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thesis entitled

VAGINAL BLEEDING DURING THE FIRST 20 WEEKS OF
PREGNANCY AND THE RISK OF PRETERM DELIVERY

presented by
VERONIKA SKOROKHOD

has been accepted towards fulfillment
of the requirements for the

MS. degree in EpidemiologL

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VAGINAL BLEEDING DURING THE FIRST 20 WEEKS OF PREGNANCY
AND THE RISK OF PRETERM DELIVERY

By

Veronika Skorokhod

A THESIS
Submitted to
Michigan State University
in partial fulfilhnent of the requirements
for the degree of
MASTER OF SCIENCE
Epidemiology

2010

ABSTRACT

VAGINAL BLEEDING DURING THE FIRST 20 WEEKS OF PREGNANCY
AND THE RISK OF PRETERM DELIVERY

By
Veronika Skorokhod

This study examined associations between vaginal bleeding in the first 20 weeks
of pregnancy and risk of preterm delivery (PTD) in two ethnic/racial groups. Data were
from the Pregnancy Outcomes and Community Health (POUCH) Study (1998-2004, 5
Michigan communities) and included only women enrolled/interviewed at 20-27 weeks
of pregnancy (78% of the cohort; 1,735 non-Hispanic White and 619 African-American).
Maternal reports of bleeding in the first half of pregnancy were grouped by time of
bleeding (weeks 1-13 only; weeks 14-20 +/- weeks 1-13), duration (524 hrs; >24 hrs) and
amount (spotting/slight; Zusual menstrual period).

The prevalence of bleeding in weeks 1-20 was similar in non-Hispanic Whites
(24.4%) and Afi'ican-Americans (23.4%). In addition these ethnic/racial groups did not
differ with respect to timing, duration and amount of bleeding. The risk of PTD was
increased among women who bled in “weeks 14-20 +/- weeks 1-13” (non-Hispanic
White odds ratio=2.0), for >24 hrs (non-Hispanic White odds ratio=2.0; African-
American odds ratio=1.7), and with amounts “_>_ usual menstrual period” (non-Hispanic
White odds ratio=2.7; African-American odds ratio=2.2). There were no significant
interactions by ethnicity/race. These results suggest that bleeding is associated with
increased risk of PTD but ethnic/racial disparities in PTD risk are more strongly linked to

pathways that do not involve bleeding in the first 20 weeks of pregnancy.

DEDICATION

To my wonderful parents, who always believe in me

iii

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my advisor Dr. Claudia Holzman
for her guidance, inspiration and valuable suggestions during the development of this
thesis; as well as for providing me with valuable research experiences and support as
a graduate assistant. But most of all I am very grateful for her endless patience and
understanding, support and encouragement throughout the difficult times I have
encountered during the last couple of years.

I thankfully acknowledge the other members of my advisory committee
Dr. Hossein Rahbar and Dr. Rachel Fisher for all the time, advice and knowledge they
have given me during the development of this thesis.

I am appreciative to the entire POUCH Study team, especially Dr. Bertha Bullen
for her never-ending patience and all the assistance she provided me with throughout my
research.

I also acknowledge the faculty and staff of the department of Epidemiology for
creating friendly and supportive learning environment.

And finally, but not least, a very special thanks to my family for all their support,
patience, confidence, and love. To my parents, thank you for encouraging me to pursue
my many interests and helping me to achieve my goals. I could not have done this

without you.

iv

TABLE OF CONTENTS

LIST OF TABLES .................................................................................... vi
LIST OF FIGURES ................................................................................. vii
KEY TO ABBREVIATIONS ..................................................................... viii
CHAPTER 1. BACKGROUND .................................................................... 1
1.1 . Introduction .................................................................................... 1
1.2. Preterm Delivery .............................................................................. 1
1.3. Risk Factors for Preterm Delivery ........................................................... 3
1.4. Ethnicity/Race and Preterm Delivery ...................................................... 4
1.5. Antenatal Vaginal Bleeding ................................................................ 6
1.6. Underlying Mechanisms for Antenatal Vaginal Bleeding
and Preterm Delivery ........................................................................ 7
1.7. Summary of Literature Review .............................................................. 9
1.8. Study Aims and Strengths .................................................................. 12
CHAPTER 2. VAGINAL BLEEIDNG DURING THE FIRST 20 WEEKS OF
PREGNANCY AND THE RISK OF PRETERM DELIVERY ............................... 27
2.1 . Introduction ................................................................................. 27
2.2. Subjects and Methods ...................................................................... 28
2.3. Results ........................................................................................ 32
2.4. Discussion ................................................................................... 42
REFERENCES ...................................................................................... 46

LIST OF TABLES

Table 1.1. Rough Guide for Survival and Handicaps among Premature Babies. . . . . . .3

Table 1.2. Studies on Association between Antenatal Vaginal Bleeding
and Preterm Delivery ................................................................................. 14

Table 2.1. Selected Sociodemographic and Pregnancy History Characteristics
of Study Participants ................................................................................. 36

Table 2.2. History of Vaginal Bleeding in the First 20 Weeks of Pregnancy
by Maternal Ethnicity/Race ......................................................................... 38

Table 2.3. Association between Vaginal Bleeding in the First 20 Weeks
of Pregnancy and a Risk of Preterm Delivery by Maternal Ethnicity/Race ................ 39

Table 2.4. Association between Vaginal Bleeding in the First 20 Weeks
of Pregnancy and a Risk of Preterm Delivery ................................................... 40

Table 2.5. Association between Vaginal Bleeding in the First 20 Weeks
of Pregnancy and a Risk of Preterm Delivery by Its Subtypes ................................. 41

vi

LIST OF FIGURES

Figure 1.1. Preterm Deliveries in the US between 1994 and 2004 ............................. 2

Figure 2.1. Underlying Mechanisms for Antenatal Vaginal Bleeding
and Preterm Delivery ................................................................................. 8

vii

APHUO

AVB

A/OR

BMI

BW

CI

D/P

GA

GT

GW

LMP

MI

N/ S

OR

PTD

PTL

PPROM

Ref

KEY TO ABBREVIATIONS

Antepartum Hemorrhage of Unknown Origin
Antenatal Vaginal Bleeding

Adjusted Odds-Ratio

Adjusted Risk-Ratio

Body Mass Index

Body Weight

Confidence Interval

During Pregnancy

Gestational Age

Genital Tract

Gestational Week(s)

Last Menstrual Period

Medically Induced Delivery

Not Specified

Odds Ratio

Preterm Delivery

Preterm Labor

Preterm Premature Rupture of Membrane
Reference Group

Relative Risk

Vaginal Bleeding

viii

CHAPTER 1.

BACKGROUND

1.1 Introduction

Preterm birth currently remains an important issue in prenatal care, since
70-80% percent of all perinatal deaths and a similar proportion of perinatal illnesses
occur in the infants delivered preterm (1,2). The numbers of preterm infants born all over
the world remains high and the problem of preterm delivery is by no means resolved.
Although a large number of studies have been conducted and many factors that increase
the risk of preterm delivery discovered (8,13,19,33) the causes of preterm delivery are not
fully understood and, at this time, often little can be done in order to prevent preterm

birth.

1.2 Preterm Delivery

Preterm delivery (defined as live birth before 37 completed weeks of pregnancy)
is a major public health concern (3). In 2004 in the United States 1 in 8 babies (12.5% of
live births) were born prematurely with 2% of these born very prematurely (live birth
before 34 completed weeks of pregnancy) (4). Preterm delivery rates are especially high
among poor, inner city, and minority pregnant mothers. The rate of preterm birth in the
United States in 2002-2004 (average) was the highest for African-American infants
(17.6%), followed by Native American (13.4%), Hispanic (11.8%), non-Hispanic White
(11.3%), and Asian (10.4%) (4). Despite improvement in many health indicators, the rate

of preterm delivery in the US showed no improvement from 1994-2004 (Figure 1.1).

In fact it continues to increase, reaching 12.7% in 2005 (5) and 12.8% in 2006 (6).

Figure 1.1. Preterm Deliveries in the US between 1994 and 2004

 

Percent Of IIVG births

15-

o 11.4 11.6 11.8115 11.9 12.1 12.3 12.5

11.0 11.0 11

       

104

 

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

 

 

 

Preterm delivery is the second leading cause of infant death in the US. In 2004,
36.5% of all infant deaths in the US were preterm-related (4). Surviving infants are likely
to be at a high risk of damage to the central nervous system resulting in serious disorders
such as cerebral palsy, chronic respiratory problems and infections, as well as long-term
neurological and developmental impairments, mental and cognitive dysfunctions,
increased rate of cardiovascular disorders, hypertension, and diabetes. They may end up

with lifelong handicaps, varying in degree from slight to severe (Table 1.1).

Table 1.1. Rough Guide for Survival and Handicaps among Premature Babies

 

 

 

 

 

 

GeStafiontlwteglfs? Delivery Survival (°/o) Handicaps (%)
24 60 6°
26 95 4°
28 96 25
3O 97 15
32-36 98+ <3

 

 

 

 

 

1.3 Risk Factors for Preterm Delivery

It is impossible to predict which women will deliver prematurely but there are risk
factors associated with an increased risk, and some but not all of these factors are
modifiable. Risk factors for preterm delivery include demographic characteristics,
obstetric history, certain maternal medical conditions, and behavioral factors.
Demographic factors for preterm delivery include African-American race (4,8), extremes
of maternal age (under 17 or over 35 years old) (9-11), low socioeconomic status (12).
Obstetric history includes multiple gestations (14,15), short cervix (less than 2 cm at less
than 24 weeks of gestation) (16,17), incompetent cervix, malformation of the uterus (8),
certain birth defects in a baby, and previous history of preterm delivery (1 8). Maternal
medical conditions include diabetes (28), hypertension (32,33), clotting disorders (64,72-
74). Infections in genitourinary tract also pose a risk (8,19-25). Behavioral factors include
smoking during pregnancy (22-24), alcohol consumption in pregnancy (8,13), illegal
drug use (especially cocaine) while pregnant (25,26), low pre—pregnancy weight, obesity

(28,29), low or excessive weight gain during pregnancy (8).

In addition preterm delivery can be associated with stressful life situations and
certain occupational factors. Some studies have found an association between high levels
of stress caused by anxiety, depression, major life events, such as loss of a job, death of
a family member, divorce, and higher rates of delivering preterm (13,27-30). The theory
is that severe stress can lead to the release of hormones that can trigger uterine
contractions and subsequent preterm delivery. There is evidence that extremely
physically demanding jobs or long working hours play a role in preterm delivery. Women
who had to stand for long periods of time (over 40 hours per week) or had extremely
tiring jobs were more likely to deliver preterm (31,32).

Despite the progress in the field of obstetrics and gynecology, the predictive value
of currently substantiated risk factors for preterm delivery is rather low and there are no

effective treatments to substantially prolong gestation once preterm labor begins.

1.4 Ethnicity/Race and Preterm Delivery

The risk of preterm delivery varies among women in different ethnic/racial
groups. African-American women are at the highest risk of delivering preterm followed
by Native American and Hispanic women. The risk is the lowest for Asian and non-
Hispanic White women (4,50). Furthermore women born in the US (except for some
Asian and non-Hispanic White) are at a higher risk of delivering preterm compared to
foreign-bom women of the same ethnicity/race (50,51).

It seems that father’s ethnicity/race may also affect pregnancy outcomes (51,53).
Compared to women partnered with men of the same race, non-Hispanic White women

partnered with African-American men are at a higher risk of delivering preterm; however

African-American women partnered with White men do not appear to be at an elevated
risk (51). While black women in general are known to have the highest risk of delivering
preterm this risk varies significantly once their ancestry and nativity are taken into
account. The risk appears to be the highest in the US-bom black women compared with
foreign-bom black women (50-52).

The cause for a high risk of preterm delivery among African-American women
remains uncertain. Many suspected demographic and socioeconomic risk factors have
been compared between African-American and White women but these risk factors seem
to account for very little ethnicity/race difference in the rates of preterm delivery (54,55).

There is a number of medical conditions that are associated with preterm delivery
for which African-American women appear to be at a higher risk. African-American
women are significantly more likely to be obese (26-29), to be affected by both chronic
and gestational diabetes (28,30), and have higher risk of developing hypertension (31-33)
than non-Hispanic White women. All of these conditions are also known to be risk
factors for development of preeclamsia, which in turn is one of the causes for preterm
delivery (33). In addition compared to women from other ethnic/racial groups African-
American women have higher rates of preterm delivery associated with prevalent
reproductive tract infections during pregnancy, particularly bacterial vaginosis,

T richomonas vaginalis and Chlamydia trachomatis (22-25).

Furthermore preterm delivery can be associated with stressful life situations
(13,39-42). While African-American women are subjected to more stress (43,44).
they may also have more adverse health effects due to stress (45,47). Cardiovascular

reactivity is one of the indicators of susceptibility to stress and in at least two studies

African-American women had higher levels of cardiovascular reactivity than White
women (45,46).

It is very important to understand why Afiican-American women are at increased
risk of preterm delivery in order to implement effective interventions. One area that has
not been commonly investigated is the role of bleeding in preterm delivery among

African-American women versus White women.

1.5 Antenatal Vaginal Bleeding

Vaginal bleeding is a common complication that may occur at any time during
pregnancy. There are many different reasons why a woman may experience antenatal
vaginal bleeding. The likely cause of vaginal bleeding changes over the course of
pregnancy. Vaginal bleeding in the first trimester of pregnancy is not uncommon,
occurring in 20-30% of all pregnancies (56). It can be associated with normal
implantation of an embryo into the uterine wall (known as implantational bleeding),
cervical changes due to pregnancy or it can be caused by more serious factors, such as
miscarriage (15-20% of pregnancies) (57), ectopic pregnancy (1 in 60 pregnancies) (58)
or molar pregnancy (1 in 1,000 pregnancies) (59).

Vaginal bleeding in the second and third trimesters of pregnancy is less common.
Causes for vaginal bleeding later in pregnancy are different from those in early
pregnancy. Most common causes of vaginal bleeding during second and/or third trimester
are problems with a placenta, such as placental abruption (about 1% of pregnancies) (60)
or placenta previa (1 in 200 pregnancies) (61). Other causes include problems with the

cervix, uterine rupture, and premature labor.

Antenatal vaginal bleeding can also be caused by conditions unrelated to
pregnancy, such as vagina] or sexually transmitted infections (8,19-21), abnormalities of
cervix or vagina, carcinoma or cervical polyps (52), and various kinds of trauma (63).
Different maternal inherited or acquired bleeding disorders can also result in antenatal
vaginal bleeding. They include hemophilia (extremely rare cause, occurs in 1 in 10,000
women) (64) or thrombophilia (72-74). Certain gynecological procedures, such as
Chorionic Villus Sampling (CVS) and Amniocentesis can cause bleeding as well.
However in about 50% of pregnancies the cause of vaginal bleeding is unknown (65,66).
Antenatal vaginal bleeding has been associated with adverse pregnancy outcomes, such

as preterm delivery, low birth weight, stillbirth, and perinatal death (75).

1.6 Underlying Mechanisms for Antenatal Bleeding and Preterm Delivery

The reason for the association between antenatal vaginal bleeding and adverse
pregnancy outcomes, including preterm delivery remains unclear. Different underlying
mechanisms have been suggested (67) (Figure 1.2).

Some cases of preterm delivery may result from thrombin activation (68-71).
Thrombin is a coagulation protein that has many effects in the coagulation cascade. Its
primary role is to convert fibrinogen (a soluble protein that is produced by the liver and
found in blood plasma) to an active form that assembles into fibrin (a protein involved
in the clotting of blood), as well as catalyzing many other coagulation-related reactions.
In addition to its activity in the coagulation cascades, thrombin promotes platelet
activation. Thrombin is also known as a potent uterotonic agonist (69). Due to the

difficulties in the direct measurement of thrombin, indirect measures have been used in

studies to assess the coagulation cascade and activated thrombin production. Most often
studies use the TAT test: thrombin—antithrombin HI (TAT) complex levels measure the
amount of activated thrombin bound to antithrombin HI, an endogenous thrombin
antagonist (68,69).

The bleeding causes the generation of thrombin, which causes an outpouring of
enzymes capable of ripening the cervix and damaging fetal membranes, resulting in
preterm premature rupture of membrane, and leading to preterm delivery (70). On the
other hand thrombin also binds to receptors on uterine muscle cells to trigger

contractions, which may promote preterm labor (71).

Figure 2.1. Underlying Mechanisms for Antenatal Vaginal Bleeding and
Preterm Delivery

 

ANTENATAL
VAGINAL
BLEEDING

 

   
 

 

URO GENITAL
INFECTIONS

 

 

 

 

PRETERM
DELIVERY

 

 

 

 

 

 

Thrombophilia is an abnormality in the coagulation pathways that predisposes an
individual to thrombosis. It can be inherited, acquired or combined. Maternal
thrombophilias increase risk of several adverse pregnancy outcomes including early or
late spontaneous abortions, pre-eclampsia, placental abruption, and intrauterine growth
restriction (72,73). The most common inherited thrombophilias consist of Factor V
Leiden and the prothrombin gene mutation G20210A, and more rare ones include
deficiencies of protein C, S and antithrombin HI. Recently, deficiency of protein Z has
been linked to pregnancy complications, including preterm delivery. It is possible for
more than one inherited thrombophilia to be present (73,74).

Importantly, in the addition to the direct effects of bleeding and thrombin,
bleeding might also result from other underlying problems, such as infection or
inflammation, which in turn can lead to preterm delivery (67). In these cases bleeding

may be more of a marker than a cause. These distinctions can be difficult to determine.

1.6 Summary of Literature Review

Studies on the association between antenatal vaginal bleeding and the risk of
preterm delivery date back to the late 1950’s. The focus in this review is on studies
conducted starting from early 1980’s, since the availability of an ultrasound in this more
recent period made it possible to obtain better estimates of gestational age.

The majority of studies were conducted in various parts of the US, however there
were also studies conducted in Australia, Brazil, China, Egypt, Finland, Germany, India,
Israel, Korea, Pakistan, Saudi Arabia, and United Kingdom. Sample sizes for these
studies range from 75 to 16,506 women. Some studies reported gestational age at the

enrollment into the study. It ranged from 10 to 29 gestational weeks (76,78,79,84).

Bleeding history was mostly collected by maternal questionnaires/interview at the
various stages of pregnancy; however some studies used reviews of medical records
instead or in addition to the maternal self-report. The majority of studies defined preterm
delivery as “live birth at less then 37 completed weeks of gestation”. Studies that
assessed timing of bleeding, did it primarily by trimesters but some studies referred to the
first or second half of pregnancy (80,91). Most studies reported assessing heaviness of
bleeding episodes (78-81,84) but only one study reported taking duration of bleeding
episodes into account (79).

The potential confounders most frequently taken into consideration were maternal
age, ethnicity/race, education, parity, marital status, cigarette smoking, and alcohol
consumption during pregnancy. Some studies also considered medical insurance status,
and elements of medical and obstetric histories. Most studies reported the prevalence of
antenatal vaginal bleeding. It ranged between 4.9% and 35.5% (76,78-80,82-84).

The majority of studies have found a moderate to severe increase in the risk of
preterm delivery associated with antenatal vaginal bleeding (76-84,86—94), particularly
bleeding during first trimester of pregnancy only (78,85), and during the second half of
pregnancy (91,92). One study reported significant increase in the risk of vaginal bleeding
during the second half of pregnancy for women that had some bleeding during the first
half (91). A very limited number of studies have assessed ethnicity/race—specific
differences for the risk of preterm delivery in association with antenatal vaginal
bleeding. Studies that did found ethnicity/race-specific odds-ratios to be greater in non-
Hispanic White than in African-American women (79,80).

There were some differences in results of prior studies. One study found

10

a significant association between preterm delivery and vaginal bleeding during the
second but not first trimester of pregnancy (83). While most of the studies that accounted
for heaviness of bleeding episodes found that the risk of delivering preterm was notably
higher among women with heavier bleeding episodes (78-80,84), one study found no
association between heaviness of bleeding episodes and preterm delivery (84).

A number of factors may potentially account for the differences in the results of
prior studies. First, there have been differences in times in pregnancy when bleeding
history was assessed. Information on bleeding was typically gathered by asking study
participants, and recall bias may have occurred in women queried after delivery or late in
pregnancy following other complications. Second, many studies have failed to include
characteristics of bleeding in their analysis, particularly duration of bleeding episodes.

It is important to take these characteristics into account, since they may influence the
association between antenatal vaginal bleeding and the risk of preterm delivery. Third,
studies have used different definitions of preterm delivery, and bleeding characteristics,
particularly there was great variability in defining heaviness of bleeding episodes.
Finally, studies differed with respect to study design, sample size, and confounders
selected during data collection and statistical analysis.

Among studies on the association between antenatal vaginal bleeding and the risk
of preterm delivery very few studies attempted to separate preterm delivery into its
clinical subtypes (i.e. preterm labor, premature rupture of membrane, and medically
induced delivery) (78,79,93,95). Only one study considered both bleeding characteristics
(timing, duration, and heaviness), and clinical subtypes of preterm delivery (79). One

more study assessed the relation between heaviness of bleeding and the risk of preterm

11

premature rupture of membrane (78). It has been found that antenatal vaginal bleeding
increases the risk of preterm delivery in all subgroups but especially for preterm labor
(79,93,95).

At present time the desirability of separating preterm delivery into its clinical
subtypes remains an open topic. Some researchers maintain that such separation should
be made (95,96) while others oppose it (97). Based on the results of some prior studies it
has been recommend that the subtypes should be examined first, and then combined back
together only if they turn out to be homogenous (95,96). It is firrther recommended that
preterm labor and preterm premature rupture of membrane could be combined into
spontaneous preterm delivery, however medically induced preterm delivery should be
kept separately (95,96).

More studies are needed in order to further understand the association between
vaginal bleeding during pregnancy and the risk of preterm delivery, the underlying
mechanism for this association, and implications for prenatal care. Consideration of
preterm delivery’s clinical subtypes might provide additional insights into these

associations.

1.7 Study Aims and Strengths
Study Aims

The aim of this study is to consider associations between antenatal vaginal
bleeding and the risk of preterm delivery. This aim will be operationalized by considering
characteristics of bleeding (timing, duration, and heaviness of bleeding episodes),

ethnicity/race-specific effect, influence of potential confounding factors, and clinical

12

subtypes of preterm delivery (preterm labor, premature rupture of membrane, and
medically induced delivery).
Study Strengths

Major strengths of this study are prospective design, the fact that women were not
selected based on their bleeding history, and the large sample size. In addition estimates
of gestational age based on the last menstrual period were confirmed using estimates by
an early ultrasound for 90% of study participants. Furthermore, recall bias was minimized
due to the fact that bleeding information was collected early in pregnancy; and
differential reporting was impossible, since at the time of the interview the outcome of
the pregnancy was unknown. Obtaining information by self-report has its limitations and
strengths. Although there is subjectivity in recalling bleeding, self-report is potentially

more accurate and complete than information obtained from medical records.

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26

CHAPTER 2.
VAGINAL BLEEDING IN THE FIRST 20 WEEKS OF PREGNANCY AND THE
RISK OF PRETERM DELIVERY
2.1 Introduction

Vaginal bleeding is common complication that may occur at any time during
pregnancy. There are many different reasons for antenatal vaginal bleeding. The likely
cause of vaginal bleeding changes over the course of pregnancy.

Vaginal bleeding in the first trimester of pregnancy is not uncommon, occurring
in 20-30% of all pregnancies (56). It can be associated with normal implantation of an
embryo into the uterine wall (known as implantational bleeding), cervical changes due to
pregnancy or it can be caused by more serious factors, such as miscarriage (IS-20% of
pregnancies) (57), ectopic pregnancy (1 in 60 pregnancies) (58) or molar pregnancy (1 in
1,000 pregnancies) (59).

Vaginal bleeding in the second and third trimesters of pregnancy is less common.
The most common causes of vaginal bleeding during the second and/or third trimester are
problems with placenta, such as placental abruption (about 1% of pregnancies) (60) or
placenta previa (1 in 200 pregnancies) (61). Other causes include problems with cervix,
uterine rupture, and premature labor.

Antenatal vaginal bleeding can also be caused by conditions unrelated to
pregnancy, such as genitourinary tract infections (8,19-25), abnormalities of cervix or
vagina, carcinoma or cervical polyps (62), and various kinds of maternal trauma (63).
Different maternal inherited or acquired bleeding disorders can also result in antenatal

vaginal bleeding, they include hemophilia (extremely rare cause, occurs in l in 10,000

27

pregnancies) (64), and thrombophilia (72-74). Certain gynecological procedures, such as
Chorionic Villus Sampling (CVS) and Amniocentesis can also cause bleeding. However
in about 50% of pregnancies the cause of vaginal bleeding is unknown (66,80).
Antenatal vaginal bleeding has been associated with adverse pregnancy outcomes, such
as preterm delivery, low birth weight, stillbirth, and perinatal death (75-87,82-92) but the
reason for this association remains unclear (80,90).

Multiple studies have reported positive association between antenatal vaginal
bleeding and preterm delivery (76-92), particularly severe bleeding (78-80,84,86). Fewer
studies have examined variations in bleeding patterns as they relate to the risk of preterm
delivery (79,86). Bleeding in the first half of pregnancy may indicate a prolonged
underlying process or a maternal predisposition. A recent study reported significant
increase in risk of vaginal bleeding in the second half of pregnancy for women that
experienced some vaginal bleeding during the first 20 weeks of pregnancy (91).

In this study we focused on bleeding patterns in the first half of pregnancy among
women who were interviewed at 20-27 weeks of gestation as part of prospective study on
preterm delivery. We were particularly interested in comparing ethnic/racial groups to
examine whether a bleeding-preterm delivery pathway contributes to ethnic/racial

disparities in the risk of preterm delivery.

2.2 Subjects and Methods
Study Protocol
The Pregnancy Outcomes and Community Health (POUCH) Study is a

prospective cohort study of women enrolled from 52 clinics in five economically diverse

28

Michigan communities. Enrollment took place during 1998-2004. A total of 3,038
women were enrolled in their 15-27 weeks of pregnancy; however 19 women were lost to
follow-up. Exclusion criteria included multi-fetal pregnancy, lack of competency in
English, maternal age less less than 15 years, known congenital abnormalities at the time
of enrollment, and pre-pregnancy diabetes mellitus. The POUCH study protocol was
approved by the institutional review boards of Michigan State University, Michigan
Department of Community Health, and all nine delivery hospitals. All study participants
provided informed written consent.

At enrollment each woman met with a study nurse and completed detailed in-
person interview, and a self-administered questionnaire. The following information was
ascertained: demographics (including self-reported ethnicity/race), socioeconomics,
reproductive history, medical conditions, substance abuse, and events during current
pregnancy. Information on vaginal bleeding during current pregnancy was also collected
at this time. Women were asked if they had any vaginal bleeding at any time during
current pregnancy, and for those who did some additional information was collected,
including the week(s) in pregnancy when bleeding began, number of days/hours it
continued for, and how heavy it was (spotting, slight; about the same as usual menstrual
period; or heavier than usual menstrual period). Such information was collected for to up
to seven bleeding episodes.

Study Sample

Our study sample contained non-Hispanic White and African-American POUCH

cohort women enrolled/interviewed at 20-27 weeks of pregnancy. Women enrolled

before 20 completed weeks of pregnancy were excluded (446 women) because of the

29

focus on vaginal bleeding in the first 20 weeks of pregnancy. In addition we excluded
women from ethnic/racial groups other than non-Hispanic White and Afiican-American
due to small numbers (48 Asian, 89 Mexican, 45 other Hispanic, 33 Native American and
4 other). After these exclusions our sample contained 2,354 women (78% the cohort;
1,735 non-Hispanic White, and 619 Afiican-American).
Outcome and Exposure Measures

Preterm delivery was defined as live birth before 37 completed weeks of
gestation, and was further subdivided into the following categories: preterm labor (PTL),
i.e. onset of labor that was not preceded by the rupture of membrane; premature rupture
of membrane (PROM), i.e. rupture of membranes that occurred at any time before the
onset of labor; and medically induced delivery (MI), i.e. delivery due to medical
intervention that was not preceded by preterm labor or premature rupture of membrane.

Gestational age was based on the first day of the last menstrual period (LMP),
and/or on estimate from an early ultrasound (performed at or before 25th week of
pregnancy). Both of these estimates were available for 90% of women. In case these two
estimates differed by more than two weeks (12.8% of women) or if LMP estimate was
unavailable (4% of women) the ultrasound estimate of gestational age was used.

Vaginal bleeding during pregnancy was summarized by three variables: duration,
heaviness, and timing of bleeding episodes. Duration of bleeding episode was divided
into two mutually exclusive categories: up to 24 hours, and over 24 hours. In case
multiple bleeding episodes were reported longest episode was used for the classification.
Heaviness (amount of blood lost during a single bleeding episode) was divided into two

mutually exclusive categories: “spotting/slight”, and “same or heavier than usual

30

menstrual period”. In case of multiple episodes classification was made based on the
most severe one. Timing was divided into two categories “bleeding in weeks 1-13 only”
(i.e. first trimester), and “bleeding in weeks 14-20 +/- weeks 1-13”. Preliminary analysis
revealed a similar risk of preterm delivery in women with bleeding during 14-20
gestational weeks only, and those with bleeding during 14-20 gestational weeks and
during l-l3 gestational weeks. As a result these two groups of women were combined
into a single group.

The potential confounding variables included maternal age, education, parity,
marital status, Medicaid status, cigarette smoking, and alcohol consumption during
pregnancy. Information on all confounders was obtained in a detailed in-person
interview, and a self-administered questionnaire at the time of enrollment into the study.
Analytic Strategy

The prevalence of bleeding (by timing, duration, and heaviness) was compared
across two ethnic/racial groups (Afiican-American versus non-Hispanic White) using a
Chi-square test. Logistic regression models were used to examine the relation between
vaginal bleeding and preterm delivery. Separate ethnicity/race-specific logit models were
constructed for each of the three bleeding variables (timing, duration, and heaviness).
Bleeding variables were categorized into three levels with “no bleeding” as a referent
category. Statistical analyses were conducted with and without adjustment for potential
confounders. The potential confounders that were adjusted for in the logistic regression
models included maternal age (categorized as 15-19, 20-29, and >30 years of age),
education (<12, =12, and >12 completed years of schooling), parity (no previous live

birth, previous live birth/preterm, and previous live birth/term), Medicaid status (yes/no),

31

marital status (married/living with husband, married/not living with husband, not
married/living with partner, and not married/not living with partner), cigarette smoking
during pregnancy (no smoking during pregnancy, quit smoking before enrollment,
smoking up to 1/2 pack per day at enrollment, and smoking over ‘/2 pack per day at
enrolment), and alcohol use during pregnancy (yes/no).

Polytomous regression was used to assess the relations between bleeding and
delivery outcome, i.e. three preterm delivery subtypes (preterm labor, preterm rupture of
membrane, medically induced), and term (referent category). Separate models were
constructed for each of the tree bleeding variables (timing, duration and heaviness).
Bleeding variables were categorized into three levels with “no bleeding” as a referent
category. All statistical analysis were performed using Statistical Analysis System

Software (Release 9.1.2, SAS Institute, Inc., and Cary, NC).

2.3 Results

The distributions of selected maternal socio-demographic and pregnancy history
characteristics of study participants are presented in Table 2.1. Among study women
84.1% were enrolled into the study in their 20th-24th week of pregnancy, 46.7% were
insured by Medicaid, and 10.4% delivered preterm.

The history of any vaginal bleeding in the first 20 weeks of pregnancy was very
similar in non-Hispanic White (24.4%) and African-American (23.4%) (Table 2.2).
Distribution of timing, duration, and heaviness of bleeding were also similar in both
groups. Percentages in Afiican-American women versus non-Hispanic White were not

statistically different. In the ethnicity/race-specific analysis, risk of preterm delivery was

32

increased in all bleeding groups; however it was especially high in women with bleeding
“in weeks 14-20 +/- weeks 1-13” (14.3% among non-Hispanic White and 13.7% among
African- American women), women with bleeding that lasted for over 24 hours (14.4%
among non-Hispanic White and 21.6% among Afiican-American), and women with the
amount of bleeding described as “same or greater then usual menstrual period” (18.1%
among non-Hispanic White and 26.1% among African-American) (Table 2.3). Within the
bleeding groups there was no significant ethnic/racial difference in the risk of preterm
delivery. Ethnicity/race—specific odds ratios (OR) for preterm delivery in association with
bleeding appeared greater in non-Hispanic White (OR range 1.6-2.7) than in Afiican-
American women (OR range 1.0-2.2) (Table 2.3); however this was due to the fact that
the “no bleeding” group in African-American women had a higher risk of preterm
delivery (13.9%) compared to that in non-Hispanic White (7.6%): OR=2.0, 95% CI: 1.4-
2.7. Adjustment for potential confounders, including maternal age, education, parity,
marital status, Medicaid status, cigarette smoking, and alcohol consumption during
pregnancy did not change odds-ratio estimates by more than 10%. Since there was no
significant interactions between ethnicity/race and any of the bleeding characteristics
(p=0.34 for timing, p=0.50 for duration, and p=0.51 for heaviness) African-American and
non-Hispanic White women were combined for further analysis.

Table 2.4 shows the association between vaginal bleeding in the first 20 weeks of
pregnancy and the risk of preterm delivery in the model that combined racial/ethnic
groups. The risk appeared to be increased in all bleeding groups but especially high in
women with amount of bleeding described as “same or greater then usual menstrual

period” (OR=2..4, 95% CI: 1.5-4.0), and women with bleeding that lasted for over 24

33

hours (OR=1.8, 95% CI: 1.3-2.7). As for the timing of bleeding, the risk of preterm
delivery appeared to be the same in both groups: bleeding “in weeks l-13 only” and “in
weeks 14-20 +/- weeks 1-13” (OR=1.6, 95% CIs: 1.1-2.2 and 1.0-2.5 respectively).

The results of analysis for the association between vaginal bleeding in the first 20
weeks of pregnancy and preterm delivery subtypes, i.e. preterm labor (PTL), preterm
premature rupture of membrane (PPROM), medically induced (MI), are presented in
Table 2.5. Of all preterm deliveries 41.2% were preceded by PTL, 26.1% were preceded
by PROM, and the remaining 32.7% were delivered with medical intervention. Women
with bleeding “in weeks 14-20 +/- weeks 1-13” were at high risk of both PROM
(OR=1.9, 95% CI: 0.9-4.1) and medically induced delivery (OR=1.8, 95% CI: 0.9-3.7).
However risk of PTL was higher in women with bleeding “in weeks l-l3 only” (OR=1.9,
95% CI: 1.2- 3.0). Women with bleeding that lasted for over 24 hours were at high risk of
medically induced delivery (OR=2.1, 95% CI: 1.2- 3.8) and PROM (OR=1.9, 95% C1:
1037). The risk of PTL was lower, and very similar in both groups: women with
bleeding that lasted for up to 24 hours, and women with bleeding that lasted for over 24
hours (OR=1.7, 95% CI: 1.0-2.9 and OR=1.6, 95% CI: 0.9-2.9 respectively). Women
with the amount of bleeding described as “same or greater then usual menstrual period”
were at very high risk of PTL (OR=3.4, 95% CI: 1.8-6.5). Risk of PROM in this group
was lower but still very high (OR=2.5, 95% CI: 1.1-6.1). However the risk of medically
induced delivery was higher in women with the amount of bleeding described as
“spotting/slight” (OR=1.7, 95% CI: l.0-2.8). Overall the strongest association was found
between heavy bleeding (described as “same or greater than usual menstrual period”) and

both spontaneous subtypes of preterm delivery (for PTL: OR=3.4, 95% CI: 1.8-6.5 and

34

for PROM: OR=2.5, 95% CI: 1.1- 6.1). Medically induced delivery was most strongly

related to bleeding that lasted for over 24 hours (OR=2.1, 95% CI: 1.2-3.8).

35

Table 2.1. Selected Sociodemographic and Pregnancy History Characteristics
of Study Participants

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Maternal Characteristics N (%)

AGE

15-19 355 (15.1)

20-29 1,325 (56.3)

230 674 (28.6)
RACE

White Non-Hispanic 1,735 (73.7)

African-American 619 (26.3)
PARITY

No Previous Live Birth 1,024 (43.5)

Previous Live Birth/Preterm 105 (4.5)

Previous Live Birth/Term 1,225 (52.0)
EDUCATION (years) T

< 12 409 (17.4)

= 12 698 (29.7)

> 12 1,244 (52.9)
MEDICAID T

Have Medicaid 1,100 (46.7)

Do not have Medicaid 1,251 (53.1)
GESTATIONAL AGE AT ENROLLMENT (wks) I

20-22 1,180 (50.1)

23-24 800 (34.0)

25-27 374 (15.9)
GESTATIONAL AGE AT DELIVERY (wks)

< 35 79 (3.4)

35-36 166 (7.0)

2 37 2,109 (89.6)

 

 

 

 

36

Table 2.1. (cont’d)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Maternal Characteristics N (%)

MARITAL STATUS T

Married, living w/husband 1,182 (50.2)

Married, not living w/husband 14 (0.6)

Not married, living w/partner 533 (22.6)

Not married, not living w/partner 618 (26.3)
CIGARETTE SMOKING IN PREGNANCY T

No smoking during pregnancy 1,689 (71.8)

Quit smoking before the enrollment 242 (10.3)

Smoking (5 ‘/2 pack p/day) during pregnancy 282 (12.0)

Smoking (>'/2 pack p/day) during pregnancy 137 (5.8)
ALCOHOL CONSUMPTION IN PREGNANCY T

Yes 443 (18.8)

No 1,896 (80.5)

 

* Women other than non-Hispanic White and African-American are not included.
T Missing values: education-3, Medicaid-3, marital status-7, smoking-4, alcohol-15.
1 Women enrolled into study during 15-19 weeks of pregnancy are not included.

37

 

Table 2.2. History of Vaginal Bleeding in the First 20 Weeks of Pregnancy by
Maternal Ethnicity/Race

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nonfiizanic African-American
(N=1,735) (N=619)
N (%) N (%)
TIMING
No Bleeding in weeks 1-20 1,311 (75.6) 474 (76.6)
Bleeding in weeks 1-13 only 298 (17.2) 94 (15.2)
Bleeding in weeks 14-20 +/- weeks 1-13 126 (7.2) 51 (8.2)
DURATION *
No Bleeding 1,311 (75.6) 474 (76.7)
Short: 5 24 hours 223 (12.8) 93 (15.1)
Long: > 24 hours 201 (11.6) 51 (8.2)
HEAVINESS T
No Bleeding 1,311 (75.6) 474 (76.7)
Light: Spotting/Slight 340 (19.6) 121 (19.6)
Heavy: Z Menstrual Period 83 (4.8) 23(3.7)

 

 

 

* 1 African-American has missing data.
T 1 African-American and l non-Hispanic White have missing data.

38

 

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39

Table 2.4. Association between Vaginal Bleeding in the First 20 Weeks of

Pregnancy and Preterm Delivery

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Term Preterm
N (%) N(%) OR ( 95% CI )
TIMING
No bleeding in weeks 1-20 1,619 (90.7) 166 (9.3) Ref
Bleeding in weeks 1-13 only 338 (86.2) 54 (13.8) 1.6 (1.1, 2.2)
Bleeding in weeks 14-20+/-1-13 152 (85.9) 25 (14.1) 1.6 (1.0, 2.5)
DURATION *
No bleeding 1,619 (90.7) 166 (9.3) Ref
5 24 hours 277 (87.7) 39 (12.3) 1.4 (0.9, 2.0)
> 24 hours 212 (84.1) 40 (15.9) 1.8 (1.3, 2.7)
HEAVINESS T
No bleeding 1,619 (90.7) 166 (9.3) Ref
Spotting / Slight 403 (87.4) 58 (12.6) 1.4 (1.0, 1.9)
2 Menstrual Period 85 (80.2) 21 (19.8) 2.4 (1.5, 4.0)

 

 

* 1 missing value in Term.
T 2 missing values in Term.
NOTE: Term is a reference category.

40

 

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41

2.4 Discussion

A number of previous studies have reported increased risk of preterm delivery
associated with antenatal vaginal bleeding (76-95), particularly during the first trimester
of pregnancy (78,85,93), and during the second half of pregnancy (91,92). It has also
been reported that vaginal bleeding during the first half of pregnancy significantly
increases the risk of vaginal bleeding during the second half of pregnancy (91).

A very limited number of studies have assessed ethnic/race—specific differences in
the relations between preterm delivery and antenatal vaginal bleeding. Those studies
reported that odds-ratios were greater in White than in African-American women (79,80).
Similarly in our study we found that ethnic/race-specific odds-ratios for preterm delivery
in association with vaginal bleeding during the first 20 weeks of pregnancy were greater
in non-Hispanic White than in African-American women; however this was primarily
due to the higher risk of preterm delivery in “non-bleeders” (reference group) among
Afi'ican-American women compared to non-Hispanic White and there were no
statistically significant interactions by race/ethnicity. Thus our study suggests that
ethnic/racial disparities in the risk of preterm delivery are not mediated by pathways
associated with vaginal bleeding in the first 20 weeks of pregnancy.

It is important to take bleeding characteristics (i.e. timing of bleeding, duration
and heaviness of bleeding episodes) into account, since they may influence association
between antenatal vaginal bleeding and the risk of preterm delivery. Many studies on
antenatal vaginal bleeding and the risk of preterm delivery assessed timing of bleeding
episodes (76,77,79-83,85,86,90-93) and some assessed heaviness (78-81,84,86);

however only one study considered duration of bleeding episodes (79). While most of the

42

studies that considered heaviness of bleeding episodes found that the risk of preterm
delivery was notably higher in women with heavier bleeding episodes (78-80,84) some
studies found no association between heaviness of bleeding episodes and the risk of
preterm delivery (81-86). Our detailed analyses using bleeding characteristics were
consistent with previous findings, and suggested a dose effect with higher risk of preterm
delivery as severity of bleeding increased. It was noted in our study that associations
between the risk of preterm delivery and less severe bleeding were evident but weaker,
an important nuance for prenatal care.

There are a number of factors that may potentially account for some of the
differences in results of prior studies. First, many studies failed to include characteristics
of bleeding in their data analysis. Second, studies used different definitions of bleeding
characteristics, especially for heaviness of bleeding episodes. Finally, different study
designs, various sample sizes, and degrees of control for potential confounders in both
data collection and statistical analysis were used by different authors.

Among the many studies on vaginal bleeding during pregnancy and risk of
preterm delivery very few have attempted to separate preterm delivery into its clinical
subtypes, (i.e. PTL, PROM, and MI) (78,79,93,95). It has been reported that antenatal
vaginal bleeding increases the risk of PTD in all subgroups but especially for PTL (79,
93,95). Only one study looked at the association between vaginal bleeding and risk of
preterm delivery using both bleeding characteristics (timing, duration, and heaviness),
and clinical subtypes of preterm delivery (79). One more study assessed the relation

between heaviness of bleeding and the risk of PPROM (78).

43

In our study we found that both heavy bleeding (described as “same or greater
than usual menstrual period”), and bleeding that lasted for over 24 hours were strongly
associated with the risk of both spontaneous subtypes of preterm delivery (PTL and
PROM). We also found increased risk of PROM in a group with bleeding described as
“spotting/slight”. All these findings were consistent with findings fiom other studies (78,
79). We also found strong associations between bleeding that lasted for over 24 hours and
the risk of medically induced delivery and between bleeding “in weeks 1-13 only” and
the risk of PTL. These findings contradicted the findings reported by Yang et a1 (79).

There has been much debate in the literature as to whether preterm delivery
should be separated into its clinical subtypes. While some researchers insist on
separation (95 ,96) others stand against it, arguing that these subtypes may not be
etiologically different, may be confounded by differences in access to medical care, and
may be subject to misclassification (97). Some investigators recommend that the subtypes
be examined first, and if they appear to be homogenous, combine them back together (95,
96). In at least two studies, results showed that the overall set of risk factors associated
with preterm labor and premature rupture of membrane was the same but different from
those for medically induced preterm delivery. Given these findings the authors
recommended that preterm labor and preterm premature rupture of membranes be
combined into spontaneous preterm delivery and that medically induced preterm delivery
be considered separately (95,96).

Our study has its strengths and limitations. Major strengths of this study are the
large sample size, prospective design, the fact that women were not selected into the

study based on their bleeding history, and confirmation of gestational age estimates based

44

on the last menstrual period using early ultrasound estimates for 90% of study women.
Furthermore, the interval fi'om period of bleeding during the first 20 weeks of pregnancy
to time of maternal interview was short, thus minimizing recall bias; women were able to
report up to seven bleeding episodes, and prospective collection eliminated the possibility
of differential reporting based on women’s knowledge of pregnancy outcome. Reliance
on maternal self-report for information about vaginal bleeding episodes has its limitations
and strengths. While there is subjectivity in recalling bleeding, self-report is potentially
more accurate and complete than information obtained from medical records. It is
possible that women might mistake an early vaginal bleedings as a menstrual period or
vise versa but confirmation of gestational dates by ultrasound helps to reduce bias
introduced by these types of mistakes. However potential reporting bias could be
introduced by the possibility that women known to be at higher risk of delivering
preterm, such as those with prior preterm deliveries, might over-report their vaginal
bleeding because of increased anxiety during the current pregnancy. It is important to
note that our study did not include women who miscarried prior to 20 weeks of
pregnancy, and women who suffered fetal loss sometime between 20th and 27th weeks of
pregnancy.

More studies are needed in order to further understand the association between
vaginal bleeding during pregnancy and preterm delivery and the underlying mechanism
for this association in order to be able to make recommendations for prenatal care. This
study points to the importance of carefully considering bleeding characteristics,
ethnic/racial differences, and clinical subtypes of preterm birth in pathways to preterm

delivery.

45

10.

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