Placental insufficiency in relation to postterm pregnancy and fetal postmaturity

CURRENT DEVELOPMENTS

Placental insufficiency in relation to postterm pregnancy and fetal postmaturity Evaluation of fetoplacental function; management of the postterm gravida HELMUTH VORHERR, M.D.

Albuquerque, New Mexico

As pregnancy extends post term, incidence of placental insufficiency, fetal postmaturity (d_wmaturity), and fetal perinatal death increases rapidly as a consequence of reduced mpiratory and nutritive placental function. Despite a compensatory fetoplacental respiratory reserve capacity, fetal distress is observed in about one third of postterm pregnancies. On a biochemical level, placental pathophysiology in postterm-postmaturity pregnancies is not well understood. Postmaturity is correlated with increased incidence of placental lesions, fetal hypoxia-asphyxia, intrauterine growth retardation, increased perinatal death, and neonatal morbidity. Early diagnosis of fetal postmaturity is difficult because currently applied test methods allow recognition on~'V when placental insufficiency is far progressed. Therefore, in postterm gravidas with a favorable cervix, induction of labor should be considered; in older primigravidas, in whom fetal losses may be sevenfold increased, or in multiparas with a history of obstetric complications, pregnancy may require termination by cesarean section. Pregnancy may be allowed to continue under close supervision in cases of uncertainty of duration of gestation, in gravidas carrying small babies, in young primigravidas, and in multigravidas in whom placentofetal function tests are normal. As long as fetal scalp blood sampling during labor does not show fetal acidosis, despite abnormal fetal heart rate pattern and meconium release, vaginal delivery may be attempted when deemed possible within a few hours. In parturients attention must be paid to the extent of uterine activity and type of medication; lateral positioning of thR gravida and maternal oxygen breathing, facilitating fetal oxygen supp~-v. are important features. Because during bearing-down efforts placentofetal respirato·ry reserves of postterm gravidas may become further compromised, immediate delivery b_~ forceps or vacuum extraction may be considered. After delivery the umbilical cord should not be clamped immediately in order to allow increased fetal blood supply and to counteract fetal hypovolemia. Dysmature newborn infants require special care by the neonatologist. From thi Department5 of Obstetrics-Gynecology and

hild july 29-30, 1974, at Louvaine, Belgium. Thf proceedings will be published in the European Journal of Obstetrics, Gynecology and Reproductive Biology.

Pharmacology, The University of New Me~ico, School of Medicine. The preparation of this manuscript and thi presentation of our research data were made possible through support provided by the National Institutes of Health, HD04028-06.

Reprint reqUI!sts: Helmuth Vorherr, M.D., Professor of Obstetrics-Gynecology and of Pharmacology, University of New Mexico, School of Medicine, 9H Stanford N. E., Albuquerque, New Mexico 8713!.

Some contents of this article were presented at the International Symposium on "Human Placentation"

67

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Vorherr Am.

Full placental development, final thickness, and specific functioning are achieved between the end of the fourth and the early fifth month of gestation. Thereafter, until birth, signs of gradual placental aging are observed (Table I) which are partly compensated by increase in the number of trophoblastic villi and surface area of vasculosyncytial membranes to maintain adequate fetal oxygen and nutrient supply. 78 • I07 Compensatory sprouting of placental villi with large capillary systems (sinusoids) progresses rapidly around the fifth gestational month and the number of villi on placental cross section increases fivefold from about 30 in the first trimester of pregnancy to 150 per square millimeter near term 105 ; increase in villous surface area is not accompanied by growth of single villi. Placental weight and villous surface area appear to be directly related to total placentofetal metabolism. 2 Because villous surface area and number of vasculosyncytial membranes increase toward term, it has been concluded that morphologic signs of placental aging or degeneration are not correlated with a functional deficiency, but rather that placental maturation and function reach a peak at term. 15 There are findings, however, which indicate that a peak of placental function (transport capacity) is reached at 36 weeks of gestation at which time chorionic DNA synthesis ceases 27 : after 36 weeks of gestation diminished rates of placental transfer of 24 Na and heavy water (deuterium oxide) are indicative of a decrease in placental efficiency with aging.m Accordingly, near term, placental transport processes gradually decline and placental and fetal growth rate is reduced (Fig. I). With increasing gestational age the curve of mean birth weights levels off until the forty-second week; thereafter the birth weight decreases slightly. 82 Amniotic fluid volume decreases rapidly from the thirty-eighth week on (Fig 1), and oligohydramnios is usually a sign of insufficient placental function. 55 • 61 From the thirty-fifth week on, intervillous blood flow decreases and villous necrosis and fibrinoid deposition increase .107 Aging processes are observed first on terminal placental villi; some villi narrow considerably and may become constricted away into the intervillous space. A decline of syncytial-trophoblastic sprouting becomes evident with a change in the syncytial sprout-villous ratio, which is 3: 1 at 8 weeks and I: 30 at term. Accordingly. diminished syncytial sprouting (syncytial hypoplasia) may be considered as a process of placental aging.a Diminished placental function during the last month of gestation is not pathognomonic per se, but may become of critical importance when abnormal maternal, placental, or fetal conditions exist (Table II). Almost all the signs of placental aging (Table I) appear

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J.

Table I. Placental aging processes l. Increase in thickness of basal membrane of chorionic epithelium, decrease in diameter of villi 2. Decrease in villous epithelium (disappearance of cytotrophoblastic cells), excess formation of syncytial knots 3. Progressive reduction in length of villi 4. Increase in free amino acids and in RNA, decrease in protein content 5. Increase in density of villous stroma (disappearance of most Hofbauer cells, sclerosis), decrease in capillaries and enhanced appearance of avascular villi---compensatory villous growth in peripheral parts of placenta 6. Increase in foci of fibrosis 7. Increase in cyst formation and excess of calcification 8. Increase in degenerative changes of decidual vessels (fibrinoid degeneration of intima)

more frequently and are more pronounced in gravidas with placental insufficiency and fetal postmaturity. In 5 to 12 per cent of all pregnancies insufficient placental function is observed, and decreased uteroplacental circulation (toxemia, multiple pregnancy) accounts for half of the cases causing chronic fetal hypoxia and growth retardation, or intrauterine asphyxia (hypoxia and acidosis) and fetal death; placental pathology is connected with 20 to 40 per cent of all perinatal fetal deaths. 107• 108 • 123 • 186 Through degenerative changes (fibrinoid necrosis, atheromatosis, arteriosclerosis) and/or spasms of decidual spiral arteries uteroplacental blood flow is reduced (critical flow, 300 ml.), circulating intervillous blood volume is decreased, and hemorrhagic infarcts accompanied by loss of functional placental tissue are the consequence. Especially in gravidas suffering from toxemia, acute degenerative changes of decidual spiral arteries (acute atherosis) have been observed regularly. 34 Reduction in intervillous blood flow and ischemia of placental tissues can lead to a reftectory increase in villous vascular resistance resulting in decreased fetoplacental circulation. In this condition placental uptake of 0 2 and nutrients is impaired, eventually leading to exhaustion of placental reserve capacity and to fetal growth retardation with an up to sixfold increased perinatal mortality rate .116 • 186 Impairment of local maternal and/or fetal placental hemodynamics may lead to trophoblastic damage and thus to insufficient placental function. Also maternafetal immune mechanisms may cause trophoblastic destruction: sera from toxemic patients as well as from puerperas immunized against the blood groups of their fetuses are highly cytotoxic toward respective placental tissue cultures. 76 Placental aging and trophoblastic tissue degeneration have recently been related to misspecification of trophoblastic changes by an insufficiently functioning fetoplacental immunosurveillance system which fails to destroy abnormal placental

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Placental insufficiency

69

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Fetal Weigh!

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Weeks of Gestation

Fig. 1. Average weights of fetus, placenta, and amniotic fluid throughout human gestation. Fetal and placental weights are similar during the first trimester of gestation. From the sixteenth week on, the fetus grows more rapidly than the placenta and the respective weight curves dissociate. Amniotic fluid correlates to placental weight until the thirty-sixth week, thereafter amniotic fluid volume declines rapidly. After the first half of gestation, the fetoplacental weight ratio is 2 to 3: l, inc1·easing to a ratio of about 6: 1 at term and remaining so during prolonged pregnancy. The standard deviation for fetal weight during the last trimester of gestation is± 500 to 600 Gm.; for placental weight and amniotic fluid volume large variations (300 to 600 Gm.) of single values are observed. The volume of amniotic fluid becomes greatly reduced postterm and only a few milliliters may be found after the forty-third week of gestation. The values presented are derived from references 55, 77, 92, 93, and 95-97.

cells. 37 In an early stage of placental predegenerative changes, syncytial edema (nuclear hyperchromasia, cell plasma vacuolation), loss of activity of enzymes of the citric acid cycle and formation of syncytiotrophoblastic protrusions ("syncytial plasma polyps") are thought to occur. 166 If this condition is not reversed, i.e., when syncytiotrophoblastic plasma protrusions become constricted away into the intervillous space, an irreversible state of trophoblastic degeneration ensues with fibrinoid transformation of trophoblastic cells; subsequently intervillous thrombosis develops through

blockade of intervillous space circulation. Intervillous thrombosis is followed by fibrinoid-syncytial swelling and degeneration of Langhans' cells of adjacent villi resulting in a focus of trophoblastic tissue degeneration, i.e., a placental infarct. 166 Intervillous th:rombosis has been observed in about 12 to 24 per cent of term placentas involving most often the central portion of the placenta and causing atrophy of adjacent villi. 21 Placental infarction (numerous microinfarcts), as often seen in cases with toxemia, is associated with a stillbirth rate of 16.7 per cent and a neonatal death rate of 8.3

70

Vorherr

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Table II. Abnormal materna!, placenta!, or fetal conditions Placental Factors Small placenta

2. Abruptio placentae, placenta previa 3.

Thrombosis, infarction (fibrin deposition!

Fetal Factors

4.

Deciduitis

I.

5.

Placentitis, vasculitis, edema

2. Rhesus erythroblastosis

6.

Chorioamnionitis

3.

7. Placental cysts, chorioangioma Maternal Systemic Factors

I

Degeneration (atheromatosis, arteriosclerosis! of decidual spiral arteries a. Monosymptomatic hypertension b. Toxemia c. Diabetes mellitus

Multiple pregnancy 1nfection

4. Heart disease

8. Umbilical cord complications

15.

Malformations

I

!

l'

2. Cardiorespiratory disease

Insufficient Placental Function

Small heart volume

Fetal Hypoxia - Asohyxia

4. Renal disease. acidosis

(Impairment of 02 and nutrient transport. and/or exchange of metabolic waste products)

3.

5.

Severe protein deficiency

6.

Anemia, rever

7.

Drugs ldiethylstilbestrol, anticancer agents! Hyperventilation I respiratory alkaiosisi

I II. 2.

1

Maternal Uterine Factors Decreased Uteroplacental Blood Flow

I I

~ •

I

Postterm - Postmaturity I ntravillous hemorrhagic infarcts and fibrin deposition

~. ~1!::~:~~~~~t~~~1 :nd

thrombosis

3. Thickening of vasculosyncytial membranes

- - - - - i 4. Ischemic villous necrosis Iedema.

I

Uterine hypertonicity

I

Supine position of patient

I

sclerosis of villous stroma. avascular villi) 5.

Increased placental calcium and fibrinoid deposition

6.

Fibrin deposition in intervillous space

7. Fibrinoid degeneration of decidual vessels 8. Oligohydramnios

3. Fibromyoma

114.

Morphologic abnormalities 1

per cent when more than l 0 per cent of the placenta is involved. 73 Reduction of vasculosyncytial membrane exchange surface area by increased thickening of vasculosyncytial membranes, villous vascular intima proliferation, intravillous thrombosis, and obliteration of small placental vessels may result in insufficient placental function and fetal distress. 22 • 73 Intravillous thrombosis affects most commonly chorionic and villous stem vessels. Initially, villous structures appear exaggerated and villous capillaries become dilated. Subsequently, the involved villous tree undergoes edema followed by villous shrinkage and villous atrophy (excess formation of syncytial knots; villous hypovascularity and avascularity) resulting in fetal oxygen deprivation. Umbilical cord compression may cause thrombosis of umbilical cord vessels and thus fetal death. 23 When placental lesions are small and progress only moderately, chronic and often symptomless placental insufficiency may lead to nutritional deficiency and term delivery of

underweight babies ("small-for-dates"). Acute reduction of placental function (abruptio placentae, cord knotting) by more than 30 per cent is critical for the fetus and may result in fetal death due to asphyxia. 186 During labor, fetal hypoxia, which may be clinically asymptomatic, can be ascribed to compression of the umbilical cord as observed in about 30 per cent of deliveries. Fetal hypoxia may also develop as a consequence of uterine contractility (hypertonicity) or of prolonged assumption of the supine position by the parturient, leading to reduction of uteroplacental blood flow and fetal oxygen supply. 107 Postterm gestation in relation to Incidence of placental insufficiency, fetal dlstress, and postmaturity

Postterm gestation. Pregnancy is considered post term when it exceeds 294 days, calculated from the first day of the last menstrual period (average duration of

Placental insufficiency 71

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Table III. Diagnosis of postterm placental

Table IV. Postmaturity: placental insufficiency and fetal distress

1. Clinical examination (uterine size, ripeness of cervix, abdominal circumference, maternal weight)* 2. Measurement of esn·iol in urine, serum, and amniotic fluid* 3. Vaginal cytologyt 4. Fetal cephalometry by ultrasound* 5. Amnioscopy, amniocentesis, and amniotic fluid analysis (amount, color, and constituents)* 6. Fetal electrocardiogram+ 7. Continuous recording of fetal heart rate (electrocardiography, phonocardiography)* 8. Recording of fetal heart rate and: a. Intravenous oxytocin challenge test (estimation of oxygen reserve of placenta and fetus)* b. Atropine and isoxsuprine testt c. Phvsical exercise test t 9. Measur~ment of human placental lactogen, heat-stable alkaline phosphatase, oxytocinase, diamine oxidaset I 0. Measurement of uteroplacental circulation by radioisotopes 4 Na)t II. Fetoscopy:j: 12. Fetal scalp blood sampling during labor (Pco2 , Po2, pH)* 13. Amniotomy during labor*

e

*Clinicallv valuable. tTheoretlcally valuable, no routine clinical application. tValue not established.

human gestation, 280 days). The chance that birth occurs on the expected date of confinement is 5 per cent, within ±3 days of due date it is 29 per cent, and within ±2 weeks of due date it is 80 per cent; prematurity is encountered in about I 0 per cent of pregnancies.103 Postterm pregnancy occurs in lO to 12 per cent of gravidas, with equal frequency among primigravidas and multiparas; approximately 7 per cent of all pregnancies extend beyond 42 weeks and about 5 per cent beyond 43 weeks of gestation. 3 1. 44 · 68 • 84 • 123 • 142 16 • " The margin of error for estimates of postconceptional age by present diagnostic techniques (Table Ill) is ±2 to 3 weeks. 77 Duration of gestation, as influenced by racial, geographic, maternal, placental. and fetal factors. varies greatly. and many "postterm" pregnancies are actually term pregnancies that can be traced back to an inan:urate menstrual history, or 4 to 6 weeks of amenorrhea. or delayed ovulation prior to conception; l 0 to 15 per cent of women of fertile age experience temporarily amenorrhea or anovulatory cycles. 45 • 137 It has been suggested that more than half of the "postterm" pregnancies are actually gravidas with normal duration of gestation. 155 It is uncertain whether early conception in lactating women may be associated with prolonged gestation. Among 23,761 gravidas, 85 conceived during lactation but no increase in duration of their gestation was observed. 30 Whereas in rodents lactation-induced prolongation of gestation is due to delayed ovum implantation, postterrn pregnancy in

l. 2. 3.

4. 5. 6. 7.

I. 2. 3.

4. 5. 6. 7. 8.

Chronic placental insufficiency (extending aver weeks): Urinary estriol on lower limit of norm ( l 0 to 12 mg. per 24 hours or less) Meconium release, slight if any Wasting of subcutaneous tissues (growth retardation), dehydration, atrophy of thymus Oligohydramnios Brain damage (disproportionate growth and ma uration, hypoxia) Rarely: changes in fetal heart rate pattern Rarely: intrauterine fetal death Subacute and acute placental insufficienf~ (extending ovn a few days or hours, usually before onset or during labor and delivrry): Subsequent decrease of urinary estriol to critkal levels (5 mg. per 24 hours or less) Aspiration of amniotic fluid Meconium release and staining of fetal skin and mem· branes Wasting of subcutaneous tissues, etc, only when superimposed on chronic insufficiency Necrosis and/or hemorrhage into adrenal glands (hypoxia) Parenchymal damage of brain. myocardium, .md liver (hypoxia) Pathologic fetal heart rate pattern (prolonged deceleration due to fetal hypoxia and metabolic acidosis) Intrauterine fetal death

human subjects always appears to be the cons,~quence of retarded onset of labor. Various facets of the fetal postmaturity syndrome (Tables IV and V) are observed in approximatdy 20 to 40 per cent of postterm gravidas, whereas in the absence of placental insufficiency, 60 to 80 pe1 cent of fetuses carried beyond term do well, and large infants (4,000 Gm. and above) in good condition are born two to three times more often than in term pregnancies. 16 ' 31. 32, 44. ol. 12. n. n · ~a. 92 . 12:1 Increased fetal weight is always accompanied by higher placental weight, both in term and postterrn pregnancies; in one newborn infant of 7,500 Gm. an excess of placental weight of 1,770 Gm. was observed. 75 Fetuses of 3.600 Gm. and above were delivered by 30.6 per cent of gravidas between 37 to 42 weeks of gestation and by 41.5 per cent of mothers after 43 weeks of pregnancy. 1" 0 Within a fetal weight range of 3,500 to 4.000 Gm., only a slight difference existed in term (28 to 29 per cent) and postterm (34 to 36 per cent) gravidas. 84 Seven w 10 per cent of the fetuses of above 4.000 Gm. were born to term gravidas and 12 to 20 per cent to postterm gravidas. 16 • 84 • 118 • 143 One per cent of fetuses with a birth weight of above 4,500 Gm. were delivered by term gravidas and 3 per cent by postterm patients. 111 In sorne of these postterrn gravidas uterine blood How was

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Vorherr Am.

Table V. Clinical parameters of fetal postmaturity syndrome* I. Over-all incidence of fetal postmaturity: 2-6%

a. Term gravidas: -3% b. Postterm gravidas: 20-43%

2. Perinatal mortality rates a. Over-all 12-36% b. Between weeks 42-44: 3-15% 3. Distribution of perinatal mortality rates a. Before onset of labor: 9-30% b. During labor: 45-93% c. All intrauterine deaths: 75% d. After birth: 7-25% (respiratory distress; brain, heart, liver, adrenal damage) 4. Postnatal rnorbidity: 16-46% (respiratory distress, mainly) 5. Congenital malformations and stillbirth rates a. Postmaturity: 9% b. All gestational ages: 6%

6. Amniotic fluid changes a. Volume: reduced to 250 mi. or below (normal term values: 800 mi.) b. Fat cells: increase of orange-staining fat cells over 50% (normal term values: 10-50%) 7. Vaginal smear: appearance of parabasal cells (normal term values: 0/85-95/5-15) 8. Fetal heart rate pattern: prolonged deceleration in cases of severe fetal asphyxia 9. Lowered urinary estriol excretion: 30% excrete less than 12 mg. of estriol per 24 hours into the urine (normal term values: 15-25 mg. per 24 hours) 10. tviyometriun1

a. Persistent quiescence ("progesterone block") b. During labor: sluggish performance (uterine inertia)

11. Umbilical venous cord blood a. Decreased oxygen saturation: below 40% (normal term values: 55-70%); oxygen content below 8 vol. %(normal term value: 12 vol. %) b. Hemoglobin concentration increased: 16.8-20.5 Gm. per 100 mi. (normal term values: 15-18.6 Gm. per 100 mi.) *The data presented are derived from References I, 31, 43, 44, 51, 77, !06, 123, 129. 142, 161, and 170.

increased. 121 Birth weight decreases slightly with increasing maternal age but increases with parity .101 Accordingly, in postterm multiparas the incidence of fetuses heavier than 4,000 Gm. was double ( 16.5 per cent versus 7.6 per cent) that in primigravidas; a similar relation was observed in term pregnancies (4.9 per cent in primigravidas versus 8.1 per cent in mul4 tiparas).143 This is confirmed by another studyB (see Table VI). In contrast, Daichman and Goid46 were unabie to detect a difference in incidence (8.1 per cent) of birth of 4,000 Gm. and heavier fetuses between term and postterm gravidas. Failure of increase in average fetal body weight after 41 to 42 weeks of gestation does not mean that all fetuses stop growing. It rather indicates

Scptcmhc! ! . 1qf.1 J. Obstcl. (;\llnol.

that some fetuses grow at a normal, some at a more or less reduced rate, whereas other fetuses do not gain weight at all or may even lose weight. 74 The postterm fetal growth curve flattens out because of increasing development of placental lesions and insufficiency (dysfunction) contributing to a steady increasing pro161 portion of postmature fetuses with lower weight. Postterm pregnancy is the second most common cause of intrapartum asphyxia. 49 Durations of gestation up to 360 days with birth of a normal child and up to 389 days with delivery of an anencephalus have been reported.25. 32. so Median fetal and placental weights of postterm pregnancies are 180 to 360 Gm. and 60 to I 00 Gm. higher, respectively, than those of term gestations; on the average, male term fetuses weigh 113 Gm. more than female ones and postterm male fetuses weigh 200 Gm. more than female ones. 64 • 69· 75 · 94 · 124 It was assumed that faster growth of male fetuses occurs during the last trimester of pregnancy but this is not uniformly agreed upon. 131 Kloosterman 103 correlated increased weight of postterm male fetuses with their higher perinatal mortality rate; however, such a relationship was not observed in other studies. 121 · 167 According to Kloosterman, 103 the perinatal fetal mortality rate was 15 per cent for males and 4 per cent for females between 42 to 44 weeks of gestation; this male to female perinatal death ratio of 4:1 increased to 8: 1 between 44 to 46 weeks of pregnancy. Perinatal mortality figures for male and female fetuses published by Karn and Penrose101 are much lower (see Table VII). The higher death rate of postterm male fetuses was explained by their more rapid growth, through which they attain 103 maximal placental capacity faster than female fetuses. pregpostterm It has to be considered, however, that nancies occur with 5 per cent more male fetuses than female ones, 101 which can explain the greater male losses. Postterm fetal death rate was lowest in the average weight group; fetuses who grew either heavier (placenta relatively too small) or lighter (small placenta per se) had a higher mortality rate. 103 Average postterm placental weight was 458 Gm. in cases of intrauterine death and 535 Gm. in live births; the respective placental infarction rates were 70 and 35 per cent. 103

Postterm fetal distress, postmaturity, and fetal perinatal death. The longer gestation extends beyond term the greater is the likelihood for deveiopmeni of placental insufficiency, fetal growth retardation, and hypoxia-anoxia, i.e., fetal postmaturity. In 4.8 per cent of pregnancies fetal postterm-postmaturit y was diag159 nosed and most of the placentas sho~'ed infarction. In prolonged gestation, both normal and postmature

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Placental insufficie'1cy

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Table VI. Fetal weight

J

Percentage of fetuses in different weight groups Postterm gravidas

Primigravidas Multiparas

2.500-J.OOOj_J.OOI-3.500 Gm. (%) Gm. (%) 9.2 10.3

46A 29.6

fetuses have higher weights than those at term. 75 · 161 (See Table VIII). From the thirty-ninth week of pregnancy on, the mean birth weight of postmature newborn infants lies 200 to 300 Gm. below that of normal neonates of the same age; the length of postmature babies is the same as of normal ones. 161 Maternal age appears not to influence the incidence of fetal postmaturity. 161 Post term, rates of fetal distress and perinatal fetal mortality increase rapidly (Figs. 2 and 3) and especially fetuses of primigravidas appear at risk. 74 Nevertheless, albeit to a very small extent, fetal distress and postmaturity are observed from the thirty-eighth week of pregnancy on, reaching a maximum at 44 to 46 weeks of gestation (Fig. 4). All in all, the fetal postmaturity syndrome, due to placental insufficiency, is observed in 2 to 6 per cent of gravidas. 43 • 129 · 161 The incidence of fetal postmaturity was found to be 3 per cent at term and 20 per cent post term 167 ; a similar fivefold increase of fetal postmaturity in postterm gravidas was found in another study. 161 Fetal postmaturity has been found in 12 per cent of primigravidas and in 13 per cent of multigravidas. Incidence of postmaturity was higher in male fetuses of both primigravidas (male fetuses, 7 per cent; female fetuses, 5 per cent) and multigravidas (male fetuses, 8 per cent; female fetuses, 5 per cent). Considering all gravidas, postmaturity was found in 8.5 per cent of male and 4 per cent of female fetuses 167 ; Lindellli• did not find the same difference between male and female fetuses. In postterm gravidas fetal distress was diagnosed in 11 to 32 per cent (primigravidas, 12 to 39 per cent; multiparas, 3 to 9 per cent) compared to values of 7 to 18 per cent in term patients (primigravidas, 6 to 9 per cent; multigravidas, 1 to 7 per cent).42. so. 125, 126, 129, 143. 179 According to McClure Browne, 121 fetal distress occurred in only about 2.4 per cent of term gravidas and 4.8 to 5.5 per cent of patients at 42 to 43 weeks of gestation. In 5 to 7 per cent of newborn infants of postterm mothers asphyxia was observed. 85 · 155 A considerable increase in perinatal fetal death occurred with increasing maternal age, both in primigravidas and multiparas 121 (see Table IX). In older postterm primigravidas of 30 to 34 years of age there was a fetal distress rate of 13 to 32 per cent

.

3,501-4.000 Gm. (%)

I

..

>4, '>00

4.001-4.500 Gm. (%)

Gm. (%)

7.5 16.8

I4 38

34.8 38.0

Table VII. Perinatal fetal death Perinatal fetal mortality rates Duration of gestation (days)

Male fetuses

Fnnal1 fetuses

(%)

(%)

3A 4.8

2.9 ?.2

290 305 and more

Table VIII. Neonatal and placental weights Average n<~wborn and placental weight

Neonates and placentas

Term gestation (Gm.)

Poslterrn gestation (Gm.t

Normal neonates Postmature neonates Placentas

3,382 3,141 578

3,741 3,500 600*

*Placentas from postmature neonates.

Table IX. Perinatal deaths Perinatal fetal mortality rates Maternal al{e (yr.)

Primi1!:favidas

(%)

Multiparas (~~)

<25 25-29 30-34 35 and above

1.7 2.1 2.8

l 4 I 4 19

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nn

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and in those 35 years of age and older a distre~s rate of 56 per cent was observed. 60 • 180 With postterm pregnancy, placental insufficiency, fetal distress, and postmaturity, the perinatal fetal mortality rate is increased from term values of l to 2 per cent to average postterm figures of 5 to 7 per cent. 68 • 103 · 149 · 155 Average perinatal mortality rates as reported by 26 different authors are 1.65 per cent for term and 4.21 per cent for postterm gravidas. 8 Most fetuses died during labor and delivery (see Table X). Seventy per cent of aii fetal perinatai dt:aths occurred prior to or during labor and 30 per cent were neonatal deaths; these figures for postterm gravidas were not very different from values reported for term

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38

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46

44

42

fOST-TERM

f..:·:·:··'"' " ' Postmaturity [==:J Per i natal Mortality

40

38

46

44

42 WEEKS OF GESTATION

Fig. 2. Relative incidence of fetal postmaturity syndrome and perinatal mortality rate. As pregnancy advances beyond term the incidence of fetal distress and postmaturity (about 3 per cent at term) increases to 20 to 40 per cent and about one out of four postmature fetuses from gravidas with placental insufficiency dies.

15 14

• - - • Primigravidas

13

12 ~

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36

37

38

39

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Weeks of Gestation

Fig. 3. Preterm, term, and postterm perinatal fetai mortality rates in primigravidas and multiparas. In preterm and term pregnancies, the perinatal fetal mortality rates are only slightly higher in primigravidas than in multiparas. As pregnancy advances beyond term, fetuses of primigravidas, especially those of older primigravidas, are much more endangered than fetuses of multiparas. This is indicated by the divergence of the fetal mortality curve for primigravidas from that for multiparas. The over-all fetal perinatal mortality rate of postterm gravidas is 5 to 7 per cent whereas that of term gravidas is I to 2 per cent.

Volume 1":> Number 1

gravidas, i.e., 80 and 20 per cent, respectively. 115 At the forty-third week of gestation fetal perinatal death was two- to fivefold and at the forty-fourth week it was three- to sevenfold increased compared to values for term pregnancies. 67 • 99 • 12 1. 136 ·• 185 Other reports state that the perinatal mortality rate rose from 2.2 per cent for 42 weeks to 10 to 14 per cent for 44 weeks of gestation. 51. 103 In gravidas with uncomplicated prolongation of pregnancy the perinatal mortality rate between the forty-third and forty-fourth week is 2 to 3 times greater than in term pregnancies and a steep tenfold rise was observed after the forty-fourth wee k 160 ; with further extrapolation of the fatality curve in relation to prolonged gestation, the fetal mortality rate would be 100 per cent at a pproximately 52 weeks of pregnancy. 103 In postterm primigravidas the fetal perinatal mortality rate is 5 to 15 per cent 51 ; at 43 weeks fetal perinatal death of primigravidas is four- to fivefold and after 43 weeks ten- to twenty-fold (twofold in multigravidas) increased compared to term patients. 103 • 114 179 • An increase in fetal perinatal death has been re ported not only in older primigravidas but also in older multiparas. 118 Fetal perinatal mortality figures of 6.3 per cent for primigravidas and l per cent for multiparas observed between 40 to 44 weeks of gestation119 are in sharp contrast with an equal two- ro tenfold increase in fetal perinatal deaths for postterm primigravidas and multigravidas as reported by Strand 167 and by Zwerdling.190 According to McClure Browne, 121 fetuses of postterm multiparas are definitely at risk too, albeit to a lesser degree than those of primigravidas (see Table XI) . Up to the age of 2 years, the mortality rate of infants of postterm gestations is twice as high as that of babies of term pregnancies.190 In neonates of mothers with prolonged gestation , in the absence of clinical signs of postmaturity , the incidence of respiratory distress ( 13 per ce nt) is almost double that of term babies (7 per cent) . In a study of 23 ,000 gravidas, the perinatal mortality rate is between 12 and 36 per cent for postmature fetuses whereas the perinatal mortality rate for m ature, eutrophic neonates is 1.3 to 1.7 per cent. 32 The many literature data on increased fetal hazards with prolongation of gestation are contradicted by reports of Bierman and co-workers , 28 Clayton ,42 Daichman and Gold ,46 Evans and co-workers,5 7 Magram and Cavanagh, 12 6 and Prystowski 147 denying an increase in fetal perinatal deaths between term and postterm primi- or multigravidas. Magram and Cavanagh 126 specifically stated that even for fetuses of older postterm primigravidas no higher risk exists; Mead and Marcus 129 found a lower perinatal mortality rate in postterm (1.9 per cent) than in term (2.5 per

Placenta! insufficiency 75

WEEKS OF GESTATION

Fig. 4. Relative incidence and severity of placental insufficiency. Placental insufficiency (in 5 to 12 per cent of gravidas) may be due to maternal, placental, and fetal factors. De~elopment of uterine contractility (prelabor, labor) with temporary restriction of uteroplacental blood flow augments the condition of fetal distress (hypoxia). As pregnancy advances post term. placental insufficiency develops more frequently , leading to placentofetal nutritive and respiratory problems and thereby to development of more or less pronounced symptoms of fetal postmaturity in 20 to 40 per ce nt of gravidas.

cent) gravidas. Clayton 42 reported that a two- to threefold increase in perinatal death is observed only in gravidas carrying fetuses of 4.000 Gm. cr above . Perlin 143 and Bierman and co-workers28 emphasized that in postterm gravidas fetal morbidity i~. not increased and that in newborn infants of postterm mothers the risk of cerebral palsy and IQ's under 80 is not higher .28 Browne35 attributed an increased fetal perinatal mortality rate of 4.3 per cent (average from annual reports of 20 hospitals) in postterm gravidas to the birth complications encoumered with larger fetuses and not to placental insufficie ncy and fetal hypoxiaanoxia. Reasons why postterm fetuses are at increased risk because of placental insufficiency and postmaturity are as follows: (I) cessation of fetal and placental growth around 41 to 42 weeks of gestation; (2) increased degenerative placenta l lesions in postterm gravidas ; (3) decreased amniotic fluid volu me and innease in incidence of meconium staining of amniotic fluid ; (4) decreased fetal oxygen (lowered oxvgen content in venous cord blood) and nutrient supply (waste of fat depots, wrinkled skin , etc.); (5) increased pathologic processes within the fetoplacental unit (Table XII); (6) increased rates of fetal distress and perinatal death in postterm gravidas as reported by most investigators.

76

Vorherr

~cptenthu

1. l ~l/.-1

Am . .J. Ob>l<·l. C1 ""' ol.

Table X. Perinatal fetal deaths Perinatal fetal deaths Authors

Hilfrich 81 Holtorff and Schmidt84 Holtorff and Sengebusch 85 Kloosterman 103 McClure Browne 121

Prior to labor (%)

During labor and delivery (%)

Postpartum

37

46

17 18 17 14 22

53 17 36 36

Table XI. Perinatal fetal deaths Perinatal fetal mortality

Weeks of gestation

42 43

44

45

Primigravido..s

M !lltiparas

(%)

(%)

'l.'t' 1.5 2.5 3.5 6.5

1.6

1.5 1.6 2.0 3.5

Accordingly, large size of some postterm fetuses does not assure a better prognosis; even in large fetuses oxygen and nutrient supply may suddenly become decompensated. 74 Fetal distress and development of postmaturity (dysmaturity) due to placental insufficiency (placental dysfunction) has to be considered as a clinical entity which ranks second only to prematurity as cause of perinatal deaths of about 25 per cent 43 · 44 · 123· 16 1 • 17° (Table V). Respiratory distress (hyaline membrane disease) is the most frequent cause of death in postmature neonates; through lack of plasminogen activator in the lung, intra-alveolar fibrin deposits, caused by aspiration of meconium-filled amniotic fluid and blood hypoperfusion (vasoconstriction) of the lungs, cannot be dissolved.n 6 • 153 The incidence of neonatal respiratory distress syndrome is further increased when postterm insufficiency of the placenta is complicated by already existing (preterm) placental insufficiency, as for instance in toxemia of pregnancy. In cases with toxemia and postmaturity, blood flow of intervillous space may drastically decrease, resulting in placental ischemia, exhaustion of placental reserve capacity, and fetal growth retardation. 186 Clinical symptoms and aspects of postterm pregnancy and postmaturity

Placental insufficiency leading to the postmaturity syndrome (Table IV) has to be considered as an imbalance between placental capacity and fetal nutritive and respiratory demands. Acute and extensive placental

29

66

50 42

(%)

disturbances can cause fetal death due to anoxia, whereas chronic and less oronounced moroholo~tic • • u and functional restrictions may lead to chronic hypoxia and to fetal malnutrition, i.e., fetal postmaturity (dysmaturity). In acute placental insufficiency fetal size is normal, but in subacute, or more so in chronic placental insufficiency, retarded fetal growth is observed as well as a certain degree of hypoxia. 99 The postmaturity syndrome (placental dysfunction syndrome) is clinically recognized in the fetus by the following symptoms: failure of growth (intrauterine inanition), dehydration, development of dry, cracked, wrinkled, and parchment-like skin (reduction of subcutaneous fat depots), long thin arms and legs, advanced hardness of the skull, absence of vernix caseosa and lanugo hair (full scalp hair), skin maceration (flexion folds, external genital area), brownish-green or yellowish discoloration of skin. umbilical cord, and membranes. 175 In the absence of vernix the fetal skin loses its protection, the normal red skin color disappears, and skin maceration develops. 44 In postmature infants the body length is increased in relation to weight; such newborn infants are alert and look almost apprehensive.44· 77 Fetal dysmaturity may be clinically recognized in the gravida by loss in body weight and decrease in abdominal circumference and uterine size. 134 Three different stages of the fetal postmaturity syndrome have been described 44 : Stage I (chronic placental insufficiency): Skin defects; malnutrition; alert, apprehensive look; absence of meconium staining. Prognosis: Normal course after delivery; in one out of three infants slight respiratory distress but no death. Stage II (acute placental insufficiency): Skin defect; malnutrition; alert, apprehensive look; green meconium staining of skin, placental membranes, and umbilical cord. Prognosis: In two out of three infants respiratory distress at birth (aspiration of meconium-filled amniotic fluid, 50 per

Volume 1:.n l'\umber I

Placental insufficiency

77

XIL Analyses of umbilical cord blood and newborn infants' urine for retrospective evaluation of fetoplacental function: pathologic processes in fetoplacental function of postmaturity*

Tabl~

Blood and urine analyses

A.

1 Norma/neonates 1 Postmatureneonates 1

Umbilical cord blood: 1. Oxygen saturation

a. Arterial (%) b. Venous(%) 2. Hemoglobin content (Gm. per 100 mi.)

36 61 16.4

3. Pentose concentration (mg. per 100 mi.) 4. Protein-bound hexose level (mg. per 100 mi.) 5. Bilirubin value (mg. per 100 mi.)

4.8

6. Non-protein-bound nitrogen content (mg. per iOO mi.) B. Urine: l. Albumin excretion(%)

2. Glucose excretion(%)

127 1.5

Increased erythropoiesis in response to placental insufficiency and fetal hypoxia and/or fetal hypovolemia with hemo-concentration Increased values in response to placental ischemia

6.5 !50

Increased values in response to placental isch•~mia and placental tissue destruction Increased values in resoonse to enhanced erythrocyte formation and concotilitantly augmented tu~nover. of hemoglobin pigments-insufficient fetal liver function due to hypoxia Increased values in response to either placental insuf~ ficiency and/or placental tissue destruction

2.3

34

24

47

1.4

Decreased oxygen saturation in response to placental insufficiency

29 54 17

29

Comments

Increased incidence of proteinuria in response to impaired renal function (renal hypoxia) Increased incidence of glycosuria in response to impaired renal and/or pancreatic function----diabetes-like clinical picture

7.8

*The data presented are derived from Sjostedt and co-workers. 181

cent mortality rate); one out of three infants has brain damage and the over-all mortality rate is 35 per cent. Stage Ill (subacute placental insufficiency): State after survival of Stage II; bright yellow staining of skin and nails (conversion of the green bile stain of meconium); yellowishgreenish-brownish staining of placental membranes, umbilical cord, and placenta. Prognosis: Mortality rate is 15 per cent, mainly due to respiratory distress and brain damage.

Biochemical alterations In fetal postterm-postmaturlty Human fetuses and placentas cease to grow around 42 to 43 weeks of gestation (Fig. 1), only growth of hair and nails continues 73 • 77 • 94 ; thereafter fetal and placental weight ievei off or may even decrease, indicating insufficient placental function. Fetal adrenal hypopiasia with greatiy reduced umbiiicai arterial corticosteroid levels has been observed with prolonged gestationH'3· 164 ; aiso ieveis of fetal hemogiobin (Hb) are decreased. Oxygen saturation of umbilical venous cord blood in uncomplicated pregnancy is about 60 per cent of that of maternal arterial blood. This maternofetal oxygen difference can be explained mainly by placen-

tal oxygen consumption and by uneven perfusion of the two sides of the placenta, i.e., functional shunting away of maternal and fetal blood 78 (Fig. 5). The fetus responds to this challenge of "Mount Everest environment'' by developing polycythemia for increased placental 0 2 uptake; the 20 per cent higher affinity of 0 2 to fetal Hb than to maternal Hb is of additional support for fetal oxygenation. 10 Under normal conditions the fetal organs are well supplied with 0 2 and no fetal hypocapnia, i.e., no decrease in Pco 2 , exists; this is in contrast to individuals exposed to high altitude in whom hyperventilation leads to respiratory alkalosis (hypocapnia). Because in the fetal blood slight hypercapnia is observed, it is not correct to apply the term Mount Everest environment to intrauterine life. 12 The fetal oxygen need amounts to 20 rnl. of 0 2 per minute at term and a minimal 0 2 saturation of about 40 per cent (Po 2 , 18 mm. Hg) of umbilical venous biood is required. 186 When oxygen saturation of fetal Hb drops below 40 per cent, placental 0 2 diffusion must increase for compensation. In the condition of chronic fetal hypoxia, placental diffusion-reserve capacity may become operative, increasing 0 2 diffusion by 50 per cent 186 ; placental diffusion reserve depends on viiious surface area, i.e., number of functioning vasculosyncytial membranes, as well as on uteroplacental and fetoplacental blood flow (Fig. 5). Intervillous

78

Vorherr

Septt'illht·l ! . 1qJ.~,

A111.

J

{)hsfcr. CnJt'{1J/.

Ultrone Artt!)l

o2 on

0

In volfo 20 2 P0 on mM. Hq : 9S 2

co2 in YOifo

olt.

12

P0 in mm. Hg 2

co2

4S

on vol"

41

PC0 on mm. Hg 2

PC0 on mm Hg 40 2

26

40

Placenta Uterus Umbiht.~l~rt~ Ute~

o2 on YOifo

IS P0 in mm. Hq : 40 2

co 2 on volfo :

SO

PC0 on mm. Hg 2

0 In Volfo S 2 P0 In mm. Hg : 16 2

co 2 on vol" •

48 PC0 on mm. Hg SO 2

46

Fig. 5. Uteroplacental-fetal circulation, blood gas content, and arteriovenous shunting pathways. Near term, uteroplacental blood flow amounts to 500 to 700 mi. per minute, intervillous blood flow to 400 to 500 mi. per minute, and fetoplacental circulation to 300 to 400 mi. per minute; the oxygen saturation of venous umbilical cord blood is 60 per cent, and that of arterial cord blood is about 40 per cent. It is thought that about 50 per cent of arterial blood does not participate in intervillous 0 2-C0 2 exchange because it is shunted ~nvay with half on the maternal and half on the fetal side. 186 _.A. 40 per cent oxygen saturation of venous umbilical cord blood is the minimum required for adequate fetal oxygenation; the fetus needs approximately 20 mi. of 0 2 per minute. When placental aging and degeneration lead to placental insufficiency and inadequate fetal oxygenation, a compensatory placental diffusion capacity for 0 2 and for uptake of nutrients becomes operative by diminution of blood shunting on maternal and fetal side. Such shunt-reversal may provide a 50 per cent reserve capacity to cover feral needs. 186 When maternal myometrial-decidual and fetal chorionic plate-villous stem shunt-reversal mechanisms are not adequately functioning, in the absence of major placental lesions, fetal hypoxia and growth retardation may occur. During normal labor fetal scalp blood P0 2 is about 20 mm. Hg. Pco 2 values range from 40 to 70 mm. Hg, and pH levels are between 7.40 and 7.20. Symbols: M = myometrium; D =decidua; IVS =intervillous space; TV= terminal villi; SV = stem villi; CP = chorionic plate.

blood flow amounts to about 400 to 500 mi. per minute and a 50 per cent drop may cause fetal asphyxia. In situations of uterine hyperactivity, producing frequent myometrial contractions of 60 to 80 mm. Hg, intervillous blood volume may increase two- to threefold due to obstruction of venous backftow; thus a hypokinetic fetal hypoxia (stagnation hypoxia) may develop. Fetoplacental blood flow (normal term value: 300 to 400 mi. per minute) is equally important for compensatory purposes, the critical limit for fetal survival being about 150 mi. per minute. In order to profit from a high 0 2 concentration gradient, fetal blood is aimed at achieving a relatively high oxygen saturation with a relatively low Po2 • The higher the Po2 concentration gradient from maternal intervillous space blood to fetal villous blood, the more 0 2 is freed for placental uptake. 186 After the fortieth week of pregnancy, placental oxygen uptake diminishes and a critical reduction of fetal

oxygen supply may occur after the forty-third gestational week. 51 • 72 ' 73 ' 125 • 175 • 179 Accordingly, the oxygen content of umbilical venous blood was measured to be 12 volumes per cent in term pregnancies and less than 8 volumes per cent in postterm gestations of 43 weeks. 179 Because the arteriovenous oxygen difference on the fetal side amounts to 6 to 7 volumes per cent (Fig. 5), at the forty-third week the fetus receives just enough oxygen for its own need in a resting stage and returns little if any 0 2 to the placenta, i.e., in the fetal system virtually all oxygen is removed from hemoglobin as a mechanism of compensation. 162 In another study,' 22 an approximately 50 per cent fall of oxygen reserve in postterm fetuses was observed (see Table XIII).Whereas no difference in oxygen saturation of umbilical cord blood was noticeable in term gravidas with uncompiicated and complicated deliveries (cesarean section, forceps, spontaneous vaginal delivery of distressed fetuses), cord blood oxygenation was de-

Volume

Placental insufficiency

1~'1

79

:--lumber I

Table XIII. Oxygen reserve in term and postterm fetuses Umbilical artery blood

Umbilical vein blood

0 2 content (vol. %)

Phase of gestation

I

15 13

Term Post term (42 and 43 weeks)

0 2 saturation

0 2 content

(%)

(val. %)

64 54

5

I

7

0 2 1aturatinn (%)

31 20

Table XIV. Cord blood oxygenation in term and postterm fetuses Oxygen saturation of umbilical cord blood Complicated deliverie1

Uncomplicated deliveries Phase of gestation

I

Umbilical artery(%)

Term Post term

Umbilical vein(%)

Umbilical artery (%)

62.6 62.1

32.9 23.1

3!.6 32.1

I

Umbilical ''Pin ( %)

56.'i 50.7

-------------------------------------------------------------------------------------------·-----Table XV. Measurement of blood gases, hematocrit, pH, base deficit, lactate, and glucose during labor, at delivery, and 1 hour post partum* At delivery First stage of labor Parameters

Po2 (mm. Hg.) 0 2 saturation (%) Hematocrit (%) pH n~~

.L\..-'.12

(mm. Hg) Base deficit (mE.Q/

Term gravidas

I

Postterm gravidas

J

Second stage of labor Term gravidas

I

Postterm gravidas

Term gravidas Umbilical vem

24

25

22

25

30

51

43

37

39

so

54

.52

55

..,.,7.29 ,

44

7.33 A I '"H

4.8

7.33 ACI

"'"

4.3

6.6

7.31

5.0

I

Umbilical artery

Umbilical vem

Postterm graviclas

73

60

26

97

83

54

57

56

56

.58

7.20 55

QA .:JJ

60

27

55

7.30

I

74

29

ACI

Term gravidas

18

17

.."

I

Umbilical artery

H~ur

postpartum

Postterm gravidas

7.31

7.21 !:::.l"l

""

6.7

9.3

6.9

9.0

3.4

3.7

2.9

3.7

7.33 <)(\

.-J::J

!"'>.6

7.29 QO

JO

6.1

L.)

Lactate (mmole/ L.)

Glucose (mg. per lOOm!.)

66

61

69

71

92

65

88

65

80

74

*The data presented are derived from Paterson and co-workers. 141

creased in postterm gravidas with complicated deliveries151 (see Table XIV). In a more recent study no differences in blood gases, pH, glucose, base deficit, and lactate were observed between fetuses of 18 term and 18 postterm gravidas; hematocrit values were slightly increased in postterm fetuses 141 (Table XV). Because measurement of oxygen content and pH in fetal cord blood upon cesarean section and vaginal delivery and in fetal scalp blood

before the onset of labor and after labor and delivery showed no difference between term and postterm fetuses, 9 • 57 • 128 · 147 it was concluded that in postmaturity no fetal hypoxia exists. 147 Admittedly, in 60 to 80 per cent of postterm gravidas no fetal hypoxia exists, and birth of a fetus lacking signs of postmaturity indicates that intrauterine respiratory and nutritive placental functions were adequate. Prystowsky's 147 conclusion. however, that in postmaturity fetal hypoxia does not

80

Vorherr

September I. I q7.-, Am.J. Obsrl't. (;lll<"ttd.

I

HYPOXIA

FETAL

ANAEROBIC GLYCOLYSIS, EXHAUSTION OF CARBOHYDRATE RESERVES- FETAL METABOLIC ACIDOSIS

ll

~:cH~:~~~o~F o:~:~:_sR~~~ ::~;:A~Y~ ~ FETAL CIRCULATORY COLLAPSE

I

IHEMOCONCENTRATI ON, HYPERKALEMI AI

~ FETAL

.----ORGAN LESIONS-HEART FAILURE-INTRAUTERINE DEATH (Shock) ICNS, cardiOYascular system, lung, liver)

Fig. 6.

occur is in contradiction to the experience of many other investigators. Moreover, failure to demonstrate correlation between oxygen content of fetal blood and prolonged gestation does not eliminate the possibility of fetal hypoxia because a single analysis of blood does not reflect over-all fetal oxygenation. Furthermore, it is well recognized that placental oxygen reserves may become further compromised due to the stress of labor leading to clinically overt placental insufficiency and fetal hypoxia. This is proved by meconium staining of amniotic fluid, irregularities in fetal heart rate pattern, and decrease in pH of fetal scalp blood. It is conceivable, therefore, that such fetuses suffer from hypoxia and their cord blood oxygen saturation is likely to be decreased. 14 • 130 • 153 • 179 Signs of hypoxia (petechiae of pleura and myocardium, amniotic debris in lungs) and of malnutrition (decrease in fat depots and organ weights) have also been found in stiilborn postterm fetuses. 6 In some postterm fetuses no placentofetal oxygen reserve exists and death ensues because these fetuses cannot withstand the stress of labor. 179 Low umbiiicai vein oxygen contelli may be partly compensated by Hb levels reaching up to 20.5 Gm. per cent for increased 0 2 uptake from the intervillous space; an

average increase in Hb levels of postterm-postmature fetuses of 1 Gm. per cent has been observed. 122 • 161 But in postterm placental insufficiency 0 2 uptake is limited and the saturation of fetal Hb remains inadequate. Whereas oxygen saturation of umbilical venous blood was between 40 to 60 per cent at term, in postterm gravidas of 43 weeks the values dropped to 15 to 25 per cent. 179 It appears that predominantly in older postterm primigravidas and postterm multigravidas with previous complicated pregnancies (abortion, stillbirth, pre-eclampsia, diabetes mellitus, dystocia, neonatal death) fetal hypoxia is likely to occur. 180 Continued loss of placental capacity will reach a point where reduction in oxygen concentration of umbilical vein blood becomes critical for the fetus; a drop of oxygen saturation below l 0 per cent (vital limit) cannot be compensated. 186 With exhaustion of piacentai reserve capacity the fetus cannot grow because brain, heart, liver, and kidneys are incapable of functioning adequately; here fetal asphyxia and death are imminent (Fig. 6). Nevertheless, fetal resistance toward hypoxia is astounding; in cases with sudden maternal death, fetal survival of up to 30 minutes has been observed. Low metabolic brain acti-

Volume 1:!3 Number I

vity (low 0 2 consumption), cardiovascular adaptation (increase in minute volume, peripheral vasoconstriction), acidosis (increased release of 0 2 from Hb), and anaerobic glycolysis protect the fetus to a certain degree from asphyxia. According to several authors, 5 • 120 • 148 156 179 maternal inhalation of 100 per cent 0 2 can • • increase oxygen content of fetal umbilical venous blood by approximately 30 per cent in cases with vaginal delivery and by about 77 per cent with cesarean section. Oliver and co-workers, 139 however, failed to observe a beneficial effect of maternal oxygen breathing on the fetus.

Factors Influencing duration of gestation and postterm-postmaturity Duration of gestation and thus the syndrome of postmaturity may depend on the mother's age and parity (longer duration of pregnancy with increasing age and parity) and on genetic factors (individual variation in time of gestation due to genetic parental influences); prolonged gestation has also been attributed to a higher standa~d of living allowing the gravida to lie down and rest more often. 44 On the other hand, a slight increase in incidence of postterm gestation has been reported for gravidas with a low socioeconomic status. 190 In gravidas with first trimester bleeding, prolongation of gestation was observed more frequently 19 ; perhaps delayed ovulation and ovum implantation as well as retarded fetoplacental growth may play a role. In one study, prolongation of gestation was not related to parity but to gravidity, with a greater incidence in primigravidas. 57 Especially with advancing maternal age, the chances for postterm gestation are higher for primigravidas than for multiparas. 45 In another report, however, no difference of duration of gestation was found between primigravidas and multiparas84; moreover, increasing maternal age was correlated by others with a decreasing incidence of postterm pregnancies 19 but with increase in perinatal mortality. 114 Several groups of investigators reported that prolongation of gestation is associated neither with age nor with parity or race of the gravida45 • 114 • 125 • 126 • 167 and only in primigravidas older than 35 years was a greater tendency for postterm pregnancy described. 167 Again, this was contradicted by data of Mead and Marcus, 129 who reported a greater incidence of postterm pregnancies in primigravidas and multiparas of age 21 to 25 years (see Table XVI). (Note: In contrast to other iiterature data, Mead and Marcus 129 found that with advancing fertile age incidence of postterm pregnancies is higher in multiparas than in primigravidas.)

Placental insuffici£mcy

81

Table XVI. Postterm pregnancies Incidence of postterm pregnancies in various agtJ groups

>35 Postierm gravidw. Multigravidas Primigravidas

6.7 21.5

31.1 44.0

30.1 18.1

17.1 13.3

15.0 3.9

Although postterm gestation appears to be equally frequent in multigravidas as in primigravidas, its incidence is lower in the former and higher in dte latter with advancing age. 190 Multigravidas with a history of obstetric complications account for about 35 per cent of postterm pregnancies. 190 Postterm pregnancy has been observed most often in older primigravidas (sixfold higher than in multiparas) as well as in cases of fetal malpresentation (occiput posterior, mainly), fetal malposition, rhesus erythroblastosis. and ceph~tlopelvic disproportion. 25 • 44 • 165 Incidence of normal and abnormal fetal position and presentation was the same in all primigravidas and multiparas. 84 Also congenital malformations (anencephaly, hydrocephaly osteogenesis imperfecta, various other malformations) are correlated with increased incidence of fetal postmaturity44 (Table V). A racial factor appears to be involved, too, as the average duration of gestation of United States blacks is 3 to 4 days shorter than that of whites. 82 Also wnstitutional factors evidenced by recurrent posttenn pregnancies in certain women have an effect 57 ; a woman who carried one pregnancy beyond term has .1 50 per cent chance for another postterm pregnancy.~ 6 Furthermore, genotype and sex of the fetus, delay tlf ovulation and implantation, as well as fetal hormonal (corticosteroids) and growth factors (uterine distention) influence the duration of gestation. 77 · 83 • 175 Because on the average term male fetuses weigh 150 Gm. more and their placentas 30 Gm. more than female: ones, a shorter duration of gestation for males (0.5 to 2 days) seems logical considering increased uterine d,tstention and myometrial irritability mainly responsible for onset of labor 64 • 69 • 82 • w1 • 117 • 124 • 175 Shorter duration of gestation of male fetuses, however, is not confirmed by the report that postterm gravidas carrv on the average 5 per cent more male fetuses than female one;,;. 101 Also in maie fetuses the iimit of piacentai support capability may be reached at an earlier gestational age, thus shortening the duration of gestation 82 ; this 5eems in contrast with the findings that in postterm pregnancy male fetuses are also on the average 200 Gm. heavier

82 Vorherr

than female ones. Moreover, it has been reported that male fetuses are carried longer than female ones, leading to an increasing percentage of male deliveries as gestation proceeds beyond term; for male calves gestation is also prolonged. 83 Albeit duration of gestation between female and male fetuses may differ by a few days, if any, sex of the fetus most likely plays no significant role in regard to prolongation of gestation. 114 • 167 It has been suggested that hypothyroid gravidas display a tendency for prolongation of gestation; to what extent fetal thyroid function plays a role in the duration of gestation is not clear. 36 In hypothyroid cows gestation was remarkably prolonged with delivery of overweight calves. 36 It is not clear to what extent environmental conditions such as nutrition and season of year influence the duration of human gestation; in mares and ewes good nutrition leads to a shorter gestation, and in mares and cows pregnancy is slightly prolonged when parturition occurs in spring. 83 It should be noted that in many of the abovedescribed conditions related to postterm pregnancies, asymptomatic placental insufficiency and fetal distress may exist.

Postterm placental pathophysiology Changes of placental biochemistry. Although clinically well defined, the biochemical nature of postterm placental insufficiency (placental dysfunction), i.e., abnormalities occurring on the cellular level in connection with the various substances transferred from mother to fetus and conversely, is not understood. mIn placental insufficiency, placental protein and deoxyribonucleic acid content are below normal whereas the ribonucleic acid concentration is elevated 116 ; calcium transport appears unimpaired and placental passage of sodium, potassium, and glucose may be reduced. 70 • 108 In acute placental insufficiency (abruptio placentae), fetal 0 2 supply and lactic acid exchange may be abruptly reduced, causing fetal asphyxia; placental C0 2 exchange appears to be of secondary importance because C02 diffuses 20 times faster through the placenta than 0 2 . In subacute and chronic placental insufficiency, transport of substances with higher molecular weigln (amino acids, lipids, y-globulins) is usually impaired, causing intrauterine growth retardation. Changes of placental morphology. A placental weight of less than 500 Gm. is correlated with an increased incidence of fetal distress and perinatal death due to fetal hypoxia in connection with progressive increase of fetoplacental mass ratio. 87 Accordingly,

Am.

St'plembcJ l. l!l/.-J Obstcl. {.\rwrrrl

J.

a small placenta is always associated with a small bab), whereas the connection of a small baby with a normal weight placenta depends on whether placental function is adequate or not. 13 In postterm pregnancies three different types of gross upon been described have placentas examination 173 : (1) Normal size placentas of 550 to 600 Gm. weight with well-formed cotyledons, few white infarcts, rarely hemorrhagic infarcts; in this group healthy infants of 3,500 to 3,800 Gm. weight were born. (2) Large, thick, pale-red placentas of 800 to I ,000 Gm. weight with dispersed white infarcts, edematous and atrophic cotyledons; in this group infants of 4,000 to 5,000 Gm. weight were born with reduced viability. (3) Small degenerative placentas of 175 to 500 Gm. weight with numerous white infarcts, thin and atrophic cotyledons, vascular degeneration of villi; in this group infants of 1,600 to 2,400 Gm. weight were born with greatly reduced viability. Usually no significant reduction of placental weight can be documented in postterm pregnancies because loss of functional placental tissues and water is compensated for by deposition of calcium and fibrinoid, 93 • 94 nor does a correlation between severity of placental lesions and placental weight exist. 98 By application of histologic techniques, a reduction of functional placental tissues has been observed in cases of fetal postmaturity. Whereas a normal villous surface area (ll to 14 M. 2 ) or even an increased one (14 to 15 M. 2 ) was found in uncomplicated postterm pregnancies with large infants, in situations of fetal postmaturity it was reduced to 6 to 9 M??· 40 Whenever fetal distress was diagnosed during labor, a decreased villous surface area of 8 M. 2 was present, explaining reduced placental respiratory function and fetal hypoxia. 41 Although in cases of fetal postmaturity an increased villous surface area of 22 M. 2 was measured on the average (normal term placentas, 13 M. 2 ), it has been suggested that such compensatory villi are functionally inadequate due to avascularity and conglutination, i.e., despite increase in villous surface area the functional deficit remains. 66 In live births from pregnancies of 296 days or more, over 40 per cent showed gross placental abnormalities; in 90 per cent of cases with fetal postmaturity and intrauterine fetal death, gross placental abnormalities existed, and in 85 per cent the placenta \Vas meconium stained. 44 However, the extent of placental lesions in cases vvith postterm fetal dysmaturity (dystrophy) is often not sufficient to explain fetal distress and symptoms of postmaturity. 158 Also the placentofetal units possess a reserve capacity (Fig. 5) for situations of emergency (abruptio placentae), where a loss of up to

Volume 1~:1 Numhn I

Placental insufficiency 83

Table XVII. Morphology of postterm human placentas* Compo'Y'.Rnts

l. Placenta

2. Intervillous space 3. Villi a. Syncytium b. Syncytial knots c. Vessels of stem and anchoring viiii d. Vessels of resorptive villi

Early postterm placentas (up to 43 weeks of gestation)

Late postterm placentas (beyond 43 toeeks of. gestation)

Increased placental thickness and blood-full- Decrease in placental thickness and blood-fullness; pronounced increase in foci ~jf infarcness; rr1oderate increase in incidence of intion, fibrin deposition and calcification farction, fibrin deposition and calcification Similar intervillous space volume as in term Diminution of intervillous space volume due to intervillous thrombosis and fibrin deposition pregnancies Overdifferentiation, i.e., diffuse hemangioma- Absence of villous regenerative effort:;; stromal edema; hypovascularity. avascularity; villous like capillarization; increase in regenerative fibrosis and shrinkage efforts; hyperplasia of cytotrophoblastic cells Decreased syncytial sprouting; membrane Syncytial edema; increased syncytial thickening, vacuolization and degeneratio11 thickening Greatly increased knot formation Increased knot formation Moderate arterial narrowing and venous di- Arterial thrombosis; vascular hyalinization and obliteration lation Reduction in sinusoidal villous capillaries, vasSinusoidal dilation and blood-fullness cular collapse, followed by processes of vascular degei:teration . -

*The data presented are derived from Stark and Kaufmann. 166

30 per cent of functional surface area may be compensated and tolerated by the fetus. 186 Senescent placental lesions. Postterm placental insufficiency is correlated with placental lesions (Tables II and XVII), and meconium staining of fetal skin and membranes; increased placental calcification has been held responsible for a two- to fourfold increase in fetal distress and intrauterine fetal death. 116 Postterm degenerative placental calcium deposition may increase to up to I 0 Gm. of calcium per I 00 Gm. of dry tissue, the normal term values being on the average 2.3 Gm. of calcium per 100 Gm. dry placental tissue. 53 Placental calcium deposition occurs in the same form (apatite structure) as in bone, and the degree of placental calcification bears close relationship to maternal serum calcium levels (dietary calcium intake, vitamin D intake, exposure to ultraviolet light). Placental calcium has been regarded as storage for the placental "calcium pump"; increased calcium deposition with placental aging has been considered as the end stage of a maternofetal immunologic interaction. 24 Increased placental calcium deposition has been correlated with progressing villous degeneration 167 ; however, some villi may degenerate without being calcified. 125 Whereas some authors have related a postterm increase in foci of placental calcification to placental insufficiency and placental regression toward a hypoplastic organ, others have denied enhanced placental calcification of postmature placentas; some investigators have aiso feit that heavy placental calcification exerts little influence upon fetal well-being. 24 In connection with postterm placental aging, vasculusyncytial membranes become thickened (5 to 10 J.t thickness) and their number decreases (normal values at term. 30 per

cent); such alterations may impair placental transport and exchange mechanisms. 116 As a response to decreased placental function with progressing placental age. the villous capillaries become dilated forming sinusoids which attach to the vasculosyncytial membrane providing a better placental transport and exchange. In response to hypoxia of trophoblastJC tissue, reactive proliferation of cytotrophoblastic Langhans' cells and of villous stem vessels is observed; if local hypoxia persists, loss in functional placental tissue occurs. 166 Degenerative placental tissue processes (edema, fibrinoid deposition, fibrosis, int<~rvillous thrombosis, focal villous infarction 20) vary greatly individually and it is believed that there are no specific gross and histologic placental changes which ue indicative of insufficient placental function." 3 · 73 Although no specific morphologic basis for explanation of decline of placental function post term exists, a typical pattern of histologic abnormalities can be traced. Recently. by phase contrast microscopy. a significant correlation was revealed between incidence and severity of placental insufficiency and placental lesions (villous stromal edema, intravillous hemorrhagi< infarcts and fibrin deposition, avascular villi, syncytial hypoplasia and hyperplasia); syncytial hyperplasia is considered an adaptive reaction to a reduced maternofetai metabolic exchange. 98 Histologic examination of postterm placentas showed the foiiowings,1 . 173 : 1 i) thickened vasculosyncytial membranes or thin, partly lost syncytium. proliferation of cytotrophoblastic 1 ells. vacuolization of syncytial cells, excess f()[mation 1 > 30 per cent) or syncytial knots; (2) degeneration of villi (villous fibrosis) containing edematous stroma (large placentas) or dense-hardened stroma (small placentas);

84

-.;eptcmht·J l.

Vorherr

Table XVIII. Placental infarcts and syncytial sprouts

I

I

1

1

Infarct tissue

per ~i}enta

Placentas r~orn1al

term gestation

Number of syncytial

sproutJe~~ ocular 00

AAO

Postterm placental insufficiency and fetal postmaturity Intrauterine fetal death (toxemia)

v-v.o

.:;.o

0.1-1.9

4.0

15-29

2.5

Table XIX. Placental infarcts White necroses or infarcts with whiie necroses (%)

Normal term gestation Postterm placental insufficiency and fetal postmaturity

1~17.-~

Am . .J. Obstt·r (;,lit'< .,J.

12

9

3

66

20

46

(3) decreased number of villous capillaries, thrombosis of villous stem vessels, hyaline changes of vessel walls; (4) reduced size of intervillous space in 50 per cent of cases due to fibrin deposition; all these changes of postterm placentas were several-fold increased compared to term placentas. 63 Proliferation of syncytial nuclei, i.e., syncytial knot formation, is considered a sign of regressive villous changes caused by reduced fetal villous blood ftow.sz Whereas 25 per cent of postterm placentas displayed no histologic features to distinguish them from term placentas, 75 per cent of postterm placentas revealed either ischemic (proliferation of cytotrophoblastic cells, thickening of trophoblastic basement membrane) or senescent changes (villous hypovascularity or avascularity, excess syncytial knots or both). 63 Accordingly, thorough histologic examination of the placenta allows recognition of prolonged gestation. 56 Also placental biopsies performed during gestation revealed that piacentai aging is connected with villous lesions such as vacuoiization, avascuiarity, syncytial hyperplasia, and subsyncytial edema. 4 Posrterm piaceniai infarcts. Whereas in toxemia of pregnancy placental white infarcts, i.e., fibrin deposition as a terminal process after hemorrhagic infarction, are more extensive and diffuse, in postmaturity white infarcts are less numerous and more circumscribed. 158 In cases with postterm placental insufficiency and signs of fetal postmaturity a slight increase of villous fibrosis

and white placental infarct tissue as a manifestation ol diffuse placental processes was reported 109 (see Table XVIII). When placental infarcts were registered, regardless of their extent, 66 per cent of placentas of gravidas with postterm placental insufficiency contained infarct tissue 159 (see Table XIX). Infarcts are most commonly observed at the placental margin and they are mostly due to disturbed maternal uteroplacental circulation with spasm, stenosis, and occlusion of decidual blood vessels. In the process of infarction, first closely packed villi are surrounded by maternal blood; then villous necrosis, lysis of maternal blood, and infiltration of leukocytes follow; no clear role of placental infarcts in relation to fetal dysmaturity can be seen. 22 Etiology of postterm placental senescence and trophoblastic tissue degeneration. Senescent placental lesions are thought to be due to disturbance of somatic maturation and development of maternofetal immune mechanisms 63 ; also, under the conditions of hypoxia and acidosis, lysis of trophoblastic tissues by maternal blood and through activation of intracellular trophoblastic lysosomal enzymes may occur. Ischemia of postterm placentas is believed to be the consequence of villous hypoxia due to decreased function of villous capillaries whereby villous pulsation is reduced, followed by stagnation of maternal blood in the intervillous space and thus reduction of intervillous minute volume. 107 Villous ischemia observed in postterm placentas is usually not attributed to abnormalities of decidual spiral arteries. 63 Of 50 postterm placentas with ischemic and senescent changes, fetal or neonatal asphyxia was diagnosed in 30 per cent and postmaturity was present in 4 infants. 63 All in all it appears that histologic abnormalities observed in postterm placentas are due to changes in vascular placental system and fetal villous circulation (overdifferentiation followed by regressive vascular processes) and to a lesser extent to primary maternal circulatory disturbances of the intervillous space. Although extent of placental lesions is related to advancement of pregnancy post term, such lesions have not been attributed to intrinsic postterm placental changes per se. 56 • 63 This view has been contested recently by suggestions that intrinsic placental t:hanges (lesions) may be due to decreased trophoblastic immunosurveillance in connection with increased fibrinoid deposition. 37 Increased fibrinoid deposition in postterm placentas has been explained as a reaction to insufficient function of the fetoplacental immune system. 37 Intravillous fibrinoid has been found very closely related to or identical with amyloid (glyco-

Volume 1:!:> Number I

protein related toy-globulins) which is always increased when immunologic tolerance exists as in early gestation. As pregnancy advances toward term, trophoblastic cells may be immunologically active similar to plasma cells and reticuloendothelial cells by destroying abnormal placental cells derived from misspecification.37 Impaired immunosurveillance, i.e., tolerance to misspecified (degenerated) placental cells may be accompanied by trophoblastic lesions and progressive accumulation of amyloid (fibrinoid). Increased fibrinoid deposition may be a cause for prolongation of gestation by acting as an immunologic barrier which separates placenta and fetus from maternal immunologic interaction and in contrast to normal conditions, labor will not set in . Changes of placentofetal hormone metabolism. Postterm placental insufficiency is correlated not only with increased placental lesions and decreased nutritive and respiratory function but also with diminished hormone production (HCG, HPL, estriol) and low Apgar scores of the neonates. At present, estriol measurements in blood and urine reflect best fetoplacental function. Plasma and urinary estriol concentrations rise progressively up to 38 to 40 weeks of gestation. Thereafter estriol values level off and from the fortysecond week on they fall slightly and steadily/6 • 59 • 99 indicating a functional decline of the fetoplacental unit post term with increased fetal risk of hypoxia and acidosis. In postterm gravidas with low urinary estriol excretion ( < 12 to 14.5 mg. per 24 hours), the incidence of fetal distress was 29 to 33 per cent whereas in postterm patients with normal estriol values, fetal distress occurred only in I 3 to 15 per cent. 16 • 99 In conclusion, it appears that postterm placental insufficiency and fetal postmaturity are mainly due to primary placental lesions and/or placental dysfunction; in rarer instances postterm placental insufficiency is secondary to maternal and fetal factors (Table II). Accordingly, primary placental insufficiency and postmaturity syndrome are to be distinguished from preterm (secondary) placental insufficiency frequently observed in patients with toxemia and diabetes mellitus. Severity of placental lesions corresponds inversely to fetal weights; in one report, however, this is not confirmed .98 Aithough pathologit: placental lesions (Table II) are associated with a 10 times greater perinatal mortality rates, 4 it seems that placental insufficiency and fetal distress may also be due to placental dysfunction on a biochemical level without noticeable placental lesions. When placental insufficiency has caused secondary fetal death. a tissue demarcation line along the

Placental insufficie-ncy

85

Fig. 7. Tissue demarcation zones in nonplacental and placental fetal death . A, In case of nonplacental sudden (primary) fetal death (umbilical cord knotting) the placenta temporarily continues to live and the tissue demarcation zone runs aiong the chorionic plate. B, In case of insufficient placental function causing (secondary) fetal death the tissue demarcation zone runs along the decidual-trophoblastic border.

decidual-trophoblastic border is established, whereas, when the cause of fetal death is non placental, th·.~ tissue demarcation line runs along the chorionic plate. 15 Accordingly, in primary acute fetal death (umbilical cord knotting, Fig. 7) when the maternal circulation remains intact, the placenta will not become necrotic but may continue to produce enzymes and hormones for some time. albeit to a diminished and unbalanced degree. 83 • 189 Whereas tissue demarcation zonf's indicate whether primary or secondary fetal death has occurred, leukocytic infiltration of the umbiiicai cord vessels (umbilical vein mainly) is observed in cases with fetal distress and h ypoxia due to hindrance of the umbilical circulation.50 Also in cases with chorioamniotic and fetal infection, polymorphonuclear let•kocyte infiltration of the wall of the umbilical Yein has been described. 20

Diagnosis of postterm placental tnsufltctency and fetal postmaturity Present diagnosiic methods (Table Ill) do not permit reliable diagnosis of early placental insufficiency. i.e., decline in felal arterial and venous oxygen 'iaturation , increase in erythrocyte and Hb concentration of fetal blood, as well as failure to transpon nutrients to the fetus and to exchange fetal carbondioxide and metabolic waste products adequately. Meconium staining of amniotic ftuid. Release of meconium into amniotic Auid by the fetus in vertex

86

-"eptc.:mbl·f I. 1~I/.~,

Vorherr Am.

Deceleration Acceleration

Deceleration

J.

Ob"o·t.

c, '"'" ,J,

Prolonged Deceieration (Serious Bradycardia!

(Type I Dip)

~ i :: Ll.-._.T_J. . . .,. . . . _

j

= TJ 120 "'"'

liicc ~

100

80

~

;;;: V>

~ ".. .2' _._ 'aE ·o; E E ~

"' E

c:

801

:J 20 10 0

r•

0

,

iiO

100 0

' 0

I

' iOO

iOO

0

Seconds

Fig. 8. Major types of fetal heart rate (FHR) patterns. Acceleration of FHR (tachycardia above 160 b. p.m.): sporadically observed, little diagnostic significance. Persistent tachycardia (160 to 170 b. p.m.) is occasionally observed in connection with placental insufficiency and fetal distress (intrauterine infection, maternal metabolic acidosis). Type I dip deceleration ofFHR (V-shaped bradycardia, 100 to 120 b.p.m.): observed rather frequently during the active phase of labor; little diagnostic significance. Type II dip deceleration of FHR (U-shaped [pathologic] bradycardia, 60 to 110 b. p.m.): sign of fetal hypoxia (augmentation of vagal tone) due to uterine hypertonicity, umbilical cord compression, placental insufficiency, increased fetal intracranial pressure. Significance: newborn infants are usually depressed (Apgar score of 6 or below). Prolonged deceleration (trough-shaped, serious bradvcardia. I 00 b. o.m. or below): sil!'n of severe olacental insufficiencv or cord comnression. .a For more details on mechanisms involved with FHR changes see Vorherr. 118 (From Vorherr: New York, 1974, Appleton-Century-Crofts.) 1

'

r

0

presentation is still a valid, albeit rather insensitive, indicator of piacentai insufficiency and fetai hypoxia. Meconium passage into amniotic fluid occurs when the oxygen saturation in the umbiiicai vein biood drops to 30 per cent, i.e., half of its normal value. Meconium passage is due to hypoxia of the smooth musculature of the gastrointestinal tract resulting in hyperperistalsis and relaxation of the anal sphincter. 27 When meconium release is noticed in postterm gravidas, the incidence and degree of acidosis measured in umbilical blood of the newborn infants is increased. 5 1 In a recent prospective study on 1,000 gravidas at risk, amnioscopy revealed that the presence of clear fluid before labor was associated with a perinatal mortality rate of0.4 per cent and a 5 per cent incidence of low Apgar score (<6 at 2 minutes); v.rhen, ho\vever, meconium \vas detected before labor, a perinatal mortality rate of 7.5 per cent and a 22 per cent incidence of lo\V . AJLpgar score occurred. Accordingly, a greenish floccular appearance of amniotic fluid meconium release is usually indicative of insufficient placental function and fetal

-

l

-

-

--;

-

-

---

.l-

-

hypoxia; after recent meconium stammg, a very low oxygen saturation of umbilical vein blood of 15 to 25 per cent was measured. 179 Fetal hypoxia was observed in 5 per cent of postterm gravidas," 7 and the amniotic fluid contained meconium in 7 per cent; in one out of three cases estriol values were low ( < 12 mg. per 24 hours) and in four out of five cases more or less pronounced placental insufficiency existed. 17 Due to the stress of labor meconium staining occurred in 22 per cent of postterm gravidas with clear amniotic fluid prior to labor. 17 Thick clumps of dark meconium indicate more severe fetal hypoxia than light greenishtinted amniotic fluid. 132 In the absence of acute fetal hypoxia, the fetal heart rate (FHR) pattern (Fig-. 8) is considered a more reliable indicator of fetal distress because meconium release is also observed under conditions of temporarily increased vagal tone (pressure on fetal head, umbilical cord compression). 86 Changes of amniotic fluid volume, constituents, and fetal urinary excretion. In postterm patients scanty forewaters may be observed by amnioscopy; in I 0 per

Placenta! insufficiency 87 Number I

amniouoon m::~v he- found O"r:.Jvirl::~s rFnt - .-----, - licmor --- no --- o--------- of

tofetal function. Among the many laboratory tests for

centesis; in two out of three such patients placental insufficiency exists. 17 The amniotic fluid volume (800 mi. at term, Fig. l) was reduced to 480 mi., 250 to 330 mi., and 160 mi. at weeks 42, 43, and 44 of gestation, respectively. 17 · 55 An amniotic fluid volume of less than 400 mi. indicates that the fetus is at risk. 134 Reduction of the volume of amniotic forewater is accompanied by a perinatal mortality rate of 2 per cent and a 10 per cent incidence of low Apgar score; therefore, labor should be induced in these patients as well as in those with meconium-containing amniotic fluid.U Maternal urinary estriol excretion, amniotic fluid sodium, chlorine, glucose, and osmolality diminish after 42 weeks of gestation. 26 · s1. 77 In contrast, potassium and creatinine contents in amniotic fluid remain constant and urea concentration increases. 26 · 142 Similar to amniotic fluid volume, fetal urine production increases as pregnancy advances. Measurements of fetal diuresis by ultrasonic technique show an hourly urinary excretion rate of I 0 mi. at 30 weeks increasing to 27 mi. at term; no increase in urine production is observed in postterm pregnancies. 184 At present, there is no evidence that estimating hourly fetal urine production rate can help to determine which fetuses are liable to develop perinatal asphyxia. Orange-staining amniotic fat cells, vaginal cytodiagnosis, and x-ray in relation to postterm gestation. In cases of prolonged gestation more than 50 per cent of orange-staining fat cells are observed in the amniotic fluid, whereas values for term pregnancy range between I 0 and 50 per cent. 77 The vaginal smear does not appear to be a good indicator for the diagnosis of prolonged gestation and placental insufficiency because cell types vary greatly, and progressive (shift to superficial cells) as well as regressive smear types (shift to intermediate and parabasal cells) have been reported. 138 · 142 Burger36 described the disappearance of intermediate cells and appearance of superficial and parabasal cells as typical for postterm pregnancies. Nevertheless, appearance of parabasal cells in the smear indicates placental insufficiency and fetal jeopardy due to postmaturityY· 71 The margin of error when estimating the fetal age by x-ray is 4 weeks or more, and diagnosis of posttermpostmaturity pregnancy by x-ray is not possible because all the epiphyseal bone nuclei are present; ossification centers have been found enlarged in postterm fetuses. 167 X-ray demonstration of placental foci of calcification has not proved useful for diagnostic purposes.44 Maternal 24 hour urinary estriol excretion and other serum hormone and enzyme tests for placen-

placental nutritive and respiratory function (Table III), estriol still plays a dominant role in the assessment of fetoplacental function, albeit great variations of single values are observed, missing more than l 0 to 50 per cent of endangered fetuses.25. zu. 110. 140. 144. 165. 182 A

---~

precipitate decrease of urinary estriol values by 60 per cent or more is usually indicative of placental insufficiency and fetal hypoxia. When maternal ~4 hour urinary estriol excretion is below 4 mg. or the urinary estrogen-creatinine ratio drops below 5. fetal death is imminent. 7· 48 • 87 In toxemia, diabetes rneUttus, or assumption of a supine position, glomerular fdtration rate and thus urinary excretion of estriol may be reduced; this can lead to wrong conclusions regarding fetal well-being. Therefore, urinary estriol-en ·atinine ratio is of greater importance for assessment of fetoplacental function than estriol values alone. 48 Urinary 24 hour estriol levels below 12 mg. indicate fetal danger, and about 30 per cent of patients with post mature fetuses excrete less than 12 mg. of estriol per 24 hours into the urine 77 ; fall in estriol values is due to impaired fetal adrenal and placental steroid metabolism. fn 20 to 22 per cent of postterm gravidas low urinarr estriol values ( < 12 to 16 mg. per 24 hours) were as~ociated with fetal distress in one third of cases, and two to four times more often in primigravidas than in multigravidas16· 119 ; in 15 per cent of postterm gravidas low urinary estriol values were not associated with fetal distress. 16 Low estriol values had been previow.ly measured in 60 per cent of gravidas with a diagnosis of placental insufficiency in connection with fetal distress based on weight and signs of postmaturity upon delivery; normal estriol values in these cases were asM>eiated with a 24 per cent fetal distress rate . 1 ~ Persistent low maternal urinary estriol excretion has also been correlated with a high incidence of neonatal morbidity and later neurologic and psychologic abnorrnalitie!. in five out of 14 cases. 181 So far. all the other placental hormone or enzyme tests (Table III) have f:tiled to fulfill the expectations because normal values scatter over a wide range. Values of heat-stabie aikaiine phosphatase and human placental lactogen (HPL) appear to correspond to estriol levels. 61 It still remain; to be confirmed whether estimates of serum oxytocinase activity are indeed superior to urinary estrogen excretion measurements for the diagnosis of placental insufficiency and intrauterine fetal growth retard.llion as reported recently. 144 Serum measurements c•f HPL have lately been considered as adjunct to other tests for placental insufticiency 29 ; however, no
88

Vorherr Am.

182 Not onlv do urinarv and serum levels of olacental ' hormones and enzymes scatter over a wide range, but it is also uncertain whether placental metabolic activity (hormone and enzyme production) can be directly related to placental respiratory and nutrient transport functions. 116 Fetal heart rate (FHR), fetal electrocardiogram (ECG), and fetal biparietal bone diameter (BPD) as diagnostic tools. FHR pattern and placentofetal stress tests. During the last decade continuous recording of FHR pattern has become an invaluable method for the observation of fetal well-being. The fetal cardioaccelerator system reacts quickly to circulate fetal blood sufficiently through the placenta for uptake of oxygen and nutrients from the intervillous space; the vagal tone continuously exerts a moderating effect on basal FHR. 178 The FHR pattern, as observed during labor, represents a collective response to uterine contractions and all the hemodynamic changes of the fetoplacental-maternal circulation, including the degree of fetal head compression caused by the forces oflabor. In 50 per cent of cases continuous monitoring of FHR allows prediction whether the fetus is in distress. Irregularities in FHR pattern (Fig. 8) usually appear in conditions of placental insufficiency when the fetus is already asphyctic. When the fetoplacental oxygen reserves are challenged through intravenous infusion of small oxytocin doses of 2 to 20 mU. per minute and elicitation of myometrial contractions, latent placental insufficiency may become overt and thus may be diagnosed. When through such an oxytocin challenge test (OCT) fetoplacental oxygen reserves are compromised to a certain degree, oxytocin-induced uterine contractions will further aggravate the condition and provoke pathologic FHR patterns such as persistent tachycardia, loss in beat-to-beat variation, variable deceleration, late or prolonged deceleration with or without compensatory tachycardia (Fig. 8). A positive OCT allows prediction of fetal distress with a 50 to 70 per cent validity. Other fetoplacental function tests in connection with FHR have also been applied. When a moderate maternal exercise test (step test, peddling in bed) shows persistent tachycardia or bradycardia (iate deceleration) followed by a compensatory tachycardia, compromised fetoplacental oxygen reserve and fetal distress may exist89 · 146 ; variable deceleration, especially when associated with compensatory tachycardia, is also an unfavorable sign. 172 Most gravidas with a positive exercise test will also show signs of fetal distress (meconium release, bradycardia) during labor. 146 Atropine sulfate or isoxsuprine, injected into the mother, ;

;

Septemb<'t I. l 1 l~_-, J Obstl't. (;\llt"t nl

cause, after a time lapse, tachycardia in the fetus: in cases with toxemia and fetal postmaturity, a delay in onset of fetal tachycardia but with increased intensity was observed. Drug-induced fetal tachycardia is not a precise enough test procedure to determine placental insufficiency satisfactorily and it does not correlate with other placentofetal function tests. Fetal ECG. Monitoring fetal ECG changes, i.e., the amplitude of R-waves as an indicator of placental insufficiency (R-waves exceeding 40 /.LV), could reduce the perinatal mortality rate due to postmaturity from 36 to 12 per cent. 32 Depression of the S-T segment and T -wave, as well as widening of the QRS complex of the fetal ECG, have also been described in fetal hypoxia 27 ; unfortunately the amplitude of the various fetal ECG waves is greatly influenced by extracardial action potentials.154 Duration of the QRS complex (ventricular depolarization) appears to be correlated with the size of the fetal heart, i.e., with fetal maturity. 154 In postterm pregnancies the conduction time (QRS interval) was found increased to 0.14 second (normal term values: 0.11 second) indicating aggravation of fetal heart work and disturbance in circulatory dynamics; arrhythmia with block formation also occurred. 154 In another study, however, no correlation between fetal ECG configuration changes, fetal bradycardia, and condition of the fetus could be established. 86 Despite favorable reports, at present, fetal electrocardiography is still of limited value for detection of fetal distress and asphyxia because of the vast individual differences in ECG patterns. 135 Fetal BPD. Measurement of fetal BPD has proved valuable for the diagnosis of postmaturity, i.e., in such fetuses BPD shows arrest of growth or even regression. whereas during normal fetal growth BPD increases on the average 1.6 mm. per week between weeks 31 and 37 and 0.7 to I mm. between weeks 38 and 41. 174 Serial BPD values showing an increase of less than 0.45 mm. per week indicate fetal dysmaturity; thus with serial BPD measurements, fetal dysmaturity could be predicted in 90 per cent of cases as compared to a 70 per cent prediction rate with serial urinary estrogen estimations. 174 By appiication of four tests for evaluation of nutritive and respiratory placental function, a prediction of respiratory placental insufficiency of 35, 41, 40, and 46 per cent of cases was possible when meconium release into amniotic fluid, fetal BPD, FHR pattern during oxytocin-induced uterine contractility, and 24 hour urinary estriol excretion, respectively, served as test methods. The respective values for prediction of fetal growth retardation were 24, 55, 33, and 33 per cent. 110

Vnlumt· !:!:> '\umhn I

Placental insufficiency 89

Table XX. Factors and mechanisms possibly involved with the onset of labor 1. Increas!ng secretion of neurohypophysial oxytocin from posterior pituitary gland for stimulation of myometrial contractility 2. Increasmg mechanical irritation (uterine distention) of myometrial fibers leading to development of contractility 3, Decreasing progesterone-supported myometrial quiescence; estrogen dominance of myometrium: lowered threshold for myometrial excitability 4. Under estrogen dominance: increasing local secretion of a-adrenergic and cholinergic neurohumoral transmitters and of prostaglandins (E and F compounds) all with oxytocic potentials 5. Decreasing activity of placental oxytocinase (diminished oxytocin destruction) and monoamine oxidase (decreased n<>repine~ phrine inactivation) facilitating development of myometrial contractility 6. Increasing uterine vascular a-receptor activity (vasoconstriction) leading ro diminished uterine blood flow and reflectorv development of uterine contractions 7. Increasing liberation of decidual and placental bradykinin and other kinins capable of inducing myometrial activity 8. Decreasing secretion of ovarian, decidual, and placental relaxin resulting in increased myometrial excitability 9. Increasing secretion of fetal adrenocorticosteroids (cortisol) supporting development of uterine contractions by facilitating local prostaglandin production and by counteracting myometrial progesterone dominance 10. Developing maternal antigenicity toward fetal trophoblastic tissues resulting in an immune reaction: rejection, i.e., ex(Dulsion of products of conception 11, Increasing placental fibrination and infarction leading to myometrial "foreign body" reaction, i.e., labor and delivery 12, Biochemical readiness of myometrium for contractility in response to various mechanical, hormonal, neumhumor'lL and immunologic stimuli

Considering all the procedures available for diagnosis of postterm-postmaturity (Table III), it appears important that a thorough menstrual history be estalr lished and periodic clinical examinations are carried out in combination with appropriate tests for evaluation of fetoplacental function in order to reduce perinatal fetal losses. Estimates of fetal weight by abdominal palpation are almost as accurate as measurement of biparietal diameter; they vary by ± 500 and ± 400 Gm., respectively. 13 Despite thorough clinical and laboratory surveillance, it may happen that a gravida who has been checked for placental insufficiency and fetal distress, without showing abnormalities, returns to the clinic a day or two after the examination because she misses fetal movements. Sudden intrauterine fetal death may be due to acute placental insufficiency and fetal anoxia.

Uterine factors in connection with postterm pregnancy and placental Insufficiency Factors affecting uterine activity at term and post term. It is commonly assumed that with progressing fetal growth, uterine distention (thinning-out of the myometrium through the growing conceptus) as well as declining placental function are major causes for the onset of labor. It is thought that an adequately functioning placenta promotes uterine quiescence, and that with progressing placental aging and decreasing function toward term, myometrial inhibition lessens and labor starts. 103 Maternal hormonal, neurohumoral, immunologic, and biochemical-myometrial as well as fetal factors appear to affect the onset of labor 175 (Table XX). With regard to postterm pregnancy the question arises: Why does the uterus not commence

labor at the proper time? At present, knowledge is lacking about the interplay of the various factor~ and mechanisms responsible for the onset of labor. Normally, uterine contractility (Braxton Hicks contractions) gradually increases in the second half of gestation, especially during the last 8 to I 0 weeks of pregnancy. If onset of labor is delayed post term, however, there is relatively little uterine activity during pregnancy. 171 At present, no concrete data exist to explain why in some gravidas the myometrium remains quiescent post term. It has been speculated that decline of systemic and/or local progesterone-estrogen rauo as well as antagonism of progesterone by fetal cottisol (displacement of myometrial progesterone, corrisolinduced enzymatic activity yielding production of myometrial stimulants) may trigger labor 152 ; mch mechanisms, if present, may be impaired in gra~·idas with prolonged gestation. Most recently endogenous prostaglandins have been considered an important regulator of the duration of gestation, and aberration in prostaglandin metabolism was held responsible for fetal postmaturity or prolonged labor 112 ; this view, however, has not yet been confirmed by measurennent of endogenous prostaglandin in respective conditiims. Because post term the myometrium does not adequately respond to normal stimuli for labor, it may be that in some patients, at term, factors supponing myometrial activity are insufficiently functioning or that mechanisms inhibiting uterine activitv prevaiL Myometrial sensitivity toward oxytocic stimuli seems to parallel neuromuscular activity of the anterior tihial muscle which increases shortly before or at the onsel of labor; in postterm-postmaturity not only myometrial but also neuromuscular irritability appears to be de-

90

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Table XXI. Spontaneous onset and induction of labor Postterm gravidas Primigravidas

Spontaneous onset of ktbor (%j

Induction of labur

89 (23)

10 (48)

(%)

deliveries.

Fig. 9. Postmaturity syndrome in the rat. Rat gestation can be prolonged by administration of progesterone (2 to 5 mg. in oil daily), starting the medication 2 to 3 days before term and extending it beyond term; duration of gestation in primigravid Sprague-Dawley rats is 21 days. Usually 4 days post

creased. 100 However, direct assessment of uterine sensitivity to intravenous oxytocin infusion and observation of the fetoplacental oxygen reserve by continuous recording of the fetal heart rate pattern is by far the better diagnostic and prognostic pwcedure. Mechanisms possibly involved with postterm myometrial quiescence. When local myometrial stimulants are low (estrogens, etc.), relative dominance of inhibitors (progesterone, etc.) may develop, and thus the myometrium remains quiescent beyond term; such a mechanism of local progesterone dominance may also be operative in cases of missed abortion. 175 But even large doses of exogenous progesterone apparently cannot prolong gestation in man 83 ; this is in contrast to rat pregnancy where progesterone medication can prolong gestation, leading to postmaturity with typical fetal and placental findings (Figs. 9 and 10). Rat postmaturity resembles to some extent the syndrome of postmaturity observed in human pregnancy. Experimental prolongation of gestation allows a study of placental insufficiency (dysfunction) in a more uniform fashion. Nevertheless, the relationship between changes in the human placenta and histologic findings in postterm rat placentas has to be inte rpreted with caution, considering species-different placental morphology and function. Human fetal factors such as insufficient secretion of

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Volume 123 ~umber I

Placental insufficiency 91

of •oostterm ullravidas Table XXII. Manallement 0 A. Continuation of pregnancy in absence of fetal distress: 1. Estirr~ted fetal \Veight below 2,500 Gm.

2. Uncertainty of duration of gestation and continuous increase in estriol values and biparietal bone diameter 3. Unfavorable cervix in younger primigravidas and multigravidas

of pregnancy in absence offetal distress: 1. Older primigravidas a. Attempt vaginal delivery; consider oxytocin cervix-ripening infusion b. Perform cesarean section Unripe cervix Failure of induction of labor Dystocia Development of fetal distress during labor 2. Toxemia patients 3. Multigravidas with complicated obstetric history

B. Termination

C. Termination of pregnancy in presence offetal distress: I. Older primigravidas and multigravidas with a complicated obstetric history whether cervix is favorable or not: cesarean section

2. Younger primigravidas, multigravidas a. Unripe cervix: cesarean section b. Favorable cervix and fetal scalp blood pH above 7.2: attempt vaginal delivery c. Favorable cervix without possibility of fetal scalp blood sampling: cesarean section .1. Management during iabor and postpartum:

I. Monitoring of mother (uterine activity) and fetus (heart rate, amniotic fluid, scalp blood)

2. 3. 4. 5. 6. 7. 8.

Lateral positioning of parturient in case of hypoactive labor and/or fetal heart rate irregularities 100 per cent oxygen breathing in case of fetal distress Avoidance of sedatives, analgesics, spinal block, inhalation anesthetics Delivery by low forceps or by vacuum extraction in case of fetal distress Cesarean section in case of serious fetal bradycardia and decrease of scalp blood pH below 7.2 Delay clamping of umbilical cord for additional fetal blood supply Close observation of newborn infant for signs of dehydration, hypoglycemia, hypovolemia, acidosis, cerebral hypoxia, lung complications, adrenocortical hypofunction

normal fetus plays a part in its own delivery by releasing posterior pituitary oxytocin. 39 However, not only did oxytocin injections into the human fetus fail to elicit labor, 90 • 91 but the reports of Chard's group 39 suggesting oxytocin secretion by the fetal pituitary during labor, could not be confirmed in recent studies.177 Failure of placentofetal immunesurveillance as exercised by trophoblastic cells 37 may be a factor for prolonged gestation. Trophoblastic inadequacy of recognition of abnormal trophoblastic behavior (misspecification of proteins) in connection with placental aging and degeneration may not only result in insufficient placental function, but also in development of immune tolerance with increased placental fibrinoid deposition. Thereby maternofetal immune reactions may be impaired and prolongation of gestation with placental insufficiency and hazards to the fetus may be the consequence. Spontaneous onset of labor occurred equally in postterm primigravidas and multiparas, but the incidence of operative delivery was greatly increased in primigravidasM (see Table XXI). In conclusion, it can be stated that prolongation of pregnancy, placental insufficiency, and fetal postmaturity are closely related to uterine quiescence post

term, uterine dystocia during labor. and increased operative deliveries.

Clinical management of poatterm gravidas Pregnancy should not be allowed to extend beyond term in gravidas with an obstetric history of c
92 Vorherr

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Fig. 10. For legend see facing page.

I, 191 :, ol

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Placental insufficiency 93

Volun1t> 1':!~~ Numher I

are at increased risk, maternal morbidity and mortality rates have been found the same in term as in postterm gravidas. 57 Evaluation of the postterm patient by applicaton of placentofetal function tests. Neither routine induction of labor nor conservative watchful waiting can be advocated as a general rule for the management of the postterm gravida; each case necessitates thorough individual assessment and attention (Table XXII). Postterm pregnancies are usually managed conservatively, i.e., by weekly, or better semiweekly checkups of FHR, estriol, HPL, amnioscopy. and biparietal bone diameter. In postterm gravidas presenting with a favorable cervix and in the absence of contraindications, indue-

tion of labor can save fetuses who might be lost due to placental insufficiency if pregnancy is allowed to continue.121· 169 For gravidas in whom the fetal weight is estimated to be less than 2,500 Gm .. pregnane~ should be allowed to continue as long as estriol value~ rise, or remain stable within normalcy. and as long as other test parameters indicate adequate fetoplau·ntal function. Because toxemia predisposes to an early fall in fetal 0 2 supply. toxemic gravidas should be delivered 1ot later than by the fortieth week irrespective ot urinal y estriol output. 104 · 179 In the absence of fetal post1·1aturity. usually no decrease in urinary estriol excretion occurs; however, in about 90 per cent of gravidas with intrauterine fetal growth retardation. urinate estriol

Fig. 10. Histology of term and postterm rat placenta. With progesterone-induced prolongation of gestation (see legend of Fig. 9) striking changes can be observed in the histology of placentas beyond the twenty-second day of gestation. All photographs presented are magnified about 300- to 500-fold; photographs A to F show a portion of trophoectodermic giant cells on the left side of the picture and the bordering parts of the labyrinthine placenta on the right side of the picture. A, Placental section (day 21 of gestation). Normal giant cells fuse the decidua with the labyrinthine placenta. Normally blood-filled maternal interlabyrinthine spaces and vessels of fetal labyrinthine placenta with normal trophoblastic cells are extendin~r from the middle into the ri~rht nart of the photograph. · v v ' B, Placental section (day 22 of gestation). Giant cells and trophoblastic cells of labyrinthine placenta still look normal; some polymorphonuclear leukocytes appear at the giant cell-labyrinthine border and fibrinoid deposition at the giant cell-labyrinthine border and beneath the chorionic plate appears slightly increased. C, Placental section (day 23 of gestation). Some polymorphonuclear leukocytes disperse within the labyrinthine placenta indicating degenerative processes. The labyrinthine placental structures become attenuated; some syncytial cells carry pyknotic nuclei; stromal components increase. Foci of fibrinous cell degeneration appear between viable trophoblastic elements. Maternal interlabyrinthine blood and blood in fetal capillaries are diminished. Beneath the chorionic plate a polymorphonuclear cell layer appears. Fibrinoid deposition beneath the chorionic plate and at the deciduo-giant cell border is increased. The rat fetus is still viable at this stage. D, Placental section (day 24 of gestation). Fibrinous· degeneration of trophoblastic cells and fibrinoid deposition involves larger parts of the placenta; karyopyknosis and fading out of giant cell nuclei are observed. Preserved trophoblastic ~ells are observed between areas of necrosis. Maternal and fetal placental blood and amniotic fluid volume are further reduced; some fetal placental vessels show hyalinization and obliteration. The fetus is usually dead or its viability is greatly reduced. E, Placental section (day 25 of gestation). Fibrinous degeneration of giant and syncytial <·ells (swelling, vacuolization) has further progressed; fibrinoid deposition beneath the chorionic platt' and at the deciduo-giant ceii border is greatiy increased. Interlabyrinthine placental spaces are empty and fetal capillaries scarcely contain erythrocytes; polymorphonuclear leukocytes diffusely infiltrate the placenta. A rather dense polymorphonuclear cell layer at the chorionic plate indicates fetal death (see G). Some fetal placental vessels show thrombosis and polymorphonuclear infiltration: maternal decidual vessels undergo fibrinoid degeneration. F; Placental section (day 25/26 of gestation). Thick fibrinoid deposits can be noted at the deciduo-giant cell border and beneath the chorionic plate; large placental areas are necrotic and amorphous; only few viable cells are left; the polymorphonuclear leukocytic demarcation zone of the chorionic plate is most prominent (see G); fetal placental vessels undergoing degeneration and focal calcification are seen at the decidua-giant cell border. G, Placental section (day 25/26 of gestation). A dense polymorphonuclear cell layer at the chorionic plate indicates that fetal death has occurred before total placental death. Below the polymorphonuclear cell layer is the chorionic plate and above it the bordering labyrinthine pla<:enta. H, Placental-amniotic space-fetal skin section (day 26 of gestation). At this stage almost all amniotic fluid has disappeared and the amniotic space has collapsed (middle white zone of picture). On the right side of the picture: autolytic skin s~parated by th~ collapsed amniotic fluid sp;ce from mostly necrotic placental cells (on the left side of the picture).

94

Vorherr An1.

Table XXIII. Duration of labor Duration of labor Primigravidas

Multiparas

(hr.)

(hr).

18

12 22

Gravidas

Term gravidas Postterm gravidas

28

excretion may decrease due to disturbance of fetoplacental function. Fetuses rarely die when 24 hour estriol excretion is above 5 mg. Nevertheless, estriol values below 8 to 12 mg. or a drop by 60 per cent of previous values is a signal for termination of pregnancy. Whereas 8.7 per cent of antenatal deaths and 75 per cent of cases with fetal growth retardation were correlated with 24 hour estriol values below 4 mg., estriol levels above 10 mg. per 24 hours were connected with only 1.6 per cent of antenatal deaths and with 3 per cent of cases with fetal growth retardation.U 0 Pregnancy in postterm gravidas may be allowed to continue under close semiweekly supervision when the duration of gestation is not exactly known or in multigravidas without signs of fetal distress. A negative oxytocin challenge test, normal estriol values, adequately increasing BPD values, and clear amniotic forewaters indicate that the pregnancy may be allowed to continue for another half week or week before labor is induced or the gravida is retested. Although postterm perinatal fetal deaths could be reduced by 40 per cent by means of amnioscopy, 153 amnioscopy has not been considered as satisfactory a method of management of prolonged pregnancy as induction of labor. 79 In general, vaginal delivery should be attempted, provided the fetus can withstand labor; a cesarean section should be performed in gravidas with signs of fetal distress and unfavorable cervix. Induction of labor in postterm gravidas may be difficult due to myometrial sluggishness; it can be accomplished by digital cervical dilation, membrane stripping, oxytocin infusion, and/or amniotomy. Before induction of labor, assessment of the state of the cervix, maternal pelvis, and fetal size and position are essential, and performance of an oxytocin chailenge test (OCT) is advisable; an OCT may be positive before estriol excretion faiis. In 25 per cent of gravidas with a positive OCT, fetal distress may be so serious tnat wnen, In aaaniOn, esrno1 ana .orv va1ues are ww, it indicates imminent fetal death. 33 • 150 About 8 to 12 per ceni of gravidas near lerm respond to an OCT with an abnormal FHR pattern and it is likely that fetuses of such gravidas may not be able to tolerate labor and are 11

11

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delivered more safely by cesarean section. 16H With a positive OCT, fetal growth retardation occurred in 37 per cent of the cases and antepartal death in 13 per cent. 110 In eight cases with a positive OCT a severe FHR deceleration pattern developed upon induction of labor with amniotomy and intravenous oxytocin infusion. 58 Late FHR deceleration is associated with fetal hypoxia and hypotension; FHR deceleration may also be provoked by supine positioning of the gravida.88 If the FHR pattern remains normal during labor, the probability of delivering a baby with a high Apgar score at 5 minutes is about 99 per cent. 88 On the other hand, sampling of fetal scalp blood is still considered a better indicator for fetal distress than an OCT. 33 Recently, the reliability of a positive OCT as an indicator for augmented fetal distress during labor and a depressed newborn has been questioned; only one out of three neonatal deaths could be correlated with a positive OCT. 33 In other studies, however, sampling of fetal scalp blood in patients with a positive OCT showed increasing development of fetal hypoxia and metabolic acidosis during labor 107 and in 53 per cent of such newborn infants the five minute Apgar score was below 7. 15° For the proper management of postterm gravidas, it appears that conclusions from a positive OCT should be drawn only in conjunction with simultaneous estriol and BPD measurements. In postterm gravidas with an unfavorable cervix and a negative OCT, the intravenous oxytocin infusion may be continued for several hours and thus considered as a cervix-ripening infusion. Induction and duration of labor in postterm gravidas. Since it is often impossible to recognize high-risk postterm pregnancies early and reliably, delivery should be attempted in gravidas with a favorable cervix considered post term after thorough clinical and laboratory evaluation. Postterm gravidas presented with an unripe cervix in about 70 per cent of cases, 167 • 180 explaining the high failure rate of induction of labor; accordingly, 27 per cent of induced postterm gravidas required cesarean section compared to an incidence of 7 per cent in term patients. 127 Moreover, postterm gravidas tolerate labor poorly, 167 and especiaiiy in postterm primigravidas with signs of placental insufficiency, labor is usually protracted. 84 Duration of labor was prolonged iu positerm primigravidas and multiparas 155 (see Table XXIII). Labor was prolonged in 9 per cent of postterm primigravidas (primigravidas at term: 6 per cent prolongation) and a sixfold increase in the intrapartum fetal death rate from 3.4 per cent at term to 20.5 per cent post term has been reported 118 ; uterine inertia occurred twice as frequently in postterm

Placental insufficie'1cy

\io\unw I :!3 -r\umber 1

(8 per cent) as in term (3.7 per cent) gestations. 42 According to Perlin 143 , however, length of labor and incidence of uterine inertia of about 2 per cent \vere not different in term and postterm gravidas. In a study of 18 term and 18 postterm gravidas, duration of labor was shorter in postterm gravidas (7 hours and 25 minutes) compared to term gravidas (9 hours and 45 minutes). 141 Induction of labor in postterm gravidas requires continuous recording of FHR and uterine activity; persistent fetal tachycardia is the most common early sign of hypoxia. 14 By positioning the parturient on her side (preferably left side) optimal uteroplacental blood flow is ensured; uterine contractions become more intense and less frequent in 80 to 90 per cent of these parturients. Administration of a 5 per cent dextrose solution (2 mi. per minute) to provide instant energy and to prevent maternal dehydration and ketoacidosis, represents a routine adjunctive measure. In addition, administration of 100 per cent oxygen by mask may alleviate fetal hypoxia as indicated by normalization of FHR irregularities. Abnormal FHR patterns (arrhythmia. bradycardia) are relatively often observed in fetuses with congenital malformations. 84 With increasing length of gestation, FHR becomes reduced from about 140 beats per minute at 32 to 36 weeks to approximately 130 beats per minute at term; conversely beat to beat variation in FHR is increased at term. 183 It is not clear whether such FHR changes become more evident in postterm gravidas. Postterm fetal distress, perinatal death, and operative deliveries. Higher birth weights of postterm fetuses which may lead to mechanical birth problems and dystocia have been regarded as causes of increased fetal death rate in postterm pregnancies. 35 However, no difference was noted between fetal deaths in term and postterm pregnancies in relation to high birth weight. 115 • m Moreover, the birth weight of postmature fetuses is on the average 200 to 300 Gm. lower than that of normal postterm fetuses 161 ; the perinatal mortality rate is highest in postmature fetuses. Cesarean section is more readily performed in postterm gravidas with large fetuses and/or fetal distress and thus mechanical and functional birth problems are eliminated. The incidence of operative delivery (cesarean section, forceps) is two- to fivefold increased in postterm gravidas. 115 • 121 Postterm pregnancy and fetal distress often necessitate cesarean section. The cesarean section rate was two- to threefold increased in postterm prin1igravidas, but was less than half in rnultigravidas m comparison with respective term gravidas 118 (see Table XXIV).

95

Table XXIV. Cesarean section rate Cesarean section raie Gravidas

Primigravidas < 35 yr. Primigravidas > 35 yr. Multigravidas all ages

Term(%)

Pos' tfrm (%)

l.i 9.9 3.2

3.3 32.0 1.3

Postterm perinatal fetal deaths are main!)' due to fetal anoxia (placental insufficiency. cord complications) which is two- to fourfold higher than in term pregnancies; also the death rate in connection with congenital malformation and neonatal infe-ction is three- to fourfold increased in postterm gestation.U 8 In other series, postterm perinatal fetal mortalit} rates of l. 76 to I. 9 per cent were attributed to congenital anomalies (0.59 per cent), asphyxia ( 1.05 to 1.17 per cent), umbilical cord complications (0.34 per cent), and intracranial hemorrhage (0.34 per cent). 8 " 85 In t former study by Clayton, 42 fetal deaths in postterm gravidas have been attributed mainly to uterine inertia (30 per cent), fetopelvic disproportion (30 per cent), .md congenital abnormalities (13 per cent); congenital abnormalities were found higher in postterm (2.5 per cent) than in term ( 1.8 per cent) pregnancies. 143 Because dysfunctional (prolonged) labor occurs in about 50 per cent of postterm primigravidas 179 and since a 5 to 15 per cent fetal perinatal mortality rate in postterm primigravidas exists, 44 elective cesarean section is recommended for delivery when conditions for induction of labor are unfavorable. 121 Common experience which indicates that labor in postterm pregnancy is prolonged is not shared by Perlin, 143 who reported the same duration of labor for term and postteJm parturients. Most investigators report a several-fold increased cesarean section rate in postterm gravidas; for instance, Magram and Cavanagh 126 stated that the cesarean section rate was threefold increased in postterm gravidas (9 per cent) compared to term Jlatients (3 per cent). In contrast, Daichman and Gold, 46 \1ead and Marcus, 129 and Perlin 143 published similar cesarean section rates of 5. 7, 4.8, and 3.3 per cent for term and 5.7, 3.7, and 3.1 per cent for postterm gravidas, respectively. Postterm gravidas with large fetuses, borderline pelvic measures, especially in cor,dition of breech position. should have an elective cesarean section. incidence of breech position was not Jound different between term (3.2 per cent) and posnerm (3.2 per cem) gravidas. 143 in gravidas undergoing- cesarean section due to fetal distress, 100 per cent oxygen breathing before surgery is benefici
96

Vorherr

Scptemht'r I, I ~17:1 A.m . .J. Obstet. (;\ llt'tol.

Table XXV. ACTH levels ACTH levels Source of blood

Maternal vein Umbilical vein

Before onset of labor

At delivery

(pg.lml. plasma)

(pg.!ml. plasma)

15-32 (x = 23)

100-300 (x = 128)

161-389 (x = 262)

Administration of sedatives, tranquilizers, and narcotics should be restricted. Any medication leading to maternal hypotension should be avoided. 168 Inhalation anesthetics which may interfere with fetal 0 2 supply should not be applied. 179 Accordingly, after induction of anesthesia with a short-acting barbiturate and succinylcholine medication for intubation, we use a 40 per cent oxygen and 60 per cent nitrous oxide inhalation mixture which contains double the oxygen of air. As soon as the fetus is delivered, additional medication (fentanyl and droperidol) is given for control of pain and maintenance of anesthesia. Effect of labor on the postterm fetus. Amniotomy performed during the first stage of labor has been found to increase frequency and severity of Dip I type FHR pattern (early deceleration, Fig. 8) from 2 to 32 per cent. 166 Although a Dip I type FHR pattern is not considered pathologic, one must carefully weigh the merits of amniotomy versus its possible harmful effects on an already compromised fetus and amniotomy should be avoided in early labor. When the fetal head is not engaged to the maternal pelvis, extensive digital separation (membrane stripping) of the lower amniotic pole from the uterine wall is often a useful procedure for induction of labor. 178 Danger to the posttermpostmature fetus is greatest during labor and delivery because further reduction in fetoplacental oxygen reserve during labor contractions will augment already existing fetal hypoxia and acidosis. In postterm gravidas 85 to 100 per cent of all perinatal deaths occur during labor and delivery; fetuses of primigravidas are especially vulnerable. 16 • 111 Increased frequency of uterine contractions and incoordinated iabor with hypertonic uterine motility may be particularly detrimental to a compromised fetus. Decreased fetal adrenocortical activity in postmature fetuses and diniinished capacity to cope with the stress of labor and delivery may also contribute to increased fetal mortality rates. In situations with acute placental insufficiency and distress (heavy meconium staining and late bradycardia), the amniotic fluid concentration of cor-

tisol rises to an average value of 7.3 }1-g per cent as a reaction to greater stress of labor and delivery 145 : during uncomplicated labor the average cortisol value is 4.8 t-tg per cent. Even normal, uncomplicated labor poses a stress for the fetus. Whereas umbilical cord blood levels of cortisol were 6.3 to 8.9 t-tg per cent in cases with spontaneous labor and delivery, in gravidas with elective cesarean section, i.e., in the absence of stress of labor, cortisol cord blood levels were only 4.3 t-tg per cent on the average. 52 • 145 Stress of labor affecting mother and fetus is also reflected by maternal and fetal ACTH plasma levels 133 (see Table XXV). ACTH does not cross the placental barrier, in contrast to cortisol. 133 Normal labor may be just barely tolerated by the distressed fetus; prolonged and complicated labor and delivery may cause fetal death from intrauterine asphyxia (Fig. 6). Even the process of normal labor and delivery is somewhat asphyxiating (respiratory acidosis) to the undistressed fetus regardless whether delivery is spontaneous or accomplished by cesarean section; in cases with fetal distress or in fetuses delivered by cesarean section, respiratory acidosis is superimposed by metabolic acidosis. 139 Whereas in 5 per cent of parturients of 38 to 42 weeks of gestation protracted labor was encountered, it occurred in 9 per cent of postterm parturients; in 50 per cent of parturients whose fetuses died, labor lasted beyond 48 hours. 103 In such parturients uterine inertia (myometrial sluggishness) with prolongation of labor is often observed and is possibly due to insufficient mechanical myometrial stretching and decreased uterine excitability. In postterm cows a remarkable insensitivity to intravenous oxytocin infusion has been observed. 83 Not only uterine contractility but aiso maternai hyperventilation (C0 2 decrease in blood) during labor may be dangerous to the distressed fetus because with maternal respiratory alkalosis the 0 2 affinity toward Hb is increased and less free 0 2 becomes available in the intervillous blood for placental uptake and fetal oxygenation; the more acid the intervillous blood, the less 0 2 is bound to maternal Hb (Bohr effect) and the higher is the transplacental 0 2 diffusion. Under normal conditions, fetal acids (C0 2 , fixed acids), released into intervillous blood, detertTiine the extent of 0 2 release from maternal Hb; 0 2 has a greater affinity to fetal Hb than to adult Hb thus facilitating transport of 0 2 from mother to fetus. Whenever Pco2 of maternal arterial blood drops belo\v 17 mm. Hg, as possible during anesthesia with artificial respiration, placental oxygen uptake is greatly impaired through decreased maternal 0 2 release from Hb of intervillous blood as well as by reactive fetoplacental vasoconstriction. 108

Volume 1~3 !'\umber I

Placental insufficiency 97

A.

B. Normal Labor and Placental Insufficiency

Normal Labor and Placental Function

Uteropiaeental

~~ ~~~ ~ I ...... [·······."\. ..... L.-............................ j t······"'·"-./ ··········/-······················1 r - -""V'200

Blood Flow

Critical Uteroplacental Blood Flow

7.30

llli

7.25 7.20

~

""

Q.

~

················································· ................................................. .

Critical Range of pH Values

55 PC0

Vl

2

~ u... P0

2

Fetal Heart Rate Beat siMi nute

Critical P0 2 Level

. 120

-

Lower Range oi Normal Fetal Heart Rate

100

70 I ntraamniotic Pressure mmHg

35 12

40

80 Seconds

120

40

80

120

Seconds

Fig. 11. Effect of uterine contractions on fetal heart rate, fetal scalp blood Po2 ,

Pc~, pH, and uterine blood flow in normal labor and normal placental function (A) and normal labor and postterm placental insufficiency {B). A, During labor each uterine contraction causes a simultaneous transient reduction of intervillous space blood flow (intervillous blood stasis) which in turn produces a transitory fall in fetal blood Po2 (hypoxemia) and a rise in Pco2 (hypercapnia). Under normal conditions, i.e., normal uteroplacental blood flow and sufficient placental respiratory function, the placentofetal oxygen reserves are adequate to satisfy the fetal oxygen needs, and neither fetal hypoxia nor n1etabolic acidosis can develop; at the end of a uterine contraction a slight and short period of fetal respiratory acidosis is observed. Fetal heart rate usually does not change during a uterine contraction. B, When uterine contractions of labor are normal but postterm placental insufficiency with compromised placentofetal oxygen reserves is present, the changes connected with uterine contractions are more pronounced. Thus, during a uterine contraction of labor, intervillous space blood flow becomes further reduced and increased fetal hypoxia triggers metabolic acidosis (accumulation of lactate and pyruvate); in this situation fetal scalp blood pH values may reach critical levels. The rate of fetal lactic acid production increases as fetal hypoxia becomes more severe. In response to fetal hypoxia, fetal heart rate decelerates due to an increment in vagal tone and by hypoxic depression of the extra vagal cardiac pacemaker fetal syste!ll. Thereby a late deceleration (late dip) of fetal heart rate is caused which is clinically indicative of fetal hypoxia and metabolic acidosis. The

bottom of the !ate dip occurs when the uterine pressure is returning to the baseline benveen uterine

contractions. This dangerous fetal situation encountered during a uterine contraction of labor can still be compensated for and is relieved during the phase of myometrial relaxation. However, persistence of late dips is dangerous for the fetus and when fetal scalp blood pH drops to critical values, pregnancy should preferably be terminated operatively. (Adapted from Caldeyro-Barcia and co-workers. 38)

98 Vorherr Am.

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Fig. 12. For legend see facing page. Fetal assessment and management of postterm gravidas during labor. In postterm parturients with insufficient respiratory placental function the effect of uterine contractions may become critical to placentofetai oxygen reserve (Fig. 11) and a dangerous situation of fetal distress may arise. Development of FHR irregulariiies, scalp blood acidosis early in labor, or meconium release during spontaneous or induced labor require immediate attention. Regarding FHR pattern, it should be remembered, however, that it is influenced by supine hypotension, sedatives, anal-

gesics, paracervical and peridural block, head compression, umbilical cord compression, and maternal acidosis, 14 i.e., an abnormal FHR is not necessarily due to primary placental insufficiency. Based on parity of the gravida, vaginal examination (station of presenting part, degree of cervix dilation), course oflabor, and estimated duration of labor, a decision regarding conservative management of the gravida, forceps delivery, or delivery by cesarean section has to be reached. Operative deliveries are usually performed in response to fetal asphyxia and uterine inertia. In gravidas with a

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ripe cervix. labor may be induced and vaginal delivery can be attempted despite meconium release or a positive OCT and some irregularity in FHR pattern, if the fetal scalp blood values are not below pH 7.20; pH values from 7.20 to 7.25 are potentially hazardous and those below 7.20 are incompatible with fetal safety. 135 When fetal distress during labor can be alleviated by maternal lateral positioning and 100 per cent oxygen breathing, the cervix being 5 to 7 em. dilated, the fetal head having entered fully the small pelvis, and uterine contractions being adequate, vaginal delivery may be anticipated. Primigravidas need special attention and the decision for cesarean section will depend on degree of fetal distress and anticipation of further duration of labor; as long as FHR shows no serious deceleration, fetal scalp blood values are not below pH 7.20, and anticipated labor is not more than 5 to 6 hours, vaginal delivery may be attempted. When the cervix is fully dilated and the fetal head near the pelvic floor, forceps deliverv or vacuum extraction may be indicated in order to circumvent bearing-down efforts which may aggravate pre-existing fetal hypoxia as indicated by decrease in umbilical cord blood oxygenation and pH. 130 During bearing-down efforts, the pH of fetal blood decreases to 7.1 to 7.15; here values are consi-· dered pathologic when the pH drops below 7.1 Critical fetal pH blood values of 6.8 or less are usually not compatible with life. Measurement of fetal scalp blood pH is the most useful clinical procedure for assessment of the fetal status during labor. However, the degree of fetal scalp blood acidosis is not the only prognostic

parameter; in addition the basic nature of tht:· disturbance as well as the duration of acidosis and ·.~ventual damage of vital fetal organs have to be considered as equally important. 108 Recording of FHR, amnioscopy, and fetal scalp blood sampling (Po 2 , pH) during labor allows prediction of the fetal distress in 85 per cent of the cases 130 ; meconium release into amniotic fluid and irregularities of FHR indicate 44 to 69 per cent of fetuse' in distress.60 Such diagnostic procedures, combined with appropriate clinical measures, may lower the perinatal mortality rate; moreover, many gravidas may be spared a cesarean section by using these dLtgnostic techniques. 14 • 153 Without above fetal monitori: 1g techniques cesarean section rate of postterm gravidas was three- to ninefold increased and 92 per cent of cases were primigravidas. 16 When the FHR pattern was disturbed but the pH of fetal scalp blood was normal (above pH 7 .2) and no cesarean section was pen(,rmed. asphyctic neonates were encountered in only 16 per cent of deliveries. 130 Therefore, the decision f. 1r cesarean section requires thorough individual assPssment of the. gravida, taking into account the available facilities for fetal monitoring. Accordingly, there is no "rule" for performing a cesarean section in any postterm patient, whether primigravida or multipara. with or without signs of fetal distress prior or during labor. The decision to perform a cesarean sect ion is 1 eached on an individual basis after maternal and fetal risks of abdominal versus vaginal deiivery have been ctrefuiiy weighed against each other; the maternal n:orta!itv

Fig. 12. Growth and development of embryo and fetus. Collective data on intrauterine growth and development resemble an "S"-curve, with an initial slow increment, followed by a rapid exponential growth to a peak value and subsequent slow decrement. Individual embryonic and fetal growth and development vary greatly due to biologic variability of intrauterine growth as well as development ol abnormal maternal, placental, and fetal conditions leading to intrauterine growth retardation. Losses due to immaturity, prematurity, intrauterine fetal demise or neonatal death are less for a population with rapid growth and development than for one with retarded growth and development. For the last 10 weeks of gestation, curves for rapid and slow growth, ninetieth and tenth percentiles. respectively, differ by at least 1,000 Gm. in fetal weight. Out of 100 pregnant women only 85 will experience a successful outcome of gestation. In early pregnancy losses due to abortion and Immaturity occur m about 10 to !2 per cent of gravidas. In approximately 7 to 9 per cent oi pregnancies fetuses will be expelled prematurely, contributing to 50 to 60 per cent of total perinatal losses. Prematurely delivered fetuses who have grown rapidly and shown signs of maturity havt> :1 better survival chance; in rare instances large (4,000 Gm.), mature fetuses are born at 34 to 35 weeks of gestation. Premature infants have a fourfold higher neonatal mortality rate than "small-for-dates·· term infants with an equally low birth weight; of all newborn infants with birth weights below 2,500 Gm., two out of three are premature and one out of three is a "small-for-dates" term baby with intrauterine growth retardation. Around the tenth month of gestation most fetuses are mature when born and the survival rate is highest. Toward the end of the gestational period, fetuses of normal or above normal weight, as well as postmature fetuses with failure of growth and decreased survival chance are expelled; postmaturity contributes to about l per cent of all perinatal deaths. Accordingtv. from conception until 28 days postpartum, the pregnancy wastage amounts to approximateh· l "' per cent.

100

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rate after cesarean section is ten- to thirtv-fold hi!!her and the neonatal death rate is at least doubled compared to spontaneous vaginal deliveries. 176 It is thought that absence of rhythmic compression and decompression of the fetal thorax (elastic recoil of chest) which takes place during spontaneous labor and delivery, as well as fetal hypovolemia and hypoproteinemia due to diminished or absent placentofetal cord blood transfusion in gravidas with cesarean section, as well as metabolic acidosis, are contributing factors for increased fetal mortality rates. 54 • 139 Through immediate clamping off of the umbilical cord, as it is often done with cesarean sections, the infant's blood volume may be reduced by 27 to 55 per cent, 187 • 188 i.e., the fetus will be deprived of 100 mi. of blood 102 ; this in turn may lead to hypovolemia, explaining the three- to tenfold increased neonatal risk of respiratory distress compared to that for vaginally delivered babies. 54 Complications in the postmature newborn infant. Postmature infants may suffer from dehydration, hypovolemia, lung complications, and symptoms of cerebral hypoxia and metabolic acidosis 94 • 123 ; special pediatric attention is therefore required for them. Besides fluid and electrolyte therapy, administration of sodium bicarbonate, glucose, and antibiotics may become necessary. Insufficient adrenocortical function may also endanger the postmature neonate; in postterm calves with an addisonian-like syndrome, glucosecortisol infusions have proved to be lifesaving. 83 Moreover, in postmature infants a tendency exists to develop hypoglycemia (decreased adrenocortical and iiver function), eventuaHy necessitating appropriate treatment. Nevertheless, once delivered alive, postmature infants have a good chance to survive with proper care. 73 '

0

Conclusions and future horizons Perinatal losses due to placental insufficiency and postmaturity are still high and it is hoped that future development and application of suitable tests for assessment of fetoplacental function will lead to reduction of perinatal fetal mortality rates. At present, however, even the best screening methods available (urinary estriol, fetal biparietal bone diameter, fetal heart rate, amniotic fluid analysis: creatinine, osmolality, lecithin-sphingomyelin ratio, optical density) show wide variations of normalcy and thus can be of only limited diagnostic value; they are usually helpful only in diagnosis of pronounced fetal distress. Moreover, the physiology of various hormones and enzymes produced by the placenta and utilized as testing parameters of fetoplacental function is not yet known. Estimates of hormonal or enzymic placental metabolic

activity do not necessarily reflect the biochemistry and physiology of placentofetal transport functions in rel!ard to fetal suonlv of oxvl!en. nutrients. and 1elimination of waste products. Until better methods for the evaluation of fetal well-being are available, a thorough patient history (basal body temperature curve, last menses, size of uterus in early pregnancy, fetal quickening, descent of uterine fundus) and periodic clinical examinations of the gravida will provide almost as good an assessment of the fetal status as any of the currently applied tests for fetoplacental function and fetal maturity. Because fetal distress and deaths rapidly increase as gestation extends beyond term, pregnancy should be terminated in postterm gravidas whenever deemed possible and necessary. Application of sound diagnostic procedures for recognition of fetal distress and judicious clinical management of the postterm gravida in collaboration with the neonatologist can certainly lower the fetal perinatal mortality rate. Approximately 10 to 20 million years ago development toward the human species occurred and presumably at that time the morphologic and functional basis was laid for the primate and human placenta. 65 The hemochorial human placenta usually fulfills its purpose by fostering growth, development, and maturation of the fetus to a degree allowing postnatal survival (Fig. 12). In some gravidas, however, pregnancy has no successful outcome because of developing complications. Presently our limited knowledge of placentofetal pathophysiology and its prevention or correction precludes significant further reduction in perinatal fetal losses. First, prophylaxis and development of techniques for early recognition of placentofetal abnormalities on the biochemical level are important future goals. Early detection of placental parenchymal defects, for instance, by development of enzymic tests corresponding to those applied for the diagnosis of myocardial infarction, may prove a valuable step toward early diagnosis of dysmaturity. Also, administration of hormone precursors or enzymic substrates imo the amniotic fluid, into the placenta, or into the fetus and investigation of respective hormone or enzyme patterns in the placentofetal unit with regard to their synthesis, body fluid concentration, metabolism, and excretion may permit a more specific assessment of placentofetal disturbances; perhaps this may contribute to their correction and better management of the gravida. Second, drugs may be developed or techniques applied in the future for improvement of uteroplacental blood flow. In cases of toxemia, perhaps, anticoagulant or fibrinolytic therapy may not only be of U

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value for improvernent of uteroplacental blood flow but may also minimize or correct placental thrombosis and infarction. Furthermore, drugs may be developed for induction and stimulation of specific placental enzyrne systen1s aimed at improvement of metabolic and transport functions; on the other hand, undesirable or abnormal placental enzymic or hormonal processes may be controlled by newly developed chemical agents. Possibly, some day the physician may be able to support fetal growth and development by transuterine (intra-amniotic, intervillous space, intraplacental, intrafetal) administration of oxygen, nutrients, and

gro\vth stimulants. !\1oreover~ by developing agents and techniques to accelerate fetal organ maturation (brain, lung) many distressed and grow·th retarded fetuses may be given the opportunity of extrauterine gro\vth, if thereby hazards such as respiratorv distress syndrome and mental retardation can be minimized or circumvented. I would like to express my gratitude to my wife, Ute, for her invaluable contributions during preparation of this article. I would also like to thank my secretaries, Mrs. Patience Klein and Mrs. Virginia Jones, for their dedicated and skillful secretarial assistance.

REFERENCES 1. Abdul-Karim, R.: Obstet. Gynecol. Surv. 23: 713, 1968. 2. Aherne, W., and Dunnill, M. S.: Br. Med. Bull. 22: 5, 1956. 3. Aladjem, S.: Obstet. Gynecol. 30: 408, 1967. 4. Aladjem, S.: In Pecile, A., and Finzi, C., editors: The Foeto-Placental Unit, Proceedings of an International Symposium, Milan, Italy, Sept. 4-6, 1968, Amsterdam, 1969, Excerpta Medica Foundation International Congress Series No. 183, p. 392. 5. Althabe, 0., Jr., Schwarcz, R. L., Pose, S. V., Escarcena, L., and Caldeyro-Barcia, R.: AM.]. OssTET. GYNECOL. 98: 858, 1967. 6. Anderson, G. G.: Obstet. Gynecol. Surv. 27: 65, 1972. 7. Aubry, R. H., and Pennington, ]. C.: Clin. Obstet. Gynecol. 16: 3, 1973. 8. Bach, H. G.: Gynaecologia 150: 197, 1960. 9. Bancroft-Livingston, G., and Neill, D. W.: J. Obstet. Gynaecol. Br. Commonw. 64: 498, 1957. 10, Barcroft, J.: Lancet 2: 1021, 1933. 11. Barham, K. A.: Aust. N. Z. J. Obstet. Gynaecol. 13: 209, 1973. 10

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n _ _.__J_ TT. "--~t... r •. ___ J._l 1no_ oo 1nC.'l Dd.llCI:ot, n •• /"U\...11. vyuaC"lii.Ul· .1.;:ro.o 4.:1 7 1:1V.:.J.

13. Battaglia, F. C.: AM.]. OssTET. GYNECOL. 106: 1103, 1970. 14. Beard, R. W.: Obstet. Gynecoi. Surv. 29: 598, 1974. 15. Becker, V.: Arch. Gynaekol. 198: l, 1963. 16. Beischer. N. A .. Brown, T. B., Smith, M.A., and Townsend, L.: AM. j. 0BsTiT. GYNECOL. 103: 483, 1969. 17. Beischer, N. A., Brown,]. B., and Townsend, L.: AM.]. 0BSTET. GYNECOL. 103: 496, 1969. 18. Beischer, N. A., and Brown, J. B.: Obstet. Gynecol. Surv. 27: 303, 1972. 19. Beischer, N. A., Evans,]. H., and Townsend, L.: AM.]. 0BSTET. GvNECOL. 103: 476, 1969. 20. Benirschke, K.: Obstet. Gynecol. 18: 309, 1961. 21. Benirschke, K., and Driscoll, S. G.: In The Pathology of the Human Placenta, New York, 1967, Springer-Verlag, pp. 183-192. 22. Benirschke, K., and Driscoll, S. G.: In The Pathology of the Human Placenta, New York, 1967, Springer-Verlag, pp. 216-232. 23. Benirschke, K., and Driscoll, S. G.: In The Pathology of the Human Placenta, New York, 1967, Springer-Verlag, pp. 234-239. 24. Benirschke, K., and Driscoll, S. G.: In The Pathology of the Human Placenta, New York, 1967, Spring-er-Verlag-, . pp. 470-472. 25. Benson, R. C.: In Handbook of Obstetrics and Gynecol-

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ogy, ed. 3, Los Altos, 1968, Lange Medical Publications, p. 52. Benzie, R. J ., Doran, T. A., Harkins, J. L., Jones Owen, V. M., and Porter, C. J.: AM.]. 0BSTET. GYNECOL. 119: 798, 1974. Bernstine, R. L.: Clin. Obstet. Gynecol. 3: 8!•2, 1960. Bierman, J. M., Siegel, E., French, F. E., and Simonian, K.: AM. J. 0BSTET. GYNECOL. 91: 37, 1965. Biggs,J. S. G.: Aust. N. Z.J. Obstet. Gynaee<>l. 13:202, 1973. Bolte, A.: Personal communication, 1972. Bolte, A., Bachmann, K. D., Hofmann, E., Rohricht, j., and Strothmann, G.: Dtsch. Med. Wochenschr. 97:671, 1972. Bolte, A., Bachmann, K. D., and Strothmann. G.: Dtsch. Med. Wochenschr. 97: 730, 1972. Boyd, I. E., Chamberlain, G. V. P., and Fergusson, I. L. C.:]. Obstet. Gynaecol. Br. Commonw. 81: 120, 1974. Brosens, I. A., Robertson, W. B., and Dixon, H. G.: ln Wynn, R. M., editor: Obstetrics and Gynecology Annual 1972, New York, 1972, Appleton-Century-Crofts, vol. l,

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45. Cope, I.: Med.]. Aust. 1: 196, 1959. 46. Daichman, I., and Gold, E. M.: AM.]. Oasn:r. GvNECOL. 68: j 129, 1954. 47. Dehnhard, F., Ardelt, W., Breinl, H., and Weiger, E.: Geburtshilfe Frauenheilkd. 33: 111, 1973. 48. Dickey, R. P., Besch, P. K., Vorys, N., and Ullery, J. C.: AM. j. 0BSTET. GYNECOL. 94: 591. 1966.

02

Vorherr

49. Dixon, H. G., and Robertson, W. B.: Pathol. Microbial. 24: 622, 1961. 50. Dominguez, R., Segal, A.].. and O'Sullivan,]. A.:]. A. M.A. 173: 346, 1960. 51. Doring, G. K.: In Kaser, 0., Friedberg, V., Ober, K. G., Thomsen, K., and Zander, J., editors: Gynakologie und Gebunshiife, Srmtgart, 1967, Georg Thieme Verlag, vol. 2, p. 534. 52. Dormer, R. A., and France,]. T.: Steroids 21:497, 1973. 53. Einbrodt, H. J., Geller, H. F., and Born, J.: Arch. Gynaekol. 197: 149, 1962. 54. Elert, R.: In Kaser, 0., Friedberg, V., Ober, K. G., Thomsen, K., and Zander,]., editors: Gynakologie und Geburtshilfe, Stuttgart, 1967, George Thieme Verlag, vol. 2, p. 1092. 55. Elliott, P. M., and Inman, W. H. W.: Lancet 2: 835, 1961. 56. Emmrich, P., and Malzer, G.: Pathol. Microbiol. 32: 285, 1968. 57. Evans, T. N., Koeff, S. T., and Morley, G. W.: AM.]. 0BSTET. GYNECOL. 85: 70 I' 1963. 58. Ewing, D. E., Farina,]. R., and Otterson, W. N.: Obstet. Gynecol. 43: 5631 1974. 59. Fischer-Rasmussen, W., and £gidius, J.: Acta Obstet. Gynecol. Scand. 51: 25, 1972. 60. Fitzgerald, T. B., and McFarlane, C. N.: Br. Med. J 2: 358, 1955. 61. Fort, A. T.: South. Med.]. 62: 1080, 1969. 62. Fox, H.:]. Obstet. Gynaecol. Br. Commonw. 72: 347, 1965. 63. Fox, H.: In Pecile, A., and Finzi, C., editors: The Foeto-Placental Unit, Proceedings of an International Symposium, Milan, Italy, Sept. 4-6, 1968, Amsterdam, 1969, Excerpta Medica Foundation International Congress Series No. 183, p. 3. 64. Fraccaro, M.: Ann. Hum. Genet. 20: 282, 1955. 65. Franzen, J.: Natur Museum 102: 161, 1972. 66. Geissler, U., and Holtorff, J.: Zentralbl. Gynaekol. 94: 888, 1972. 67. Gibberd, G. F.: Lancet 1: 64, 1958. 68. Gibson, G. B.: Br. Med.]. 2: 715, 1955. 69. Gibson,j. R., and 1ricKeown, T.: Br.j. (Prev.) Soc. rvfed. 6: 152, 1952. 70. Gitsch, E., and Janisch, H.: Wien. Klin. Wochenschr. 83: 329, 1971. 71. Greenhill, .J. P., and Friedman, E. A.: In Biological Principles and Modern Practice of Obstetrics, Philadelphia, London, Toronto, 1974, W. B. Saunders Company,p.17l. 72. Greenhill, J. P., and Friedman, E. A.: In Biological Principles and Modern Practice of Obstetrics, Philadelphia, London, Toronto, 1974, W. B. Saunders Company, p. 567. 73. Gruenwald, P.: Bioi. Neonate 5: 215, 1963. 74. Gruenwald, P.: AM.J. 0BSTET. GYNECOL. 89:503, 1964. 75. Griinberger, V.: Zentralbl. Gynaekol. 87: 1367, 1965. 76. Halbrecht, 1., and Komlos, L.: Obstet. Gynecol. 38: 594, !971. 77. Harbert, G. M.,Jr.: Clin. Obstet. Gynecol. 16: 171, 1973. 78. Hellegers, A. E.: Yale]. Bioi. Med. 42: 180, 1969. 79. Henry, G. R.: J. Obstet. Gynaecol. Br. Commonvi. 76: 795, 1969. 80. Higgins, L. G.: Lancet 2: ll54, 1954. 81. Hiifrich, H.J.: Zentraibi. Gynaekoi. 86:1155,1964. 82. Hoffman, H. J., Stark, C. R., Lundin, F. E., Jr., and Ashbrook,]. D.: Obstet. Gynecol. Surv. 29:651, 1974. 83. Holm, L. W.: Adv. Vet. Sci. Comp. Med. 11: 159, 1967. 84. Holtorff, J., and Schmidt, H.: Zentralbl. Gynaekol. 88: 441, 1966. 85t Holtorff, J., and Sengebusch, D.: Zentralbl. Gynaekol. 89: 1521, 1967.

St·plemhcr I. l:f;.-~ Am . .J. Ohstet. (;,"'''"I

86. Hon, E. H.: Clin. Obstet. Gynecol. 3: 860, 1960. 87. Hon, E. H.: In Greenhill,]. P., editor: Obstetrics, ed. 13, Philadelphia and London, 1965, W. B. Saunders Company, p. 818. 88. Hon, E. H.: AM. J. OssTET. GYNECOL. 118: 428, 1974. 89. Hon, E. H., and Wohlgemuth, R.: AM. J. OssTET. GYNECOL. 81; 361, 1961. 90. Honnebier, W. ] .. Ji:ibsis, A. C., and Swaab, D. F.: J. Obstet. Gynaecol. Br. Commonw. 81: 423, 1974. 91. Honnebier, W. J., and Swaab, D. F.: J. Endocrinol. 57: XXX, 1973. 92. Hosemann, H.: Arch. Gynaekol. 176: 109, 1949. 93. Hosemann, H.: Arch. Gynaekol. 176: 453, 1949. 94. Hosemann, H.: Arch. Gynaekol. 176: 636, 1949. 95. Hughes, J. G.: In Synopsis of Pediatrics, ed. 3, St. Louis, 1971, The C. V. Mosby Company, p. 228. 96. Hytten, F. E., and Leitch. 1.: In The Physiology of Human Pregnancy, Philadelphia, 1964, F. A. Davis Company, p. 262. • 97. Hvtten, F. E., and Thomson, A. M.: In Assali, N. S., editor: Biology of Gestation, New York and London, 1968, vol. 1, Academic Press, Inc., p. 471. 98. Janisch, H. and Mii!!er-Tyl. E.: \r\7ien. K!in. Wochenschr. 86: 194, 1974. 99. Jenkins, D. M., Farquhar, J. B., and Oakey, R. E.: Obstet. Gynecoi. 3i: 442, 1971. 100. Jung, H .. Klock, F. K., and Miilbert, F.: Arch. Gynaekol. 207:42,1969. 101. Karn, M. N., and Penrose, L.S.: Ann. Eugenics 16: 147, 1951-2. 102. Klebe, J. G., and Ingomar, C. J.: Pediatrics 54: 213. 1974. 103. Kloosterman, G. J: Gynaecologia 142: 373, 1956. 104. Klopper, A.: In Klopper, A., and Diczfalusy. E., editors: Foetus and Placenta, Oxford and Edinburgh, 1969, Blackwell Scientific Publications, p. 4 71. 105. Knopp, J.: Z. Anat. Entwicklungsgesch. 122: 42, 1960. 106. Kolonja, S.: Zentralbl. Gynaekol. 90: 1410, 1968. 107. Krantz, K. E., and Kubli, F.: In Kaser, 0., Friedberg. V., Ober, K. G., Thomsen, K., and Zander, J., editors: Gynakologie und Geburtshilfe, Stuttgart, 1967. Georg Thieme Verlag, vol. 2t p. 52. 108. Kubli, F.: In Kaser, 0., Friedberg, V., Ober, K. G., Thomsen, K., and Zander, J., editors: Gynakologie und Geburtshilfe, Stuttgart, i 967, Georg Thieme Veriag, vol. 2, p. 1029. 109. Kubli, F., and Budliger, H.: Geburtshilfe Frauenheilkd. 23:37,1963. 110. Kubli, F. W., Kaeser, 0., and Hinselmann, M.: In Pecile, A., and Finzi, C., editors: The Foeto-Placental Unit, Proceedings of an International Symposium, Milan. Italy, Sept. 4-6, 1968, Amsterdam, 1969, Excerpta Medica Foundation International Congress Series No. 183, p. 323. Ill. Lanman,]. T.: N. Engl. J. Med. 278:993, 1047, 1092, 1968. 112. Lewis, R. B., and Schulman,]. D.: Lancet 2: 1159, 1973. 113. Liggins, G. C.: Clin. Obstet. Gynecol. 16: 148, 1973. 114. Lindell, A.: Acta Obstet. Gynecol. Scand. 35: 136, 1956. 115. Lindgren, L.,. ~ormann, P., and Viberg, L.: Acta Obstet. GynecoL Scand. 37: 482, 1958. 116. Longo, L. D.: In Assali, N. S., editor: Pathophysiology of Gestation, New York and London, 1972, Academic Press, Inc., voi. 2, p. l. 117. Lubchenco, L. 0., Hansman, C., Dressler, M., and Boyd, E.: Pediatrics 32: 793, 1963. 118. Lucas, W. E., Anctil, A. 0., and Callagan, D. A.: AM. J OBSTET. GvNECOL. 91: 241, 1965. 119. Lundwall, F., and Stakemann, G.: Acta Obstet. Gynecol. Scand. 45: 301, 1966. 120. McClure, J. H.: Obstet. Gynecol. 11: 696, 1958.

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12!. McClure Browne, J. C.: AM. J. 0BSTET. GvNECOL. 85: 573, 1963. 122. MacKay, R. B.: J. Obstet. Gynaecol. Br. Commonw. 64: 1 nl"" 10~,

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