Ovarian Cycle Review

Modest suppression of pituitary gonadotropin

secretion during pill intake and recovery of FSH release

during the pill-free week creates a situation resembling the

early follicular phase of the normal menstrual cycle and

allows for substantial residual ovarian activity.

Resting primordial follicles continuously enter the growing

pool throughout life (for review see Refs. 1–3). The magnitude

of depletion of the primordial follicle pool is dependent

on age and is most pronounced during fetal

development. Oocytes are detectable in fetal ovaries after 16

weeks of gestational age. The great majority of oocytes are

lost after the fifth month of intrauterine life, when a maximum

of approximately 7 million germ cells have been reported

(3). The presence of growing follicles in fetal ovaries

has been substantiated extensively (4). At birth, both ovaries

contain approximately 1 million primordial follicles. Reproductive

life starts with approximately 0.5 million primordial

follicles at menarche. Thereafter, loss of follicles takes place

at a fixed rate of around 1000 per month, accelerating beyond

the age of 35. Studies in the rat model suggest indeed

that follicle loss is inversely related to the number of primordial

follicles present in the ovaries (9). Once follicles are

stimulated to grow, they can either reach full maturation and

ovulate or become atretic. Follicles are present in the ovary

at different stages of development, and large numbers of

follicles of different sizes can be observed at any given point

of the menstrual cycle (10). The distribution of developmental

stages of follicles entering atresia may vary with age (11).

It is generally believed that, especially at an early age, loss of

follicles is largely due to atresia of primordial follicles (12).

It is unknown as yet which factors regulate initiation of

growth of primordial follicle (12, 13) and whether maturing

follicles may enter atresia at all developmental stages.

When primordial follicles enter the growth phase they

enlarge by an increase in size of the oocyte together with

granulosa cell proliferation (primary follicle). Transition into

the secondary follicle stage involves alignment of stroma

around the basal lamina and the development of an independent

blood supply. The stroma subsequently differentiates

into a theca externa (similar to surrounding stroma cells)

and a theca interna layer. Theca interna cells express LH

receptors early on (15). Development of an antral cavity (at

a follicle size ;100 to 200 mm) divides granulosa cells in cells

surrounding the oocyte (cumulus) and cells that border the

basement membrane. During early preantral follicle development,

FSH receptors also become detectable on granulosa

cells. The time span between a primary and an early

antral follicle in the human is unknown but is proposed to

be several months. Subsequent stages from early antral to

preovulatory follicles exhibit clear morphological characteristics,

and the time interval is assessed to be approximately 3 months.

An increase in the

number of granulosa cells is critically important for the advancement

in developmental stages of the follicle.

Under normal conditions, only about 400 follicles reach the

mature preovulatory stage and ovulate in a lifetime. Hence,

loss of follicles due to atresia — with apoptosis [i.e. programmed

cell death (18)] as the underlying cellular mechanism—

rather than growth and subsequent ovulation should

be considered the normal fate of follicles. The importance of

oxidative stress in inducing atresia (19) and gonadotropins

and various growth factors (‘survival factors’) to suppress

apoptosis (20, 21) has been emphasized recently. FSH decreases

apoptosis in granulosa cells obtained from hypophysectomized

rats (22) and prevents apoptotic changes of cultured

preovulatory follicles.

In the human the process of initiation of follicle growth

and subsequent exhaustion of the resting pool of primordial

follicles appears to be regulated independently of stimulation

by gonadotropins (24). Follicles become dependent on

stimulation by FSH only at an advanced developmental

stage, as will be discussed later.

For instance,

follicles grow up to the early antral stage in long-term hypophysectomized

animals

It appears in the human that follicle development

up to the antral stage continues throughout life until

depletion of follicles around menopause, even under conditions

in which endogenous gonadotropin release is diminished

substantially (5, 29). Such conditions include prepubertal

childhood (30 –33), pregnancy (34 –37), and the use of

steroid contraceptives (see Section IV). In addition, follicle

growth up to the early antral stage has been described in

women with absent gonadotropin secretion, either due to

hypophysectomy, as discussed by Block (1), or to hypothalamic/

pituitary failure.

In the rat

model it has been suggested that theca cell differentiation

and early preantral follicle growth is dependent on subtle

stimulation byLH.

In contrast to early follicle development, stimulation by

FSH is an absolute requirement for development of large

antral preovulatory follicles. Duration and magnitude of FSH.

stimulation will determine the number of follicles with augmented

aromatase enzyme activity and subsequent E2 biosynthesis.

High FSH levels usually occurring during the luteo-

follicular transition give rise to continued growth of a

limited number (cohort) of follicles. Subsequent development

of this cohort during the follicular phase becomes dependent

on continued stimulation by gonadotropins.

in the human only a single follicle from the cohort is

selected to gain dominance and ovulate every cycle. Remaining

cohort follicles enter atresia due to insufficient support

by reduced FSH levels. The only exception to this rule is

familial dizygotic twins in which ongoing growth and ovulation

of multiple follicles occur (46, 47). A reduced rate of

follicle atresia due to altered intrafollicular steroidogenesis

independent from gonadotropins has recently been proposed

as the underlying cause

Intrafollicular endocrine changes: The majority of enzymes involved in the biosynthesis of

ovarian steroids belong to the cytochrome P-450 gene family

(for review see Refs. 49 and 50). This group of enzymes

includes: 1) Cholesterol side-chain cleavage enzymes (P-

450SCC), which convert cholesterol to pregnenolone. 2) The

P-450C17 enzyme (involving both 17a-hydroxylase and

C17,20-lyase activity) converts both progestins (pregnenolone

and progesterone) to androgens [dihydroepiandrosterone

and androstenedione (AD), respectively]. 3) The aromatase

enzyme complex (P-450A ROM), converts androgens [AD

and testosterone (T)] to estrogens (estrone and E2, respectively)

Two enzymes that are not members of the P-450 gene

family are also important for gonadal steroid synthesis: 3bhydroxysteroid

dehydrogenase, converting D5-steroids

(such as pregnenolone) to D4-steroids (such as progesterone),

and 17 ketosteroid reductase converting AD to T and estrone

to E2.

The cholesterol side-chain cleavage enzyme represents the

major rate-limiting step in steroid hormone synthesis. Moreover,

proteins involved in the acquisition of cholesterol (including

lipoprotein receptors and enzymes involved in de

novo cholesterol synthesis) have also been shown to be im-

In vitro studies using cells isolated from human ovarian

follicles have demonstrated convincingly that theca cells are

the source of follicular androgens (54, 55) — predominantly

AD(56, 57)—whereas granulosa cells only produce E2 when

androgens are added to the culture medium (58–60). In the

human ovarian follicle, immunocytochemistry (with the use

of antibodies against specific enzymes, allowing direct visualization

of the distribution of the enzyme in tissue) as well

as Northern blot analysis of RNA has shown the P-450C17

enzyme to be restricted to the theca cell layer (61, 62), consistent

with the notion that these cells are the major site of

intrafollicular androgen production. mRNA levels for

P-450C17 are increased dramatically in preovulatory follicles

(63), which correlate well with augmented 17a-hydroxylase

activity of human theca cells in culture

. However,

appreciable quantities of mRNA (63, 65, 66) and the aromatase

enzyme (62, 67) were observed in dominant follicles

in the late follicular phase. These observations are in keeping

with the high level of aromatase enzyme activity expressed

in vitro by granulosa cells obtained from preovulatory follicles

(59, 68). In addition, mRNA expression is in good agreement

with immunolocalization of the aromatase enzyme

(66). Synthesis of the P-450AROM enzyme could also be

induced by FSH administration to human granulosa cells in

culture (69). When follicles mature, granulosa cells also exhibit

elevated mRNA levels for P-450SCC, LH receptor, activin,

and inhibin (70).

The theca interna layer of developing follicles responds to

LH and synthesizes androgens (71, 72). AD and its immediate

metabolite T are transferred from the theca layer to the

intrafollicular compartment. For this reason these steroids

are present in large quantities in ovarian follicles of all sizes

and represent the main steroid produced by early antral

follicles (73–75). Atretic follicles of all sizes (between 2 and

13 mm diameter) also contain high androgen levels (57, 76)

and low E2 concentrations (77). Granulosa cells become responsive

to FSH only at more advanced stages of development

and are capable of converting the theca cell-derived

substrate AD to E2 by induction of the aromatase enzyme.

This so-called ‘two-gonadotropin, two-cell’ concept emphasizes

that adequate stimulation of both theca cells by LH and

granulosa cells by FSH is required for adequate E2 biosynthesis,

as has been recognized since the 1940s

Large (.8 mm diameter) follicles in the mid- and late

follicular phase of the menstrual cycle contain appreciable

(up to 10,000-fold) higher quantities of E2 compared with

small follicles, as has been shown by numerous authors (60,

75, 76, 83–87). Intrafollicular E2 concentrations were up to

40,000-fold higher than those in peripheral plasma, and 20

It has

been demonstrated in IVF patients that a correlation exists

between the E2/androgen ratio in follicle fluid and follicular

health and fertility potential of oocytes

The magnitude of E2 synthesized by granulosa cells in vitro

is dependent on the size of the follicle from which cells were

obtained, with AD metabolized to E2 only by granulosa cells

from follicles beyond 8–10 mm in diameter (59, 68, 92). Follicle

fluid E2 concentrations are also correlated with the

amount of aromatase activity expressed in vitro (60). In addition,

granulosa cells in culture produce larger quantities of

E2 in response to similar doses of FSH if cells were obtained

from larger (.8 mm) follicles (59, 68, 92), suggesting increased

sensitivity

Numerous in vitro studies have shown for the rat model

that E2 plays important autocrine roles in stimulating FSHinduced

granulosa cell proliferation (76, 96), aromatase enzyme

induction (97–99), production of inhibin (100), increase

in E2 and FSH receptors (101), and formation of LH receptors

on granulosa cells (102, 103). In addition, E2 exhibits a paracrine

action on adjacent theca cells by inhibiting androgen

production.

Based on these observations,

the concept has arisen that augmented intrafollicular

E2 production is a conditio sine qua non for ongoing

follicle maturation. In fact, absent induction of aromatase

enzyme activity has been widely accepted as the underlying

cause of follicle maturation arrest and subsequent anovulation

in PCOS.

In another patient suffering from a

partial P-450C17 (17, 20-lyase step) deficiency, follicle growth

could also be achieved after the administration of exogenous

FSH despite low intrafollicular E2 levels.

Despite a significant increase in serum

FSH levels, in the same order of magnitude as the intercycle

rise in FSH during the normal menstrual cycle, serum E2

levels remained low. However, development of multiple preovulatory

follicles emerged within 14 days. In a single subject,

three large follicles between 13 and 18 mm in diameter

were aspirated, and extremely low intrafollicular levels of

AD and E2 were found

These observations in the human confirm the two-cell, twogonadotropin

concept for adequate E2 synthesis but also

demonstrate convincingly that increased E2 production is not

mandatory for normal follicle growth up to the preovulatory

stage. It is still uncertain whether estrogen receptors are present

on granulosa cells from higher primates, including the human.

Collectively, these data suggest that in the human, E2 is not

required for follicle development. It appears that, under normal

conditions, augmented E2 synthesis is merely associated

with dominant follicle development, where growth of the

follicle is, in fact, driven by other nonsteroidal (growth) factors.

During the follicular phase of the normal menstrual cycle

E2 is clearly important for other crucial physiological processes

such as stimulation of endometrial proliferation, cervical

mucus production, and induction of the midcycle LH

surge and subsequent ovulation. Whether oocyte maturation

in the human requires exposure to estrogens remains unclear

at this stage

Ovarian response to exogenous

gonadotropins (as estimated by rising serum E2 levels)

was equal, regardless of whether gonadotropins were administered

in the follicular or midluteal phase of the cycle

The dominant follicle requires continued

though reduced support by FSH. In fact, growth of a single

dominant follicle could be sustained in GnRH antagonisttreated

monkeys by the administration of exogenous FSH in

decremental doses (Fig. 4) (143), suggesting enhanced sensitivity

for FSH when the dominant follicle matures.

Early follicular phase administration of E2

caused a significant reduction in serum FSH and a lengthening

of the follicular phase (144). Moreover, administration

of antiestrogen antibodies in the early to midfollicular phase

gives rise to elevated serum FSH levels, which interferes with

single dominant follicle selection resulting in ongoing maturation

of additional cohort follicles

provide in vivo evidence for

the concept that gonadotropin-responsive follicles are maintained

throughout the entire cycle. Follicles can be stimulated

to ongoing and gonadotropin-dependent development

when the appropriate endocrine signal (i.e. elevated serum

FSH levels) is operative. Under normal conditions, elevated

FSH concentrations are present during the luteo-follicular

transition only. Augmented E2 production by the most mature

(dominant) follicle starting around the midfollicular

phase causes a subsequent decrease in FSH levels due to

negative feedback effects of E2 on the hypothalamic-pituitary

axis. The dominant follicle restricts ongoing maturation of

other, less mature follicles from the cohort since FSH levels

drop below their threshold for stimulation of gonadotropindependent

growth. The dominant follicle is spared from the

inhibitory influence of reduced FSH stimulation because of

increased sensitivity to FSH

FSH threshold and follicle recruitment. Due to the demise of

the corpus luteum and the subsequent decrease in estrogen

production (148), FSH levels rise at the end of the luteal phase

of the human menstrual cycle (149). This intercycle rise is

closely synchronized with ovulation, and FSH levels start to

increase 12 days after the preceding LH surge (150). As

mentioned previously, initiation of growth of primordial

follicles occurs continuously and in a random fashion

only follicles that happen to be at a more advanced

stage of development during the intercycle rise in

FSH will gain gonadotropin dependence. The concept that

FSH concentrations above a certain level, referred to as the

‘FSH threshold,’ are needed for ovarian stimulation was first

introduced by Brown in 1978 (151) and substantiated more

recently by Schoemaker and colleagues. The individual variation

in FSH serum levels at which follicle growth was initiated

could be assessed to be between 5.7 and 12.0 IU/liter

with the use of intravenous administration of gonadotropins

in PCOS patients.

The threshold level should be

surpassed to ensure ongoing preovulatory follicle development.

This process of rescue of a cohort of follicles from

atresia by FSH stimulation is referred to by most authors as

‘recruitment.’ The recruited cohort represents a group of

follicles at a comparable (but not identical) developmental

stage. This group of follicles, by chance, happened to leave

the pool of resting follicles around the same period of time

several months before. In contrast, other investigators reserve

this term for the initiation of growth of primordial

follicles. Morphological and endocrine studies suggest that healthy

early antral follicles less than 4 mm in diameter are present

throughout the cycle (89), in keeping with the concept that follicles are continuously available for stimulation by FSH

At the end of the luteal phase, the largest healthy follicles

observed by morphological criteria have been described to be

between 2 to 5 mm in diameter (10, 89, 154), and the number

of recruitable follicles present is believed to be between 10

and 20 for both ovaries.

The largest healthy

follicles at the start of the follicular phase of the cycle have

been reported to exhibit a diameter between 4 and 8 mm (94,

155), and no morphological differences exist between these

follicles. These observations strongly suggest that the dominant

follicle is selected at a later stage of the follicular phase

of the cycle. Indeed, exogenous HMG administered during

different phases of the menstrual cycle is most effective in

stimulating follicle recruitment if administered during the

late luteal or early follicular phase.

Enucleation of the corpus luteum in 10 women

was followed by an immediate and rapid decline of E2 and

progesterone levels. This was followed by rising FSH levels,

renewed follicle growth, and ovulation within 16–19 days

after enucleation (159). These experimental results are in full

If the intercycle rise in

serum FSH is shortened by the early to midfollicular phase

administration of GnRH antagonist, follicle growth is arrested

and new follicle recruitment will follow once medication

is withdrawn

It may

be proposed that the follicle selected to gain dominance is the

one that has most rapidly acquired the highest sensitivity for

FSH. This may be the follicle that was at the most advanced

developmental stage when recruited.

with more pronounced E2 production

by cells obtained from larger follicles (59, 68, 92, 162).

Responsiveness to FSH stimulation is also increased in preovulatory

follicles (164). In addition, in the late follicular

phase, steroidogenic function of granulosa cells from the

dominant follicle is also stimulated by LH (165). Finally,

observations in the monkey suggest that increased vascularization

of individual follicles (resulting in the preferential

exposure to circulating factors) may also be instrumental in

the selective maturation of preovulatory follicles

The FSH ‘gate’ (168) or

‘window’ (169, 170) (Fig. 6, upper panel) concept has been

introduced to emphasize the significance of a transient elevation

of FSH above the threshold. This concept emphasizes

the importance of time (i.e. duration of elevated FSH levels)

rather than dose (magnitude of FSH elevation) for single

dominant follicle selection

However, it seems that the initiation

of declining serum FSH levels precedes augmented

ovarian estrogen output. We have observed a clear association

between the magnitude of decrease in endogenous FSH

serum levels and the E2 rise, indicating that the duration of

FSH stimulation (duration of serum FSH above the threshold)

is a major determinant for ovarian E2 production.

The magnitude of multiple

follicle growth in IVF patients has been shown to be

proportional to the late follicular phase accumulation of FSH

in serum (172). These experiments confirm that the duration

(related to the window concept) rather than the magnitude

(threshold concept) of FSH stimulation determines the number

of developing follicles.

Inhibin levels did not change during the early

follicular phase.

Follicular phase serum patterns of

inhibin A appear to be comparable to previously used less

specific assays (175). In contrast, a profound rise in inhibin

B serum levels was observed early in the follicular phase,

suggesting that it is secreted by recently recruited cohort

follicles in response to FSH. This rapid rise in inhibin B occurs

just after the intercycle rise in FSH. It may be proposed that

inhibin B limits the duration of the FSH rise (narrowing the

FSH window) through negative feedback at the pituitary

level and may therefore be crucial for mono follicle development.

Follicles could be visualized from

8–10mmonward (181), and usually two to three follicles per

ovary could be identified. Growth of the dominant follicle is generally

mentioned to be linear, with a mean daily growth rate

around 2–3 mm

TVU: Up to 11 follicles (.2 mm in diameter)

could be observed throughout the cycle in each ovary, and

a dominant follicle could be visualized from 10 mm onward

(Fig. 9) on cycle day 9 (Table 1). The size of nondominant

follicles visualized by TVS always remains below 11 mm.

The ultrasound observation of dominant follicle

selection correlates strongly with a sudden increase in serum

E2 concentrations

1. Heterogeneity of FSH. Variant forms of FSH are synthesized

and secreted by the anterior pituitary, on the basis of differences

in oligosaccharide structure of these glycoproteins

as well as the number of incorporated terminal sialic acid

residues.

Depending on the sophistication of techniques

used, up to 20 isoforms have been characterized for

human FSH. Heavily sialylated (more acidic) FSH has been

described to exhibit reduced receptor binding and in vitro.

bioactivity, whereas circulating half-life of these forms is

extended. These forms may be desialylated in the circulation.

In contrast, basic isoforms have been described to be more

biopotent in vitro (2- to 5-fold), whereas the circulating halflife

is significantly reduced.

It has been speculated that ovarian follicles are

recruited in the early follicular phase (when gonadal steroid

feedback is low) predominantly by more acidic FSH isoforms,

whereas follicle selection and rupture later during the

follicular phase is dependent chiefly on more basic FSH

isoforms

The majority of growth factors, such as

insulin-like growth factors (IGF) (226), transforming growth

factor-b, fibroblast growth factor, and activin (227), have

been shown to enhance FSH action in vitro. In contrast, other

growth factors have been shown to inhibit FSH-stimulated E2

biosynthesis by cultured human or primate granulosa cells,

including inhibin (228), epidermal growth factor (229 –231),

and IGF binding protein (IGFBPs) (232). Decreased follicle

fluid epidermal growth factor and transforming growth factor-

a concentrations have been described when follicles mature

(233–235). Moreover, white blood cell-derived cytokines,

such as like tumor necrosis factor, interferon, or

interleukins, have been proposed to be relevant for human

ovarian physiology.

Expression of IGF-II and their

binding protein (IGFBPs), as well as IGF receptors, has been

shown to be dependent on the developmental stage of the

follicle (238, 239). IGFBP-3 was shown to exhibit structural

similarity with the FSH-binding inhibitor (240), and the IGFBP

profile in follicle fluid has been described to vary during

follicle development, independent from changes in serum

(241). Moreover, proteases capable of specifically decreasing

the level of IGFBP-4 could be demonstrated in estrogendominant

follicle fluid only

Ovarian manipulation

HMG preparations (FSH to LH activity ratio,

1:1), obtained from urine of postmenopausal women, are

administered to stimulate follicle growth, whereas pregnant

women provide the urine source for hCG preparations (with

LH-like activity) to induce ovulation.

It should be stressed that the goal of induction of

ovulation is completely different from ‘controlled’ ovarian

hyperstimulation for IVF, where the goal is to interfere with

selection of a single dominant follicle to obtain multiple

oocytes for IVF.

The threshold level was arbitrarily

extrapolated from the first day a follicle beyond 12mmcould

be observed by transabdominal ultrasound or TVS. No difference

in the FSH threshold was observed, comparingHMG

vs. FSH.

For a given anovulatory woman, FSH levels ‘within

the normal range’ may simply mean FSH levels below the

threshold for ovarian stimulation. Hence, only the intercycle

rise in FSH above the threshold may be lacking in these

patients.

Normogonadotropic anovulatory women frequently suffer

from PCOS. This heterogeneous group of patients is characterized

by ovarian abnormalities (polycystic ovaries) combined

with distinct endocrine features (elevated serum LH

and/or androgen levels) (282). Various lines of evidence

indicate that early follicle development is normal in these

patients, whereas anovulation is caused by disturbed dominant

follicle selection (74). This abnormal condition may be

caused by disturbed intraovarian regulation of FSH action

(129), and therefore response to exogenous FSH may be different

from normal. Hence, the presence or absence of ovarian

abnormalities in patients may influence treatment outcome

after exogenously administered gonadotropins. This

may explain major differences in the FSH threshold and

duration of stimulation needed to induce preovulatory follicle

development in these patients.

Correlations between serum

E2 levels and number and size of follicles have been studied

(194, 306), and it was shown that E2 production is the net

result of all developing follicles. This is in sharp contrast to

normal follicle development where estrogens are produced

by a single dominant follicle only.

Concomitant medication, in addition to gonadotropins,

may include: 1) dexamethasone suppression of adrenal androgen

production (310); 2) GnRH agonists to suppress endogenous

release of LH (and FSH) (311, 312); 3) dopamine

agonists therapy in case of hyperprolactinemia; 4) GH in an

attempt to improve ovarian responsiveness (313); and 5)

luteal support either by hCG or progestins.

1. Conventional step-up protocol. Conventional step-up dose

regimens for gonadotropin induction of ovulation are characterized

by initial daily doses of two ampoules (5 150 IU of

bioactive FSH). Doses may be increased after 5 days in the

event that ovarian response is judged to be insufficient.

Low dose-regimen: step-up regimen for gonadotropin induction of ovulation has

been the preferred method of stimulation in Europe since

1990. This dose regimen is characterized by low initial daily

gonadotropin doses ranging between one-half and one ampoule

(38–75 IU of bioactive FSH), and doses are only increased

by one-half ampoule per day after 14 days, in cases

of insufficient ovarian response. Pharmacokinetic studies have indicated that it takes approximately

5 days before steady state FSH levels are reached

when similar gonadotropin doses are administered daily

through the intraperitoneal route

Initial dose finding studies have generated a dose regimen

that can be used in clinical practice. We have abandoned the

use of GnRH agonists since 1992 without any loss of clinical

efficacy. A similar FSH dose regimen is applied; i.e. a twoampoule/

day starting dose shortly after a spontaneous or

progestagen-induced bleeding, followed by a decrease to one

and one-half ampoules/day once a dominant follicle can be

visualized by TVS (at least one follicle $ 10 mm). The dose

is further decreased to one ampoule/day 3 days after the first

dose reduction.

Reference

- Manipulation of Human Ovarian Function: Physiological

Concepts and Clinical Consequences-1997

Post-term Pregnancy Management Recomendations

Fetal Growth Restriction - Williams 23th Review

Each year, approximately 20 percent of the almost 4 million infants in the United States are born at the low and high extremes of fetal growth. Although most low-birthweight infants are preterm, approximately 3 percent are term

Lin and Santolaya-Forgas (1998) have divided cell growth into three consecutive phases. The initial phase of hyperplasia occurs in the first 16 weeks and is characterized by a rapid increase in cell number. The second phase, which extends up to 32 weeks, includes both cellular hyperplasia and hypertrophy. After 32 weeks, fetal growth is by cellular hypertrophy, and it is during this phase that most fetal fat and glycogen deposition takes place

The corresponding fetal-growth rates during these three phases are 5 g/day at 15 weeks, 15 to 20 g/day at 24 weeks, and 30 to 35 g/day at 34 weeks

For example, there is considerable evidence that insulin and insulin-like growth factor-I (IGF-I) and II (IGF-II) have a role in the regulation of fetal growth and weight gain

Fetal-Growth Restriction

Low-birthweight infants who are small-for-gestational age are often designated as having fetal-growth restriction. The term fetal-growth retardation has been discarded because "retardation" implies abnormal mental function, which is not the intent. It is estimated that 3 to 10 percent of infants are growth restricted.

Definition

In 1963, Lubchenco and co-workers published detailed comparisons of gestational ages with birthweights in an effort to derive norms for expected fetal size at a given gestational week. Battaglia and Lubchenco (1967) then classified small-for-gestational-age (SGA) infants as those whose weights were below the 10th percentile for their gestational age.

Because of these disparities, other classifications have been developed. Seeds (1984) suggested a definition based on birthweight below the 5th percentile. Usher and McLean (1969) suggested that fetal-growth standards should be based on mean weights-for-age with normal limits defined by ±2 standard deviations. This definition would limit SGA infants to 3 percent of births instead of 10 percent.

Normative data for fetal growth based on birthweight vary with ethnic and regional differences. For example, infants born to women who reside at high altitudes are smaller than those born to women who live at sea level.

example, a fetus with a birthweight in the 40^th percentile may not have achieved its genomic growth potential for a birthweight in the 80^th percentile. The rate or velocity of fetal growth can be estimated by serial sonographic anthropometry. Reports suggest that a diminished growth velocity is related to perinatal morbidity.

Economides and Nicolaides (1989a) found that the major cause of hypoglycemia in SGA fetuses was reduced supply rather than increased fetal consumption or diminished fetal glucose production. These fetuses had hypoinsulinemia along with hypoglycemia.

By comparison, Economides and colleagues (1989b) measured the glycine:valine ratio in cord blood from growth-restricted fetuses and found ratios similar to those observed in older children with kwashiorkor. Moreover, protein deprivation correlated with fetal hypoxemia. Economides and associates (1990) then measured plasma triglyceride concentrations in SGA fetuses and compared those with the concentrations of appropriately grown fetuses. Growth-restricted fetuses demonstrated hypertriglyceridemia that was correlated with the degree of fetal hypoxemia. They hypothesized that hypoglycemic, growth-restricted fetuses mobilize adipose tissue and that hypertriglyceridemia is the result of lipolysis of their fat stores.

Elevated plasma concentrations of interleukin-10, placental atrial natriuretic peptide, and endothelin-1, as well as a defect in epidermal growth factor function, have also been described in growth-restricted fetuses. In animals, chronic reduction in nitric oxide—an endothelium-derived, locally acting vasorelaxant—has been shown to result in diminished fetal growth (Diket and associates, 1994). Conversely, Giannubilo and co-workers (2008) showed that placenta-induced nitric oxide synthase was significantly increased in growth restriction, possibly representing an adaptive response to placental insufficiency.

Risk is increased threefold at 26 weeks compared with only a 1.13-fold increased risk at 40 weeks.

Symmetrical versus Asymmetrical Growth Restriction

Campbell and Thoms (1977) described the use of the sonographically determined head-to-abdomen circumference ratio (HC/AC) to differentiate growth-restricted fetuses. Those who were symmetrical were proportionately small, and those who were asymmetrical had disproportionately lagging abdominal growth.

The onset or etiology of a particular fetal insult has been hypothetically linked to either type of growth restriction. In the instance of symmetrical growth restriction, an early insult could result in a relative decrease in cell number and size. For example, global insults such as from chemical exposure, viral infection, or cellular maldevelopment with aneuploidy may cause a proportionate reduction of both head and body size.

Asymmetrical growth restriction might follow a late pregnancy insult such as placental insufficiency from hypertension. Resultant diminished glucose transfer and hepatic storage would primarily affect cell size and not number, and fetal abdominal circumference—which reflects liver size—would be reduced. Such somatic growth restriction is proposed to result from preferential shunting of oxygen and nutrients to the brain, which allows normal brain and head growth—so-called brain sparing. The fetal brain is normally relatively large and the liver relatively small. Accordingly, the ratio of brain weight to liver weight during the last 12 weeks—usually about 3 to 1—may be increased to 5 to 1 or more in severely growth-restricted infants.

These researchers concluded that asymmetrical fetal-growth restriction represented significantly disordered growth, whereas symmetrical growth restriction more likely represented normal, genetically determined small stature.

a woman begins pregnancy weighing less than 100 pounds, the risk of delivering an SGA infant is increased at least twofold.

concluded that the environment provided by the recipient mother was more important than the genetic contribution to birthweight.

Poor maternal nutrition and social deprivation.

Mechanisms affecting fetal growth appear to be different with each. Cytomegalovirus is associated with direct cytolysis and loss of functional cells. Rubella infection causes vascular insufficiency by damaging the endothelium of small vessels, and it also reduces cell división. Hepatitis A and B are associated with preterm delivery but may also adversely affect fetal growth (Waterson, 1979). Listeriosis, tuberculosis, and syphilis have also been reported to cause fetal-growth restriction. Paradoxically, with syphilis, the placenta is almost always increased in weight and size due to edema and perivascular inflammation (Varner and Galask, 1984). Toxoplasmosis is the protozoan infection most often associated with compromised fetal growth.

In a study of more than 13,000 infants with major structural anomalies, 22 percent had accompanying growth restriction.

According to Droste (1992), significant fetal-growth restriction is not seen with Turner syndrome (45,X) or Klinefelter syndrome (47,XXY).

First-trimester prenatal screening programs to identify women at risk for aneuploidy may incidentally identify pregnancies at risk for fetal-growth restriction unrelated to karyotype. In their analysis of 8012 women, Krantz and associates (2004) identified an increased risk for growth restriction in those with extremely low free -human chorionic gonadotropin (-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels despite normal chromosomes. Similar findings have also been reported for second-trimester quad screening by the First- and Second-Trimester Evaluation of Risk (FASTER) Trial Research Consortium

Placentary insufficiency

Reanl disease and prediabetes, multiple fetouses

Conditions associated with chronic uteroplacental hypoxia include preeclampsia, chronic hypertension, asthma, smoking, and high altitude

A number of placental abnormalities may cause fetal-growth restriction. These are discussed further throughout Chapter 27 and include chronic placental abruption, extensive infarction, chorioangioma, marginal or velamentous cord insertion, circumvallate placenta, placenta previa, and umbilical artery thrombosis. Growth failure in these cases is presumed to be due to uteroplacental insufficiency.

Two classes of antiphospholipid antibodies—anticardiolipin antibodies and lupus anticoagulant—have been associated with fetal-growth restriction. Pathophysiological mechanisms appear to be caused by maternal platelet aggregation and placental thrombosis

Risk factors, including a previous growth-restricted fetus, increase the possibility of recurrence. Specifically, the rate of recurrence is believed to be nearly 20 percent

1.      Femur length (FL) measurement is technically the easiest and the most reproducible

2.      Biparietal diameter (BPD) and head circumference (HC) measurements are dependent on the plane of section and may also be affected by deformative pressures on the skull

3.      Abdominal circumference (AC) measurement is more variable, but it is most commonly abnormal in cases of fetal-growth restriction because mostly soft tissue is involved (Fig. 38-5).

An abdominal circumference within the normal range for gestational age reliably excludes growth restriction, whereas a measurement less than the 5^th percentile is highly suggestive of growth restriction. Despite its accuracy, sonography used for detection of fetal-growth restriction has false-negative findings. Dashe and colleagues (2000) studied 8400 live births at Parkland Hospital in which fetal sonographic evaluation had been performed within 4 weeks of delivery. They reported that 30 percent of growth-restricted fetuses were not detected.

Doppler Velocimetry

Abnormal umbilical artery Doppler velocimetry—characterized by absent or reversed end-diastolic flow—has been uniquely associated with fetal-growth restriction (see Chap. 16, Umbilical Artery). The use of Doppler velocimetry in the management of fetal-growth restriction has been recommended as a possible adjunct to techniques such as nonstress testing or biophysical profile. Abnormalities in Doppler flow characterize early versus severe fetal-growth restriction and represent the transition from fetal adaptation to failure. Early changes in placenta-based growth restriction are detected in peripheral vessels such as the umbilical and middle cerebral arteries. Late changes are characterized by abnormal flow in the ductus venosus and aortic and pulmonary outflow tracts, as well as by reversal of umbilical artery flow.

In a series of 604 neonates < 33 weeks who had an abdominal circumference < 5^th percentile, Baschat and colleagues (2007) found that the ductus venosus Doppler parameters were the primary cardiovascular factor in predicting neonatal outcome. These late changes are felt to reflect myocardial deterioration and acidemia, which are major contributors to adverse perinatal and neurological outcome. In their longitudinal evaluation of 46 growth-restricted fetuses, Figueras and colleagues (2009) determined that Doppler flow abnormalities at the aortic isthmus preceded those in the ductus venosus by one week. Similarly, Towers and co-workers (2008) prospectively observed 104 fetuses with abdominal circumference < 5^th percentile. They broadly identified two patterns of progression of Doppler abnormalities: (1) mild placental dysfunction, which remained confined to umbilical and middle cerebral arteries, and (2) progressive placental dysfunction, which progressed from peripheral vessels to the ductus venosus at variable intervals depending on gestational age. Both groups of investigators stressed that knowledge of these patterns of progression is critical for planning subsequent fetal surveillance and timing of delivery

 

D Alloimmunization Management

Algorithm for the overall management of the pregnant patient with RhD alloimmunization.

Rh, rhesus; MCA, middle cerebral artery; MoM, multiple of the median; Hct, hematocrit; EGA, estimated gestational age.

Moise. Rhesus Alloimmunization in

Pregnancy. Obstet Gynecol 2008.

Preterm Birth - Williams 23th Edition

Threshold of Viability

It appears generally accepted that births before 26 weeks, especially those weighing less than 750 g, are at the current threshold of viability and that these preterm infants pose a variety of complex medical, social, and ethical considerations (American College of Obstetricians and Gynecologists, 2002, 2008c). For example, Sidney Miller is a child who was born at 23 weeks, weighed 615 g, and survived but developed severe physical and mental impairment (Annas, 2004). At age 7 years, she was described as a child who "could not walk, talk, feed herself, or sit up on her own . . . was legally blind, suffered from severe mental retardation, cerebral palsy, seizures and spastic quadriparesis in her limbs." An important issue for her family was the need for a lifetime of medical care estimated to cost tens of millions of dollars

According to current guidelines developed by the American Academy of Pediatrics (Braner and co-workers, 2000), it is considered appropriate not to initiate resuscitation for infants younger than 23 weeks or those whose birthweight is less than 400 g. The involvement of the family is considered critical to the decision-making process with regard to resuscitation. Thus, infants now considered to be at the threshold of viability are those born at 22, 23, 24, or 25 weeks. These infants have been described as fragile and vulnerable because of their immature organ systems (Vohr and Allen, 2005). Moreover, they are at high risk for brain injury from hypoxic-ischemia injury and sepsis (Stoll and associates, 2004). In this setting, hypoxia and sepsis start a cascade of events that lead to brain hemorrhage, white-matter injury that causes.periventricular leukomalacia, and poor subsequent brain growth eventuating in neurodevelopmental impairment (see Chap. 29, Periventricular Leukomalacia). It is thought that because active brain development normally occurs throughout the second and third trimesters, those infants born at 22 to 25 weeks are especially vulnerable to brain injury because of their extreme immaturity.

Considerable outcome data for preterm live births between 22 and 25 weeks have become available since the last edition of this textbook. Shown in Table 36-3 are rates of overall survival as well as survival with selected complications in 250-g birthweight increments for very-low-birthweight infants. Of those with birthweights 500 to 750 g, only 55 percent survived, and most had severe complications. Survival, even with no complications apparent at initial hospital discharge, does not preclude serious developmental impairment at age 8 to 9 years (Fig. 36-3). Importantly, survival of very low-birthweight infants with and without complications of prematurity was not substantially improved when two epochs—1997 to 2002 and 1995 to 1996 are compared (Eichenwald and Stark, 2008). Saigal and Doyle (2008) collated 16 reports based on geographically defined cohorts from Australia and several European countries. Survival increased progressively from 1.7 percent at 22 weeks to 54 percent at 25 weeks. Overall, 25 percent of infants born at 22 to 25 weeks had severe neurological disabilities, and 72 percent of those with birthweights < 750 g experienced difficulty in school. Marlow and colleagues (2005) identified all infants born between 22 and 25 weeks in the United Kingdom and Ireland between March and December 1995 and examined the children at age 6 years. As shown in Table 36-4, survival was rare at 22 weeks—only 2 of 138 infants lived. This rate increased to 10 percent, 26 percent, and 43 percent, at 23, 24 and 25 weeks, respectively. Moderate to severe disability at age 6 years was identified in more than 90 percent of infants surviving following birth at 22 to 24 weeks. As shown in Figure 36-4, cognitive scores were much lower for infants born at 22 to 25 weeks compared with those of normal term births.

Importantly, female gender, singleton pregnancy, corticosteroids given for lung maturation, and higher gestational age improved the prognosis for these infants born at the threshold of viability.

Cesarean delivery at the threshold of viability is controversial. For example, if the fetus-infant is perceived to be too immature for aggressive support, then cesarean delivery for common indications such as breech presentation or nonreassuring fetal heart rate patterns might be preempted. This aside, national data clearly show a high frequency of cesarean delivery for the smallest infants (Fig. 36-5). Moreover, neonatal mortality rates in the very smallest infants—500 to 700 g—are approximately half if cesarean delivery is used compared with vaginal birth

Parkland guidelines: From an obstetrical standpoint, all fetal indications for cesarean delivery in more advanced pregnancies are practiced in women at 25 weeks. Cesarean delivery is not offered for fetal indications at 23 weeks. At 24 weeks, cesarean delivery is not offered unless fetal weight is estimated at 750 g or greater. Aggressive obstetrical management is practiced in cases of growth restriction.

Late Preterm Birth

Infants between 34 and 36 weeks account for approximately 75 percent of all preterm births, as shown in Figure 36-7, and are the fastest increasing and largest proportion of singleton preterm births in the United States

Thus, late preterm births accounted for three fourths of all preterm births. Approximately 80 percent of late preterm births were due to idiopathic spontaneous preterm labor or prematurely ruptured membranes (Fig. 36-8). Complications such as hypertension or placental accidents were implicated in approximately 20 percent of cases. Neonatal mortality rates were significantly increased in each late preterm week compared with those at 39 weeks as the referent and as shown in Figure 36-9.

Reasons for Preterm Delivery

There are four main direct reasons for preterm births in the United States:

1. Delivery for maternal or fetal indications in which labor is induced or the infant is delivered by prelabor cesarean delivery

2. Spontaneous unexplained preterm labor with intact membranes

3. Idiopathic preterm premature rupture of membranes (PPROM)

4. Twins and higher-order multifetal births.

Of preterm births, 30 to 35 percent are indicated, 40 to 45 percent are due to spontaneous preterm labor, and 30 to 35 percent follow preterm rupture of membranes. Reasons for preterm birth have multiple, often interacting, antecedents and contributing factors. This complexity has greatly confounded efforts to prevent and manage this complication. This is particularly true for preterm ruptured membranes and spontaneous preterm labor, which together lead to 70 to 80 percent of preterm births.

Medical and Obstetrical Indications

Ananth and Vintzileos (2006) used Missouri birth data from 1989 to 1997 to analyze factors leading to indicated birth before 35 weeks. Preeclampsia, fetal distress, small for gestational age, and placental abruption were the most common indications for medical intervention resulting in preterm birth. Other less common causes were chronic hypertension, placenta previa, unexplained bleeding, diabetes, renal disease, Rh isoimmunization, and congenital malformations.

Preterm Prematurely Ruptured Membranes

Defined as rupture of the membranes before labor and prior to 37 weeks, preterm premature rupture of membranes can result from a wide array of pathological mechanisms, including intra-amnionic infection. Other factors implicated include low socioeconomic status, low body mass index—less than 19.8, nutritional deficiencies, and cigarette smoking. Women with prior preterm ruptured membranes are at increased risk for recurrence during a subsequent pregnancy (Bloom and associates, 2001). Most cases of preterm rupture, however, occur without risk factors

Spontaneous Preterm Labor

Most commonly, preterm birth—up to 45 percent of cases—follows spontaneous labor. Goldenberg and colleagues (2008b) reviewed the pathogenesis of preterm labor and implicated: (1) progesterone withdrawal, (2) oxytocin initiation, and (3) decidual activation. Deviations from normal fetal growth have also been noted in spontaneous preterm labor and suggest a fetal role (Morken and co-workers, 2006).

The progesterone withdrawal theory stems from studies in sheep. As parturition nears, the fetal-adrenal axis becomes more sensitive to adrenocorticotropic hormone, increasing the secretion of cortisol (see Chap. 6, Actions of Corticotropin-Releasing Hormone on the Fetal Adrenal Gland). Fetal cortisol stimulates placental 17--hydroxylase activity, which decreases progesterone secretion and increases estrogen production. The reversal in the estrogen/progesterone ratio results in increased prostaglandin formation, which initiates a cascade that culminates in labor. In human beings, serum progesterone concentrations do not fall as labor approaches. Even so, because progesterone antagonists such as RU486 initiate preterm labor and progestational agents prevent preterm labor, decreased local progesterone concentrations may play a role.

Because intravenous oxytocin increases the frequency and intensity of uterine contractions, oxytocin is assumed to play a part in labor initiation. But serum concentrations of oxytocin do not rise before labor, and the clearance of oxytocin remains constant. Accordingly, oxytocin is an unlikely initiator.

An important pathway leading to labor initiation implicates inflammatory decidual activation. At term, such activation seems to be mediated at least in part by the fetal-decidual paracrine system and perhaps through localized decreases in progesterone concentration. In many cases of early preterm labor, however, decidual activation seems to arise in the context of intrauterine bleeding or occult intrauterine infection.

Threatened Abortion

Vaginal bleeding in early pregnancy is associated with increased adverse outcomes later

Cigarette smoking, inadequate maternal weight gain, and illicit drug use have important roles in both the incidence and outcome of low-birthweight neonates (see Chap. 14, Tobacco). In addition, Ehrenberg and colleagues (2009) found that overweight women at risk for preterm birth had lower rates of preterm delivery before 35 weeks than at-risk women with normal weight. Some of these effects are undoubtedly due to restricted fetal growth, but Hickey and colleagues (1995) linked prenatal weight gain specifically with preterm birth. Other maternal factors implicated include young or advanced maternal age, poverty, short stature, vitamin C deficiency, and occupational factors such as prolonged walking or standing, strenuous working conditions, and long weekly work hours

In the United States and in the United Kingdom, women classified as black, African-American, and Afro-Caribbean are consistently reported to be at higher risk of preterm birth.

Studies of work and physical activity related to preterm birth have produced conflicting results (Goldenberg and colleagues, 2008b). There is some evidence, however, that working long hours and hard physical labor are probably associated with increased risk of preterm birth.

Vergnes and Sixou (2007) performed a meta-analysis of 17 studies and concluded that periodontal disease was significantly associated with preterm birth—odds ratio 2.83 (CI 1.95–4.10). In an accompanying editorial, Stamilio and colleagues (2007) concluded that the data used were not robust enough to recommend screening and treatment of pregnant women.

Birth Defects

Short intervals between pregnancies have been known for some time to be associated with adverse perinatal outcomes. In a recent meta-analysis, Conde-Agudelo and co-workers (2006) reported that intervals shorter than 18 months and longer than 59 months were associated with increased risks for both preterm birth and small-for-gestational age infants. Prior Preterm Birth

A major risk factor for preterm labor is prior preterm delivery (Spong, 2007). Shown in Table 36-6 is the incidence of recurrent preterm birth in nearly 16,000 women delivered at Parkland Hospital (Bloom and associates, 2001). The risk of recurrent preterm delivery for women whose first delivery was preterm was increased threefold compared with that of women whose first neonate was born at term Self-reported coitus during early pregnancy was not associated with an increased risk of recurrent preterm birth (Yost and co-workers, 2006).

Infection: It is hypothesized that intrauterine infections trigger preterm labor by activation of the innate immune system. In this hypothesis, microorganisms elicit release of inflammatory cytokines such as interleukins and tumor necrosis factor (TNF), which in turn stimulate the production of prostaglandin and/or matrix-degrading enzymes. Prostaglandins stimulate uterine contractions, whereas degradation of extracellular matrix in the fetal membranes leads to preterm rupture of membranes. It is estimated that 25 to 40 percent of preterm births result from intrauterine infection. Potential routes of intrauterine infection are shown in Figure 36-10.

Two microorganisms, Ureaplasma urealyticum and Mycoplasma hominis, have emerged as important perinatal pathogens. Goldenberg and colleagues (2008a) reported that 23 percent of neonates born between 23 and 32 weeks have positive umbilical blood cultures for these genital mycoplasmas.

Morency and Bujold (2007) performed a meta-analysis of 61 articles and suggested that antimicrobials given in the second trimester may prevent subsequent preterm birth. Andrews and colleagues (2006) reported results of a double-blind interconceptional trial from the University of Alabama in Birmingham. A course of azithromycin plus metronidazole was given every 4 months to 241 nonpregnant women whose last pregnancy resulted in spontaneous delivery before 34 weeks. Approximately 80 percent of the women with subsequent pregnancies had received study drug within 6 months of their subsequent conception. Such interconceptional antimicrobial treatment did not reduce the rate of recurrent preterm birth. Tita and co-workers (2007) performed a subgroup analysis of these same data and concluded that such use of antimicrobials may be harmful. In another study, Goldenberg and colleagues (2006) randomized 2661 women at four African sites to placebo or metronidazole plus erythromycin between 20 and 24 weeks followed by ampicillin plus metronidazole during labor. This antimicrobial regimen did not reduce the rate of preterm birth nor that of histological chorioamnionitis.

Bacterial vaginosis has been associated with spontaneous abortion, preterm labor, preterm rupture of membranes, chorioamnionitis, and amnionic fluid infection

Diagnosis

Patient Symptoms

Early differentiation between true and false labor is difficult before there is demonstrable cervical effacement and dilatation. Uterine activity alone can be misleading because of Braxton Hicks contractions, which are discussed in detail in Chapter 18, Patterns of Uterine Activity. These contractions, described as irregular, nonrhythmical, and either painful or painless, can cause considerable confusion in the diagnosis of true preterm labor. Not infrequently, women who deliver before term have uterine activity that is attributed to Braxton Hicks contractions, prompting an incorrect diagnosis of false labor. Because uterine contractions alone may be misleading, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (1997) had earlier proposed the following criteria to document preterm labor:

1. Contractions of four in 20 minutes or eight in 60 minutes plus progressive change in the cervix

2. Cervical dilatation greater than 1 cm

3. Cervical effacement of 80 percent or greater

In addition to painful or painless uterine contractions, symptoms such as pelvic pressure, menstrual-like cramps, watery vaginal discharge, and lower back pain have been empirically associated with impending preterm birth

Cervical Dilatation

Asymptomatic cervical dilatation after midpregnancy is suspected as a risk factor for preterm delivery, although some clinicians consider it to be a normal anatomical variant, particularly in parous women. Studies, however, have suggested that parity alone is not sufficient to explain cervical dilatation discovered early in the third trimester. Cook and Ellwood (1996) longitudinally evaluated cervical status with transvaginal sonography between 18 and 30 weeks in both nulliparous and parous women who all subsequently gave birth at term. Cervical length and diameter were identical in both groups throughout these critical weeks.

Iams and co-workers (1996) measured cervical length at approximately 24 weeks and again at 28 weeks in 2915 women not at risk for preterm birth. The mean cervical length at 24 weeks was approximately 35 mm, and those women with progressively shorter cervices experienced increased rates of preterm birth.

These investigators correlated sonographic cervical length, funneling, and prior history of preterm birth with delivery before 35 weeks. Funneling was defined as bulging of the membranes into the endocervical canal and protruding at least 25 percent of the entire cervical length (Fig. 36-11). As shown in Figure 36-12, a short cervix by itself was the poorest predictor of preterm birth, whereas funneling plus a history of prior preterm birth was highly predictive.

Incompetent Cervix

Cervical incompetence is a clinical diagnosis characterized by recurrent, painless cervical dilatation and spontaneous midtrimester birth in the absence of spontaneous membrane rupture, bleeding, or infection

Fibronectin: Lockwood and co-workers (1991) reported that fibronectin detection in

cervicovaginal secretions prior to membrane rupture was a possible marker for impending preterm labor. Fetal fibronectin is measured using an enzyme-linked immunosorbent assay, and values exceeding 50 ng/mL are considered positive. Sample contamination by amnionic fluid and maternal blood should be avoided

Prevention of Preterm Birth

Weekly intramuscular injections of either inert oil or 17-hydroxyprogesterone caproate were given from 16 through 36 weeks. Rates of delivery before 37, 35, and 32 weeks were all significantly reduced by progestin therapy. But similar studies of 17-hydroxyprogesterone caproate in both twins and triplets done by the Network showed no improvement in preterm birth rates. In the first study, 142 women with a prior preterm birth, prophylactic cervical cerclage, or uterine malformation were randomly assigned to daily 100-mg progesterone or placebo suppositories. Progesterone suppositories were associated with a significant reduction in births before 34 weeks.

At this time, the American College of Obstetricians and Gynecologists (2008c) has concluded that progesterone therapy should be limited to women with a documented history of a previous spontaneous birth at less than 37 weeks. Further studies are needed as to optimal preparation, dosage, and route of administration.

Cervical Cerclage

There are at least three circumstances when cerclage placement may be used to prevent preterm birth. First, cerclage may be used in women who have a history of recurrent midtrimester losses and who are diagnosed with an incompetent cervix (see Chap. 9, Incompetent Cervix). A second circumstance is in women identified during sonographic examination to have a short cervix. The third indication is "rescue" cerclage, done emergently when cervical incompetence is recognized in the women with threatened preterm labor

Management of Preterm Rupture of Membranes and Preterm Labor

In the absence of maternal or fetal indications warranting intentional delivery, interventions are intended to forestall preterm birth. Although many of these interventions are described in the following sections, they are not necessarily recommended. Some may produce borderline improvement at best, and others are unproven. For example, the American College of Obstetricians and Gynecologists (2003, 2008b), in its review of preterm labor management, has concluded: "Despite the numerous management methods proposed, the incidence of preterm birth has changed little over the past 40 years. Uncertainty persists about the best strategies for managing preterm labor."

Diagnosis of Preterm Prematurely Ruptured Membranes – check

Although this complication was identified in only 1.7 percent of pregnancies, it contributed to 20 percent of all perinatal deaths. By the time they presented, 75 percent of the women were already in labor, 5 percent were delivered for other complications, and another 10 percent were delivered within 48 hours. The time from preterm ruptured membranes to delivery is inversely proportional to the gestational age when rupture occurs (Carroll and associates, 1995). As shown in Figure 36-15, very few days were gained when membranes ruptured during the third trimester compared with midpregnancy

Most clinicians hospitalize women with preterm ruptured membranes. Concerns about the costs of lengthy hospitalizations are usually moot, because most women enter labor within a week or less after membrane rupture. Carlan and co-workers (1993) randomly assigned 67 women with ruptured membranes to home or hospital management. No benefits were found for hospitalization, and maternal hospital stays were reduced by 50 percent in those sent home.

Fetal lung maturity, as evidenced by mature surfactant profiles, was present in all cases. Intentional delivery reduced the length of maternal hospitalization and also reduced infection rates in both mothers and neonates. Cox and Leveno (1995) similarly apportioned 129 women between 30 and 34 weeks. Fetal lung maturity was not assessed. One fetal death resulted from sepsis in the pregnancies managed expectantly. Among those intentionally delivered, there were three neonatal deaths—two from sepsis and one from pulmonary hypoplasia. Thus, neither management approach proved to be superior.

Despite extensive literature concerning expectant management of preterm ruptured membranes, tocolysis has been used in few studies. In randomized studies, women were assigned to receive either tocolysis or expectant management. The investigators concluded that active interventions did not improve perinatal outcomes.

McElrath and associates (2002) studied 114 women with cerclage in place who later had ruptured membranes prior to 34 weeks. They were compared with 288 controls who had not received a cerclage. Pregnancy outcomes were equivalent in both groups.

Risks of Expectant Management

Maternal and fetal risks vary with the gestational age at membrane rupture. Morales and Talley (1993b) expectantly managed 94 singleton pregnancies with ruptured membranes prior to 25 weeks. The average time gained was 11 days. Although 41 percent of infants survived to age 1 year, only 27 percent were neurologically normal. Similar results were reported by Farooqi (1998) and Winn (2000) and their associates. Lieman and colleagues (2005) found no improved neonatal outcomes with expectant management beyond 33 weeks. In contrast, McElrath and co-workers (2003) found that prolonged latency after membrane rupture was not associated with an increased incidence of fetal neurological damage

Virtually all women with oligohydramnios delivered before 25 weeks, whereas 85 percent with adequate amnionic fluid volume were delivered in the third trimester. Carroll and colleagues (1995) observed no cases of pulmonary hypoplasia in fetuses born after membrane rupture at 24 weeks or beyond. This suggests that 23 weeks or less is the threshold for development of lung hipoplasia.

Corioamnionitis: Clinical Chorioamnionitis

Most authors report that prolonged membrane rupture is associated with increased fetal and maternal sepsis (Ho and colleagues, 2003). If chorioamnionitis is diagnosed, prompt efforts to effect delivery, preferably vaginally, are initiated. Fever is the only reliable indicator for this diagnosis, and temperature of 38°C (100.4°F) or higher accompanying ruptured membranes implies infection. Maternal leukocytosis alone has not been found to be reliable. During expectant management, monitoring for sustained maternal or fetal tachycardia, for uterine tenderness, and for a malodorous vaginal discharge is warranted

Accelerated Pulmonary Maturation

A variety of clinical events—some well defined—were once proposed to accelerate fetal surfactant production (Gluck, 1979). These included chronic renal or cardiovascular disease, hypertensive disorders, heroin addiction, fetal-growth restriction, placental infarction, chorioamnionitis, and preterm ruptured membranes. Although this view was widely held for many years, subsequent observations do not support this association

Antimicrobial therapy: To further address this issue, the Maternal-Fetal Medicine Units Network designed a trial to study expectant management combined with a 7-day treatment of ampicillin, amoxicillin plus erythromycin, or placebo. The women had membrane rupture between 24 and 32 weeks. Neither tocolytics nor corticosteroids were given. Antimicrobial-treated women had significantly fewer newborns with respiratory distress syndrome, necrotizing enterocolitis, and composite adverse outcomes (Mercer and colleagues, 1997). The latency period was significantly longer. Specifically, 50 percent of women given an antimicrobial regimen remained undelivered after 7 days of treatment compared with only 25 percent of those given placebo. There was also significant prolongation of pregnancy at 14 and 21 days. Cervicovaginal group B streptococcal colonization did not alter these results

Comparing these same epochs, the rate of Escherichia coli sepsis increased—from 3.2 to 6.8 per 1000 births. Almost 85 percent of coliform isolates from the more recent cohort were ampicillin resistant. Neonates with early-onset sepsis were more likely to die, especially if they were infected with coliforms. Kenyon and co-workers (2008a) found that the prescription of antimicrobials for women with preterm rupture of membranes had no effect on the health of the children at age 7 years.

Corticosteroids: Since then, a number of meta-analyses have addressed this issue, and according to the American College of Obstetricians and Gynecologists (2007), single-dose therapy is recommended from 24 to 32 weeks. There is no consensus regarding treatment between 32 and 34 weeks. They are not recommended prior to 24 weeks.

Preterm Labor with Intact Membranes

Women with signs and symptoms of preterm labor with intact membranes are managed much the same as described above for those with preterm ruptured membranes. The cornerstone of treatment is to avoid delivery prior to 34 weeks, if possible. Drugs used to abate or suppress preterm uterine contractions are subsequently discussed

The American College of Obstetricians and Gynecologists (2003) has concluded that there is no evidence to support routine amniocentesis to identify infection.

The issue of the fetal and infant safety with single versus repeat courses of corticosteroids for lung maturation has been the topic of two major trials. Although both found repeated courses to be beneficial in reducing neonatal respiratory morbidity rates, the long-term consequences were much different. Specifically, Crowther and colleagues (2007) studied outcomes in 982 women from the Australian Collaborative Study. These women were given a single weekly dose of 11.4 mg of betamethasone. These investigators found no adverse effects in the infants followed to age 2 years. Wapner and colleagues (2007) studied infants born to 495 women in a Network study who were randomized to receive two weekly 12-mg betamethasone doses given 24 hours apart. They were concerned by their finding of a nonsignificant increase in cerebral palsy rates in infants exposed to repeated courses. The twice-as-large betamethasone dose in the Network study was worrisome because there is some experimental evidence to support the view that adverse corticosteroid effects are dose dependent. Bruschettini and colleagues (2006) studied the equivalent of 12-mg versus 6-mg betamethasone given to pregnant cats. They reported that the lower dose had less severe effects on somatic growth without affecting cell proliferation in the fetal brain.

"Rescue" Therapy

This refers to administration of a repeated corticosteroid dose when delivery becomes imminent and more than 7 days have elapsed since the initial dose. The 2000 Consensus Development Conference recommended that rescue therapy should not be routinely used and that it should be reserved for clinical trials. The first randomized trial reported by Peltoniemi and colleagues (2007) allocated 326 women to placebo or 12-mg betamethasone single-dose rescue regimens. Paradoxically, they found that the rescue dose of betamethasone increased the risk of respiratory distress syndrome! Subsequently, the American College of Obstetricians and Gynecologists (2008a) also recommended such therapy for trials

Elimian and co-workers (2007) randomized 299 women between 24 and 33 weeks in a double-blinded trial of betamethasone versus dexamethasone. These two drugs were comparable in reducing the rates of major neonatal morbidities in preterm infants.

Antimicrobials: As with preterm ruptured membranes, antimicrobials have been given to arrest preterm labor. Here too, results have been disappointing. A Cochrane meta-analysis by King and Flenady (2000) of 10 randomized trials found no difference in the rates of newborn respiratory distress syndrome or of sepsis between placebo- and antimicrobial-treated groups.

Emergency or Rescue Cerclage There is support for the concept that cervical incompetence and preterm labor are part of a spectrum leading to preterm delivery. Consequently, investigators have evaluated the role of cerclage done after preterm labor begins to manifest clinically. Harger (1983) concluded that if cervical incompetence is recognized with threatened preterm labor, emergency cerclage can be attempted, albeit with an appreciable risk of infection and pregnancy loss. Althuisius and associates (2003) randomly assigned 23 women with cervical incompetence prior to 27 weeks to bed rest, with or without emergency McDonald cerclage. Delivery delay was significantly greater in the cerclage group compared with that of bed rest alone—54 versus 24 days.

Inhibition of Preterm Labor

Although a number of drugs and other interventions have been used to prevent or inhibit preterm labor, none has been shown to be completely effective. The American College of Obstetricians and Gynecologists (2007) has concluded that tocolytic agents do not markedly prolong gestation, but may delay delivery in some women for at least 48 hours. This may facilitate transport to a regional obstetrical center and allow time for administration of corticosteroid therapy. It is estimated that 72,733 women giving birth in the United States in 2006 received tocolytic drugs (Martin and colleagues, 2009). The rate of tocolysis use was 1.7 percent in 2006, a rate that has fluctuated only slightly since 1996. Norwitz and co-workers (2004) performed an interactive survey of tocolytic treatment at the 2004 Annual Meeting of the Society of Maternal-Fetal Medicine. As shown in Figure 36-16, intravenous magnesium sulfate was the most commonly used tocolytic—about 70 percent of respondents. Approximately the same proportion of respondents would not prescribe maintenance therapy

Bed Rest

Hydration and Sedation

Helfgott and associates (1994) compared hydration and sedation with bed rest in a randomized trial of 119 women with threatened preterm labor. Women who were randomly selected to receive 500 mL of crystalloid over 30 minutes and 8 to 12 mg of intramuscular morphine sulfate had outcomes similar to those prescribed bed rest. Although women with preterm contractions treated with 0.25-mg subcutaneous terbutaline may have contractions that cease more quickly and may be discharged significantly earlier compared with women not treated, pregnancy outcomes are similar

-Adrenergic Receptor Agonists: A number of compounds react with -adrenergic receptors to reduce intracellular ionized calcium levels and prevent activation of myometrial contractile proteins (see Chap. 6, Regulation of Myometrial Contraction and Relaxation). In the United States, ritodrine and terbutaline have been used in obstetrics, but only ritodrine had been approved for preterm labor by the Food and Drug Administration.

Ritodrine: In a multicenter trial, neonates whose mothers were treated with ritodrine for threatened preterm labor had lower rates of death and respiratory distress. They also achieved a gestational age of 36 weeks or a birthweight of 2500 g more often than did those of untreated mothers (

The infusion of -agonists has resulted in frequent and at times, serious and fatal side effects. Pulmonary edema is a special concern, and its contribution to morbidity is discussed in Chapter 42. Tocolysis was the third most common cause of acute respiratory distress and death in pregnant women during a 14-year period in Mississippi (Perry and associates, 1996). The cause of pulmonary edema is multifactorial, and risk factors include tocolytic therapy with -agonists, multifetal gestation, concurrent corticosteroid therapy, tocolysis for more than 24 hours, and large intravenous crystalloid volume infusion. Because -agonists cause retention of sodium and water, with time—usually 24 to 48 hours, these can cause volume overload (Hankins and colleagues, 1988). The drugs have been implicated as a cause of increased capillary permeability, disturbance of cardiac rhythm, and myocardial ischemia. Finally, maternal sepsis—a relatively common occurrence with preterm labor—appreciably increases this risk

Terbutaline: Elliott and co-workers (2004) have used continuous terbutaline subcutaneous infusion in 9359 patients and reported that only 12 women experienced severe adverse events—primarily pulmonary edema. Two randomized trials found no benefit for terbutaline pump therapy. Oral terbutaline therapy to prevent preterm delivery has also not been effective.

Magnesium Sulfate

Ionic magnesium in a sufficiently high concentration can alter myometrial contractility. Its role is presumably that of a calcium antagonist. Clinically, magnesium in pharmacological doses may inhibit labor. Steer and Petrie (1977) concluded that intravenously administered magnesium sulfate—a 4-g loading dose followed by a continuous infusion of 2 g/hr—usually arrests labor. Women given magnesium sulfate must be monitored closely for evidence of hypermagnesemia. PE in 8.5%. These women were at appreciable risk, and few reached 33 weeks. Magnesium-treated women and their fetuses had identical outcomes compared with those given placebo. Because of these findings, this method of tocolysis was abandoned at Parkland Hospital.

In intriguing reports, very-low-birthweight neonates whose mothers were treated with magnesium sulfate for preterm labor or preeclampsia were found to have a reduced incidence of cerebral palsy at 3 years (Grether and associates, 2000; Nelson and Grether, 1995). This was logical, as magnesium has been shown in adults to stabilize intracranial tone, minimize fluctuations in cerebral blood flow, reduce reperfusion injury, and block calcium-mediated intracellular damage (Aslanyan and colleagues, 2007; Marret and associates, 1995). Magnesium reduces synthesis of cytokines and bacterial endotoxins and thus, also may minimize the inflammatory effects of infection (Nelson and Grether, 1997.

This trial was interpreted differently depending upon statistical philosophy. Those who disdain subgroup analysis opted to interpret these findings to mean that magnesium sulfate infusion prevents cerebral palsy regardless of the gestational age at which the therapy is given. Those with a differing view concluded that this trial only supports use of magnesium sulfate for prevention of cerebral palsy before 28 weeks. What is certain, however, is that maternally administered magnesium sulfate infusions cannot be implicated in increased perinatal deaths as reported by Mittendorf and colleagues (1997.

Because of these findings, at Parkland Hospital, our policy is to give magnesium sulfate for threatened preterm delivery from 24 to 28 completed weeks. At the University of Alabama at Birmingham Hospital, we administer neuroprotection magnesium from 23 to 32 completed weeks. In both, a 6-g loading dose is followed by an infusion of 2 g per hour for at least 12 hours.

Morales and co-workers (1989, 1993a), however, compared indomethacin with either ritodrine or magnesium sulfate and found no difference in their efficacy to forestall preterm delivery. Berghella and colleagues (2006) reviewed four trials of indomethacin given to women with sonographically short cervices and found such therapy to be ineffective.

Indomethacin is administered orally or rectally. A dose of 50 to 100 mg is followed at 8-hour intervals not to exceed a total 24-hour dose of 200 mg. Serum concentrations usually peak 1 to 2 hours after oral administration, whereas levels after rectal administration peak slightly sooner. Most studies have limited indomethacin use to 24 to 48 hours because of concerns of oligohydramnios, which can develop with these doses. If amnionic fluid is monitored, oligohydramnios can be detected early, and it is reversible with discontinuation of indomethacin

Case-control studies have been performed to assess neonatal effects of indomethacin exposure given for preterm labor. In a study of neonates born before 30 weeks, Norton and associates (1993) identified necrotizing enterocolitis in 30 percent of 37 indomethacin-exposed newborns compared with 8 percent of 37 control newborns. Higher incidences of intraventricular hemorrhage and patent ductus arteriosus were also documented in the indomethacin group. The impact of treatment duration and its timing in relation to delivery were not reported. In contrast, several investigators have challenged the association between indomethacin exposure and necrotizing enterocolitis (Muench and co-workers, 2001; Parilla and colleagues, 2000.

Using the Cochrane Database, Keirse (1995a) compared nifedipine and -agonists and concluded that although nifedipine treatment reduced births of neonates weighing less than 2500 g, significantly more of these were admitted for intensive care. Other investigators have also concluded that calcium-channel blockers, especially nifedipine, are safer and more effective tocolytic agents than are -agonists (King and colleagues, 2003; Papatsonis and co-workers, 1997). Lyell and colleagues (2007) randomized 192 women at 24 to 33 weeks to either magnesium sulfate or nifedipine and found no substantial differences in efficacy or adverse effects. Finally, oral nifedipine does not significantly prolong pregnancy in women initially treated with intravenous magnesium sulfate for preterm labor (Carr and colleagues, 1999).

The combination of nifedipine with magnesium for tocolysis is potentially dangerous. Ben-Ami and co-workers (1994) and Kurtzman and associates (1993) reported that nifedipine enhances neuromuscular blocking effects of magnesium that can interfere with pulmonary and cardiac function

In randomized clinical trials, however, atosiban failed to improve relevant neonatal outcomes and was linked with significant neonatal morbidity.

In many women, tocolytics stop contractions temporarily but rarely prevent preterm birth. In a meta-analysis of tocolytic therapy, Gyetvai and colleagues (1999) concluded that although delivery may be delayed long enough for administration of corticosteroids, treatment does not result in improved perinatal outcome. Berkman and associates (2003) reviewed 60 reports and concluded that tocolytic therapy can prolong gestation, but that -agonists are not better than other drugs and pose potential maternal danger. They also concluded that there are no benefits of maintenance tocolytic therapy.

As a general rule, if tocolytics are given, they should be given concomitantly with corticosteroids. The gestational age range for their use is debatable, but because corticosteroids are not generally used after 33 weeks and because the perinatal outcomes in preterm neonates are generally good after this time, most practitioners do not recommend use of tocolytics at or after 33 weeks (

Recommended Management of Preterm Labor

The following considerations should be given to women in preterm labor:

1. Confirmation of preterm labor as detailed in Diagnosis

2. For pregnancies less than 34 weeks in women with no maternal or fetal indications for delivery, close observation with monitoring of uterine contractions and fetal heart rate is appropriate. Serial examinations are done to assess cervical changes

3. For pregnancies less than 34 weeks, corticosteroids are given for enhancement of fetal lung maturation

4. Consideration is given for maternal magnesium sulfate infusion for 12 to 24 hours to afford fetal neuroprotection

5. For pregnancies less than 34 weeks in women who are not in advanced labor, some practitioners believe it is reasonable to attempt inhibition of contractions to delay delivery while the women are given corticosteroid therapy and group B streptococcal prophylaxis. Although tocolytic drugs are not used at Parkland Hospital, they are given at University of Alabama at Birmingham Hospital

6. For pregnancies at 34 weeks or beyond, women with preterm labor are monitored for labor progression and fetal well-being

7. For active labor, an antimicrobial is given for prevention of neonatal group B streptococcal infection

Group B streptococcal infections are common and dangerous in the preterm neonate. Tachycardia in preterm fetus-->> sepsis.

Malloy and colleagues (1991) analyzed 1765 newborns with birthweights less than 1500 g and found that cesarean delivery did not lower the risk of mortality or intracranial hemorrhage. Anderson and co-workers (1988), however, made an interesting observation regarding the role of cesarean delivery in the prevention of neonatal intracranial hemorrhages. These hemorrhages related to whether or not the fetus had been subjected to the active phase of labor. They emphasized that avoidance of active-phase labor is impossible in most preterm births because the route of delivery cannot be decided until the active phase of labor is firmly established