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CHAPTER 2 Prenatal Environment: Effect on Neonatal Outcome
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19
distress syndrome (RDS), and long-term neurologic problems.18 In terms of predicting perinatal
morbidity and mortality, the prognostically bad
signs of pregnancy include diabetic ketoacidosis, hypertension, and maternal noncompliance,
though risk of adverse neonatal outcome occurs
on a continuum with no clear threshold.
18,51
For the woman with GDM, the standard therapy
remains subcutaneous insulin, because multiple studies have documented its safety. For women using an
oral agent, several medications have been studied for
use during pregnancy. Metformin does not cause any
short-term adverse effects, but long-term effects on
the fetus are unknown because of lack of long-term
neonatal follow-up.11 If metformin is used, it is discontinued after the first trimester because metformin
crosses the placenta. Oral glyburide has been studied
for women who cannot or will not use subcutaneous
insulin. When glyburide was compared to insulin for
prevention of perinatal complications (i.e., macrosomia,
neonatal hypoglycemia, neonatal hyperbilirubinemia),
there was no clear evidence that the use of glyburide
resulted in significantly fewer perinatal complica-
144
tions.
Therefore, these researchers concluded that the
use of glyburide as a first-line treatment is not justified.
In preparing for the delivery of an IDM, the
neonatal team should consider the classification
of maternal diabetes (type 1 or 2, or gestational). In addition, the quality of metabolic control
throughout the pregnancy and labor, maternal
complications, and the duration of the pregnancy should be considered, along with indicators
of fetal growth and well-being.70 In cases in
which oral hypoglycemic agents have been
used, there should be careful assessment of the
neonate because sulfonylurea (i.e., glyburide)
may cause neonatal jaundice. Glyburide crosses the placenta, as does metformin, with the
potential to affect neonatal physiology.26 Both
of these medications are thought to be safe for
the neonate during lactation (see Chapter 18).
THYROID DISEASE
Thyroid disorders during pregnancy are relatively
common. The thyroid hormones triiodothyronine (T3)
and thyroxine (T4) cross the placenta in small amounts,
though the significance of the transfer has not been
well elucidated. The fetus depends on maternal T4
in the first trimester of pregnancy. Maternal T4 is
transferred to the fetus throughout pregnancy.13 At 8
to 10 weeks of gestation, the fetal thyroid begins to
concentrate iodine and produce T4. At approximately 24 weeks, thyroid-stimulating immunoglobulins
(TSIs) or thyroid-stimulating hormone receptor antibodies (TRAbs), which are classes of immunoglobulin G (IgG), cross the placenta and stimulate fetal
thyroid. Iodine is readily transferred from the mother
to the fetus. The fetal thyroid gland concentrates
iodine and synthesizes its own hormones as early
as 10 to 12 weeks of gestation; this is independent
of maternal thyroid function. Maternal T4 contri-
bution continues to remain important throughout
gestation.
113
Maternal thyroid hormones are believed
to be important for fetal neurologic development in
the first trimester, and untreated hypothyroidism has
been associated with a decrease in the intelligence
quotient (IQ) of offspring.
2,51,92
In analyzing thyroid function tests during pregnancy, reference ranges for normal function are different. Thyroid-stimulating hormone (TSH) is the
best test of thyroid function in pregnancy. However,
both the lower and upper limits of normal for
pregnant women are lower than for nonpregnant
women.
2
Subclinical hypothyroidism is defined as an elevated TSH with a normal free T4 level. In patients
with subclinical hypothyroidism, thyroid peroxidase
antibody (TPO-Ab) levels should be measured. If
the pregnant woman has subclinical hypothyroidism
and is TPO-Ab positive, treatment with levothyroxine is indicated because of the increased risk of
pregnancy loss, preterm delivery, and neonatal hospitalization.
2,113
Pregnant woman who are TPO-Ab
negative do not need treatment. Pregnant women
with overt hypothyroidism, defined as an elevated
TSH with low free T4 levels, should be treated with
levothyroxine53 Lack of treatment during pregnancy
is associated with increased neurodevelopmental
delay in offspring, pregnancy loss, prematurity,
preeclampsia, low birth weight, and placental abruption.2 Treatment with replacement hormone during
pregnancy is well tolerated by the fetus and reduces
these risks.53 However, a recent study showed that
children of women treated for subclinical hypothyroidism did not have significantly better cognitive
outcomes through 5 years of age than children
whose mothers were not treated.
39
Maternal hyperthyroidism presents a different
situation. Thyroid-stimulating antibodies, commonly found in patients with Graves’ disease, as well as
many of the drugs used to treat hyperthyroidism,
cross the placenta and can have a significant effect
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on the fetus. Antibodies, including long-acting thyroid stimulant and TSIs, can increase fetal thyroid
hormone production. High levels are associated
with fetal and neonatal hyperthyroidism. Untreated
Graves disease with maternal thyrotoxicosis has
been linked to preterm delivery, intrauterine growth
restriction (IUGR), low birth weight, and still-
128
birth.
In rare cases, the offspring of women
with Graves’ disease may themselves have this
condition. In fetuses and newborns, this is
evidenced by elevations in heart rate, growth
restriction, prematurity, goiter, and congestive
heart failure.53 Administration of antithyroid medi-
cation to the mother can decrease thyroid hormone
production in both the mother and the fetus but
may result in fetal hypothyroidism and goiter.53 In
the first trimester, propylthiouracil (PTU) is the
safest therapy, since methimazole has been associated
with increased rate of congenital malformations.53
In the second and third trimester, either propylthiouracil or methimazole are equally safe.
2
Another maternal antibody, TSH-binding inhibitor immunoglobulin, also crosses the placenta and can
prevent the expected fetal thyroid response to TSH.
The result is a transient fetal and neonatal hypothyroidism. Iodine deficiency in the mother is another
cause of fetal and neonatal hypothyroidism and, in its
severe form, leads to cretinism because of the fetus’s
dependence on maternal iodine reserves.
PHENYLKETONURIA
53
Phenylketonuria (PKU) is an inherited disorder in
which an enzymatic defect precludes conversion
of the essential amino acid phenylalanine to tyrosine.
This metabolic derangement is evidenced by an
accumulation of excessive amounts of phenylalanine and alternative pathway byproducts in the
blood, and these are toxic to the central nervous
system (CNS). Historically, PKU resulted in virtu-
ally certain mental retardation; affected individuals
often were institutionalized and rarely reproduced.
With the advent of universal neonatal screening
in the United States since the 1960s and effective
dietary treatment to prevent hyperphenylalaninemia
during infancy and early childhood, genetically
affected persons may avoid the devastating effects of
this disease, have relatively normal development, and
become pregnant. For women who do conceive,
PKU poses a significant environmental risk for their
developing fetus. The care of these women and their
infants presents a unique perinatal challenge.
An estimated 3000 healthy young women of
childbearing age with successfully treated PKU
are in the United States.
105
However, most discontinued their special diet in childhood because, at
the time, most doctors believed it was safe to do
so. Unfortunately, their blood phenylalanine levels
are very high when they become pregnant if they
are eating a normal diet. In up to 90% of such
cases, the offspring will be microcephalic, and/
or have severe developmental delay. These babies
also have an increased incidence of low birth
weight, congenital heart defects, and characteristic facial features regardless of whether they are
themselves affected with PKU, as well as preterm
birth and intrauterine fetal death.
129,161
They
cannot be helped by the PKU diet, or they suffer
from brain damage caused entirely by their mothers’ high phenylalanine levels during pregnancy.
To prevent such damage, these women should
resume their PKU diets, consuming specific types
of protein low or free of phenylalanine, during
preconception and pregnancy.
8,148,161
Studies have
identified improved long-term outcomes when
desirable phenylalanine levels (2 to 8 mg/dL) are
achieved at least 3 months before pregnancy and
maintained throughout gestation.83 Phenylalanine
levels drop quickly once dietary restrictions
are instituted, and there is a strong correlation
between maternal blood levels and neonatal
outcome.
103,129,148,161,162
PKU is an inborn error of metabolism, and
approximately 1 baby in 14,000 inherits PKU
when both parents have the PKU gene and
both pass it on to their baby. Neonatal blood
screening will identify these PKU babies. If
this screening is performed within the first
24 hours of life, the American Academy of
Pediatrics recommends rescreening at 1 to 2
weeks of age to avoid missed cases of PKU.
Once identified, infants with PKU are fed a
combination of special formula and breastfeeding
with close monitoring of blood and urine levels
of phenylalanine (see Chapter 18). When mothers
of PKU babies are invested in breastfeeding, they
need support to be successful.23 When treatment
is discontinued too soon, risks include blindness,
learning disabilities, behavioral disturbances, and
a decrease in IQ. When no treatment is instituted
at all, phenylalanine accumulates in the bloodstream and causes brain damage and severe developmental delay.
25,29
CHAPTER 2 Prenatal Environment: Effect on Neonatal Outcome
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21
RENAL DISEASE
Maternal adaptation to pregnancy involves major
changes in renal function and structure. Renal
hemodynamic changes begin early in pregnancy
and before significant expansion of plasma volume.
Renal blood flow increases in the first trimester by
35% to 60% and then decreases from the second
trimester to term. Additional changes include an
increase in the glomerular filtration rate and effective renal plasma flow, a decrease in renal vascular
resistance, an activation of the renin-angiotensinaldosterone system, and increased retention of sodium
and water. 51These changes place unique demands on
the renal system. Women with preexisting renal disease may have a successful pregnancy outcome with
proper prenatal care; however, some women experience fetal loss and deterioration in renal function.
Furthermore, moderate or severe renal dysfunction
complicates pregnancy and increases maternal and
fetal risks and adverse outcomes.
73
Renal disease in pregnancy may occur as a
result of urinary tract infections, nephrolithiasis,
glomerular disease, or severe hypertension or as a
complication of systemic diseases, including diabetes and systemic lupus erythematosus. Regardless
of the underlying etiologic factors, pregnancy
outcome relates most closely to these factors: the
presence of hypertension and the degree of renal
insufficiency before and during pregnancy.73 Many
women with renal disorders are hypertensive before
pregnancy, and they often develop a superimposed
pregnancy-induced hypertension leading to preeclampsia.
152
Even those with previously normal
blood pressures run an increased risk for developing
hypertension during pregnancy. The presence of
hypertension in these pregnancies represents
a significant risk to the fetus and is strongly
associated with IUGR, preterm delivery, and
perinatal loss.
Drug therapy to control chronic hypertension
has been shown to have a beneficial effect on fetal
outcome and generally is continued throughout
pregnancy. Renal insufficiency, as measured by creatinine clearance or serum creatinine level, also has
implications for fetal outcome. Mild to moderate
renal insufficiency (serum creatinine <1.5 mg/dL)
is associated with a generally favorable outcome,
whereas severe insufficiency (serum creatinine >1.6
mg/dL) often carries an increased risk for perinatal
death. Persistent proteinuria also may increase fetal
loss, and a urinary protein excretion rate higher than
0.5 g per 24 hours may be an independent predictor
of fetal outcome. As a rule, the number of preterm
deliveries and growth-restricted infants increases
with increasing blood pressure and decreasing renal
function.
73
Bacteriuria occurs in 2% to 7% of pregnancies.
If untreated, asymptomatic bacteriuria may lead to
pyelonephritis or acute cystitis. Risks for the fetus
are preterm birth and IUGR. Fetal death is an
additional risk with pyelonephritis. Prophylactic
antibiotics (suppressive therapy) should be given
to women with persistent or frequent recurrence
of bacteriuria or a history of pyelonephritis in
pregnancy.
170
Two special circumstances in chronic renal disease are dialysis during pregnancy and pregnancy
after renal transplant. Previously, it was felt that
women with end-stage renal disease undergoing
dialysis rarely become pregnant, and if pregnancy
did occur, it was associated with significant perinatal morbidity and mortality risks, with spontaneous
abortions reaching 50%. However, more recently,
studies show that intensive hemodialysis improves
fertility, although the rate of pregnancy is still
lower, and can improve pregnancy outcomes.
124
Pregnancy after transplantation is more common
and has a more favorable prognosis than pregnancy managed by dialysis.
165
Where maternal serum
creatinine remains less than 1.5 mg/dL and the
woman is on a stable immunosuppressive regimen,
outcomes can be expected to be positive.
73,165
Neonatal outcomes are typically favorable unless
there is maternal hypertension with impaired kidney functioning, in which case rates of preterm
birth, small-for-gestational-age (SGA) infants, and
neonatal mortality increase.
NEUROLOGIC DISORDERS
73,165
The risks that accompany pregnancies complicated
by maternal neurologic disorders vary according to
the individual disease entity and pertain to both the
course of the mother’s disease and the pregnancy
outcome. The physiologic and hormonal changes
of pregnancy can influence the course of chronic
neuromuscular disorders, such as epilepsy, multiple
sclerosis, and myasthenia gravis. The medications
used to control these disorders can be particularly
problematic for the fetus.
The prevalence of maternal seizure disorders
is about 4 in 1000 pregnancies, and most are
treated with antiepileptic drugs (AEDs). The
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disorders and/or the AEDs have been associated
with increased fetal and neonatal risks, including spontaneous abortion, prematurity, low
birth weight, SGA infants, congenital defects,
intrauterine demise, neonatal depression, and
hemorrhage.
160
In women with preexisting seizure disorders, prepregnancy planning is essential
to minimize the risk of congenital malformations.
Women anticipating pregnancy should begin daily
folic acid supplementation. Maternal folic acid
supplementation improves pregnancy outcomes
for women taking AEDs and decreases the risk of
spontaneous abortion, lower verbal IQ, and birth
defects.77 Women who are anticipating pregnancy
should have the dose of their AED changed to
the lowest effective dose, and valproic acid should
be discontinued.68 European recommendations
include avoiding the use of valproate in women of
childbearing age unless there are situations in which
pregnancy is highly unlikely.
156
Significant numbers of epileptic women experience an increase in seizure activity during pregnancy. This may be caused by decreased compliance
with medication regimens, physiologic changes
associated with pregnancy, and gestational changes
in plasma levels of anticonvulsant drugs.
66,94
There
is evidence that maternal seizures may compromise
fetal oxygenation, possibly because of diminished
placental blood flow or maternal hypoxemia resulting from postseizure apnea. For these reasons, control of maternal seizure activity with anticonvulsants
is one of the primary goals of prenatal care.
Placental transport of anticonvulsants does
occur, resulting in fetal levels that approximate or, in some cases, exceed maternal levels.77 Although the majority of infants born to
women with epilepsy are normal, these infants are
at increased risk for poor outcomes.
156
There is
an increased risk of congenital malformations
and adverse cognitive outcomes in offspring
of epileptic women treated with some types of
anticonvulsants.
77,156
The risks of congenital malformations are highest with the use of valproic acid,
and there is some increased risk with topiramate.68
There is also a higher risk with polypharmacy
than for those women on a single agent.
159
The
AEDs with the greatest safety profile for use during
pregnancy are levetiracetam and lamotrigine, and
these medications are recommended if an AED is
necessary.
114
Phenytoin, phenobarbital, and carba-
mazepine are intermediate-risk medications, being
much safer than valproic acid and topiramate, but
with a lower safety profile than levetiracetam and
lamotrigine. The most common major congen-
ital malformations associated with AEDs are
neural tube defects (e.g., spina bifida), orofacial defects (e.g., cleft lip, cleft palate), heart
malformations (e.g., ventricular septal defect),
urogenital defects (e.g., hypospadias), and skeletal abnormalities (e.g., radial ray defects, phalangeal hypoplasias).66 The influence of the seizure
disorder itself, as well as genetic makeup, cannot be
ignored. Infants born to mothers treated with
anticonvulsants, especially barbiturates, may
exhibit signs of generalized depression, including decreased respiratory effort, poor muscle
tone, and feeding difficulties. They also may
have symptoms indicative of drug withdrawal
(see Chapter 11). These symptoms are usually
present in the first week of life and include
tremors, restlessness, hypertonia, and hyperventilation.35 In addition, abnormal clotting and
hemorrhage in the offspring of women treated
with phenytoin, phenobarbital, and primidone
have been reported. This appears to be caused
by a decrease in vitamin K–dependent clotting
factors. Hemorrhage usually starts within the
first 24 hours, is often severe, and may result
in death. Infants born to these mothers should
have cord blood clotting studies done, vitamin
K prophylaxis soon after birth, and close observation. Breastfeeding should be encouraged,
though adverse effects may occur if the mother
is taking phenobarbital77 (see Chapter 18).
Multiple sclerosis (MS) frequently strikes women
during their reproductive years. The onset of MS
usually is insidious; the course is marked by a seemingly capricious cycle of exacerbation and remission. A wide range of sensory, motor, and functional
changes is associated with this disease; the type and
severity of symptoms vary dramatically from one
individual to another and in any one patient over
time. The disease is a T-cell–mediated autoimmune
disease of the CNS triggered by unknown exogenous agents in individuals with specific genetics.50
Pregnancy usually is well tolerated and may be
associated with MS stability or improvement. The
reported effects of the disease on pregnancy outcomes, including risk for malformations, cesarean
section rates, newborn birth weight, and rate of
preterm delivery, are inconsistent. Some groups
report no increase in adverse pregnancy outcomes,
CHAPTER 2 Prenatal Environment: Effect on Neonatal Outcome
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23
whereas others report a higher cesarean and infection rate and a greater number of preterm births in
mothers with MS.
102
Alterations in neural function,
fatigue, and general weakness may play a role in
pregnancy outcomes. However, in women with
MS, the disease process itself is not a threat to fetal
or neonatal well-being.50 The priority for neona-
tal care providers is to determine the extent of
the mother’s disability, including her level of
fatigue and her ability to care for her infant. The
availability of appropriate support systems, both
personal and professional, should be assessed,
and the required follow-up and referrals should
be made.
Even though the prognosis for these infants
is excellent, some factors associated with MS are
potentially problematic. Bladder dysfunction, common in women with MS, often results in urinary
tract infections during pregnancy. Associated fetal
and neonatal problems include preterm delivery and
sepsis. Early identification and prompt treatment
with appropriate antibiotics should minimize these
risks. Despite the fact that many women do have
improvement or remission during pregnancy, 17%
of women do experience a relapse of their MS,
which is more likely in the late second and third
trimesters.
5
An additional area of concern is the variety of drugs administered to MS patients.
Immunosuppressants are frequently used during
severe exacerbations. The placental transport and
fetal risk vary with the individual agent used. It
is generally recommended that pregnant women
with MS discontinue their disease-modifying
drugs (DMDs) prior to conception. If they have
to continue their medication because of the risk
for relapse, then it is recommended to avoid
mitoxantrone, fingelimod, and terflunomide.82
Conversely, glatiramer acetate, interferon B, and
steroids are considered safe.
50,82
A final consideration is the long-term one: The incidence of
MS in offspring of a parent with the disease is
about 2.5%, compared with 0.13% in the general
population; the risk is even greater when a sibling
has MS.
50
Myasthenia gravis (MG) is a chronic autoim-
mune disease that causes neuromuscular dysfunction and is encountered rarely in pregnancy; only
1 in 20,000 pregnancies is complicated by MG.90
Cells of the immune system make proteins called
antibodies that block nerve impulses to the muscles.
Antibodies to acetylcholine receptor (AchR) have
been found in most affected persons. Distinguishing
features include generalized weakness and muscle
fatigue with activity. Pregnant women with MG
also may experience respiratory compromise resulting from muscle weakness compounded by pressure
of the fetus against the diaphragm,
109
as well as
difficulty swallowing.90 The course of MG during
pregnancy is unpredictable and may vary in different pregnancies in the same woman.64 Unmasking
or exacerbations of MG occur in approximately
40% of pregnancies and remission in 30%, with the
remaining 30% experiencing no change. During
the first trimester and the first month postpartum,
exacerbations are more likely.90 Corticosteroids
can be used to maintain the remissions of MG and
should be continued on the lowest possible doses
throughout the pregnancy and postpartum period.
Certain immunosuppressive agents, such as methotrexate, cyclophosphamide, mycophenolate mofetil,
and rituximab are contraindicated in pregnancy. If
a patient is already on azathioprine or cyclosporine
A, it may be continued, but these drugs should not
be started in pregnancy.74 Plasmapheresis and intravenous immunoglobulins are the safest modalities to
use for an exacerbation and can be effective in the
treatment of myasthenic crises during pregnancy.67
Though uterine smooth muscle is not compromised during labor because it is not affected by
AchR, patients with MG may become exhausted
during the second stage of labor necessitating
instrumental delivery.
90,109
Infants born to myasthenic mothers may be
affected by the drug therapy and the underlying
immunologic dysfunction. Increased rates of premature rupture of membranes (PROM), preterm
delivery, and cesarean birth have been reported,
although a nationwide study found no increased risk
in prematurity, LBW, SGA infants, or cesarean deliv-
59,64,167
e r y.
An additional risk stems from trans-
placentally acquired anti–acetylcholine receptor
antibodies, which cause approximately 12% to
13% of these newborns to experience a transient, self-limited course of neonatal myasthenia
gravis.59 It is difficult to predict which pregnancies
will result in an affected infant, although infants
born to women with very high AchR antibody
titers may be at highest risk.90 Affected infants
usually present within the first 48 hours of life
with transient neonatal MG, demonstrating
generalized weakness, a feeble cry, diminished
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suck and swallow, and a decreased respiratory
effort that may require mechanical support.64
Therefore, plans should be made in advance for
delivery of the mother with MG, and intensive
care facilities for the newborn should be available immediately. Neonatal MG generally subsides within 3 to 4 weeks after birth and does
not recur.
64
MG is not a contraindication to pregnancy and
can usually be managed well with relatively safe and
effective therapies, including maternal rest. Standard
therapies for some obstetric complications, such
as preeclampsia and preterm labor, may need to
be altered in women with MG.51 Vaginal delivery
is recommended if possible.51 Breastfeeding is
not contraindicated but depends on maternal
medications and on infant and maternal health
postpartum (see Chapter 18).
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus (SLE) is an autoimmune disease that presents primarily in women of
childbearing age. The pathogenesis involves the production of autoantibodies and immune complexes.
The clinical effects of lupus range from mild or subclinical disease to serious illness affecting multiple
organ systems. The leading causes of death are infections and renal failure. In pregnancy, SLE is associated with an increased incidence of preeclampsia, thromboembolic events, spontaneous abortion,
preterm delivery, IUGR, congenital defects, and the
need for neonatal intensive care.
36,123
Outcome is
most favorable when infections, renal disease, and
hypertension do not complicate pregnancy and
when pregnancy occurs with prolonged disease
remission.
57,106,139
One study suggests that 4 months
of disease quiescence before pregnancy is enough
to ensure a safe pregnancy.
122
The presence of lupus
nephritis is the highest risk factor for perinatal
complications.
91,122
Lupus nephritis is associated
with an increased rate of hypertension, preeclampsia, and preterm delivery.91Additionally, it can cause
a disease flare, with worsening of renal function.91
Overall reported frequency of SLE flares in pregnancy is 15% to 60%.1 When necessary, treatments
used with pregnancies complicated by SLE include
antiinflammatory, antimalarial, immunosuppressive,
and biologic drugs and/or anticoagulants.
57,106
The neonatal manifestations of SLE are rare
and are attributed to the placental transfer of
maternal antibodies to the fetus. Usual findings
of neonatal lupus include a transient lupuslike
rash (erythematous lesions of the face, scalp,
and upper thorax), thrombocytopenia, and
hemolysis.1 These findings generally are transient and clear within a few months. A strong
association has been established between maternal antibodies to the anti–Ro/SS-A and anti–La/
SS-B antigens and congenital heart block, a rare
manifestation of neonatal lupus syndrome.
1,122
The fetal heart block may be detected with antenatal testing; some authors believe that antenatal
fetal surveillance with nonstress tests (NSTs) should
begin at 28 weeks of gestation. Infants are treated
with cardiac pacemakers (64% of neonates) after
delivery; however, about one-third of affected
infants die within 3 years.
HEART DISEASE
106,122
Significant changes in cardiovascular function
accompany normal pregnancy. Plasma and red
blood cell volumes rise, heart rate and cardiac
output increase, and peripheral vascular resistance
falls. These changes facilitate increased uterine
blood flow, placental perfusion, and fetal oxygenation and growth. They also increase maternal
oxygen consumption and cardiovascular workload
and can further compromise the cardiovascular
status of women with preexisting serious heart
disease. Approximately 2% to 4% of childbearing-age women have concomitant heart disease,
which may be congenital (the most common type
in the United States) or acquired (which includes
valvular disease, cardiomyopathy, and pulmonary
hypertension).
101,140,164
In the United States from
2003 to 2012, the incidence of pregnant women
with heart disease increased by 24.7%.
101
Pregnancy
creates a risk for maternal cardiovascular complications, but especially for those with underlying
heart disease, and includes an increased incidence
of arrhythmias, heart failure, thromboembolism, and
sudden death.
69,115,164
In the United States, cardiac disease during pregnancy is the leading cause
of maternal morbidity and mortality.
107
In some
cases, such as Eisenmenger’s syndrome and primary pulmonary hypertension, the risk to maternal
survival is so great that pregnancy is contraindicat-
164
ed.
Pulmonary hypertension is associated with
an increased risk for major adverse cardiac events
during the hospitalization for delivery, especially
when there is concomitant cardiomyopathy.
101,154
In general, how well the woman with heart disease
CHAPTER 2 Prenatal Environment: Effect on Neonatal Outcome
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25
tolerates pregnancy depends on the specific disease
process and the degree to which her cardiac status
is compromised.
Maternal heart disease also affects the fetus. Fetal
risks are the result of genetic factors, alterations in
placental perfusion and exchange, and the effect of
maternally administered drugs. The genetic risk
is demonstrated by the increased incidence of
congenital heart defects that occur in the offspring of parents who have such a defect. The
exact risk depends on the specific parental lesion,
mode of inheritance, and exposure to environmental triggers.
115,140
Alterations in placental perfusion and gas
exchange occur when the mother’s condition
involves chronic hypoxemia or a significant decrease
in cardiac output. These factors increase the threat
to the fetus, with fetal risk increasing as maternal
cardiac status declines. Chronic maternal hypoxemia
results in a decrease in oxygen available to the fetus
and is associated with fetal loss, prematurity, and
IUGR. Significant reductions in maternal cardiac
output create decreased uterine blood flow and
diminished placental perfusion with a resulting
impairment in the exchange of nutrients, oxygen,
and metabolic wastes. Possible fetal and neonatal
consequences include spontaneous abortion;
IUGR; neonatal asphyxia; CNS damage; need
for preterm delivery; and intrauterine, intrapartum, or neonatal death.
115,140,164
A wide variety of drugs are used in the management of maternal cardiovascular disease. Although
sometimes it is difficult to differentiate drug effects
from the effects of the underlying disease, some
associations between drug administration and fetal
outcomes can be made. Anticoagulants are used
to decrease the risk for thromboembolism, especially in women with artificial valves, a history of
thrombophlebitis, or rheumatic heart disease. Oral
anticoagulants, specifically warfarin sodium
(Coumadin), have been associated with fetal
malformations, including nasal hypoplasia and
epiphyseal stippling, when administered during
the first trimester. They also have been associated with eye and CNS abnormalities when
administered later in pregnancy. The incidence
of warfarin embryopathy is estimated to be
15% to 25%. Warfarin also is associated with
maternal and fetal hemorrhage. Because of these
risks, warfarin is contraindicated in pregnancy
except in special circumstances, such as pregnancy
in women with prosthetic heart valves. Heparin
is considered the preferred agent for anticoagulation therapy during pregnancy. Heparin does
not cross the placenta; therefore it does not
result in fetal anticoagulation or neonatal hemorrhage (although maternal hemorrhage still
may occur), nor has it been associated with
congenital defects. Low-molecular-weight heparin is another alternative for anticoagulation
during pregnancy.
115,140
In general, patients being
treated with low-molecular-weight heparin during
pregnancy are converted to unfractionated heparin
during the final weeks of pregnancy because of
the ease of rapid reversal of anticoagulation for
labor and delivery. Some studies, however, did not
demonstrate any difference in bleeding complications for gravidas continued on low-molecular-weight heparin versus those who were converted to unfractionated heparin.
115
Antiarrhythmic medications and cardiac glycosides used during pregnancy cross the placenta to
varying degrees. They have not been implicated in
fetal malformations and, although several have been
associated with minor complications, generally are
considered safe for use in pregnancy.
115
Reported
complications include uterine contractions (quinidine, disopyramide), decreased birth weight (digoxin, disopyramide), and maternal hypotension with a
sudden decrease in placental perfusion (verapamil).
Antihypertensives and diuretics also have been
used in the treatment of cardiovascular disease
during pregnancy. Labetalol and methyldopa are
commonly used in pregnant women with chronic
hypertension. These medications have been studied
in prospective trials that revealed no adverse fetal
or maternal outcomes, though methyldopa is not
recommended postpartum because it is associated
with increased incidence of depression.
115
Their use
in the first trimester has also demonstrated safety.
Atenolol has been associated with fetal IUGR and
abnormal placental growth.
115,140
Calcium channel
blockers, such as nifedipine, are also safely used
during pregnancy without an increase in major
birth defects or adverse neonatal outcomes.
115,140
Diuretic use in pregnancy remains an area of some
controversy. Fetal and neonatal compromise can
result from diuretic-induced electrolyte and glucose imbalance and decreased placental perfusion caused by maternal hypovolemia. The use
of thiazide diuretics has been linked to neonatal
liver damage and thrombocytopenia. In general,
UNIT TWO Support of the Neonate26
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diuretic use is restricted to women with pulmonary
edema or acute cardiac or renal failure.
115
Although a great number of complications
are possible, remember that, with few exceptions, most of the drugs used in the treatment of
maternal heart disease can be used in pregnancy if
the maternal condition warrants it. Angiotensin-
converting enzyme inhibitors are contraindicated in pregnancy because of an association
with fetal injury (renal dysfunction, fetal oliguria, oligohydramnios, fetal skull hypoplasia)
and fetal death.
RESPIRATORY DISEASE
Respiratory function is altered even in normal
pregnancy. Changes include a decrease in lung
volume and increases in oxygen consumption,
tidal volume, and minute ventilation.79 Significant
decreases in maternal respiratory function and
oxygenation can result in fetal growth restriction
and fetal hypoxia with negative outcomes, but
careful management of respiratory disease during
pregnancy generally results in a favorable outcome.
Asthma is the most common respiratory
disease in pregnancy, occurring in 4% to 12% of
women, and the prevalence among pregnant women
is rising.4 For about two-thirds of pregnant women,
the course of asthma worsens.4 Infants born to
women whose asthma is well controlled usually
do well; unstable or worsening disease, especially
status asthmaticus, increases fetal risk. Commonly
used asthma medications (e.g., long-acting beta
agonists, inhaled corticosteroids, oral corticosteroids,
other bronchodilators, and cromones) are generally
considered safe for use in pregnancy.
111
Although
children of women with asthma are 10% more likely to have malformations than those of nonasthmatic mothers, large controlled studies have concluded
that most asthma medications had no impact on the
overall risk for malformations.
108
The exception is
cromone exposure, which slightly increases the risk
of fetal musculoskeletal malformation.
108
Additional
research is needed to determine whether a real risk
exists and to guide asthma treatment during pregnancy. Presently, clinical evidence supports pharmacologic asthma control because the fetus is at greater
risk from inadequate control of asthma than from
asthma medications.
108
Fetal risks related to maternal asthma depend
on the severity of the condition. Controlled
asthma carries few risks for the fetus. However,
severe or uncontrolled asthma increases the risk
for infant death and the incidence of low birth
weight, IUGR, preterm birth (possibly influenced by steroid use), and the need for cesarean
delivery.
108
Risks are higher in poorly controlled
asthma patients.20 Noncompliance with treatment,
respiratory tract infections, allergens and irritants,
smoking, gastroesophageal reflux, and exercise can
lead to asthma exacerbations.
111
Cystic fibrosis (CF) was once considered a lethal
childhood disease, but the life expectancy of a person with CF has increased, and one study reports
that those who had CF in 2000 will have a life
expectancy of over 40 years.62 With careful planning
and appropriate medical care, women with CF of
childbearing age may conceive and have successful pregnancies with favorable neonatal outcomes,
especially if their nutritional state and lung function
remain good.
61,132,155
Women with severe disease
may be cautioned to avoid conception because
there is a risk for significant deterioration during
gestation. Women who are positive for Burkholderia
cepacia in sputum also have a poorer prognosis.
155
Pregnancy in women with CF is likely to be associated with increased health care utilization and more
antibiotic use compared with that of nonpregnant
women with CF; a high rate of GDM (14%) compared with non-CF pregnancies; and aggressive
interventions to ensure weight gain, including
the use of total parenteral nutrition for some.
155
Although pregnancy with CF does not increase
maternal mortality risk, women with CF have a
shorter life span, and therefore their days as a parent
may be limited. Twenty percent of mothers with CF
will not live to see their child’s tenth birthday and
for those with severe CF, 40% will have died.
Fetal risks related to CF include prematurity,
IUGR, and perinatal death, caused primarily
by maternal hypoxemia and infection. Because
all infants born to mothers with CF will be
heterozygous carriers for CF (at least), genetic
counseling and carrier testing of the father are
important components of preconceptual care
and early prenatal care.
7,155
Maternal Behavior
Maternal health behavior is an important component of neonatal and childhood health and
may even be the single most important factor
for the overall health of a child.
117, 136
Health
CHAPTER 2 Prenatal Environment: Effect on Neonatal Outcome
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27
behaviors evaluated here are smoking, substance
abuse, and nutrition, but other maternal behaviors
also influence pregnancy outcomes, such as sleep
patterns and exercise. Appropriate preconceptual
and prenatal counseling regarding maternal health
behaviors can help optimize neonatal health.
SMOKING
117,135
According to the latest Pregnancy Risk Assessment
and Monitoring System (PRAMS) data, 10% of
women in the United States smoked during the
last 3 months of pregnancy.
22,39,98
Of women
who smoked 3 months before pregnancy, 55%
quit during pregnancy, and 40% of those who
quit during pregnancy resumed smoking within 6
months after delivery.39 Smoking during pregnancy is an even bigger problem globally.99 Maternal
smoking during pregnancy is a risk factor for
stillbirth, IUGR, placental abruption, placenta
previa, PROM, and preterm labor.
22,43
Mothers
with pregestational diabetes who also smoke have an
increased risk of congenital anomalies and preterm
birth.32 Long-term effects include childhood
obstructive airway disease, sudden infant death
syndrome (SIDS), neurodevelopmental abnormalities (i.e., movement, eating, developmental disorders, and attention-deficit/hyperactivity
disorder), early puberty in both boys and girls,
and childhood cancer,
22,33,43,72
and concerns
about exposure to secondhand smoke continue
to escalate. The exact mechanism by which fetal
growth is restricted or fetal health is compromised
is not entirely clear; reduced uterine artery blood
flow, reduced placental blood flow resulting from
vasoconstriction of smaller fetal capillaries in the
placental capillary bed, elevated nicotine and carbon
monoxide levels, and chronic fetal hypoxia all may
play a role. Fetal risk increases with the number of
cigarettes smoked, maternal anemia, and poor nutri-
120
tion.
Complications of fetal growth are the most
common issues of infants born to smoking mothers.
These neonates are at increased risk for low-birthweight birth (<2500 g) and preterm birth, which
is both dose-dependent and time-specific.22 The
babies of smokers may undergo withdrawal-like
symptoms manifested by jittery movements, and
may be more difficult to soothe.
120
Eliminating or reducing smoking, especially by
the end of the first trimester, can improve fetal
growth and health. Smoking cessation programs
consistently implemented during prenatal visits
have been shown to significantly improve smoking cessation rates.34 Smoking cessation during
pregnancy must be a major priority in counseling
women preconceptually and prenatally because
these are times when women may be most receptive
to quitting because of a strong desire for a healthy
pregnancy and baby.34 A recent systematic review of
digital interventions for smoking cessation during
pregnancy found that text messaging and computer-based interventions were the most effective
platforms.71 Nicotine replacement therapy (NRT)
may increase smoking cessation rates, but a systematic review cites evidence that when potentially-biased and non-placebo randomized controlled trials
(RCTs) are excluded, NRT is no more effective
than placebo.46 Only one trial followed infants after
birth and found that NRT promotes healthy developmental outcomes.
SUBSTANCE ABUSE
47
Prenatal substance abuse rates vary greatly; however, it is estimated that about 11% of childbearing
women have used illegal substances.
120
There is
a strong association between maternal smoking
during pregnancy and use of other substances
including cannabis, opioids, cocaine, amphetamines,
tricyclic antidepressants, and benzodiazepines.
118
Use of drugs and alcohol by the mother places
the fetus and newborn at risk for a plethora of
structural, functional, and developmental problems. Perinatal morbidity is related to the direct
effects of the abused substance on the developing
fetus, its sudden withdrawal, the interactions of
multiple abused substances, the nutritional effects of
addiction on the mother, and the social and health
care implications of substance abuse.
80,120
Alcohol is one of the most commonly abused
substances during pregnancy. Although known to be
a teratogen since the 1970s, about 40% of women in
the United States drink some alcohol during pregnancy, and about 1% to 5% drink heavily throughout pregnancy.88 Alcohol in the maternal circulation
crosses the placenta, resulting in direct fetal exposure
to alcohol and its metabolites.88 There may be
a wide range of effects on the exposed fetus;
these include developmental and behavioral
abnormalities, spontaneous abortion, stillbirth,
craniofacial malformations, growth restriction,
preterm birth, CNS dysfunction, and organ or
joint abnormalities.
83,89
The mechanism of fetal
injury is not entirely clear but is likely related to
UNIT TWO Support of the Neonate28
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three main factors: a teratogenic effect, hypoxia as
a result of increased oxygen consumption, and a
diminished ability to use amino acids in protein
synthesis.37 The expression of fetal alcohol effects
ranges from subtle to extreme and depends on
the timing of exposure, the dose, and the genetic
response of the mother and fetus to the effects of
alcohol. Secondary factors, such as maternal age,
nutritional status, general health, and the effects of
other abused substances also may influence out-
75,117
come.
When the more severe effects are exhibited,
the condition is known as fetal alcohol syndrome
(FAS). FAS is characterized by growth restriction; physical dysmorphic features, including
facial anomalies (small palpebral fissures, low
nasal bridge, indistinct philtrum, thin upper
lip, shortened lower jaw); and neurologic
dysfunction, including mental retardation and
neurodevelopmental deficits.83 Other physical
abnormalities involve the heart, skeletal system,
and ears. Fetal alcohol spectrum disorders (FASD)
is an umbrella term for FAS and other less physically noticeable yet long-term effects of alcohol
exposure on the fetus.37 Infants with FASD
also may exhibit problems with suck, tremors,
irritability, and hypertonus related to alcohol
withdrawal. Continued abnormalities in motor,
behavioral, and intellectual development often persist into childhood. Safe levels of alcohol intake have
not been established; therefore women should be
advised to avoid alcohol intake during pregnancy.
Chemical dependency in pregnancy is a com-
plex problem and creates a high-risk patient. The
mother’s reporting of drug use often is unreliable;
frequently, more than one substance is involved,
and there may be a cycle of drug use and periodic abstinence during pregnancy. In addition, a
host of medical and social problems are associated
with maternal drug abuse. Substance abusers generally have poor health; infectious diseases, such as
pneumonia, sexually transmitted diseases (including human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome
[AIDS]), urinary tract infections, and hepatitis are
common.
24,80,120
Nutrition and prenatal care often
are inadequate; anemia frequently is seen. These
factors contribute to a poor pregnancy outcome
and make it difficult to isolate the effects of any one
drug on the fetus. However, several generalizations
can be made. The majority of drugs used by the
mother, including opiates (e.g., methadone, heroin),
barbiturates, and sedative-hypnotic drugs, cross the
placenta and affect the fetus. Fetal risks include
growth restriction, malformations, intrauterine
demise, prematurity, asphyxia, CNS dysfunction, and neurobehavioral abnormalities. Fetal
drug dependence does occur and is associated
with neonatal abstinence syndrome (NAS),
which is manifested by CNS irritability and
vasomotor, metabolic, respiratory, and gastrointestinal dysfunction
120
(see Chapter 11).
Marijuana (cannabis) is the most commonly used
illicit drug during pregnancy.34 With legalization of
marijuana in many states in the United States, about
1 in 20 pregnant women report using marijuana.
151
Perinatal effects of marijuana use on the fetus/newborn include low birth weight and preterm delivery,
which is attributable to concomitant tobacco and
other substance use,
41,48
altered neurobehavior/
sleep, and minimal alteration on motor develop-
163
ment.
Long-term effects include altered attention/executive function, academic achievement,
and behavior.
marijuana use during pregnancy and lactation.
163
Recommendations are to cease
17,131
Cocaine use by the mother merits special atten-
tion. Cocaine is a CNS stimulant that produces
vasoconstriction, tachycardia, and hypertension in
both the mother and the fetus. Its use during preg-
nancy has been linked to IUGR, smaller head
circumference, genitourinary tract anomalies,
placental abruption, stillbirth, RDS, congenital
infection, NAS, and cerebral infarcts, as well
as impaired performance as measured with the
Brazelton behavioral assessment tool.
38
All prenatal care providers should thoroughly
assess pregnant women for alcohol and substance
abuse at each prenatal visit, and treatment interventions should be initiated when abuse is identified.
Toxicology screening of maternal blood or urine
can verify suspicions of abuse; however, universal
screening is not currently recommended. Neonatal
urine or meconium screening can provide an
accurate indication of exposure when there are
clinical indications of drug effect. Laws in some
states consider prenatal drug exposure to be a form
of child abuse; thus the practitioner may be required
to report positive drug tests in pregnant women or
their newborns (see Chapter 11 for a complete discussion of complications in drug-exposed neonates).
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