PRETERM BIRTH AND THROMBOPHILIAS
| PRETERM-BIRTH PREVENTION —Kirk D. Ramin, MD, Associate Professor, Department of Obstetrics,
Gynecology and Women’s Health, and Director, Maternal Fetal Medicine Fellowship Program, University of
Minnesota Medical School, Minneapolis
|
| General considerations: definition—delivery <37 wk gestation; birth weight <2500 g if pregnancy does not have
accurate dating; incidence—8% to 9% of live births (unchanged since 1950s); rate rising despite tocolytic therapy;
currently affects 12% of births in United States (15% in nonHispanic blacks); accounts for 70% to 80% of
overall neonatal mortality from infectious morbidity, respiratory disease, necrotizing endocolitis, and intraventricular
hemorrhage; historically, two thirds of deaths occurred within first 24 hr; at present, mortality tends to be later
because of improved management of respiratory problems by neonatal care specialists; survival >50% for neonates
25 to 26 wk gestation and >90% for neonates 29 to 30 wk
|
| Risk factors: high parity, low or high hemoglobin, previous abortion, lower socioeconomic class, bacteriuria, and
nulliparity; possible causes—Lettieri et al identified faulty placentation in 50% of women with preterm labor, intrauterine
infection in 38%, immunologic factors in 30%, cervical incompetence in 16%, uterine factors in 14%,
and trauma/surgery in 8%; idiopathic conditions in 4%; Goldenberg et al suggest etiology single potent risk factor
(infection or placental abruption) at, eg, 20 wk; multiple factors likely play role later on; Romero showed 3-fold increased
risk for membrane rupture at 32 wk in women who had abnormal bleeding early in second trimester (immunologic
factors may cause membrane erosion); rabbit model of Escherichia coli–induced preterm pregnancy
loss—showed fewer preterm deliveries in rabbits treated with antibiotics at inoculation or 2 or 4 hr after inoculation
than in untreated rabbits (may explain why treating existing bacterial vaginosis [BV] does not change outcome
in many women with preterm birth)
|
| Progesterone: role in early gestation critical—progesterone receptor antagonist can induce abortion at <7 wk;
role in later gestation unclear—limited production of stimulatory prostaglandins; inhibits expression of genes
for contraction-associated protein; affects ion channels, prostaglandin receptors, oxytocin receptors, and gap junctions;
functional progesterone withdrawal before labor may be mediated by changes in expression of progesterone
receptors A and B (PR-A and PR-B), with an increase in PR-A/PR-B expression ratio; anti-inflammatory agent—
pregnancy maintained by tonic suppression of uterine prostaglandin synthesis; nuclear factor-kappaB (NF-kappaB) activity
depressed; inhibits production of thrombin-induced interleukin (IL)-11; secretory component of IgA inhibits phospholipase
A2 (PLA2 ); progesterone-receptor coactivators in myometrium decrease near term—progesterone
binding induces conformational changes in PR; promotes dissociation of complex heat shock protein and immunophilin,
which keeps immune complex from causing delivery; 9-fold fall in PR binding to cognate estrogen receptors
in labor, compared to prelabor; progesterone may interfere with cortisol-mediated regulation of placental
gene expression—corticotropin-releasing hormone (CRH) may play role in timing of labor; cortisol and progesterone
have antagonistic role in fetoplacental unit; cortisol increases prostaglandin production by placenta and fetal
membranes via cyclooxygenase 2 (COX-2; cyclooxygenase pathway); progesterone may act through nongenomic
pathways—metabolite 5- β-dihydroprogesterone can enter cell membrane and bind G-protein–coupled heptahelical
oxytocin receptor; decreases oxytocin-induced myometrial contractility in vivo; possible role for
membrane-bound PR in myometrium—distinct membrane-bound PR confirmed in humans (sperm and aortic endothelial
cells); role remains unclear
|
| Treatment: progesterone administration—meta-analysis of 7 trials concluded unproven whether administration
of progesterone reduced perinatal morbidity or mortality; 17-hydroxyprogesterone (17P) for prevention of preterm
delivery—17α-hydroxyprogesterone caproate (17P) 250 mg vs inert oil started at 16 wk gestation (some patients
20 wk) and continued to 36 wk gestation; neonatal outcome not statistically significant for delivery <37 wk
(17P, 36% compared to placebo, 54%), but reduced necrotizing enterocolitis, intravenous hyperalimentation, and
need for oxygen supplementation; vaginal progesterone—da Fonseca showed deliveries <34 wk statistically less
frequent (2.7%) in women receiving 100 mg vaginal progesterone, compared to placebo group (18.6%); exact medication
used unclear; American College of Obstetricians and Gynecologists (ACOG) Committee Opinion on
use of progesterone to reduce preterm birth—appropriate for women with previous spontaneous preterm birth
<37 wk, singleton gestations, and women who are asymptomatic; ideal progesterone formulation unknown; larger
study needed to prove benefit of vaginal formulation
|
| 17P for prevention of preterm delivery: studied by Meis; secreted by corpus luteum and placenta; many actions
beneficial to maintenance of pregnancy, (eg, relaxes smooth muscle, suppresses T lymphocytes, blocks effects of
oxytocin on myometrium, acts as potent inhibitor of formation of gap junctions [gap junctions facilitate delivery]);
17P occurs naturally; placental production many times greater than pharmacologic doses; fetus exposed to high
concentrations of progesterone in utero; no androgenic activity; patient selection—evidence supports use in
women at high risk for preterm birth, with previous preterm birth, or with previous preterm rupture of membranes;
no evidence to support use in women with multiple gestations, with short cervix, or pregnancy >24 wk; short or
funneling cervical os—meta-analysis showed cervical cerclage worsened outcome in multiple gestations and did
not change outcome for singleton gestations; more on 17P—meta-analysis of 7 trials (1300 subjects; <37 wk)
showed significant reduction in preterm delivery in 17P treatment arm (26%), compared to nontreatment arm
(35%); Koontz showed no difference in preterm rate whether treatment initiated at 16 to 18 wk of gestation or 19 to
20 wk; important to initiate treatment early enough in pregnancy (not at, eg, 29 wk if previous pregnancy’s preterm
delivery 30 wk); randomized trial in twins—661 women with similar baseline demographics; did not show reduction
in rate of preterm birth in women with twins (no difference whether monochorionic or dichorionic); trial
now underway for use of 17P in shortened cervix; trial of vaginal progesterone supplementation also underway;
survey results—67% of maternal-fetal medicine specialists surveyed in 2005 reported recommending progesterone
for women with history of spontaneous preterm delivery (38% in 2003); among users, 38% recommend use for
indications other than spontaneous preterm birth (eg, short cervix, twins); users less concerned with patient’s lack
of insurance than nonusers; nonusers more concerned with safety, efficacy, lack of data, and neonatal effects;
speaker emphasizes intangible costs associated with not using 17P for prevention of preterm birth; meta-analysis
of 3 trials—showed progestational agents significantly reduced risk for delivery at <37 wk; no significant effect
on perinatal mortality or serious neonatal morbidity (numbers not large enough); concluded that larger randomized
controlled trials needed
|
| Costs: $26.2 billion annually attributed to preterm birth ($51,600/infant); speaker believes costs associated with preterm
birth underestimated; using 17P to treat expectant mothers who have had previous spontaneous preterm birth
(reducing incidence of another preterm birth) would reduce short-term and lifetime medical costs in offspring by
$2 billion
|
| Treatment considerations: discontinuing treatment—not recommended; of those who discontinued treatment at
<37 wk gestation, 48% delivered early, compared with 33% who continued treatment; at <35 wk, 31% delivered,
compared with 14% who did not discontinue (same results for <32 wk); adverse outcomes—data from Maternal-
Fetal Medicine Units (MFMU) Network showed no evidence of physical abnormalities in 94% of infants exposed
to 17P (equivalent to placebo group); 28% of infants in treatment and placebo groups scored low for developmental
outcome
|
| BV and preterm birth: data show treating asymptomatic predominantly low-risk women who have BV with 2
doses of 2 g of metronidazole (48 hr apart) on 2 occasions did not reduce preterm birth; antibiotics in women with
preterm labor and intact membranes—studies do not support routine use; preterm premature rupture of membranes
(PPROM)—7 published trials showed antibiotics reduced adverse outcomes for infants; 7-day course
recommended; fetal fibronectin (FFN)—basement membrane protein; produced primarily by fetal tissue, placenta,
and membranes; may help to adhere placenta and membranes to decidua; marker for upper genital tract infection
due to basement membrane disruption; twice as common in women with BV; 16- to 20-fold more common
in women who developed clinical chorioamnionitis; all women with FFN had histologic chorioamnionitis; 6-fold
more common in women whose infants developed sepsis; speculated that, at 24 wk, FFN in vagina or cervix acts as
marker for asymptomatic upper genital tract infection; this later manifests as spontaneous preterm labor or
PPROM, frequently in conjunction with perinatal infection; randomized trial of antibiotic use in 700 women positive
for FFN showed no benefit in reducing spontaneous preterm birth
|
| Tocolysis with magnesium sulfate (MgSO4): Cochrane data—9 high-quality trials showed no difference at 48
hr, compared to control; no benefit in delivery <37 wk or <34 wk; neonatal death higher with MgSO4 (may alter
calcium levels in fetus); insignificant reduction in cerebral palsy
|
| THROMBOPHILIAS: WHEN TO SCREEN AND WHEN TO TREAT DURING PREGNANCY— Baha M.
Sibai, MD, Professor, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine,
Cincinnati, OH
|
| Introduction: conflicting evidence on screening for thrombophilia in pregnancy; every person has some form of
thrombophilia
|
| Adverse pregnancy outcomes: maternal—venous thromboembolism, arterial thrombosis, and severe preeclampsia;
placental—thrombosis and infarcts, abruptio placentae; fetal—recurrent miscarriage, severe intrauterine
growth restriction (IUGR), demise, and stroke (in utero or neonatal stroke)
|
| Frequency of asymptomatic thrombophilia in pregnancy in United States: factor V Leiden mutation present
in ≈2.7% of normal obstetric population (whites 6.1%, blacks 0.8%, Hispanics 1.7%, and Asians 0.7%); prothrombin
gene mutation 3.6%; methylenetetrahydrofolate reductase (MTHFR) common in population (screening not recommended);
combination of factor V Leiden and prothrombin G mutation 3.6%, and combination of factor V
Leiden and MTHFR 12%; speaker believes statistics from early studies associating thrombophilias with adverse
pregnancy outcomes overestimated and exaggerated prevalence, encouraging unnecessary screening
|
| Preeclampsia and antiphospholipid antibody (APA) syndrome: Branch et al (1989) first reported association;
recommended patient with severe preeclampsia at <34 wk be screened for APA; studies throughout United States
suggest prevalence 12% to 33%; subsequent studies have shown no association between APA and preeclampsia;
routine screening for APA syndrome in women with severe preeclampsia not recommended
|
| Adverse outcomes in pregnancy and thrombophilic conditions: preeclampsia—numerous studies worldwide
fail to find evidence supporting association; multicenter Italian study did not find association with mild preeclampsia,
but found association with factor V Leiden, prothrombin gene mutation, and hyperhomocysteinemia and severe
preeclampsia; IUGR—worldwide data conflicting; currently, screening women with IUGR not recommended; fetal
loss—study comparing women having late fetal loss to those with normal outcome in pregnancy showed slight association
with factor V or prothrombin gene mutation; no association with MTHFR; thrombi, vasculopathy, ischemic
necrosis, and villous infarction evident in 76% of observed placentas; speaker concludes underlying
pathophysiology present in placentas of women experiencing fetal loss, whether thrombophilia present or not; subsequent
studies have failed to confirm association; speaker believes no evidence to support screening for thrombophilias
in women with history of stillbirth; abruptio placentae—study from Israel found increased association between
factor V Leiden and prothrombin gene mutation and abruption; study from Africa involving 100 women with abruption
found no evidence of factor V Leiden mutation; data from MFMU Network showed none of 31 women having
abruption positive for factor V Leiden mutation
|
| Obstetric indications for testing for APA: unexplained fetal death, recurrent pregnancy loss, recurrent adverse
outcome, and systemic immunologic disease; diagnosis of APA syndrome—requires one clinical criterion and
one laboratory criterion; required laboratory criteria include lupus anticoagulant, IgG >20 g/L, or IgM 20 g/L
(weakest criterion); prophylaxis for APLA syndrome and pregnancy loss—several randomized trials looked at
use of low-dose aspirin in women with APA syndrome and history of recurrent pregnancy loss; inconsistent results
seen; no evidence-based treatment guidelines available because syndrome complex, and well-designed randomized
controlled trials lacking
|
| Candidates for screening: obtain tests for genetic and acquired thrombophilia in patients with—personal history
of thromboembolism or stroke; speaker does not recommend screening for patients with family history of thromboembolism
or adverse pregnancy outcome (eg, unexplained fetal death, severe preeclampsia, fetal growth
restriction, recurrent miscarriages at 12-20 wk, recurrent miscarriage at <12 wk); counseling against treatment after
screening may be difficult when patient misinformed; risk for thromboembolism postpartum—risk 0.2% in asymptomatic
patient with factor V Leiden heterozygous mutation and no history of adverse event; risk increases to
10% with history of thromboembolism (speaker recommends treatment with adjusted-dose heparin); risk 22% with
factor V Leiden homozygous mutation (patient requires prophylaxis during pregnancy); tests to obtain in women
with adverse pregnancy outcome—ACOG recommends testing for lupus anticoagulant and anticardiolipin antibodies;
speaker does not recommend screening fetus for factor V Leiden mutation or prothrombin gene mutation
because of lack of evidence and lack of treatment options (heparin does not cross placenta); conclusions—
pharmacologic management of woman with thrombophilia should be based on individual risk/benefit assessment;
eg, speaker treats patient with systemic lupus erythematosus (SLE) with hydroxychloroquine; know when to seek
consultation for difficult case
|
Suggested Reading
da Fonseca EB et al: Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of
spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J
Obstet Gynecol 188:419, 2003; Dizon-Townson D et al: The relationship of the factor V Leiden mutation and
pregnancy outcomes for mother and fetus. Obstet Gynecol 106:517, 2005; Grimes DA et al: Magnesium sulfate tocolysis:
time to quit. Obstet Gynecol 108:986, 2006; Hauth JC et al: Reduced incidence of preterm delivery with
metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 333:1732, 1995; Keirse MJ:
Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol 97:149, 1990; Lettieri
L et al: Does “idiopathic” preterm labor resulting in preterm birth exist? Am J Obstet Gynecol 168:1480, 1993;
Kupferminc MJ et al: Severe preeclampsia: high frequency of genetic thrombophilic mutation. Obstet Gynecol
45:96, 2000; Kutteh WH et al: Thrombophilias and recurrent pregnancy loss. Semin Reprod Med 24:54, 2006;
McDuffie RS et al: A rabbit model for bacterially induced preterm; pregnancy loss: intervention studies with ampicillin-sulbactam.
AM J Obstet Gynecol 165:1568, 1991; Meis PJ et al: 17 hydroxyprogesterone for the prevention
of preterm delivery. Obstet Gynecol 105:1128, 2005; Sanchez-Ramos L et al: Progestational agents to prevent
preterm birth: a metaanalysis of randomized controlled trials. Obstet Gynecol 105:273, 2005; Sibai BM et al:
Thrombophilia in pregnancy: who to screen, when to treat. OBG Management 19:50, 2007.
Educational Objectives
| The goals of this program are to reduce the incidence of spontaneous preterm birth and to refine the screening process
for thrombophilias in pregnancy. After hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Identify patients at risk for preterm birth and recognize possible causes of this condition.
|
| 2. Determine appropriate candidates for progesterone therapy for the prevention of preterm birth.
|
| 3. Counsel and manage patients administered progesterone therapy.
|
| 4. Assimilate trial data about the association between thrombophilias and adverse pregnancy outcome.
|
| 5. Determine when to screen for and treat thrombophilia in pregnancy.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Ramin receives
grant and/or research support from Cytokine Pharma Sciences Inc.
Acknowledgements
Dr. Ramin was recorded at the 25th Annual OB/GYN Update, sponsored by HealthPartners Institute for Medical Education,
held on April 12-13, 2007, in Oakdale, MN. Dr. Sabai was recorded at New Concepts in Obstetrics and Gynecology
Conference, sponsored by the University of Miami Miller School of Medicine, held on February 28 to
March 3, 2007, in Miami Beach, FL.
|
