleep, which is subdivided into four stages. Hormonal changes alter sleep during pregnancy. Progesterone has a sedative effect and increases NREM sleep.^209,212 Estrogens and cortisol decrease REM, whereas prolactin increases both REM and NREM sleep.^61,212 Changes in sleep stages are seen by 11 to 12 weeks.¹³⁹ In general, pregnant women tend to have less deep and lighter sleep and more awakenings (from less than 5% to 10% by the third trimester).¹³⁹

During the first trimester, total sleep time increases, as does napping. By the second half of gestation, pregnant women have less overall sleep time and more night awakenings than nonpregnant women do. The pregnant woman has decreased REM sleep in the third trimester, along with increased awakenings and napping, and diminished alertness during the day.^{59,104,106,137,212} Early-onset REM sleep is reported in pregnant women with depression or mood disorders.¹³⁹ Alterations in NREM sleep with an increase in stage 1 (sleep latency or transition between wakefulness and sleep) and a decrease in stages 2 and 4 (delta sleep or deep sleep stage) during late pregnancy have also been noted.^122,137 The decrease in stage 4 NREM sleep has implications for the pregnant woman’s functioning, because this stage is important for basic biologic processes such as tissue repair and recovery from fatigue.¹⁴⁰ In summary, changes to sleep reported during the first trimester include increased total sleep, napping, daytime sleepiness and insomnia, and decreased REM, and stage 3 and stage 4 NREM sleep; changes during the second trimester included increased awakenings with normal total sleep times and decreased REM, stage 3 NREM, and stage 4 NREM sleep; third trimester changes included increased daytime sleepiness, insomnia, nocturnal awakenings, and stage 1 NREM sleep, and decreased REM, stage 3 NREM, and stage 4 NREM sleep.^{59.106,122,137,212,218,236} During pregnancy, night awakenings are often associated with nocturia, dyspnea, heartburn, uterine activity, nasal congestion, muscle aches, stress, and anxiety and can lead to sleep disturbances and insomnia. The major reasons given by women for sleep alterations include urinary frequency, backache, leg cramps, restless legs, heartburn, and fetal activity.^{61,104,139,236} Interventions include establishing regular sleep-wake habits and periods, avoiding caffeine, relaxation techniques, massage, heat and support for lower back pain, modifying the sleep environment, and limiting fluids in the evening.²¹² Sleep medications should be avoided because these drugs alter the physiologic mechanisms of sleep by suppressing REM and NREM stages 3 and 4 and may cross the placenta to the fetus. Sleep loss (i.e., sleeping less than 6 hours per night) in the last 3 to 4 weeks of pregnancy may increase labor length and need for cesarean birth.^{76,94,138,259}

A pregnancy-associated sleep disorder has been described by the American Sleep Disorders Association.⁹ Individuals with sleep disorder breathing may have an increase in severity during pregnancy due to partial airway obstruction by otolaryngeal changes.^29,208,209 Increases are also reported in snoring and possibly obstructive sleep apnea (OSA), although the prevalence of OSA during pregnancy is not well documented.^{29,75,208,209} The prevalence of snoring during pregnancy is 15% to 30% by the third trimester.¹³⁹ An increase in hypertension, preeclampsia, gestational diabetes, and fetal growth restriction has been reported in pregnant women who snore.^28,29,75,168

The woman in labor experiences two types of pain: visceral and somatic. Visceral pain is related to contraction of the uterus and dilation and stretching of the cervix. Uterine pain during the first stage of labor results from ischemia caused by constriction and contraction of the arteries supplying the myometrium. Somatic pain is caused by pressure of the presenting part on the birth canal, vulva, and perineum. Visceral pain is experienced primarily during the first stage of labor; somatic pain is experienced during transition and the second stage.⁶⁸ Somatic pain is more intense and localized.

The corpus of the uterus is relatively denervated by late pregnancy while the cervix remains densely innervated.²⁴⁰ This suggests that the cervical area maybe the major site of pain in labor.²⁴⁰ Near term numbers of nerve cells and fibers in the sensory area of the spinal column decrease accompanied by increased excitability of mechanosensitive efferents in the cervix.^125,181 The pain threshold may be altered in late pregnancy, enhanced by elevated β-endorphins, leading to a proposed “pregnancy-induced hypoanalgesia” (see next section).^79,125,181

Pain from uterine contractions and dilation of the cervix during the first stage of labor is transmitted by afferent fibers to the sympathetic chain of the posterior spinal cord at T10 to T12, and L1. In early labor, pain is transmitted primarily to T11 to T12 (Figure 15-2).^68,79,206 As activation of peripheral small A-delta (myelinated) and C afferent (unmyelinated) nerve fibers of these nerve terminals (by kinin-like substances released from the uterine and cervical tissues) intensifies, transmission spreads to T10 and L1. Pain during the first stage may be referred; that is, the nerve impulses from the uterus and cervix stimulate spinal cord neurons, innervating both the uterus and the abdominal wall. As a result, the woman experiences pain over the abdominal wall between the umbilicus and symphysis pubis, around the iliac crests to the gluteal area, radiating down the thighs, and in the lumbar and sacral regions.^79,231 During transition and the second stage, somatic pain impulses from distention of the birth canal, vulva, and perineum by the presenting part are transmitted by the pudendal nerves through the posterior roots of the parasympathetic chain at S2, S3, and S4.^41,79

Peripheral tissue injury and inflammation change the transcription and function of channels and receptors in the peripheral and central nervous systems.^102,240 Inflammation (mediated by prostaglandins, cytokines, granulocytes, integrins, and metalloproteases) activates nociceptive nerve fibers, decreasing their threshold and increasing action potentials.^102,127 This visceral hypersensitivity is mediated by ion- and acid-sensitive channels, and by prostaglandin E₂, N-methyl-d-aspartate (NMDA), and other receptors.¹⁰² Stimulation of dorsal root NMDA receptors mediates central hypersensitivity.¹²⁷

As the A-delta and C nerve fibers enter the dorsal horn of the spinal cord, they synapse and ascend to the brainstem by the spinothalamic tract (see Figure 15-2). The pain impulses entering the brain stimulate a variety of neurons, including cortical neurons and those of the brainstem reticular formation (integrative function), thalamus, hypothalamus, and limbic system.²⁰⁶ The result is a conscious sensation of pain as well as a variety of ventilatory, circulatory, and metabolic responses. Spatial and temporal summation is processed in the cortex.^151,206 These responses include increases in ventilation, cardiac output, peripheral resistance, gastric acid secretion, metabolic rate, oxygen consumption, and catecholamine release.

The perception of pain is influenced by physiologic, psychologic, and cultural factors. Pain can lead to anxiety and influence maternal physiologic responses and the course of labor. For example, physical manifestations of anxiety may include muscular tension, hyperventilation, increased sympathetic activity, and norepinephrine release, which can lead to increased cardiac output, blood pressure, metabolic rate, and oxygen consumption and impaired uterine contractility (Figure 15-3).^18,119,205 Anxiety can also increase fear and tension, reducing pain tolerance, which decreases uterine contractility.^18,119,151 Relaxation techniques such as progressive muscle relaxation, touch, breathing, imagery, and autosuggestion help reduce anxiety and prevent or stop this cycle.¹¹⁹

Descending spinal tracts in the dorsal horn modulate nociception via input from the cortex and limbic system with release of endogenous opioids such as β-endorphins and enkephalins (see next section).²⁰⁵ These modulating factors are produced by the placenta as well as the mother and may include an opioid-enhancing factor.²⁰⁵ Other modulating factors include analgesia induced by mechanical stimulation of the hypogastric (uterine mechanical stimulation) and pelvic (vaginal distention) nerves.²⁰⁶ Exogenous modification of labor pain includes both pharmacologic (opioids, sedatives, analgesics, anesthetics) interventions and nonpharmacologic cognitive, behavioral, and sensory techniques.^70,156 These techniques include relaxation, cognitive and behavioral childbirth preparation, hypnosis, acupuncture, movement, positioning, vocalizations, touch, massage, music, biofeedback, transcutaneous electrical nerve stimulation (TENS), and hydrotherapy (Table 15-1).^{13,15,18,41,62,70,113,119,206,225,227,229}

The gate control theory postulates that nervous stimuli can be inhibited at the level of the substantia gelatinosa and dorsal horn of the spinal cord from reaching the thalamus and cerebral cortex:

“The theory proposes that a neural mechanism in the dorsal horns of the spinal cord acts like a gate which can increase or decrease the flow of nerve impulses from peripheral fibers to the central nervous system. Somatic input is therefore subjected to the modulating influence of the gate before it evokes pain perception and response. The degree to which the gate increases or decreases sensory transmission is determined by the relative activity in large-diameter (A-beta) and small diameter (A-delta and C) fibers and by descending influences from the brain. When the amount of information that passes through the gate exceeds a critical level, it activates the neural areas responsible for pain experience and response.”^{163, p. 222}

Techniques to close the gate (inhibit) include stimulation of large nerve fibers to block impulses from the smaller pain fibers. This provides a basis for use of massage and effleurage during labor. With continued use of these techniques, the large nerve fibers become habituated and stimuli from smaller fibers are no longer blocked. Thus, as labor progresses, the woman needs to stimulate other fibers (using techniques such as heat, pressure with change of position, and massage of other areas). Because descending fibers may also inhibit transmission to the brain, concentration techniques may also be useful.^41,119,157

The neuromatrix theory of pain expands on the gate control theory and emphasizes that pain is a multi-dimensional, whole body-mind-spirit experience that may underlie the basis for the efficacy of nonpharmacologic pain interventions during labor.^114,162,243

“The neuromatrix theory incorporates many of the same elements of the gate control theory. Both theories view the brain as the ultimate arbitrator of the multiple dimensions of pain. However, the gate control theory emphasizes the opening or closing of a gate at the level of the spinal cord as the preeminent mechanism controlling the ultimate perception of pain. The neuromatrix theory of pain recognizes the simultaneous convergence of a panoply of influences, including one’s past experiences, cultural factors, emotional state, cognitive input, stress regulation, and immune systems, as well as immediate sensory input . . . The multiple influences that create pain perception are generated from 3 parallel processing networks: sensory-discriminative (somatosensory components), affective-motivational (limbic system components), and evaluative-cognitive (thalamocortical components). Additional contributions of the autonomic nervous system, the stress response system, and immune system modulation are also recognized in this model.”^243,p.483

Postpartum period

B-EP levels decrease by 24 hours after birth. Levels are higher after vaginal versus cesarean birth.²⁶⁰ Levels of B-EP are twice as high in colostrum as in maternal plasma and may assist the newborn in the transition to extrauterine life and mediate the stressful events of labor and delivery.²⁶⁰

During the postpartum period the ocular and otolaryngeal changes resolve as the physiologic and hormonal adaptations of pregnancy are reversed. Sensitivity of the cornea returns to the usual parameters by 6 to 8 weeks postpartum.¹⁷² Intraocular pressure returns to prepregnancy levels by 2 to 3 months postpartum.²²⁴ Both ptosis and subconjunctival hemorrhages disappear spontaneously.¹⁷² Nasal congestion, ear stuffiness, tinnitus, and laryngeal changes and related discomforts usually disappear within a few days after delivery.^{65,94,129,215,216} Headaches, generally bilateral and frontal, are a common discomfort in the first week after delivery. Postpartum headaches tend to begin around the time of postpartum weight loss and have been attributed to alterations in fluid and electrolyte balance.

Ocular adaptations

Although ocular alterations during pregnancy generally do not have major clinical significance, they can result in minor discomforts, particularly for women who wear contact lenses. Some women may be unable to tolerate their lenses and may occasionally develop corneal edema. The basis for this intolerance is believed to be retention of water by the cornea, changes in the composition of tears, and alterations in corneal topography.^182,224 Changes in tear composition can make the contact lenses feel greasy shortly after insertion and cause blurring of vision.^172,182 Pregnancy may also alter healing following photorefractive keratectomy. Myopic regression and corneal haziness are reported in about 10% of postpartum women.²²² Alterations in refractory power along with occasional transient insufficiency of accommodation can cause difficulty in reading and in near vision or blurred vision in someone who is farsighted.^172,217,238 These alterations resolve in the postpartum period. New prescriptions for glasses or contact lenses should be delayed until several weeks after delivery.

Women with specific disorders such as preeclampsia and diabetes mellitus may have ocular complications associated with their disease process. Preeclampsia is associated with vasospasm of the conjunctival vessels and narrowing of the retinal arterioles. The latter may progress to severe arteriolar spasm or multiple retinal hemorrhages. Most of these changes reverse within 3 weeks postpartum.^224,238 In severe disease retinal detachment may occur.²³⁸ Mild to moderate visual disturbances are most common; severe or complete loss of vision is rare.²³⁸ However, up to 15% of women with severe preeclampsia develop cortical blindness that is almost always transient, lasting 4 hours to 8 days.²²⁴ The changes that occur with preeclampsia may be related to vascular changes, endothelial damage, coexisting systemic vascular disease, altered cerebral autoregulation, and hypoperfusion with ischemia or hyperperfusion with edema.²²⁴

Development and progression of diabetic retinopathy in pregnant women are more closely correlated with the duration of the disorder, severity of the diabetes, coexisting hypertension or preeclampsia, and degree of glycemic control.^182,217,224 Pregnant diabetic women (particularly those with established proliferative retinopathy) often demonstrate deterioration related to the metabolic and hormonal changes of pregnancy. Some women without diabetic retinopathy at the onset of pregnancy may develop mild nonproliferative diabetic retinopathy (NPDR) during pregnancy and those with NPDR may have progression.^217,224 Although reversal of these pregnancy-induced changes usually occurs over the first 6 to 12 months postpartum, some women, especially those with preexisting retinopathy, do not experience complete return to their prepregnant status.^{54,217,224,238} Careful baseline assessment and surveillance during pregnancy are essential. Women with gestational diabetes are not at increased risk for retinopathy during pregnancy.^54,217

Because intraocular pressure falls during pregnancy, the pregnant woman with glaucoma may experience an improvement with a decreased need for medications.^54,182,238 This has an additional advantage of reducing fetal exposure to these agents, which should be used with caution and carefully monitored.²¹⁷ Many ocular inflammatory disorders improve during pregnancy, possibly because of increased cortisol and other glucocorticosteroids, with exacerbation postpartum.

Any symptoms of eye infections in the pregnant woman must be assessed, because some sexually transmitted organisms such as herpes simplex virus and chlamydia may cause concurrent ocular infections. The presence of these organisms can have adverse consequences for the neonate if the mother also has a genital infection. For example, genital chlamydia can cause conjunctivitis and pneumonia in the newborn, and genital herpes simplex virus can cause disseminated or localized neonatal infection. Treatment of maternal ocular disorders during pregnancy should be done cautiously and with attention paid to the possible effects of the medication on the fetus. Even topical eye ointments must be used with caution because they can be absorbed systemically and cross the placenta to the fetus.²³⁸ If these agents must be used, nasolacrimal occlusion after instillation may reduce systemic absorption.²²⁴

Musculoskeletal discomforts

The pregnant woman may experience discomfort or pain associated with breast changes or stretching of the round ligament with growth of the uterus, pressure of uterine nerve roots, or pressure of the presenting part on the perineum. The latter type of pain is most prominent close to the onset of labor and is aggravated by vascular engorgement of these tissues. Increased joint mobility can result in muscle and ligament strain and discomfort. Pregnant women also have an increased risk of falls.^103,159,193 Falls are reported in 27% of pregnant women and are the leading cause of emergency department visits during pregnancy.^158,159 The increased risk of falls is related to weight gain, shift in the center of gravity, edema, deceased abdominal muscle strength, changes in mechanical load, ligament laxity, and changes in joint kinetics.^158,159 Regular exercise may be useful in reducing the risk of falls.¹⁵⁹

Hip and knee joint pain may occur due to ligamentous laxity, joint strain, and weight gain.^26,203 A 20% weight gain increases the force on weight-bearing joints by 50% to 100% during pregnancy.²⁰³ Knee pain is due to patellofemoral dysfunction from ligamentous laxity, increased femoral torsion, and increased pelvic width.²⁰³ Preexisting knee pain may increase or pain may occur for the first time. These changes are usually benign and reverse postpartum.²⁰³ Pubic pain results from inflammation of the symphysis pubis and usually responds to rest and ice.²⁰³

Many pregnant women experience low back pain (including lumbar pain and pelvic girdle pain) during pregnancy due to a combination of hormonal and mechanical factors including exaggeration of the lumbar lordotic curve due to shifting of the center of gravity, weight gain, and relaxation of ligaments, or from muscle spasm due to pressure on nerve roots.^26,95,247 The sacroiliac ligaments, which usually resist femoral rotation, are less likely to do so during pregnancy. This along with the lumbar lordosis “shifts the center of gravity anteriorly, causing a strain on the lower back and sacroiliac joint. As the strong sacroiliac ligaments become increasingly lax during pregnancy, this allows an increase in the forward shift of the uterus, thereby placing more strain on the pelvic floor and back.”²⁰³

Backache occurs in about 45% to 50% of women, most commonly after 18 weeks of pregnancy, although high backache earlier may result from breast alterations.^{57,90,95,103,116,165,247,254} Approximately 10% of these women experience severe back pain, peaking in intensity during the evening and night, and localized to the lower back or sacroiliac region.

An increased frequency of backache is reported in multiparas, in individuals with a history of back pain before pregnancy or with a previous pregnancy, and with increasing maternal age.^{103,116,203,254} Backache has not been associated with weight gain in pregnancy, height, or infant birth weight.^{26,103,116,203,247} Women tend to experience less pain if they are physically fit before pregnancy, exercise during pregnancy, and have had education on postural adjustments (e.g., upright posture, tucking the pelvis, rotating shoulders) to reduce back pain.²⁴⁷ Other recommendations include avoiding anything that increases the lordosis (e.g., high-heeled shoes), application of local heat, exercises to increase lower abdominal and back muscle tone beginning early in pregnancy, abdominal pillows, backrubs, use of a firm mattress, bed board, or back support, pelvic tilt exercise, aerobic exercise such as swimming, and conditioning before subsequent pregnancies.^{57,116,188,247} Acupuncture has also been found to provide relief.^131,228 Backache, round ligament pain, or other discomfort should be assessed to distinguish “normal” discomfort from other processes such as preterm labor.

Exacerbation of intervertebral disk disorders is seen during pregnancy and the immediate postpartum period, probably because of postural changes and an increase in mechanical stress.^11,26,230 The most frequently affected areas are the fifth lumbar and first sacral nerve roots. Management usually involves bed rest. Spondylolisthesis (slipping of one lumbar vertebra forward onto the vertebra below) especially at L4 to L5 or at L5 to S1 is aggravated.²⁰³ True herniation of the disk is rare.^95,203,230

During the third trimester, the woman may experience numbness and tingling of the arms, fingers, legs, and toes. Paresthesia of the upper extremities may be caused by marked lordosis along with anterior flexion of the neck and slumping of the shoulders, placing traction on the brachial, ulnar, and median nerves. In the legs and toes, paresthesia may be caused by pressure of the uterus on the blood vessels and nerves supplying the lower extremities. Painful legs are experienced by many pregnant women and arise either from the mechanical effects of the uterus (e.g., the altered gait and posture during pregnancy and compression of the inferior vena cava and iliac veins when supine) or from systemic alterations. Systemic alterations that can lead to painful legs include musculoskeletal changes, reduced serum albumin (decreasing colloid osmotic pressure and increasing dependent edema), changes in coagulation, and alterations in calcium and phosphorus metabolism and diet. These causes must be differentiated from thromboembolic disorders, which are also more prevalent during pregnancy (see Chapter 8). Leg cramps during the last few months of gestation are common. These cramps may be related to alterations in calcium and phosphorus metabolism (see Chapter 17) or to pressure of the enlarged uterus on pelvic blood vessels or nerves supplying the lower extremities.

Headache

Heacaches are common complaints during pregnancy and the postpartum period.¹²⁶ The most common forms of headaches in pregnant and breastfeeding women are those caused by muscular contraction/tension or migraines without aura.^57,155 Tension headaches are characterized by a persistent bandlike or viselike pain extending from the base of the neck to the forehead. The woman often notices the headache on awakening, with worsening of symptoms during the evening.^11,57 The discomfort may be aggravated by postural changes or stress. Tension headaches during pregnancy may also be due to hormonal influences, eye strain secondary to ocular changes, nasal congestion, emotional tension, muscle spasm, fatigue, altered cerebral fluid dynamics, or the mild respiratory alkalosis characteristic of pregnancy (see Chapter 10). Reproductive hormones, especially estrogens, interact with the trigeminovascular system to alter cerebral blood flow and neurochemical release.

Because headaches may also be a symptom of disorders such as preeclampsia, however, any pregnant woman complaining of headaches must be carefully evaluated. Management includes massaging neck and shoulder muscles, application of heat or ice to the neck, rest, warm baths, and minimal use of simple analgesics (acetaminophen).⁵⁷ Sedatives and hypnotics are not recommended for routine use in pregnant or lactating women because they are ineffective and metabolites cross the placenta and the blood-milk barrier and are excreted more slowly by the fetus and infant.¹¹

The pregnant woman with a chronic neurologic disorder

The physiologic and hormonal changes of pregnancy can influence the course of chronic neurologic and neuromuscular disorders such as epilepsy, myasthenia gravis, and multiple sclerosis. These disorders also have ramifications for the health and well-being of the mother and her infant. The implications of epilepsy and selected other neurologic and neuromuscular disorders during pregnancy are summarized in Table 15-2.

Common embryonic anomalies of the central nervous system

The most common CNS anomalies arise in the embryonic period during the period of primary neurulation and result from failure of neural tube closure. These anomalies include anencephaly, myelomeningocele, encephalocele, and spina bifida occulta. NTDs are usually accompanied by alterations in vertebral, meningeal, vascular, and dermal structures and arise from a complex interaction of environmental and genetic factors. NTDs have a familial pattern with an increased recurrence rate. Approximately 2% to 16% of infants with isolated NTDs have cytogenic abnormalities. NTDs also occur in infants with other congenital defects. These infants may have normal or abnormal karyotypes. A small number of NTDs occur secondary to teratogen exposure.¹⁷¹ 

Periconceptional folic acid supplementation significantly reduces the risk of NTDs in women with a history of a previous infant with an NTD and in the general public.^161,171 Current recommendations are that women of childbearing age consume 0.4 mg of folic acid daily, with higher recommendations (4 mg beginning 3 months before pregnancy and lasting through the first trimester) for women who have previously had a child with an NTD.⁸ Research continues regarding folate-related and other metabolic pathways and NTDs, the role of gene polymorphisms, and the roles of other nutrients such as vitamin B₁₂.^50,171

α-Fetoprotein leaks into the amniotic fluid and maternal serum in infants with open NTDs. Maternal serum screening at 16 to 18 weeks is used to identify infants at risk for NTDs, with follow-up ultrasound screening for diagnostic confirmation (see Chapter 3).

Anencephaly is due to failure of the neural tube to fuse in the cranial area. Because this area forms the forebrain, anencephalic infants have minimal development of brain tissue above the midbrain. Tissue that does develop is poorly differentiated and becomes necrotic with exposure to amniotic fluid. This results in a mass of vascular tissue with neuronal and glial elements and a choroid plexus with partial absence of the skull bones.¹⁷³ Because anencephaly arises from failure of the neural tube to close cranially, the insult occurs at or before 24 days.²⁴⁹

Encephaloceles also arise from failure of closure of part of the caudal portion of the neural tube and occur no later than 26 days.²⁴⁹ About 70% to 80% of these defects occur in the occipital region, with the sac protruding from the back of the head or base of the neck.^23,249 The protruding sac varies considerably in size, but the size does not correlate with the presence of neural elements. Ten percent to 20% of encephaloceles contain no neural elements.²⁴⁹ Hydrocephalus occurs in up to 50% of occipital encephaloceles due to alterations in the posterior fossa.²⁴⁹ Hydrocephalus may be present at birth or develop after repair of the defect. Encephaloceles may occur in association with meningomyelocele.

Spina bifida is a general term used to describe defects associated with malformations of the spinal cord and vertebrae that usually arise from defects in closure of the caudal neuropore. Approximately 80% occur in the lumbar area, which is the final area of neural tube fusion. Thus, spina bifida, arising from defects in primary neurulation, occurs at or before 26 days.²⁴⁹ Defects range from minor malformations to disorders that result in paraplegia or quadriplegia and loss of bladder and bowel control. The degree of sensory and motor neurologic deficit depends on the level and severity of the defect. The two major forms of spina bifida are spina bifida occulta and spina bifida cystica.

Spina bifida occulta (occult dysraphic state) is a vertebral defect at L5 or S1 that arises from failure of the vertebral arch to grow and fuse.^23,246 These are defects of secondary neurulation during formation of the caudal portion of the spinal cord. Most people with this defect have no problems and the defect may be unrecognized. A few have underlying abnormalities of the spinal cord or nerve roots, which are manifested externally by a hemangioma, dimple, tuft of hair, or lipoma in the lower lumbar or sacral area.

Spina bifida cystica describes NTDs characterized by a cystic sac, containing meninges or spinal cord elements, along with vertebral defects, covered by epithelium or a thin membrane, and usually occurring in the lumbar or lumbosacral area. Spina bifida cystica is usually due to alterations in primary neurulation. The three main forms of spina bifida cystica are meningocele, meningomyelocele, and myeloschisis. Meningocele (5% of infants with spina bifida cystica) involves a sac containing meninges and cerebrospinal fluid (CSF) but with the spinal cord and nerve roots in their normal position. These infants usually have minimal residual neurologic deficit if the defect is covered with skin and is managed appropriately.

With a meningomyelocele, the most common (80% to 90%) form of spina bifida cystica, the sac contains spinal cord or nerve roots in addition to meninges and CSF. During development, nerve tissues become incorporated into the wall of the sac, impairing differentiation of nerve fibers.²³ These infants have a neurologic deficit below the level of the sac. Most infants have hydrocephalus and an Arnold Chiari malformation in which the medulla protrudes downward below the foramen magnum and overlaps the spinal cord.²⁴⁶

Myeloschisis is a severe defect that occurs no later than 24 days.²⁴⁹ With this disorder there is no cystic covering; the spinal cord is an open, exposed, flattened mass of neural tissue. These infants have a high mortality rate and significant neurologic deficits and are at great risk for infection. This defect can involve the entire length of the spinal cord and can occur in association with anencephaly.²³

Intrauterine repair of meningomyelocele has been associated with short-term benefits including reversal of hindbrain herniation, which may enhance brain growth and reduce hydrocephalus. Some studies have found improved lower extremity function; other have not.³³ However, intrauterine repair is also associated with risks, including increased perinatal mortality, and most all infants are preterm.^2,171 A large trial randomizing infants to prenatal (before 26 weeks) or postnatal repair with follow-up to 30 months was recently completed.² Intrauterine surgery significantly reduced the need for shunting after birth and improved outcomes at 30 months, but was associated with an increased risk of preterm delivery and uterine dehiscence at delivery.²

Disorders of ventral induction are thought to arise no later than 5 to 6 weeks’ gestation. Disorders of forebrain development often have concurrent facial anomalies and include holoprosencephaly (failure of the brain to divide into 2 cerebral hemispheres) and holotelencephaly (see Table 15-6).

Neuronal proliferation

Neuronal proliferation (neuronogenesis) is a period of massive production of neurons and their precursors. The maximal rate of neuronal proliferation occurs between 12 and 18 weeks’ gestation.²⁴⁹ During proliferation the walls of the neural tube thicken, forming layers. The ependyma is the interior lining of the neural tube that later becomes the lining of the ventricles and the central canal of the spinal cord. In the subependymal layer the neurons and glial cells of the CNS are formed in the ventricular and subventricular zones of the germinal layer (germinal matrix).²⁴⁹ Neuronal proliferation begins at 6 weeks in the ventricular zone and at 7 weeks in the subventricular zone; both zones reach their peak proliferation by 12 weeks.³⁹ In conjunction with the proliferation of neurons, glial cells also increase in number; however, with the exception of radial glial cells, the peak in glial cell numbers occurs roughly from 5 months’ gestational age through the first year of life.²⁴⁹ Radial glia have two major functions. First they serve as guides during neuron migration (see next section) and secondly they are neuronal progenitors in the ventricular zone.²⁴⁹ Thus neurons arise from both neuronal and radial glial cell progenitors. Although most of the neuronal complement is formed early in fetal life, a few areas, notably the cerebral subventricular zone and the external granular layer of the cerebellum, continue to acquire neurons during the early months after birth (see Development of the Cerebellum).²⁴⁹ This pattern of neuronal formation produces a particular vulnerability in the preterm infant. In late gestation the ventricular and subventricular zones disappear almost completely (a subventricular zone remnant persists to adulthood) and proliferation shifts to intermediary and subplate zones for continued production of glial cells.³⁹

Alterations in neuronal proliferation can lead to increases or decreases in number and size of cells in the brain and associated structures. Micrencephaly arises from a decrease in size (micrencephaly vera) or number (radial microbrain) of neuronal-glial stem cell units.^246,249 Micrencephaly vera may be due to unknown causes; have a familial basis; or be associated with teratogens such as alcohol, cocaine, radiation, and maternal phenylketonuria.²⁴⁹ Excessive proliferation (macrencephaly) may also be due to unknown causes, have a familial basis, or occur with growth disturbances (e.g., achondroplasia or Beckwith-Wiedemann syndrome) and chromosomal disorders (fragile X and Klinefelter syndromes). Macrencephaly is also seen with neurocutaneous syndromes (such as multiple hemangiomas and neurofibromatosis) that involve excessive proliferation of cells within the central nervous system and of mesodermal structures.²⁴⁹

Migration

Once formed, neurons travel from the germinal layer in the subependymal region below the lateral ventricles to the areas of the nervous system where they will further differentiate, forming the gray matter, and take on unique and individual functions.²⁴⁹ The bulk of migration occurs from 10 to 20 weeks’ gestation (usually completed by 22 weeks; Figure 15-7).^53,167,249 Two types of neuron migration are seen in the cerebrum and cerebellum: radial and tangential. Radially migration accounts for much of the cortex and involves radial glia, which appear by 10 weeks’ gestation (Figure 15-8).^115,167,249 The nuclei of the radial glia are in the germinal matrix. The basal process of each cell is attached to the ventricle and the apical process is attached to the pia matter.¹¹⁵ These processes extending from the radial glia guide the neuron to its respective site. Radial glia also act as progenitors for neuron and astrocyte generation.²⁴⁹ Migration is mediated by signaling proteins, surface molecules, and receptors on both the neurons and the radial glia.²⁴⁹ Cajal-Retzius cells in the external cortical layer secrete reelin, an extracellular matrix glycoprotein. Reelin is thought to exert a stop signal for the migrating neurons.^167,249 Radial glial–assisted migration also occurs in the cerebellum. Cortical and cerebellar neurons migrate tangentially without radial glia guidance.¹⁶⁷

The neocortex develops in six zones, which are, from innermost to outermost, the ventricular zone, subventricular zone, intermediate zone, subplate, cortical plate, and marginal zone. Neurons forming in the ventricular and subventricular zones migrate through the cortical plate to form more and more superficial layers. The initial neurons migrate toward the cerebral walls to form the preplate. The next neurons migrate to areas deep within the cortex, whereas later neurons migrate further to the surface of the cortex. As a result, neurons formed early come to lie in deeper layers of cortex and subcortex; those formed later end at more superficial layers.²⁴⁹ Thus neocortex formation follows an “inside-first-outside-last” pattern, except for the early neurons of the subplate.^198,249 The subplate and marginal zone are transient structures that develop in parallel with the cortical plate, and then regress after the cortex is formed.¹⁶⁷ Most cortical neurons have reached their sites by 20 to 24 weeks’ gestation.²⁴⁹

The subplate zone and subplate neurons are critical structures in neocortex development. The roles of the subplate are listed in Table 15-7. The subplate is the first place where synapses form within the cortex and receive input from thalamic and other regions.⁴⁰ The subplate, located just below the developing cortex, serves as a “waiting room” or temporary site for thalamocortical and corticocortical projections and helps guide axons to cortical and subcortical targets and in establishing functional connections between brain regions.^48,53 For example, thalamic fibers enter the subplate area before their target neurons are in place and transiently form synaptic connections with subplate neurons.²⁴⁹ These are held in the subplate until the cortical plate is ready.

Subplate formation begins at 12 weeks, and reaches its maximum size at 27 to 30 weeks.^49,53,252 Thalamic afferents develop at 12 to 16 weeks and reach the subplate by 20 to 24 weeks.^118,252 Between 24 and 32 weeks axonal growth to the subplate and cortex increases and thalamocortical afferents move from the subplate to the cortex. Callosal and corticocortical axons enter the subplate from 24 to 32 weeks and enter the cortex from 32 to 26 weeks as the subplate begins to regress.^249,252 Thus the subplate is “a significant reservoir of functional connectivity in the preterm infant.”⁵³ The subplate is vulnerable to perinatal injury in these infants.

The subplate undergoes programmed cell death after birth, although subplate neurons remain as interstitial neurons.^128,249 Interstitial neurons are embedded in superficial white matter. Alterations in interstitial neurons or in their role in cortical circuitry may play a role in some forms of schizophrenia.¹²⁸

Disorders of migration alter gyral development and lead to hypoplasia or agenesis of the corpus callosum. Gyral development is most prominent during the last 3 months of gestation (see Figure 15-6,), with the most rapid increase between 26 and 28 weeks. The increased gyri result in a change in head shape (from oval to biparietal prominence). Gyral disorders arise secondary to inborn errors of metabolism, such as fatty acid oxidation defects, chromosomal anomalies, and exogenous insults, especially in preterm infants.^172,246,249

Organization

Organization refers to the processes by which the nervous system takes on the capacity to operate as an integrated whole. This phase of neurodevelopment begins at approximately 6 months’ gestation (see Figure 15-7) and extends many years after birth, and probably continues into adulthood. Neuron growth and connections lead to development of sulci and gyri (see Figure 15-6), with a brain growth spurt seen from 26 to 30 weeks. With increasing organization, fetal and infant behaviors become more complex.^6,249 Alterations in organization are seen in infants with Down, fragile X, and Angelman syndromes; periventricular leukomalacia (PVL); inflammation and infection; and hypothyroxinemia.^199,200,249 Injury to the cortex and subcortical area white matter can lead to disorders such as cerebral palsy. Focal lesions in the immature brain can lead to reorganization of sensory, motor, and related tracts.⁴⁰

During the period of organization, six processes occur.²⁴⁹ The first is differentiation and development of subplate neurons (see Migration). These neurons migrate to cortex early and guide ascending and descending projections to target neurons. Subplate neurons provide a connection site for axons ascending from the thalamus and other sites, until the neurons that these axons will eventually connect with have migrated from the germinal matrix. The subplate reaches its peak from 22 to 34 weeks.²⁴⁹

The second and third processes involve arrangement of cortical neurons in layers and arborization, wherein the dendrites and axons undergo extensive branching. This latter process is sometimes referred to as the “wiring of the brain” (Figure 15-9). The increase in cellular processes and in the size of the neuronal field is prerequisite for communication throughout the nervous system. This process is followed by the formation of connections or synapses between neurons, the fourth component of organization. The intracellular structures and enzymes that will produce neurotransmitters also develop at this time. Connections between cells are critical for integration across all areas of the nervous system. Throughout development, synapses continue to restructure; this process is believed to be the basis for memory and learning. Impulse conduction provides for functional validation of connections. Evidence suggests that use of conduction pathways may increase or alter connections.²⁴⁹ Characteristics of early neuronal activity include poor spontaneous neuronal activity, slow conduction velocity, slow synaptic potentials, and synaptic transmission uncertainty. Immaturity of neurotransmitters and hypersensitivity of NMDA receptors increases the risk of receptor overstimulation with hypoxic-ischemic events (see Hypoxic-Ischemic Encephalopathy).

Synaptogenesis is mediated by excitatory neurotransmitters such as glutamate.^73,132 Glutamate acts on N-methyl-d-aspartate (NMDA) receptors to enhance neuronal proliferation, migration, and synaptic plasticity. During the brain growth spurt, NMDA receptors are hypersensitive. Blockage of these receptors in animal models by substances such as ethanol leads to apoptosis.^{73,115,132,211,249} Other substances, such as erythropoietin, may also be important in enhancing brain organization and for neuroprotection.^{130,160,211,258}

The fifth organizational process entails reduction in the number of neurons and their connections through the death of up to half of the original neurons as well as regression of many dendrites and synapses.²⁴⁹ Neuronal survival has been likened to survival of the fittest, because neurons compete for resources such as nutrients, electrical impulses, and synapses. Neuronal death assists in elimination of errors within the nervous system. The appropriate number of neurons and their connections is retained while neurons that are improperly located or fail to achieve adequate connections are eliminated. Numbers of neurons are maximal in the fetus and survival is dependent on neurons or groups of neurons getting appropriate numbers of connections. From 8 months’ gestation to adulthood, numbers of neurons and synapses decrease. For example, there are an estimated 620,000/m³ neurons in the visual cortex at 7 months’ gestation versus 100,000/m³ at term and 40,000/m³ in the adult.¹⁵⁰

Cell death and selective elimination of neuronal processes is important in adjusting the size of individual neurons to their anticipated need and in brain plasticity in infants. In the developing brain, neuronal processes targeted for elimination can be saved if they are needed, for example, because of damage to other processes in order to preserve functional ability. Excitatory neurotransmitters, such as glutamate, mediate neural development and organization by acting on NMDA receptors.²³

The final organizational process is differentiation of glia from the general precursor cells into specific types and glia proliferation. The increase in glia begins at approximately 30 weeks’ gestation, continues into the second year, and then plateaus. There are three main types of glia: myelin-building (oligodendrocytes and Schwann cells), guiding (radial glia [for neuron migration], and Schwann cells), and “clean-up” (astroglia and microglia). The astroglia and microglia remove waste and dead tissue and occupy space left by neurons that have died, among other functions. Astrocytes also provide support for neurons. Astrocytes undergo rapid proliferation from 24-32 weeks (peak 26 weeks).^226,249 These glia are found primarily in deep cortical layers and white matter. They assist with axonal guidance, growth, brain structural development, and functioning of the blood-brain barrier.²²⁶ Astrocytes can release transmitters (such as glutamate) to send signals to neighboring neurons. Each astrocyte may interact with several neurons and hundreds to thousands of synapses to integrate information.^226,249 Microglia are the brain macrophages and immune cells. They also have a role in brain development with increased numbers seen in the third trimester. Activated microglia with white matter injury can lead to cellular injury initiated by ischemia and inflammation (mediated by reactive oxygen species, cytokines, and glutamate).^226,249 Oligodendrocytes produce myelin in the CNS. During the premyelinating period (before 32 weeks’ gestation), oligodendrocytes are especially vulnerable to hypoxic-ischemic injury. Damage to these glial cells is a prominent feature in brain injury in preterm infants (see White Matter Injury).²⁵³ Schwann cells produce myelin for the peripheral nerves. Schwann cells also act as guiding glia following peripheral nerve injury to guide regenerating axons to their targets.²⁴⁹

Myelinization

Myelinization refers to the laying down of myelin, the lipoprotein insulating the covering of nerve fibers. Myelinization increases the speed of transmission along axons by 100-fold.¹⁵⁰ This process occurs in both the central and peripheral nerve systems. Glia migrate to locations along the developing nerve fibers. Myelin is formed as the glia (either Schwann cells in the peripheral nervous system or oligodendroglia in the CNS) wrap around the nerve fiber. The glia’s cellular membrane, once wrapped around the fiber, fuses to become myelin.

Myelinization begins during the second trimester and continues into adulthood.²⁴⁹ The process of myelinization occurs at differing times in areas throughout the nervous system. For example, myelinization of somatosensory and auditory areas is nearly complete by term, whereas prefrontal lobe myelinization is not completed until after 20 years.¹⁵⁰ Myelinization of the forebrain is most rapid after birth. Myelinization first begins in the peripheral nervous system, with motor fibers becoming myelinated before sensory fibers. In the CNS, myelinization of sensory areas precedes that of motor areas, with the primary sensory areas becoming myelinated relatively early in development. Incomplete myelinization does not prevent function. However, because incomplete myelinization affects nerve conduction, it does alter the speed of impulse conduction. The order of myelinization parallels overall nervous system functional development and generally precedes mature function.¹⁷³ Areas of the brain that support higher-level functions, such as cognition and learning, myelinate later in life.²⁴⁹ Some brain areas continue to lay down myelin well into adulthood. Because myelin is a lipoprotein, dietary adequacy of fats and protein is important for normal myelinization. Disorders of myelinization are seen with amino and organic acidopathies, hypothyroidism, undernutrition, and perinatal insults such as PVL.²⁴⁹

Cerebellar development

The cerebellum is one of later brain structures to mature. The cerebellum undergoes a rapid growth spurt from 24 to 40 weeks with a fivefold increase in volume reflecting underlying histogenic and cytogenic changes; the cerebellar cortex increases more than 30-fold during this period.^36,146 Prior to 20 weeks two proliferation zones are established that give rise to the major cerebellar structures. Between 20 and 40 weeks increased external surface foliation is seen with development of the external granular layer, Purkinje cell (neuron) differentiation, and migration.^36,146 The lateral hemispheres of the cerebellum are involved in cognitive and motor function; the middle layers in regulation of emotion, social behavior, and affect.¹⁴⁸ The cerebellum is important in cognition and acts as a node in distribution of neural networks with interconnections with thalamus, parietal, and prefrontal cortex.¹⁸⁴ Cerebellar damage (see Cerebellar Injury in Preterm Infants) can alter language development, behavioral function and cognitive function.^{36,146,148,184,249}

Development of specific systems

Sensory abilities

Generally the somatic sensory and special sensory systems develop in the following chronologic order: touch, proprioception, vestibular, chemoreception (smell and taste), hearing, and vision.⁹² As noted in the section on Myelinization, in the peripheral areas, motor fibers myelinate before sensory fibers, whereas in the central nervous system sensory fibers myelinate before motor fibers. Thus in terms of rate of impulse transmission, differences in myelinization are one basis for limited integration of sensory and motor actions in the fetus.

The early fetus has been shown to respond to touch around the mouth at around 2 months of gestational age; hands become touch sensitive by 10 to 11 weeks.²⁴⁵ Touch in utero entails contact with amniotic fluid that is approximately at body temperature and contact with body parts or the wall of the uterus. Maternal movement and buoyant amniotic fluid provide rich vestibular stimulation for the fetus in utero.

Nociceptors appear at 6 to 8 weeks’ gestation, initially around the mouth; by 11 weeks in the face, palms, and soles; by 15 weeks in the trunk, arms, and legs; and by 20 to 22 weeks are abundant throughout the fetus (Table 15-8).^{49,118,152,167,245} The fetus can process pain at the subcortical level before cortical structures are in place.²⁴⁵ Sensory fibers to dorsal interneuron areas may develop as early as 6 weeks with development and differentiation of dorsal horn afferents beginning at 12 to 13 weeks.^1,152 Afferent synapses in the dorsal spinal cord and peripheral receptors start as early as 8 weeks’ gestation.¹⁵² Connections to the thalamus begin at 14 weeks and are complete by 20 weeks; thalamocortical connections are seen by 13 weeks and are more developed by 26 to 30 weeks.^49,152,1 These connections are myelinated by 29 weeks.²⁴⁵ By at least 24 weeks noxious stimuli cause a response in the primary sensory cortex. Completion of these connections stimulates development of axons and synaptogenesis with selective elimination of excess connections and cell populations.⁴⁹

Proprioception, which is involved with perception of joint and body movement and the position of the body, is interrelated with tactile and vestibular receptors. Vestibular sensation is a form of proprioceptive sensation involved in balance and postural control. Vestibular sensation, mediated by receptors in the ear, detects changes in direction and rate of head movement. Vestibular receptors mature by 14 to 15 weeks.¹³⁶

Smell is mediated by three groups of receptors that bind fragrant molecules: (1) main ciliated neuroreceptors (seen by 11 weeks), (2) trigeminal nerve endings (respond by 7 to 10 weeks), and (3) vomeronasal (appear by 5 to 6 weeks and are maximal by 20 weeks).^145,256 Olfactory marker protein is present by 28 weeks.⁴³ Odor molecules in amniotic fluid stimulate the fetal smell receptors by the third trimester.²⁵⁶ The fetus may detect aromatic substances and flavors from the maternal diet in amniotic fluid. This stimulation may have a role in programming later dietary preferences.^{16,43,118,133,164} Responsiveness to odors is observed in preterm infants beginning at approximately 28 weeks and is readily documented by 32 weeks’ gestation in most infants.⁴³

Taste occurs by activation of the taste buds and stimulation of the trigeminal nerve. Taste buds appear by 7 to 8 weeks and are morphologically mature by 13 to 15 weeks.⁴³ Taste receptors are present by 16 weeks, reaching adult numbers by term.¹³⁶ The fetus ingests amniotic fluid (see Chapter 3). Although variations occur in the composition of the amniotic fluid, it is unknown to what extent the fetus experiences taste. However, injection of a sweet substance increases fetal swallowing, whereas a bitter substance decreases swallowing.⁴³ Preterm infants respond to sweet taste by as early as 24 weeks and consistently by 28 to 32 weeks.⁴³

The structures of the auditory system, including the inner ear and cochlea, are mature enough to support hearing by approximately 20 weeks’ gestation; fetal hearing begins at 24 to 25 weeks.⁹³ At this point the fluid spaces in the cochlea are still poorly developed, the basal membrane is thick, hair cell innervation and arrangement are immature, and sensitivity to sound is poor. Sound sensitivity matures rapidly from 24 to 35 weeks.²⁵⁵ The tympanic membrane is similar to that in the adult by 28 weeks.²⁵⁵ The cochlea matures slowly during the third trimester, undergoing “tuning” during this period. Tuning of the cochlea so that areas are frequency-specific involves mechanical maturation of the basilar membrane and outer hair cells.²⁵⁵ Tuning begins in the base (high-frequency sounds) and proceeds toward the apex (low-frequency sounds). Changes in the sound environment, as occurs with preterm birth, may alter this process.

Auditory evoked potentials can be recorded as early as 25 to 26 weeks’ gestation, but are not reliable until after 28 weeks.^91,93,255 The fetus in the third trimester can discriminate between maternal live voice and tape-recorded voice and familiar versus novel sounds.⁸⁵ Responses to sound are observed in preterm infants at approximately 25 to 28 weeks’ gestational age.⁹¹ The preterm infant can be observed to orient to sound, with evidence of arousal and attention. The hearing threshold decreases with gestational age. For example, in infants of 28 to 34 weeks’ gestational age, the hearing threshold is approximately 40 decibels, whereas in term infants the hearing threshold is approximately 20 decibels.

Intrauterine recordings demonstrate that sounds in the external environment are audible to the fetus. High-frequency sounds are attenuated, whereas low-frequency sounds are not. External sound is reduced by about one-half its strength by the time it reaches the fetus.¹³³ For example, a 90-dB sound in a midrange frequency would be decreased to 45 dB by the time it reached the fetus.⁸⁵ The intrauterine auditory environment includes sounds within the mother such as breathing, movement of blood through the umbilical cord, and intestinal peristalsis and differs significantly from the sound environment of the preterm infant.⁸³ Hearing in preterm infants of different gestational ages is summarized in Table 15-9.