During pregnancy, the total blood volume normally increases 40%, reaching a maximum of about 5 liters.

This 40% increase is accompanied by a smaller increase (about 33%) in the red cell mass. Because the red cell mass doesn’t quite keep up with the total blood volume, there is a naturally-occurring decrease in both the hemoglobin and the hematocrit.

• • The hemoglobin can normally dip to 5 grams
  • The hematocrit can normally dip to 33%

This normal physiologic event is sometimes called a physiologic anemia of pregnancy, or a dilutional anemia of pregnancy. It is an expected, non-pathologic event.

That said, true anemia during pregnancy is a relatively common event, being caused by a collection of nutritional, genetic, and medical issues. True anemia during pregnancy is usually defined as:

• • Hemoglobin less than 0 grams
  • Hematocrit less than 30 %

Iron Deficiency

Of the anemias seen during pregnancy, iron deficiency is the most common, representing about 90% of all anemias in the North American population.

In the event of iron deficiency anemia, a peripheral blood smear will typically demonstrate the classical finding of a microcytic, hypochromic anemia, in other words, a low mean corpuscular volume, and a low mean corpuscular hemoglobin, small, pale red cells.

Other associated laboratory findings include a low total serum iron, a low serum ferritin, and an increased total iron binding capacity.

A number of causes of iron-deficiency during pregnancy can be listed, but the more common are:

1. 1. Nutritional deficiencies of iron and/or folate
   2. Chronic blood loss
   3. Hemolysis
   4. Intestinal helminth infection

In the case of mild iron-deficiency anemia during pregnancy, the consequences, if any, are difficult to quantify. But for the more severe iron deficiencies, with hemoglobin values of 7 or less, there are significant risks of oligohydramnios, abnormal fetal heart rate tracings, prematurity, fetal growth restriction, and maternal mortality.

The diagnosis of iron deficiency anemia during pregnancy is usually made following the first laboratory testing that includes a complete blood count.

Sometimes, the diagnosis is not made until a later blood draw, or if the patient becomes symptomatic with unusual amounts of fatigue, shortness of breath on exertion, or developing pallor.

The diagnosis is confirmed with a number of laboratory tests including:

• • Complete blood count with peripheral smear, to document the severity of the anemia, and identify the degree of hypochromicity and microcytosis
  • Reticulocyte count, to confirm the bone marrows ability to respond to the low hemoglobin
  • Serum iron, which is expected to be low
  • Serum TIBC, which is expected to be elevated, reflecting the body’s attempts to maintain homeostasis
  • Serum ferritin, a somewhat more reliable reflection of the body’s iron stores

Some physicians, when dealing with mild degrees of anemia during pregnancy, will presume iron deficiency to be present, and go directly to a therapeutic trial of oral iron supplementation. A prompt response is then considered confirmatory of the diagnosis. A failed response would then prompt a detailed laboratory evaluation.

• • Of course, should there be little response, one never knows whether this is due to patient non- compliance, incorrect diagnosis, ongoing loss, or multiple factors leading to anemia
  • There are a few anemic women, for example, some of those with sickle cell disease, who should not be taking extra iron, as they already have too much. Attempting a therapeutic trial of iron in these patients will not only postpone an accurate diagnosis, but will also add to their iron load.

Because iron deficiency is so commonly seen among pregnant women, we routinely give prenatal vitamin supplementation to all pregnant women, ideally starting at least 3 months prior to the pregnancy.

Each prenatal vitamin contains about 27 mg of elemental iron. This is sufficient to boost the oral intake of iron modestly, but is not enough iron to reverse more severe cases. In these cases, we prescribe oral iron supplements containing 60-65 mg of elemental iron.

These are ideally taken 3 times a day, but patient intolerance may dictate less frequent dosing. Even if taken once every other day, it is better than not taking it at all.

The intolerance is due to gastric distress, or constipation, or both. The best absorbed form of iron, ferrous sulfate, also causes the most side effects. The least well absorbed, ferrous fumarate, is the most well tolerated. So there are trade-offs in choosing the best oral preparation for this problem.

Injectable iron can also be given, but also has significant, but different, side effects, and is only infrequently necessary.

Folate Deficiency:

A less common cause of anemia is folic acid deficiency. This is caused by a number of problems, among them:

• • Dietary deficiency (lack of leafy green vegetables)
  • Alcoholism (interfering with absorption of folate)
  • Intestinal disease, such as Crohn’s or tapeworm, diminishing digestion and absorption of folate
  • Various medications, including phenytoin, triamterene, sulfasalazine, pyrimethamine, and trimethoprim-sulfamethoxazole

In contrast to the small, pale red cells of iron deficiency, the folate-deficient red cells are large and pale, called megaloblasts.

Folate deficiency during pregnancy has special significance beyond just making the patient anemic. It is associated with fetal neural tube defects, such as meningomyelocele. For that reason, 400 mcg of folic acid is included in all prenatal vitamins, and it is recommended that these vitamins be started several months prior to conception.

An additional 4 mg of folic acid is given in high risk settings, including:

• • Women with a history of neural tube defects
  • Multiple gestations
  • Women taking anticonvulsant

Hemoglobinopathy

Another less common cause of anemia, particularly among some population subgroups, are the hemoglobinopathies. The two most prevalent of these in North America are:

• • Sickle Cell Anemia, and
  • Thalassemia

Screening for these conditions can be done among those at risk, for example, those of African or Mediterranean ancestry. But because of increasing ethnic mixing, reliance on ethnic heritage may prove ineffective in identifying all those with hemoglobinopathies.

Sickle Cell Trait is found in about 10% of African- Americans. It is a generally innocent carrier state with a combination of one strand of normal beta hemoglobin A, and one strand of the abnormal beta hemoglobin S. Sickle Cells trait is not particularly worrisome or dangerous during pregnancy, but has three important significances:

1. 1. These women are somewhat more vulnerable to urinary tract
   2. These women are somewhat protected against malaria (not so important if one lives in Chicago).
   3. These women and their partners need genetic In the event both parents carry the Sickle Cell trait, then there is a one in four chance of their offspring having sickle cell disease, a pretty serious condition.

While less common, Sickle Cell Disease is a much more dangerous hemoglobinopathy, and frequently associated with anemia. The diagnosis is made through hemoglobin electrophoresis, although most pregnant patients with this conditional will already be aware they have the condition.

Pregnancy complications are increased, including:

• • Abortion
  • Stillbirth
  • Neonatal Death
  • Pre-eclampsia
  • Growth restriction
  • Infections of all types
  • Thromboembolic events
  • Acute chest syndrome
  • Preterm labor
  • Premature rupture of the membranes
  • Preterm delivery
  • Abruption
  • Pulmonary hypertension

While these complications are common among these patients, it is also true that the majority of these patients will experience a good outcome. But because of the relatively high risk of bad outcome, they are best managed in high-risk centers, by teams of obstetricians, internists, hematologists, and geneticists skilled and experienced in managing these patients.

There are several key obstetrical management issues:

• • Hydration is important to prevent pain and crises, so aggressive use of IV therapy and antinausea medication in the first trimester is undertaken.
  • Many of these women are taking hydroxyurea and iron chelating agents, and current recommendations are to stop both during the pregnancy.
  • Routine blood transfusion is not needed, but selective transfusions can be indicated in some high risk patients.
  • Oral iron therapy is withheld, but large doses of folate (4 mg/day) are given.
  • Watch for infections (urine, pulmonary)
  • Serial fetal monitoring of both heart rate and ultrasound will be needed.
  • Patients should undergo labor induction or cesarean section only for normal obstetrical indications.
  • During labor, maintain oxygen saturation at > 95% at all times.

Thalassemia represents a spectrum of hemoglobinopathies, characterized by abnormal globin chain synthesis leading to abnormal hemoglobin. These are further categorized as major, intermediate, or minor in nature. Most are minor.

With beta thalassemia minor during pregnancy, the main problem is incorrectly labeling the hypochromic, microcytic anemia as an iron deficiency anemia, which will lead to the unncecessary prescription of iron to these patients. They do need extra folate, but they don’t need extra iron.

Beta thalassemia major usually results in infertility, so the occurrence of a pregnant woman with this problem would be quite rare, but definitely dangerous, cardiovascular overload and thrombosis being major risks.

Intermediate forms of thalassemia during pregnancy require little other than extra folate, avoidance of iron, and monitoring of maternal and fetal condition as the pregnancy advances.

For alpha thalassemia major, also known as Bart’s syndrome, there is a significant risk of fetal hydrops, so close monitoring of the fetus is necessary.

During pregnancy, there are a number of normal physiologic changes that occur in the kidney:

• • The kidneys increase 30% in size, from increased vascularity and interstitial space.
  • The GFR increase 40%, which is reflected in a normal drop of serum creatinine to 0.4-0.8 during pregnancy. In other words, a creatinine of 1.0, normal in a non-pregnant woman, is considered abnormally high during pregnancy. Similarly, BUN normally drops to 8-10 during pregnancy.
  • The renal pelvis and ureters become soft and dilated, able to hold several hundred cc of urine.
  • Some mild glucosuria during is common since the glucose load presented to the kidneys frequently exceeds the renal threshold for reabsorbtion.
  • The urine has a somewhat higher pH, with increased levels of bicarbonate.

The incidence of asymptomatic bacteruria is usually the same, pregnant or not pregnant, but the consequences during pregnancy are more significant. Because of the physiologic changes of stasis, alkaline urine, and glucosuria both lower and upper urinary tract infection risk is increased. We screen all pregnant women are screened for asymptomatic bacteruria at the initial prenatal visit, and for those at high risk, we may screen again after mid-pregnancy. Treatment of lower and upper urinary tract infections during pregnancy is the same as when not pregnant.

Nephrolithiasis or stone formation risk is about the same during pregnancy as when not pregnant. The diagnosis is based on the same criteria as when non-pregnant. To avoid x-rays, ultrasound can be used to identify hydroureter and sometimes the stone, but is only about 60% sensitive, and its specificity is limited by the normal, physiologic ureteral changes. When needed, x-rays may be safely used on a limited basis to identify the stone in questionable cases. The standard therapies of hydration, analgesia, urine straining and antibiotics for those with infection are also used during pregnancy.

Up to 85% of symptomatic stones will pass spontaneously during pregnancy, in part due to the normally dilated ureters. For those that do not, a number of options are available:

• • Ureteroscopic stone removal
  • Ureteroscopic laser lithotripsy
  • Ureteral stent placement
  • Shock wave lithotripsy is contraindicated during pregnancy, although for the few reported cases of inadvertent use during pregnancy, the pregnancy outcomes have been good.

For women with pre-existing renal disease, the disease will generally remain about the same or get worse. If it worsens, the primary risks to the mother will be renal failure and hypertension. For the pregnancy, the primary risks are pre-eclampsia, prematurity, and fetal growth abnormalities.

The prognosis for renal deterioration during pregnancy is reflected by the pre-pregnancy serum creatinine:

• • Creatinine < 1.5, prognosis good
  • Creatinine 1.5-3.0, prognosis guarded
  • Creatinine > 3.0, may have serious deterioration of renal function

For women on dialysis, prematurity is common, even after optimizing all of the controllable factors. In one large study, the mean gestational age at delivery was 30.5 weeks. Prematurity, in combination with the problem of pre-eclampsia has led many centers to report neonatal survival rates of about 50% among infants born to women on dialysis.

The outlook is better for women with a transplanted kidney, in whom a pregnancy success rate of better than 90% is expected. The pregnancy will not have an adverse effect on the transplanted kidney, although depending on where it is located, it may or may not obstruct labor, requiring a cesarean section. Some immunosuppressive drugs are acceptable for use during pregnancy and others are not. It is best to manage these patients in a setting where expert consultation is readily available.

The body controls glucose metabolism through excretion of insulin from the pancreas. Those unable to produce, release, or make use of the necessary amounts of insulin are said to have diabetes mellitus.

Pregnancy affects glucose metabolism. The placenta produces hPL (Human Placental Lactogen) in large quantities that decreases glucose uptake an promotes lipolysis, leading to increases in circulating free fatty acids. The placenta also produces large amounts of estrogen, progesterone and insulinase, all of which have the effect of increasing the insulin requirements of the mother.

Pregestational Diabetes

Women with pre-existing diabetes (Type 1 or Type 2) are said to have pre-gestational diabetes. We find it useful to further categorize these women according to White’s Criteria:

• • Class B – onset over age 20, for less than 10 yr
  • Class C – onset age 10-19, for less 19 yrs
  • Class D – onset < age 10, for more than 20 yr
  • Class F -nephropathy
  • Class R – proliferative retinopathy

During the course of their pregnancy, insulin requirements usually change, typically with increased insulin needs early, then less, then more insulin as the pregnancy advances, sometimes with a drop in insulin requirements towards the end of pregnancy.

In managing these pregnant women, we aim for very tight control of their blood sugars, tighter than they normally would expect. The reason for this tight control is to minimize the additional risks of pregnancy complicated by diabetes, namely:

• • Increased risk of miscarriage
  • 3-fold increase in major malformations
  • 5-fold increase in stillbirth
  • 3-fold increase in neonatal death
  • 5-fold increase in respiratory distress syndrome
  • 4-fold increase in preterm deliveries <37 weeks
  • 8-fold increase in Large for Gestational Age infants
  • 4-fold increase in cesarean sections, approaching 50%
  • More than 50-fold increase in shoulder dystocia at delivery, leading to about a 2% Erb’s palsey risk
  • Increased risk of polyhydramnios, pre-eclampsia, heart disease, thyroid disease, retinopathy, and
  • Increased risk of maternal diabetic ketoacidosis

With good control, these risks can be substantially reduced. Good control means:

• • FBS ≤ 95
  • 1-hour PP ≤ 140
  • 2-hour PP ≤ 120
  • HgbA1C < 6%

To accomplish this tight control patients usually respond best to multiple insulin injections each day, with a varying mixture of longer and shorter acting insulin.

Some insulins are better for use during pregnancy than others, reflecting their varying abilities to cross the placenta and be immunogenic. Usually, Lantus insulin is avoided and NPH and Regular insulin are used.

Ideally, patients with pregestational diabetes will enter the perinatal care system prior to their pregnancy, so that gycemic control is already achieved and preconceptual counseling completed. Because hyperglycemia is teratogenic, with heart defects being the most commen, it is best to initiate tight control prior to attempting to conceive. Frequently, this ideal is not met.

The best outcomes occur when a team approach is taken, including obstetricians, endocrinologists, dieticians, and supporting laboratory specialists, all skilled in managing these high risk patients.

Initial obstetrical care of these patients includes all of the normal prenatal evaluation, plus:

• • Hemoglobin A1c every 4 weeks as a long term measure of glycemic control
  • Glucose fingersticks taken and recorded at least 4 times daily
  • Baseline TSH and FT4 as thyroid disease is a common association with diabetes
  • Baseline eye evaluation with a retinologist, as retinopathy can worsen during pregnancy
  • Baseline ECG since cardiovascular disease is more common among these patients
  • Serum creatinine (repeated in 2nd and 3rd trimester) since nephropathy may not be picked up otherwise.
  • Urine protein/glucose dipsticks at each visit, watching for the development of pre-eclampsia or renal disease
  • Urine protein/creatinine ratio (repeated in each trimester) as a useful surrogate to the annoying and often inaccurate 24 hour urine protein
  • 1st trimester ultrasound scanning for accurate gestational age and nuchal translucency, to screen for anomaly
  • Usually an increase in calories of 250 to 300 per

The patients are seen every 2-4 weeks. By the 20th week of pregnancy, we prefer that all of these patients undergo a detailed fetal anatomic ultrasound survey, looking for abnormalities.

By the 32nd week of pregnancy, we usually initiate sequential fetal monitoring:

• • Weekly non-stress testing with EFM to screen for problems with fetal well-being. We’ll increase this to twice weekly NSTs at the 34th
  • Periodic assessments of amniotic fluid volume to assure the absence of oligohydramnios and deal effectively with polyhydramnios
  • Periodic fetal weight estimates to assure a normal growth pattern and allow earlier intervention in the event of abnormal growth.

40 years ago, a common protocol was to perform elective cesarean section on diabetic patients at 36 weeks, because to wait longer risked an unacceptable number of stillbirths. We don’t practice that way anymore because the combination of our much tighter glycemic control and antepartum monitoring have made unexpected stillbirths a rare event, and also because elective delivery at 36 weeks carries an unacceptably high risk of neonatal complications from immaturity.

Instead, we will generally induce labor at term, between the 39th and 40th week of gestational age, if the cervix is favorable, although some physicians will continue to monitor past the 40th week.

For estimated fetal weights > 4500 grams, we recommend a scheduled cesarean section, and consider the cesarean with the patient for those > 4000 grams.

This is done to try to reduce the risk of shoulder dystocia and Erb’s Palsy.

Gestational Diabetes

Pregnancy has a tendency to push people toward diabetes. The placental hormones create some degree of insulin resistance; there are increased adipose stores, increased caloric intake and decreased maternal activity, accompanying markedly increased glucose needs, mostly for the fetus.

For most women, this nudge toward diabetes is not a problem, but for a few more vulnerable women, they can become diabetic, in degrees ranging from mild to severe.

Depending on the severity, there are risks associated with this diabetic state that include all of the risks associated with pregestational diabetes. The more severe the metabolic abnormality, the greater the risk.

Many physicians favor screening all pregnant patients between 24 and 28 weeks for gestational diabetes. In the U.S., the most common method involves giving a 50 gram glucose liquid meal, and drawing a blood glucose level 1 hour later. If the glucose level exceeds 140 (some say 135, some say 130), then the patient undergoes a full 3-hour glucose tolerance test following a 100 g glucose load. If any two of the four values from the GTT are elevated, then gestational diabetes is diagnoses.

• • Other physicians favor a one-step, 75 gram load, followed by a one and two-hour glucose
  • Some physicians favor screening only those at increased risk for gestational diabetes

Regardless of how the issue is approached, it’s important to remember that the change in risk with increasing glucose intolerance is gradual, not abrupt. Consequently, the distinction between those determined not to have GDM, and those designated as having it, is not as great as you might think.

While we also check the urine of each pregnant woman for glucose at each prenatal visit, this is not as useful a screening test since pregnant woman normally lose up to 300 mg/day of glucose in their urine.

Once diagnosed, it is best to engage the services of obstetricians, endocrinologists and dieticians skilled in managing this clinical problem. Some of these patients will be able to control their GDM with diet alone (A1GDM) while others will require insulin (A2GDM). Oral hypoglycemic agents have not been studied extensively in this setting. While some centers report good experience with such hypoglycemic agents as glyburide and metformin, others are much more comfortable in the well-studied application of insulin for those needing medication.

The obstetrical management of those women with insulin-dependent gestational diabetes is quite similar to the management of Type 1 or Type 2 pregestational diabetes, including close monitoring of blood sugars, fetal growth and well-being, and evidence of maternal complications.

But for gestational diabetics well-controlled with diet alone, the primary increased risk is for fetal macrosomia. For that reason, the A1 GDM patients may not be induced early, and may not undergo serial electronic fetal monitoring, depending on the training and opinions of their own physicians, combined with their past history. The other guidelines for cesarean section with EFW > 4500 grams are generally followed.

While it is true that as soon as delivery occurs, gestational diabetes goes away, it is also true that some of the women diagnosed with GDM actually have recently-diagnosed pregestational diabetes, so followup is necessary.

Even when GDM completely resolves, the patient has already demonstrated a vulnerability to a collection of diabetogenic factors, and this vulnerability may persist throughout her life. Some have found a 10% per year risk of the patient developing overt diabetes in the years following delivery.

Labor Management

During labor, insulin-dependent diabetics have their blood glucose checked every 2 hours and remain NPO. The target range for their glucose is 70-120. If they fall below 70, we initiate a D10W drip sufficient to return their glucose back to normal. If their glucose exceeds 120, then insulin is initiated sufficient to lower their glucose back into the normal range.

After delivery, insulin requirements usually drop substantially and these patients are watched closely for hypoglycemia. For gestational diabetics, their problem is resolved once the placenta is delivered, but they are counseled for followup testing at 6 weeks, because a few of them actually have Type 2 diabetes that has been unmasked by the pregnancy.

The Newborn

Following delivery, it’s important to make sure the pediatricians understand that the mother has diabetes, as they will need to follow the newborn closely for a reactive hypoglycemia.

There are some clinically important changes in respiratory anatomy and physiology during pregnancy.

The upper respiratory tract becomes edematous, predisposing pregnant women to nasal stuffiness, nosebleeds, and postnasal drip.

The chest cavity widens at the base and the diaphragm rises about 4 cm from its pre-pregnancy position. Despite these changes, there is no change in the basic airway mechanics.

Pregnancy represents a state of mild hyperventilation:

• • The respiratory rate remains unchanged, but
  • The tidal volume increases 40%, leading to an increase minute ventilation.
  • This increase in minute ventilation leads to an increase in PO2 from 100 to 110, and a decrease in PCO2 from 40 to 30. More oxygen is being brought in and more CO2 is being blown off.
  • The decrease carbon dioxide causes a mild respiratory alkalosis, which in turn is tempered by an increased renal excretion of bicarbonate, leaving the arterial pH only slightly alkalotic, between 7.40 and 7.45.

Most cases of reactive airway disease or asthma occurring during pregnancy are pre-existing. New onset asthma is occasionally seen, but is not common. When it does occur, the diagnosis is made on the basis of history, physical, and response to empiric therapy, since methacholine testing is not recommended during pregnancy.

In broad strokes, about a third of asthmatics will get worse during pregnancy, about a third will get better, and the remaining third will remain about the same as they were prior to pregnancy.

Should it get worse, the worsening is usually seen early in the 3rd trimester. Should it get better, the improvement is generally gradual throughout pregnancy. Acute exacerbations are uncommon during labor and delivery.

Asthma is associated with significant maternal and fetal problems, including:

• • Increased perinatal mortality
  • Prematurity
  • Low birth weight
  • Fetal growth restriction
  • Pre-eclampsia
  • Placental abruption

Management consists of three goals:

1. 1. Prevention of acute exacerbations
   2. Early intervention to thwart acute exacerbations
   3. Monitoring of the mother and fetus for complications

Prevention includes reducing or eliminating such asthmatic triggers as smoking, environmental factors and allergens. In addition, we frequently use medium-dose inhaled glucocorticoids on a daily basis to keep the airway quiet. Some patients may also require a daily, long acting beta agonist, such as Solu-Medrol, to suppress airway reactivity.

Early intervention means encouraging the patient to identify worsening of her condition with prompt intervention with an inhaled beta agonist, usually albuterol. Fever may indicate a superimposed respiratory infection requiring antibiotics and should not be ignored.

Monitoring of the mother includes monthly visits and twice daily outpatient measurements of Peak Expiratory Flow Rate. PEFR meters are inexpensive and each pregnant asthmatic patient should have her own at home.

Monitoring of the pregnancy will include weekly non-stress testing of the fetus, and serial ultrasound measurements of fetal growth.

During labor and delivery, some commonly-used medications should be avoided because of their tendency to cause bronchoconstriction:

• • Prostaglandin F2-alpha
  • Ergotamine
  • Morphine
  • Demerol

Other medications pose no significant threat to the pregnant asthmatic and some have a bronchodilating effect. Safe drugs for use in labor and delivery include:

• • Oxytocin
  • Prostaglandin E2
  • Butorphanol
  • Fentanyl
  • Epidural anesthesia
  • Ketamine
  • Magnesium Sulfate

Dilaudid, an opioid narcotic during labor, has been used with good success during labor with many asthmatic patients, but causes a mild histamine release, which theoretically could provoke or aggravate a reactive airway. If used in this setting, airway monitoring should be particularly thorough.

Pulmonary infections occurring during pregnancy need special attention to prevent hypoxemia, and reduce fever. Maternal fever accelerates fetal enzyme systems significantly increasing fetal oxygen requirements.

Appropriate antibiotics, combined with antipyretics, nasal decongestants, and oxygen supplementation as needed to maintain oxygen saturation above 95% may be needed in the case of bacterial airway infections.

Seasonal influenza poses a greater risk to the pregnant woman than to her non-pregnant friends. For that reason, we usually give oseltamivir (Tamiflu) 75 mg bid to those women felt clinically to have the flu, even prior to laboratory confirmation.

A number of predictable changes occur in the thyroid gland during pregnancy that has consequences for those evaluating and managing pregnant patients.

The thyroid gland normally enlarges as much as 18% in volume, a change that can be measured sonographically, and occasionally detected clinically. A more significant change may reflect an underlying abnormality.

Inadequate amounts of iodine intake can lead to a maternal goiter. There is both increased renal clearance of iodine and increased fetal uptake of iodine can lead to maternal goiter if maternal iodine intake does not match these losses.

Thyroid nodules occur with the same frequency during pregnancy as in non-pregnancy, and are evaluated with fine needle aspiration. In the event a thyroid cancer is found, surgery is generally postponed, without penalty, until after delivery, to reduce surgical complications.

Human chorionic gonadotropin, or HCG, has a mild, direct stimulatory effect on thyroid hormone production.

During the first trimester, as maternal HCG levels rise, maternal free T4 and T3 levels also rise. This elevation usually remains at the upper limit of normal, but is accompanied by a reactive drop in TSH.

Whenever HCG levels are unusually elevated, for example with multiple gestations, hyperemesis gravidarum, or gestational trophoblastic disease, these changes in thyroid indices can be even more dramatic. In such cases, the patient may develop a transient and usually subclinical hyperthyroidism that occasionally causes some mild symptoms.

Estrogen, produced in large quantities during pregnancy, leads to a significant increase in TBG because of increased production and decreased clearance. This increased TBG binds more thyroxine and triiodothyronine.

Consequently, if a pregnant woman’s total T4 or total T3 is measured, they often will both be elevated, reflecting this increase in bound hormone. But even though the total T4 and T3 are elevated, the free, unbound T4 and T3 will be normal.

So, considering the HCG and estrogen changes, if a pregnant woman in her first trimester were to be evaluated for thyroid hormone levels, it would not be surprising to find elevated total T4 and T3, and a modestly depressed TSH. Someone who doesn’t understand these normal pregnancy changes might be tempted to conclude that this woman is hyperthyroid, but that person would likely be wrong. If they were to test her free T4 and T3, they would find normal values in this symptom-free patient.

That’s not to say that hyperthyroidism does not exist in early pregnancy. To the contrary, uncontrolled or poorly controlled hyperthyroidism is associated with a number of adverse pregnancy outcomes, including:

• • Spontaneous abortion
  • Stillbirth
  • Preterm labor
  • Low birth weight
  • Pre-eclampsia
  • Maternal heart failure

The most common cause of overt hyperthyroidism during pregnancy is Grave’s disease, although there can certainly be other causes.

Because of the normally elevated total T4 and T3, and the normal modest suppression of TSH during pregnancy, the diagnosis of hyperthyroidism hinges on the elevation of Free T4 and T3, accompanied by a TSH level < 0.01 mU/L.

Beta blockers, thionamides, and surgery can be used to treat hyperthyroidism during pregnancy, but there are complexities regarding the optimum gestational age and duration of use. Radioactive iodine therapy is not used during pregnancy as it crosses the placenta and concentrates in the fetal thyroid gland.

Pregnancies complicated by hyperthyroidism require close monitoring of the fetus for evidence of thyrotoxicosis, cardiac and growth problems. Thyroid hormone does cross the placenta, but only to a limited extent. Same with TSH. But TSH-receptor antibodies do cross the placenta in clinically significant amounts and can lead to fetal hyperthyroidism, with tachycardia, cardiac failure, fetal hydrops, fetal goiter and poor growth.

Hypothyroidism may also complicate pregnancy and also carries significant risks, among them:

• • Preterm delivery
  • Pre-eclampsia
  • Perinatal morbidity and mortality
  • Cognitive impairment
  • Placental abruption

But there are two mitigating factors to the problem of hypothyroidism during pregnancy. The more severe forms of hypothyroidism are the ones more often associated with these adverse outcomes, but those are also the women least likely to get to the point in pregnancy where these issues can arise, because of anovulation and infertility, and also the increased miscarriage rates found among these patients with the more severe forms of the disease.

Because of the normal lowering of TSH during pregnancy, the diagnosis of hypothyroidism is based on a TSH > 2.5, at least during the first trimester. Screening for this condition is controversial, with some physicians recommending universal screening in the first trimester, and others recommending testing only of those symptomatic or at high risk.

Treatment involves aggressive use of thyroid hormone, sufficient to make the patient euthyroid, with TSH levels less than 2.5 and greater then 0.1. Because it may take weeks for full equilibration to occur, followup TSH levels are monitored 4 weeks after any change in dosage, and many physicians will follow TSH at 4 week intervals throughout the pregnancy.

For women with pre-existing hypothyroidism who are already on a stable dose of thyroid hormone, their dosage needs can be expected to increase up to 50% during pregnancy. Because it is important to avoid low thyroid levels at any time during pregnancy, many physicians will increase the pre-pregnancy thyroid hormone dose by 30% at the first prenatal visit, and then follow the 4-week TSH levels, making additional adjustments as needed to keep the TSH between 0.1 and 2.5.

Postpartum, up to 10% of women will experience a transient thyroiditis, and up to 25% among those with type 1 diabetes. During the hyperthyroid phase, beta blockers may be needed to control symptoms. During the hypothyroid phase, thyroxine may be needed, and is usually continued for 6 months before tapering to determine if the hypothyroid status will be permanent, or has resolved.