MATERNAL ENDOCRINOLOGY

MATERNAL COMPARTMENT

Little information is definitively known about the endocrine alterations of the maternal hypothalamus during pregnancy. Thought to result from estrogen stimulation, the anterior pituitary undergoes a 2- to 3-fold enlargement during pregnancy, primarily because of hyperplasia and hypertrophy of lactotroph cells. Thus, plasma prolactin levels parallel the increase in pituitary size throughout gestation. In contrast to the lactotrophs, the size of the other pituitary cells decreases or remains unaltered during pregnancy. In line with these findings, maternal levels of growth hormone (GH) are low and the level of thyroid-stimulating hormone (TSH) remains unchanged. Adrenocorticotrophic hormone (ACTH) levels do increase with advancing the gestation. Corticotrophin-releasing hormone (CRH) in the maternal plasma increases during pregnancy due to increased placental secretion, but alterations in binding-protein concentrations prevent increased biologic activity of this releasing hormone. Maternal plasma arginine vasopresssin (AVP) levels remain low throughout gestation and are not believed to play a pivotal role in human pregnancy. Maternal oxytocin levels are low and do not vary much throughout pregnancy, until they increase during the later stages of labor.

Maternal Thyroid Gland

As a result of increased vascularity and glandular hyperplasia, the thyroid gland increases slightly in size during pregnancy; however, true goiter is not usually present. During gestation the mother remains in an euthyroid state. Total thyroxine (T₄) and tri-iodothyronine (T₃) levels increase but do not result in hyperthyroidism because there is a parallel increase in T₄-binding globulin that results from estrogen exposure (Figure 15). The increase seen in binding-protein concentrations is similar to that observed in women who use oral contraceptives (OC). A modest increase in the basal metabolic rate (BMR) rate occurs during pregnancy secondary to increasing fetal requirements. Some T₄ and T₃, but no TSH, are transferred across the placenta.

Fig_15_maternal thyroid function during pregnancy.jpg

Figure 15. Relative changes in maternal thyroid function during the course of human pregnancy from conception to term.

Maternal Adrenal Glands

The maternal adrenal gland does not change morphologically during pregnancy. Plasma adrenal steroid levels increase with advancing gestation. The increase in total plasma cortisol is due, principally, to a concomitant increase in cortisol-binding globulin. There is a slight increase in plasma and urinary free cortisol, but pregnant women do not exhibit any overt signs of hypercortisolism. Levels of renin and angiotensin rise during pregnancy, which leads to elevated angiotensin II levels and markedly elevated levels of aldosterone

Maternal Endocrine Pancreas

A dual-hormone secretion mechanism is partially responsible for the metabolic adaptation of pregnancy in which glucose is spared for the fetus by the maternal endocrine pancreas. Compared to the non-pregnant state, in response to a glucose load, there is a greater release of insulin from the beta cells and a greater suppression of glucagon release from the alpha cells. Associated with the increased release of insulin, the maternal pancreas undergoes beta-cell hyperplasia and islet-cell hypertrophy, with an accompanying increase in blood flow to the endocrine pancreas. During pregnancy, when fasting blood glucose levels fall, they rise to a greater extent in response to a glucose load than do levels in non-pregnant women. The increased release of insulin is related to insulin resistance due to hPL, which spares transfer of glucose to the fetus. Glucagon levels are also suppressed in response to a glucose load, with the greatest suppression occurring near term.

REGULATION OF FETO-MATERNAL STEROIDOGENESIS

Using in vitro investigations utilizing placental tissue explants as well as, in vivo, catheterized primate models to study steroidogenic regulation in pregnancy, researchers have determined LDL-cholesterol, fetal pituitary hormones, intra-placental regulators, and intra-adrenal regulators act as the primary modulators of feto-placental steroid production

Regulation by Low-density Lipoprotein Cholesterol (LDL)

A limiting factor in adrenal steroid output is the availability of, LDL-cholesterol, the primary lipoprotein used in fetal adrenal steroid steroidogenesis (Figure 16). Circulating LDL-cholesterol accounts for 50-70% of the cholesterol utilized for fetal adrenal steroidogenesis. The fetal adrenal is known to contain high affinity, low capacity LDL binding sites. The presence of ACTH increases this binding capacity . Within the adrenal, hydrolysis of LDL makes cholesterol available for conversion to steroids. The majority of fetal LDL-cholesterol is made, de novo, in the fetal liver . In addition, cortisol from the fetal adrenal cortex and estradiol (aromatized from fetal DHEAS) augment this de novo synthesis within the fetal liver. These systems interact in a manner that is linked, self-perpetuating, and serves to increase steroid production to meet the needs of the maturing fetus.

Fig_16_maternal, placental and fetal compartments for estrogen and progesterone synthesis.jpg

Figure 16. Shown are the maternal, placental and fetal compartments for estrogen and progesterone synthesis in human pregnancy. The fetal adrenal gland lacks 3b-hydroxysteroid dehydrogenase, but has sulfation and 16a-hydroxylase capabilities. Likewise, the placenta lacks 17a-hydroxylase activity but contains sulfatase in order to cleave the sulfated fetal products.

Regulation by Fetal Pituitary Hormones

Fetal ACTH regulates steroidogenesis in both adrenal zones. Adrenocorticotropic hormone receptor activity is diminished in the fetal zone of the cortex during the early second trimester when other factors, such as hCG, are more important in the maintenance of this zone. In vitro studies, in human fetal adrenal tissue, demonstrate that ACTH stimulates the release of D5 pregnenolone sulfate and DHEAS, whereas in adult adrenal cortex secretes only cortisol when stimulated by ACTH. Moreover, ACTH can act on its own adrenal-cell membrane receptor to express a direct stimulatory effect on steroidogenic enzymes.

Adrenocorticotropic hormone extracted from the human fetal pituitary gland has been shown, in vitro, to stimulate the production of DHEAS and cortisol. Interestingly, concentrations of ACTH throughout the gestation do not correlate with the increasing mass of the fetal adrenal cortex or the increasing steroidogenic function that are hallmarks of the third trimester. Fetal pituitary ACTH is detectable by 9 weeks gestation. Thereafter, levels of ACTH increase steadily until 20 weeks gestation. The levels remain stable until approximately 34 weeks, when a significant decline is initiated and persists until term.

Prolactin may act as a co-regulator, along with ACTH, hCG and certain growth factors, in fetal adrenal steroid production. Both in vitro and in vivo, prolactin augments ACTH-stimulated adrenal androgen production. Fetal pituitary prolactin is detectable at 10 weeks gestation. Umbilical cord prolactin levels increase with advancing gestational age and rise in parallel with increased fetal adrenal mass.

Regulation by Intra-placental Mechanisms

The placenta is an important co-regulator of the fetal adrenal zone due its ability to secrete hCG, placental CRH, progesterone and estradiol. In vitro and in vivo, hCG receptor activity is present in the fetal zone, and hCG stimulates fetal adrenal production of DHEAS. However, after the 20th week of gestation ACTH primarily influences the fetal zone of the adrenal, and at this time, hCG plays only a minor role. Placental CRH, acts in a paracrine relationship with placental ACTH, to complement the actions of the fetal hypothalamus and pituitary in producing the surge in fetal glucocorticoids notable in the late third trimester as fetal growth and maturity become increasingly important.

Placental progesterone inhibits D5 to D4 steroid transformations in the fetal zone of the adrenal. This effect is another explanation for fetal adrenal 3bHSD deficiency. Placental estradiol modifies the production and metabolism of corticosteroids and progesterone. In vivo, the placenta regulates the inter-conversion of maternal cortisol to cortisone, and the fetal pituitary production of ACTH. Modulation of the transfer of maternal cortisol across the placenta, into the fetus, is the primary mechanism through which this effect occurs.

Regulation by Intra-adrenal Mechanisms

With advancing gestational age, the fetal adrenal becomes more sensitive to circulating ACTH. Between 32 and 36 weeks gestation, the fetal adrenal mass increases. Blood flow to the fetal adrenal is affected by many factors that, in turn, affect the exposure of the fetal adrenal receptors of the different trophic stimuli. Growth factors modulate adrenal steroid pathways just as they do in the adult adrenal cortex. The fetal adrenal produces IGF-I and IGF-II; ACTH originating from either the fetal pituitary or the placenta can stimulate production of their respective mRNAs.

Normal Maternal Physiology:

Implications for Prenatal Care

Definitions

Dilutional anemia of pregnancy: lower hematocrits are seen in pregnancy because the expansion of plasma volume is greater than the increase in red blood cell mass

Hypercoagulable state of pregnancy: increased predilection for pregnant women to have venous clotting episodes

Hegar's sign: cervical changes of pregnancy such that the uterine cervix appears bluish and engorged

MSAFP (Maternal serum alpha-fetoprotein): Screening test of maternal blood done in the early second trimester to screen pregnant women for fetal anomalies and chromosomal abnormalities

Estimated delivery date (EDD): the estimated date of delivery based on either dating or ultrasound parameters

Bacterial vaginosis: a bacterial infection of the vagina associated with preterm labor and birth

Glucola: a screening test performed on maternal blood for gestational diabetes

Rhogam: an antibody preparation of anti-Rh factor given to Rh (-) women to prevent Rh isoimmunization

Neural tube defect (NTD): an abnormality in closure of the neural tube, resulting in a spectrum of anomalies from anencephaly (no cranium or cerebrum) to spina bifida

Intrauterine growth restriction (IUGR): pathological condition of abnormal placentation resulting in an undergrown fetus

Small-for-gestational age (SGA): the lower 10% of birthweights

Large-for-gestational age (LGA): the upper 10% of birthweights

Macrosomia: an abnormally large infant (usually > 4000 gm)

Outline

Introduction

The primary goal of prenatal care is to deliver a healthy term infant without impairing the mothers health and to identify and optimally treat the high-risk parturient.

Pertinent Changes in Normal Maternal Physiology

Cardiovascular system
1. Cardiac
  1. Cardiac output increases about 30-50% (from 4.5 to 6.0 L/min)
  2. Stroke volume increases about 10 to 15%
  3. Pulse increases about 15-20 bpm
  4. Systolic ejection murmur and S3 gallop is common (about 90% of pregnant women)
2. Blood pressure
  1. Peripheral vascular resistance falls
  2. There is normally a fall in BP during the second trimester (5-10 mmHg systolic, 10-15mmHg diastolic), and then returns to normal during the third trimester Pertinence: Many of the effects of the altered cardiovascular system mimic heart failure (edema, gallops, dyspnea, distended neck veins, abnormal cardiac silhouette on CXR, EKG changes).
Respiratory system
1. Unchanged: respiratory rate, vital capacity, inspiratory reserve volume
2. Decreased: functional residual capacity (by 20%), expiratory reserve volume (by 20%), residual volume (by 20%), total lung capacity (by 5%)
  
  .
3. Increased: inspiratory capacity (by 5%), tidal volume (by 30-40%)
4. Arterial blood gasses: pH= 7.44, pCO2=30, bicarbonate=20-25, pO2=>100 Pertinence: A normal pregnant woman has a compensated respiratory alkalosis and a diminished pulmonary reserve.
Renal system
1. Anatomic: increase in kidney size and weight, ureteral dilatation (Right > left), bladder becomes an intra-abdominal organ
2. Hemodynamics:
  1. GFR increases 50%, renal plasma flow increases by 75%
  2. Creatinine clearance increases to 150-200 cc/min
3. Metabolic changes
  1. BUN and serum creatinine decreases by about 25%
  2. Plasma osmolarity decreases about 10 mOsm/kg H2O
  3. Increase in tubular reabsorption of sodium
  4. Marked increase in renin and angiotensin levels, but markedly reduced vascular sensitivity to their hypertensive effects
  5. Increase in glucose excretion Pertinence: Pregnant women are more prone to pyelonephritis and bladder rupture during abdominal trauma.

Hematologic System

Plasma volume and RBC mass
1. Plasma volume increases by about 50%
2. RBC volume increases by about 30%
3. The result: the "dilutional anemia of pregnancy", such that the mean hemoglobin during pregnancy is about 11.5 g/dl
.

WBC and platelets

WBC count increases during pregnancy
Platelet count decreases, but stays within normal limits

. Uterine blood flow at various stages of pregnancy

The flow increases significantly with the duration of pregnancy.

Coagulation system: pregnancy as a "hypercoagulable state"
1. Increased levels of fibrinogen, factor VII-X
2. The placenta produces a plasminogen activator inhibitor Pertinence: Blood loss is well-tolerated during labor, but maternal vital signs do not change for blood loss of 1500 cc, so vital signs cannot be trusted as an indicator of blood loss. Also, serious thromboembolic disease is more common during pregnancy.

Gastrointestinal System
1. Decreased motility, probably due to influence of progesterone
2. Reduced gastric acid secretion Pertinence: A pregnant woman is considered to have a full stomach even if she has had nothing to eat or drink for several hours. Peptic ulceration is rare during pregnancy.

Reproductive System

The Uterus

Weight: increases from 70 gm to 1100 gm

Blood flow: increases to about 750 cc/min, or about 10-15% of cardiac output

Height of fundus at comparable gestational dates

The hight of the fundus at comparable gestational dates varies greatly from patient to patient. Those shown are most common. Convenient rule of thumb is that at five months' gestation, fundus is usually at or slightly above umbilicus.

Pertinence: Laceration of the uterine arteries can result in massive hemorrhage in a short period of time

The Cervix
1. increase in water content and vascularity (Hegar's sign)
2. increase in cervical mucous secretions

Nutritional Considerations in the Normal Pregnancy
1. Weight gain: both weight gain and pre-pregnancy weight are directly related to infant birthweight
  1. Average weight gain (no one knows optimal weight gain)
    1. Normal weight for height: about 20 lbs
    2. Underweight women: about 30 lbs
    3. Overweight women: about 16 lbs
  2. Average weight gain by organ system
    1. Fetus--7 1/2 lbs
    2. Placenta and amniotic fluid--3 lbs
    3. Blood volume--4 lbs
    4. Breasts--1 to 2 lbs
    5. Maternal fat--4 lbs
2. Daily dietary requirements for common nutrients
  1. Calories: increased 15% kcal/day, or you need about 2200 cal/day
  2. Protein: an additional 10 to 30 gm /day (about 75 gm/day total)
  3. Iron: supplement 30 to 60 mg of elemental iron per day
  4. Calcium: 1200 mg needed per day, usually provided by a quart of milk per day (can use 2 Tums day, each have 600 mg of calcium carbonate)
  5. Folate: supplement 200 to 400 g per day (most vitamins have 1 mg)
    1. In women with a prior history of having a baby with a neural tube defect, supplementing with 4 mg per day has been shown to decrease the risk of a recurrence in the next pregnancy
3. The pregnant patient is best served by having a healthy balanced diet with iron and folate supplementation. Only rarely are other vitamin supplements needed.
Prenatal Care for the Normal Pregnancy
1. The first visit--The basic decision: normal vs. high-risk
  1. History
    1. Menstrual history: confirm the pregnancy
      
      (1) Regularity, interval, duration
      
      (2) Last normal menstrual period (LMP): characteristics and bleeding since then?
      
      (3) Assign an estimated date of delivery (EDD): it is inappropriate for a patient to be past 20 weeks of pregnancy without a definite EDD
    2. Past obstetric history (if any): for many conditions, if the patient had an abnormality in the first pregnancy, then she is predisposed to a recurrence in subsequent pregnancies
      
      (1) Length of gestation
      
      (2) Birth weight: low (IUGR/SGA) vs. high (LGA/macrosomia)
      
      (3) Fetal/neonatal outcome: alive vs. dead, impairments
      
      (4) Length of labor
      
      (5) Type of delivery: vaginal vs. cesarean, breech vs. cephalic
      
      (6) Other complications
      
      (7) Type of anesthesia used
    3. Past medical history
      
      (1) Significant past illnesses
      
      (2) Permanent conditions: hypertension, diabetes, seizure disorder, thyroid disease, and so on
      
      (3) Previous surgeries: C/S, gynecologic/abdominal surgery
      
      (4) Medications: prolonged therapy
    4. Family history
      
      (1) Look for conditions with familial predilection: hypertension, diabetes, cardiac disease, genetic abnormalities
    5. Social history
      
      (1) alcohol use, smoking, drug abuse
      
      (2) 8-9% of pregnant women in the Salt Lake Valley have a positive urine for at least one drug of abuse
      
      (3) occupational hazards
    6. Genetic screening: evaluate from patient and family history the risk for genetic abnormalities (is it above the usual 2-3% of all pregnancies?)
      
      (1) Risk of chromosomal abnormalities increases with maternal age:
      
      Age 35    1/204
      Age 38    1/103
      Age 40    1/65
      Age 42    1/40
      Age 44    1/25
  2. Physical examination
    1. Vital signs: are they normal or not?
    2. General physical examination: are there any concurrent undiagnosed medical conditions?
    3. Abdominal exam: scars?, enlarged uterus?, other masses?
    4. Pelvic examination: uterine size (confirm dates), cervical examination, Pap smear, clinical pelvimetry
    (1) uterine size large for dates: think twins or incorrect dates
    
    (2) uterine size small for dates: think IUGR or incorrect dates
    
    (3) the next step: ultrasound evaluation of the pregnancy
2. Laboratory data
  1. CBC: make certain the patient is normal for pregnancy
  2. Serology for syphilis: RPR, VDRL, confirm with FTA
  3. Blood type, Rh, and indirect Coomb's test: evaluate for blood group isoimmunization
  4. Rubella titer
  5. Hepatitis screen
  6. Maternal serum alpha-fetoprotein (MSAFP) at 15-18 weeks
    
    (1) If elevated, then the patient should be evaluated with a targeted ultrasound for fetal anomalies, including neural tube defects and abdominal wall defects (gastroschisis and omphalocele)
    
    (2) If low, then the patient should be offered a genetic amniocentesis to evaluate the fetus for trisomy 21 (Down's syndrome)
  7. Urinalysis and urine culture
  8. Pap smear: abnormal smears must be evaluated during pregnancy
  9. Bacterial vaginosis (BV) screening: wet mount
3. Subsequent visits
  1. Frequency: the usual regimen
    1. Monthly up to 32 weeks
    2. Every two week until 36 weeks
    3. Weekly after 36 weeks until delivery
  2. Interval history
    1. General health and well-being
    2. Presence or absence of contractions
    3. Fetal movement: increased, decreased
    4. Leaking clear fluid: rule out spontaneous rupture of membranes
    5. Vaginal bleeding: all vaginal bleeding after the first trimester mandates an evaluation
  3. Examination
    1. Maternal weight
    2. Blood pressure: get worried if it is much above 120/80
    3. Fundal height, estimated fetal weight, fetal position
    4. Always confirm the presence of fetal heart tones (FHT's)
    5. Urinalysis for protein and glucose: simple inexpensive screens for pre-eclampsia and diabetes
  4. Laboratory evaluation
    1. CBC in the early third trimester: rule out anemia
    2. Glucola (diabetes screen) in the early third trimester
    3. Rhogam at 26-28 weeks if the patient is Rh negative
  5. Ultrasound evaluation: routine vs. indicated?
  6. Preparation for labor
    1. Childbirth education classes
    2. Physician input
4. Some common complaints during pregnancy: the "Discomforts of Pregnancy"
  1. Nausea and vomiting: usually dissipates by 15 weeks or so
  2. Constipation: common throughout pregnancy
  3. Heartburn: often worsens as pregnancy progresses
  4. Vaginitis: treat only if symptomatic
  5. Varicose veins and hemorrhoids: treat symptomatically
  6. Headaches
  7. Edema: lower extremity edema is very common
  8. Backache: lordosis is common with change in the center of gravity
  9. Leg cramps: especially in lower leg
  10. Faintness and light-headedness
  11. Breast tenderness
  12. Carpal tunnel syndrome
5. Common questions for which you will need to have an answer
  1. Activity and exercise: moderation should be encouraged
  2. Sexual activity: no problem as long as pregnancy progresses normally
  3. Diet: a general balanced diet is usually all that is required
  4. Bathing and swimming: no high speed sports or jet skis
  5. Douching: OK if pregnancy is normal, best avoided if possible
  6. Dentition: a dental check-up is recommended, any work is OK
  7. Immunizations: should probably avoid live virus vaccines
  8. Travel: no problems, but should have frequent stops to stretch
  9. Employment: usually no contraindication as long as pregnancy is normal

Dr Mahmoud Ahmad Fora

Last Updated Mar 25, 2006