Serum constituents in pregnancy

99

SERUM CONSTITUENTS IN PREGNANCY TABLE 1 SERUMCONSTITUENTSIN 350 PREGNANTAND65 NON-PREGNANTWOMENASDETERMINED BYATECHNICONSMAII ANALYSER

Units Total Protein Albumin Calcium Inorganic Phosphorus Cholesterol Urea Nitrogen Uric Acid Creatinine Bilirubin Alkaline Phosphatase Lactate Dehydrogenase Aspartate Aminotransferase

mg/100 mg/100 mg/100 mg/100 mg/100 mg/100 mg/100 mg/100 mg/100 IU/l IU/I IUfl

Mean ml ml ml ml ml ml ml ml ml

7.4 4.7 9.6 3.1 206 14 4.4 0.8 0.6 55 179 21

Non-Pregnant Range 6.8-8.0 4.1-5.3 8.8-10.4 2.1-4.1 139-274 8-20 2.4-6.4 0.6-1.0 0.2-1.0 18-93 109-249 9-33

Pregnant (Third Trimester) Mean Range 6.3 3.6 9.1 3.7 290 9 4.9 0.6 0.3 148 144 16

5.5-7.1 3.2-4.0 8.3-9.9 2.7-4.7 184-396 3-15 2.3-7.5 0.4-0.8 0.1-0.5 49-246 85-204 2-26

* NOTE: The p value for all parameters was less than .001 according to Student's t-test. bilirubin. Cholestatic jaundice related to pregnancy was suspected in these subjects. Two other p r e g n a n t subjects were eliminated from the group used to determine reference ranges because of grossly elevated alkaline phosphatase values. These women were investigated further. Later in the study, two more subjects were discovered to have elevated alkaline phosphatase levels in excess of the range determined for p r e g n a n t women. These four cases had alkaline phosphatase values ranging from 810 to 1435 IU/l as shown in Table 2, and the elevations were not t r a n s i e n t but were sustained until term. Post-partum levels dropped precipitously and in one case the decrease was 40% at 48 hours post-partum, in a second case 59% after 72 hours. The source of the elevations in alkaline phosphatase was investigated. The heat stable form of the enzyme ranged from 85 to 93% of the total. Electrophoresis indicated the major isoenzyme to be the placental type in two patients. The p a t t e r n was undefined for the third patient and the fourth was not tested. All four patients had normal serum levels of lactate d e h y d r o g e n a s e , a s p a r t a t e amino t r a n s f e r a s e and bilirubin. Either alanine amino transferase or gamma glutamyl transpeptidase was estimated on each patient TABLE 2 ELEVATEDSERUMALKALINEPHOSPHATASELEVELS

Case

Gestational Age (Weeks)

Alkaline Phosphatase Levels IU/1

R.N.

40

1170

C.L.

34 38 39 40

810 1065 1345 1435

S.J.

37 38 48 hours post partum

1260 1280 810

F.M.

35 36 37 40 72 hours post partum

1110 1120 1180 1240 515

as a secondary liver function test and results were normal in 3 cases. The fourth patient had a borderline level for gamma glutamyl transpeptidase. These results are shown in Table 4. One case, R.N., required a Caesarean section because of placenta previa, but the other patients had normal deliveries. All babies were normal. The serum estriol levels are given in Table 5; all were essentially normal. DISCUSSION The levels of serum constituents reflect the physiological and biochemical changes that accompany pregnancy. An increase in blood volume occurs with the degree of expansion varying up to 45%. The increase starts as early as six weeks and expands rapidly in the second t r i m e s t e r and an increase of at least 20% is expected in the third t r i m e s t e r (21). This hypervolemia results in a dilution of serum constituents such as total protein, albumin, calcium and bilirubin. The low levels of urea nitrogen and creatinine are due in part to an increased glomerular filtration rate which accompanies the dilution process (22); they are about one-third lower in p r e g n a n t women than in non-pregnant subjects. If the non-pregnant range is taken as normal, then urea nitrogen and creatinine would almost have to double before being called abnormally high. This makes these serum tests very insensitive markers and Sims (22) has suggested that creatinine clearance is the test of choice for renal disease in pregnancy. While total protein is reduced, electrophoresis shows an i n c r e a s e in the alpha-2 and b e t a globulin fractions (23). A n u m b e r of binding proteins such as thyroxine binding globulin and ceruloplasmin are elevated in pregnancy. The same occurs with estrogen therapy implicating hormone stimulation as the cause (24). In pregnancy there is an increase in beta l i p o p r o t e i n s with an a c c o m p a n y i n g i n c r e a s e in cholesterol. The increased cholesterol is thought to reflect changes in specific protein synthesis (25). The enzymes lactate dehydrogenase and a s p a r t a t e amino transferase are decreased in pregnancy; this is probably the result of hypervolemia. The alkaline phosphatase levels show a distinctive in-

COLLINS

100

TABLE 3 BILIRUBINANDSERUMENZYMELEVELSIN PATIENTSWITHGROSSLYELEVATEDALKALINEPHOSPHATASELEVELS Case

R.N. C.L. S.J. F.M.

Bilirubin* mg/dl

Lactate Dehydrogenase* UI/I

0.5 0.3 0.2 0.3

Aspartate Amino* Transferase

Alanine Amino** Transferase

Gamma Glutamyl*** Transpeptidase

IU/l

IU/l

IU/l

18 18 17

14 12 --

8

--

--6 32

116 95 123 101

* See Table 1 for normal levels. ** Normal level 1-20 IU/l *** Normal level 0-29 IU/1 TABLE 4 ESTRIOL LEVELS Case

Gestational Age (Weeks}

Estriol Level

**Reference Range

R.N. C.L.

40 34 38 39 40 38 35 40

*34 mg/24 hr +3 ng/ml 6 8 10,8 14 12 17

15-50 mg/24 hr 6-20 ng/ml 6-25 8-30 8-30 6-25 6-20 8-30

S.J. F.M.

* Urine estriollevel + Serum estriol level ** The reference range for the method was established in our own laboratories.

crease. This is due to the presence of placental alkaline phosphatase in the m a t e r n a l circulation (2). The levels rise gradually during the first 2 t r i m e s t e r s with a more rapid rise in the last t r i m e s t e r (5). In our study, the a v e r a g e value at 38-42 weeks was 156 IUfl with a maximum of 250 or about 2-1/2 times the non-pregnant normal level. F o u r s u b j e c t s had g r o s s l y e l e v a t e d a l k a l i n e p h o s p h a t a s e levels, at least four times g r e a t e r than the maximum found in the normal p r e g n a n t group. The r e s u l t s w e r e abnormal enough to cause some concern. The source of the alkaline phosphatase was thought to be the placenta. P o s t - p a r t u m samples from two pat i e n t s showed a dramatic decline in the s e r u m level of alkaline phosphatase in keeping with the half-life of 4-7 days for t h e placental isoenzyme (26). The heat stability t e s t d a t a s u g g e s t t h a t the major portion of activity was due to placental isoenzyme. Other liver function t e s t s w e r e normal for t h e s e four subjects, ruling out liver disease as the source of the e l e v a t e d enzyme level. One case, R.N., p r e s e n t e d with a placenta previa. The block was complete and a C a e s a r e a n d e l i v e r y was performed. A small amount of bleeding occurred at 38 weeks. F o r a second case, S.J., the pathology r e p o r t on the placenta showed infarction involving more than 300/0 of the tissue with some calcification b u t no evidence of inflammation. A third patient, C.L., had lownormal estriol levels which s u g g e s t e d a problem with t h e functioning of the fetal-placental unit. No information about the placenta was obtained for the fourth case. The studies s t r o n g l y s u g g e s t t h a t the e l e v a t e d alkaline

posphatase is of placental origin and indicates some placental problem. The significance of the problem to fetal well-being is not clear since all four subjects d e l i v e r e d normal babies. A similar case was r e p o r t e d by L. Ewen (27), whose p a t i e n t had alkaline phosphatase levels over ten times the u p p e r limit of normal. The enzyme was heat-stable and electrophoresis showed a large amount of the placental isoenzyme. Other liver function t e s t s were normal, b u t the pathology r e p o r t on the placenta indicated a large central infarction. Cuzen and Morris (28) and Sagen and co-workers (5) r e p o r t e d e l e v a t e d alkaline p h o s p h a t a s e in preeclampsia and slightly e l e v a t e d levels in h y p e r t e n s i v e pregnancies. T h e y s u g g e s t e d t h a t s t r e s s producing a higher than normal level of cortisol might cause an induction of placental alkaline p h o s p h a t a s e leading to higher m a t e r n a l levels. Other possible causes might be p r e m a t u r e placental aging, infarction, or r e g e n e r a t i o n of the t r o p h o b l a s t (29). In the cases described in the p r e s e n t s t u d y the source of the grossly e l e v a t e d alkaline p h o s p h a t a s e level was the placenta and placental damage was the most likely cause. Grossly e l e v a t e d alkaline p h o s p h a t a s e levels in pregnant women are a cause for concern and w a r r a n t isoenzyme studies. If the placental alkaline p h o s p h a t a s e levels a r e being used to monitor fetal well-being, one should be a w a r e t h a t placental d a m a g e can produce high alkaline p h o s p h a t a s e levels. Also, these levels can be sustained over a long period of time as shown in this

S E R U M C O N S T I T U E N T S IN P R E G N A N C Y

s t u d y and t h u s add a n o t h e r v a r i a b l e to be c o n s i d e r e d when interpreting results.

15.

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