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A Bell & Howell information Company
300 North Zeeb Road. Ann Arbor. M l 48106-1346 USA
313/761-4700 800/521-0600
RHESUS INCOMPATIBILITY AS A PRE- AND PERINATAL
RISK-FACTOR OF SCHIZOPHRENIA
IN MALE ADULTS
by
Julia Megginson Hollister
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(Clinical Psychology)
August 1995
Copyright 1995 Julia Megginson Hollister
UMI Number: 9616969
Copyright 1995 by
Hollister, Julia Megginson
All rights reserved.
UMI Microform 9616969
Copyright 1996, by UMI Company. AH rights reserved.
This microform edition is protected against unauthorized
copying under Title 17, United States Code.
UMI
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UNIVERSITY OF SOUTHERN CALIFORNIA
THE GRADUATE SCHOOL
UNIVERSITY PARK
LOS ANGELES. CALIFORNIA 90007
This dissertation, written by
Julia Megginson Hollister
under the direction of hzr. Dissertation
Committee, and approved by all its members,
has been presented to and accepted by The
Graduate School, in partial fulfillment of re
quirements for the degree of
DOCTOR OF PHILOSOPHY
Dean o f Graduate Studies
Date
DISSERTATION COMMITTEE
Chairperson
ACKNOWLEDGEMENTS i i
There are a number of people I would like to acknowledge for the important roles
they played in my professional and personal development, without whom this dissertation
could not have been completed.
I would like to thank Bill McClure who, when I was an unfocused 19 year-old,
redirected me to the paths of academia and reminded me that I had a brain in my head that
I should use. Next, I would like to thank Mike Dawson who, when I was 21 taught me
the basics of research design, inspired me with his love of research, and helped me
establish research as my own focus. Then, at 24, there is Samoff Mednick who believed in
me enough to see that I got into the graduate program, who has inspired my creative side
with his own extremely creative mind, and has been such a generous mentor, thank-you.
And, at 25, during that first year of the program, when personal doubts surfaced, I'd like
to thank Adrian Raine who talked me out of my doubts, and has provided an eager ear for
my research ideas. I would like to thank Mitch Earleywine in helping me overcome my
phobia of statistics. I count all of you as indispensable in my professional development,
and see you as life-long friends as well as colleagues.
Speaking of indispensable, I would like to thank Susan Stack, without whom our
lab would fall apart, and who has provided a constant place of support and encouragement
for me over the past five years. I also consider her as very instrumental in the
development of my dissertation topic. Being Rh negative as I am, she was, early on, very
interested in my ideas about Rh incompatibility. And, there is Patty Brennan, the
friend/resident therapist/statistician/colleague who has been there for me on so many
occasions. I feel very fortunate to have gained both of you as friends who will remain in
my life, long past graduate school.
A smile and a chuckle, Karen Dykes, my partner in crime, without whom I
probably wouldn't have made it through that first year of graduate school not to mention
I l l
the next four. Thanks for the countless times you listened to my self-doubts, and patiently
listened to me rehearse my talks over and over and over. Thanks Karen for your unfailing
friendship.
The last and most important thank-you is reserved for my very special family,
Mom, Dad, John and Annick. I just wanted to say that I'm pretty damn proud of all of us
for taking a tragic turn of events such as a family member developing as debilitating an
illness as schizophrenia, and being able to redirect the pain, anger, and frustration into
positive avenues. Thank-you Mom, Dad, John and Annick for being a family that has held
together and supported one another. I love you all very much.
CONTENTS iv
LIST O F TA BLES..................................................................................................................... vi
A BSTRA CT...............................................................................................................................viii
CH A PTER 1 INTRO D U CTIO N........................................................................................... 1
1.1 Obstetric Complications....................................................................................................1
1.2 Infuenza Studies.................................................................................................................6
1.3 Rhesus Incompatibility, Rhesus Hemolytic Disease in the Fetus and
Newborn........................................................................................................................... 10
1.4 Hypotheses........................................................................................................................ 13
CH A PTER 2 M ETH OD ..........................................................................................................14
2.1 Sample............................................................................................................................... 14
2.2 Risk Group Classification.............................................................................................. 15
2.3 Psychiatric Diagnoses...................................................................................................... 15
2.4 Birth Order........................................................................................................................ 16
2.5 Demographic Features of Rh Incompatible and Rh Compatible
Schizophrenics................................................................................................................ 16
2.6 Possible Clinical Signs of Hemolytic Disease of the Fetus and Newborn................ 17
2.7 Possible Confounds......................................................................................................... 17
2.8 Statistical Procedures...................................................................................................... 17
CH A PTER 3 RESULTS.........................................................................................................20
3.1 Psychiatric Diagnoses..................................................................................................... 20
3.2 Birth Order........................................................................................................................20
3.3 Demographic Features of Rh Incompatible and Rh Compatible
Schizophrenics................................................................................................................ 21
3.4 Possible Clinical Signs of Hemolytic Disease of the Fetus and Newborn............... 23
3.5 Possible Confounds.........................................................................................................26
3.6 Comparisons Using a Subsample of Rh Compatible Subjects..................................27
CH A PTER 4 DISCUSSION.................................................................................................32
4.1 Limitations of Study....................................................................................................... 32
4.2 Advantages of Study....................................................................................................... 33
4.3 Psychiatric Diagnoses..................................................................................................... 34
4.4 Birth Order........................................................................................................................36
4.5 Demographic Features of Rh Incompatible and Rh Compatible
Schizophrenics................................................................................................................ 37
4.6 Possible Clinical Signs of Hemolytic Disease of the Fetus and Newborn............... 38
4.7 Suggestions for Future Research................................................................................... 39
4.8 Conclusions..................................................................................................................... 41
G LOSSARY................................................................................................................................43
R EFER EN C ES..........................................................................................................................45
LIST OF TABLES v i
TABLE
1 Studies examining the relationship between childhood psychoses and obstetric
complications (page 2)
2 Studies examining the relationship between schizophrenia and obstetric complications
using siblings, psychiatric patients and normals as controls (page 3)
3 Studies examining the relationship between schizophrenia and obstetric complications
using monozygotic discordant and concordant twin pairs (page 4)
4 Maternal exposure to the 1957 influenza epidemic during pregnancy and risk for
schizophrenia in those offspring (page 7)
5 Multi epidemic studies of influenza exposure during pregnancy and risk for
schizophrenia in those offspring (page 8)
6 Rate of psychiatric diagnoses in Rh incompatible and Rh compatible male adults (page
20)
7 Rate of schizophrenia in Rh incompatible and Rh compatible adult males by birth order
(page 21)
8 Comparison of demographic variables (continuous and descriptive) in Rh incompatible
and Rh compatible schizophrenics (page 22)
9 Comparisons of demographic variables (dichotomous) in Rh incompatible and Rh
incompatible schizophrenics (page 23)
10 Possible clinical signs of HDN in Rh incompatible and Rh compatible groups
(page 24)
11 Possible clinical signs of HDN in schizophrenic and non schizophrenic groups
(page 25)
12 Comparison of Rh incompatible and Rh compatible groups on demographic variables
related to characteristics of the parents (page 27)
13 Comparison of the Rh incompatible group and the Rh compatible group #2 on
demographic variables related to characteristics of the parents (page 28)
14 Rate of psychiatric diagnoses in the Rh incompatible group and the Rh compatible
group #2 (page 29)
15 Rate of schizophrenia in the Rh incompatible group and the Rh compatible group
#2 by birth order (page 29)
16 Possible clinical signs of HDN in the Rh incompatible group and the Rh compatible
group #2 (page 30)
ABSTRACT v i i i
Hemolytic disease of the fetus and newborn is the result of transplacentally
transmitted maternal antibodies and can result in permanent neurological damage to the
affected newborn. The most common and most serious cause of hemolytic disease of the
fetus and newborn is Rhesus incompatibility. Rhesus incompatibility occurs in pregnancies
in which the offspring is "Rh positive" and the mother is "Rh negative". This study
examines the hypothesis that Rhesus incompatibility may be a risk factor of schizophrenia
in adulthood.
The research was conducted using data from the Danish Perinatal Cohort. The
sample consisted of 1,867 male subjects who were bom in Copenhagen between 1959 and
1961. Extensive data were collected concerning the pregnancy, the birth, and the
condition of the newborn. In 1992-1993, the Danish Psychiatric Register was accessed to
obtain psychiatric hospital diagnoses (ICD-8) of all individuals in this cohort (mothers,
fathers, and children). The 1,867 subjects were separated into two groups— the Rhesus
incompatible group (n=535)-and the Rhesus compatible group (n=1332) and compared
on rate of serious psychiatric illnesses.
The rate of schizophrenia was significantly higher in the Rhesus incompatible
group as compared to the Rhesus compatible group, 2.1% and 0.8%, respectively (p<.03).
In addition, since the risk of Rhesus hemolytic disease increases with second and later
incompatible pregnancies, birth order was also considered in the hypotheses. Later born
Rhesus incompatible offspring were hypothesized to be at greater risk for schizophrenia
and no differences in rate of schizophrenia were predicted among first born offspring. The
findings supported the hypotheses. Second and later bom Rhesus incompatible offspring
were significantly more likely to develop schizophrenia than second and later bom Rh
compatible offspring (p<.05), 2.6% versus 0.8%, respectively. Also, as predicted, the rate
of schizophrenia among first bom Rhesus incompatible subjects was not significantly
different from that of first bom Rhesus compatible subjects (1.1% versus 0.7%). There
were no significant differences observed between the two groups for other serious
psychiatric illnesses. These data indicate that Rhesus incompatibility may be a risk factor
that is specific to schizophrenia.
In addition, further analyses were conducted to ascertain whether clinical signs of
hemolytic disease at birth were associated with later development of schizophrenia, and to
examine whether the clinical picture of the Rhesus incompatible and Rhesus compatible
schizophrenics differed in any way. The Rhesus incompatible group had more clinical
signs of hemolytic disease, however, no conclusions could be made regarding the
relationship of these factors to schizophrenia. Likewise, no significant differences were
observed between the two groups of schizophrenics. However, due to the small number
of schizophrenics in both groups, further research is warranted before firm conclusions can
be drawn.
CHAPTER 1
Introduction
Increasing focus in the scientific community is directed toward the
neurodevelopmental model of schizophrenia. Studies examining risk factors for
schizophrenia are finding evidence of a link between gestational factors and the
development of schizophrenia later in life. Influenza exposure or infection during the
second trimester of gestation and the preponderance of pregnancy and birth complications
in those individuals who develop schizophrenia in adulthood lend support for the
contention that schizophrenia has its origins in prenatal life. This dissertation will provide
a brief review of studies examining the relationship between pre- and perinatal factors such
as obstetric complications, and influenza exposure and infection during gestation, and risk
for schizophrenia before presenting a novel hypothesis that combines considerations from
both these areas.
1.1 Obstetric Complications
In 1939, Barney Katz presented his dissertation which was the first empirical test
of the hypothesis that obstetric complications are important in the etiology of
schizophrenia (Katz, 1939). In the 1960's, research again turned towards obstetric
complications as a possible cause of schizophrenia, and today obstetric complications
stand out as a solidly replicated risk factor of schizophrenia. Obstetric complications
(OCs) are broadly defined as deviations from a normal, expected course of fetal
development during pregnancy, labor-delivery, and the early neonatal period. Temporally,
OCs are divided into pregnancy complications (PCs, from conception to labor's onset),
birth complications (BCs, during labor and delivery), and neonatal complications (NCs,
from postpartum through the first 4 weeks of life) (McNeil, 1988).
Studies examining the relationship between OCs and schizophrenia include
comparisons of schizophrenics to normal twins, to normal siblings, to unrelated normal
controls or to psychiatric controls. Some studies examine specific items, other studies use
scales, and still others use weighted scores with specific items. Some of the studies focus
on PCs, BCs, and NCs individually, and others combine them into a broad category of
OCs. The method of acquiring data varies from retrospective collection or review of
medical charts, retrospective interviews with mothers of schizophrenics, to prospective
collection of data in large perinatal cohort designs. The relationship between OCs and
schizophrenia has been examined in many different countries, using different obstetric
systems, different schizophrenic samples, and over a span of many years. Tables 1, 2 and
3 present a summary of the many studies examining OCs and schizophrenia.
TABLE 1
Studies examining the relationship between childhood psychoses and obstetric complications
Study Sample Findings
Vorster (1960) Childhood schizophrenia More PCs and BCs
Knobloch &
Pasmanick (1962)
Childhood schizophrenia
Autism
More PCs and BCs
Hinton (1963) Childhood psychotics More PCs
Taft & Goldfarb (1964) Childhood schizophrenia More PCs and BCs
Zitrin, Ferber & Cohen
(1964)
Childhood schizophrenia
Autism
No difference
Terris, LaPouse,
& Monk (1964)
Childhood schizophrenia No difference
Whittam, Simon,
& Mittler (1966)
Childhood psychotics More BCs
Rutt & Offord (1971) Childhood schizophrenia More BCs
Bender(1973) Childhood schizophrenia More BCs
Mura (1974) Childhood psychotics More PCs and BCs
Torrey & Hersch (1975) Childhood psychotics More PCs
3
T A B L E 2
Studies examining the relationship between schizophrenia and obstetric complications using siblings,
psychiatric patients and normals as controls.
Study N Findings
100 schizophrenics
100 controls
52 schizophrenics
115 siblings
33 schizophrenics
33 siblings
34 schizophrenics
42 siblings
46 schizophrenics
37 normal siblings
17 abnormal siblings
54 process schizoprenics
46 psychotics
100 controls
63 schizophrenics
63 controls
12 schizophrenics
25 schizotypals
55 high risk controls
Lewis & Murray (1987) 955 psychiatric patients
Katz (1939)
Lane & Albee (1966)
Pollack et al. (1966)
W oem eretal. (1971)
Woemer et al. (1973)
McNeil & Kaij (1978)
Jacobsen & Kinney
(1980)
Pamas et al. (1982)
Owens etal. (1988)
DeLisi etal. (1988)
61 schizophrenics
11 schizophrenic sibling
pairs; 2 schizophrenics
18 controls
Nimgaonkar et al. (1988) 18 "familial"
30 "non-familial"
Eagles etal. (1990)
Foerster et al. (1991)
schizophrenics
27 schizophrenics
27 normal siblings
51 schizophrenics
5 schizophreniform
38 affective psychotics
Schizophrenics more OCs
Schizophrenics lower birth weight
No difference
Schizophrenics lower birth weight
Schizophrenics more PCs & BCs than
normal sibs
Process schizophrenics more PCs & BCs
Schizophrenics more frequent & severe BCs
Schizophrenics worse OCs
Schizotypals least OCs
Schizophrenics more OCs than other
psychiatric patients
Large VBR more OCs
Schizop.hrenics more OCs, no differences
between schizophrenics with and without
BCs
No difference
Schizophrenics more OCs
Schizophrenics more OCs
McGreadie et al. (1992) 54 schizophrenics
114 siblings
Verdoux & Bourgeois
(1993)
Heun & Maier (1993)
Gurcjeetal. (1994)
Gunther-Genta ct al.
(1994)
Cantor-Graae et al.
(1994)
23 schizophrenics
23 bipolar
23 normal controls
43 schizophrenics
74 siblings
28 schizoaffectives
59 siblings
26 schizophrenics
12 manics
42 schizophrenics
40 siblings
174 controls
70 schizophrenics
70 controls
No differences
Schizophrenics more PCs
Female more PCs, males no difference
Patients more OCs
Male schizophrenics more OCs
Female schizoaffectives more OCs
Perinatal and early childhood head trauma
more in schizophrenics
PC, BC scales-no difference
Asphyxia scale schizophrenics higher than
sibs but not conrols
Schizophrenics more OCs
TABLE 3
Studies examining the relationship between schizophrenia and obstetric complications using
monozygotic discordant and concordant twin pairs
Study N
Polin & Stabenau (1968) 100 disc MZ twins
Goltesman & Shields
(1972)
McNeil & Kaij (1978)
R eveleyetal. (1983)
Onstadetal. (1992)
Torrey et al. (1994)
McNeil et al. (1994)
82 disc twin pairs
39 disc twin pairs
21 cone sz MZ twin pairs
18 normal MZ twin pairs
8 cone sz MZ twin pairs
14 disc sz MZ twin pairs
23 disc sz MZ twin pairs
23 disc sz MZ twin pairs
10 cone sz MZ twin pairs
7 normal MZ twin pairs
Findings
Schizophrenic twin lower birth weight
No difference
Schizophrenic twin more BCs
Schizophrenics with family history no
OCs;schizophrenics fewer OCs than
normals
No differences between or within groups
Early divergence schizophrenics more OCs
(separated into early
versus late divergence)
OCs most frequent in discordant pairs, least
common in controls; LCs more common in
disc pairs than cone pairs
Judging from the numerous findings supporting a relationship between OCs and
schizophrenia, there is no question that OCs are somehow associated with the
development of schizophrenia. The fact that increases of OCs among individuals with
schizophrenia has been reproduced in many settings, with different methodologies, and
over many years provides strength to this association. However, a causal relationship
between schizophrenia and OCs has not been established. In fact, no specific OC has been
pinpointed as critical in the development of schizophrenia. Although, complications that
have hypoxic or anoxic features are becoming of key interest since McNeil suggested that
the common denominator among the many implicated OCs appears to be oxygen
deprivation (McNeil, 1988).
What teratogenic effect may oxygen deprivation have that leads to schizophrenia?
In 1970, Mednick first proposed that anoxia from OCs selectively damages the
hippocampus, and in interaction with unidentified genetic factors can lead to the later
development of mental disturbance in high-risk subjects (Mednick, 1970). Support for his
hypothesis has been established through reports that neuropeptides are reduced in the
hippocampi of negative symptom schizophrenics. This reduction in neuropeptides was
interpreted as possibly indicating neuronal losses in the hippocampal area (Crow, 1985).
Additionally, a post-mortem study of the brains of 10 chronic schizophrenics found
disarray of pyramidal cell orientation in hippocampal regions, which was interpreted as
abnormal cell migration during prenatal development (Kovelman & Scheibel, 1984).
Theoretical etiological models of schizophrenia have been presented that include
OCs as a factor (Dykes et al., 1991). The first model suggests that certain individuals may
be genetically predisposed to serious OCs that are sufficient to cause schizophrenia. This
model is unlikely because many individuals are subjected to equal or more OCs and do not
develop schizophrenia. Furthermore, many individuals who develop schizophrenia do not
have a history of OCs. A second model posits that some cases of schizophrenia result
from purely genetic causes while others develop solely or mainly from OCs (Lewis &
Murray, 1987). Gottesman & Shields (1972) provide an argument against this model by
pointing out that many identical twins are discordant for schizophrenia and therefore some
environmental factors must interact with genetic factors to increase the risk for the
affected twin. However, it could be argued that the affected monozygotic twin developed
the illness due to OCs and not genetics since it is well known that twins can receive
differential amounts of nutrients from the mother as is seen in twin-to-twin transfusion
syndrome (Munsinger, 1977). Dykes et al. (1991) favor a third model suggesting a two-
hit approach. In this model, a high risk fetus suffers a genetically predisposed (or
teratogenic) disruption of fetal neural development during a critical period of gestation
(first hit). This prenatal disruption may make the fetus especially susceptible to further
damage from OCs (second hit) increasing the risk for schizophrenia.
In conclusion, it is widely accepted that OCs are somehow related to risk for
schizophrenia. The mechanism through which OCs impair neurodevelopment leading to
schizophrenia is probably via oxygen deprivation. The oxygen deprivation, in turn, causes
damage to the hippocampus, a region of the brain implicated in neuropathology studies of
schizophrenia. It is generally agreed that OCs alone do not cause schizophrenia and that
they probably act in interaction with some, as yet, unidentified genetic factor or factors.
1.2 Influenza Studies
Menninger in 1926 reported the onset of many psychoses occurring in close
conjunction with influenza and suggested that because of the "almost unequaled
neurotoxicity of influenza, it should be a critical test of the pathological basis of
schizophrenia" (Menninger, 1994). In the next decades, Menninger's observations
disappeared into scientific obscurity until 1988 when Mednick and colleagues reported
that influenza exposure during the second trimester of gestation increased the risk for later
7
development of schizophrenia (Mednick et al., 1988). The Mednick study precipitated
numerous further investigations in the years since, many resulting in similar findings, while
others not (See Tables 4 & 5).
TABLE 4
Maternal exposure to the 1957 influenza epidemic during pregnancy and risk for schizophrenia in
those offspring
Study Location Sample Size Findings
Mednick etal. (1988) Helsinki 1781 Second trimester exposure increased risk
Kcndcll & Kemp (1989) Scotland
Edinburgh
13540
2371
Partial replication
Replication-associalion with 6 month
Bowler & Torrey (1990) U.S.A. 43,814 Non-replication
O'Callaghan et al. (1991) England &
Wales
1670 Rcplication-association with 5 month
especially with females
Kunugi et al. (1992) Japan 836 Replication-associalion with 6 month
Crow & Done (1992) United Kingdom 16268 Non-replication
Fahy etal. (1992) Afro Caribbcans
in England
1722 Replication-association with second
trimester
Wclham et al. (1993) Australia 7858 Replication-associalion with second
trimester especially with females
Adams etal. (1993) England
Scotland
Denmark
22021
16960
18723
Replication-association with second
trimester in all Scottish and English
patients, only female Danish patients
Cannon etal. (1994) Ireland 980 Non-replication
Susser et al (1994) Holland 99388 Non-replication
Erlenmeyer-Kimling Croatia 77662 Non-replication
eta l (1994)
Mednick et al. (1988) conducted this original study in the context of a major
influenza epidemic for several reasons. First, influenza epidemics frequently have a short
duration with a relatively definite beginning and end, providing the ability to pinpoint
gestational periods at the height of the epidemic. Second, since influenza epidemics are
fairly frequent occurrences, the opportunity for retrospective study of individuals, who
were exposed in utero and are now at an age for developing schizophrenia, is possible.
And, finally, since epidemics tend to be world-wide, attempts at replication across national
settings can be undertaken (Machon et al., 1995). The studies examining the
influenza/schizophrenia relationship fall into three categories: 1. Study of populations
exposed to the 1957 influenza epidemic; 2. Study of multiple epidemic populations; and, 3.
Study of populations infected with influenza during the 1957 epidemic.
TABLE 5
Multi epidemic studies of influenza exposure during pregnancy and risk for schizophrenia in those
offspring
Study Location Epidemics Sample Size*
Watson C L al. (1984) U.S.A. 1916-1958 3246
and
Findings
Associations found with
diphUieria, pneumonia
influenza
Toney etal. (1988) U.S.A. 1920-1955 2519 Associations found with
measles, polio, varicella-
zostcr, but only trend with
influenza
Ban etal. (1990) Denmark
Sham etal. (1992) U.K.-
1911-1950 7239
1939-1960 14830
Associations for sixth
month o f gestation
Associations between 3rd
and 7th months
Adam etal. (1993)
Takei etal. (1993)
Denmark
ScoUand
England
U.K.
1911-1965
1932-1960
1921-1960
1938-1965
18723
16960
22021
3827
Association found in
English data only
Association found for 2nd
trimester
9
Until recently, a major argument against the influenza studies was that the study
design examined exposed mothers and not infected mothers. Recently, however,
Mednick, Huttunen, and Machon (1994) found that a majority of schizophrenics whose
mother had been exposed to influenza during the second trimester were also known to
have been infected with influenza during this time (13 of 15). However, only a small
number of schizoprenics whose mothers had been exposed to influenza during the first and
third trimesters had also been infected (2 of 10). The expected rate of influenza infection
for the population during this epidemic was around 23-30%, and so the elevated rate of
second trimester maternal infection supports Mednick's original hypothesis that second
trimester influenza exposure is a risk factor for schizophrenia.
How might influenza exposure during the second trimester impair fetal
neurodevelopment leading to schizophrenia in adulthood? Direct fetal infection by the
influenza virus is unlikely because of the placental barrier (Wright et al., 1993).
Epiphenomena of influenza infection such as maternal fever, circulatory changes, stress
responses, changes in nutrition , and over the counter medicines have also been considered
as possible teratogens. However, if these factors were important in the etiology of
schizophrenia, then associations between schizophrenia and other infectious illnesses that
include these epiphenomena should be observed, and this is not the case (McGrath et al.,
1995). A third possibility is that maternal autoantibodies or alloantibodies elicited by the
influenza virus cross the placental barrier and disrupt fetal neurodevelopment by acting
upon fetal brain tissue antigens (Wright et al., 1993; Laing et al., 1995). Although there is
evidence from animal experiments that maternal autoantibodies can interfere with fetal
brain development with both neuroanatomical and behavioral consequences (Rick et al.,
1981;Adinolphi et al., 1982; Karpiak et al., 1975), there is as yet no direct evidence that
autoantibodies can perturb brain development in man.
10
In conclusion, although there are some conflicting findings, maternal influenza
exposure during pregnancy is associated with an increase risk of schizophrenia in those
offspring. Furthermore, many of the studies implicate the second trimester of gestation as
critical for the neurodevelopment of schizophrenia. And, although a causal mechanism has
yet to be determined, the influenza studies have inspired interesting speculations regarding
the possible importance of the maternal immune system in the etiology of schizophrenia.
1.3 Rhesus hemolytic disease of the fetus and newborn
Rhesus (Rh) incompatibility is the commonest and most serious cause of hemolytic
disease of the fetus and newborn (HDN). Rh incompatibility refers to pregnancies in
which the mother is Rh negative and the fetus is Rh positive. Rh positive indicates a
person has Rhesus(D) antigens on the surface of the his/her erythrocytes, and the Rh
negative individual does not. The functional role of the Rhesus(D) antigen is unknown.
However, some suggest that the Rhesus(D) antigen may have an important role in the
viability and maintenance of the erythrocyte cytoskeleton (Ridgwell et al., 1984). An Rh
negative (d) woman may become isoimmunized to Rh positive (D) blood following the
delivery of a D infant, occasionally through prior miscarriage or induced abortion of a D
fetus, and very occasionally through transfusions of D blood. Thus, HDN rarely affects a
firstborn D infant because it is unlikely that the mother became immunized while pregnant.
The incidence/severity of HDN is about fivefold greater (in terms of stillbirth rate) in
second and later affected neonates than in first affected neonates (Mollison, 1993; Walker
et al., 1957). In addition, several studies indicate that male fetuses are disproportionately
represented among those suffering from Rh HDN (Scott, 1976; Renkonen & Seppala,
1962; Renkonen &Timonen, 1967).
Once the mother has become immunized, hemolytic disease of the fetus and
newborn can result from the lysis of fetal erythrocytes by transplacentally acquired
maternal erythrocyte alloantibodies. The erythrolysis occurs initially in the fetal liver, and
subsequently also in the spleen of the fetus and newborn. In severe cases, death may
occur in utero as early as week 18 of gestation as a consequence of hydrops fetalis
secondary to profound anemia and associated hypoxia (Mollison, 1993). At birth, infants
may suffer from obstetric complications such as asphyxia, pulmonary edema, and other
respiratory difficulties secondary to HDN (Halitsky, 1990). In the first few days of life,
HDN results in an accumulation of bilirubin in the neonate's circulation which may, if
untreated, result in icterus gravis neonatorum which is characterized by the yellow
staining of neuronal elements of the brain (including the basal ganglia and hippocampus)
known as kernicterus (Rorke, 1992). Those infants who survive kernicterus often suffer
from lasting brain damage which may manifest as choreo-athetosis and spasticity,
sensorineural hearing deficits, and/or mental retardation (Watchko & Oski, 1992).
As discussed previously, maternal infection with influenza during the second
trimester of gestation is associated with an increased risk for schizophrenia in the offspring
(Mednick et al., 1988; Mednick et al., 1994). Influenza viruses elicit the production of
various autoantibodies in man and animals (Loza-Tulimowska et al., 1976; Fox & Plescia,
1973; Laing et al., 1989; Guldner, 1990). Since certain autoantibodies of the IgG class
cross the placenta and have adverse effects on the developing fetus (Munro et al., 1992;
Papazian, 1992; Harley et al., 1992), it is conceivable that maternal autoantibodies or
alloantibodies might have adverse effects on the developing fetal brain, in some cases
resulting in schizophrenia. Hemolytic disease of the fetus and newborn is a condition
caused by maternal transfer of alloantibodies that is known to cause neurological damage
in the developing fetus.
The neuroanatomical abnormalities observed in schizophrenia have been ascribed
to perturbations of fetal brain development, occurring especially during the second
trimester (Mednick et al., 1988; Beckman & Jakob, 1991; Bogerts, 1991). The fetal
expression of HDN, being evident during the second-trimester of gestation is consistent
with the view that the fetal phase of HDN may be responsible for the perturbed brain
development that results, at times, in schizophrenia. Furthermore, since some of the
neuropathological and clinical manifestations of kernicterus parallel those observed for
some individuals with schizophrenia (i.e. disturbed cytoarchitecture of the hippocampal
region (Kovelman & Scheibel, 1984; Altschuler et al., 1987;), choreoathetosis and other
neuromotor disturbances in infancy and childhood (Walker et al., 1994; Mednick &
Silverton, 1988), spontaneous abnormal movements in adults (Fenton et al., 1994), and
mental retardation (Jones et al., 1995)), the postpartum hyperbilirubinemic phase of HDN
may also be related to increased risk of schizophrenia in some individuals.
Others have suggested that some of the neuropathology of schizophrenia is, in
part, due to oxygen deprivation secondary to OCs (Mednick, 1970; McNeil, 1988). Rh
incompatibility can cause pre- and perinatal complications via HDN. As noted earlier,
HDN can involve chronic hypoxia in utero as well as BCs and NCs associated with
oxygen deprivation. The importance of maternal immune system functioning, the
timecourse of HDN (development as early as week 18 of gestation), and the variety of
OCs associated with HDN that have hypoxic qualities are consistent with speculations
derived from studies examining second trimester influenza and OCs as risk factors for
schizophrenia. It is important to point out that implicating HDN as a risk factor for
schizophrenia incorporates considerations from both influenza and OC studies.
If Rh HDN is a risk factor for schizophrenia, certain demographic and clinical
features in the adult schizophrenics might be expected. First, since Rh HDN is more
prevalent among males it is possible that a similar preponderance of male schizophrenics
may be expected among individuals who are Rh incompatible. Second, since Rh HDN
almost exclusively affects non first-born offspring, later-born Rh incompatible individuals
might be expected to be at greater risk for schizophrenia than first-born Rh incompatible
individuals. Third, since there are many pregnancy and birth complications secondary to
Rh HDN, individuals at risk for this condition may be at greater risk for OCs, and to brain
damage such as enlarged ventricles. Associations between OCs, enlarged ventricles, and
schizophrenia have been reported (Cannon et al., 1989;Silverton et al., 1985). An
association between ventricular enlargement and poor premorbid history in schizophrenics
has also been reported (DeLisi et al., 1983; Jeste et al., 1982; Weinberger et al., 1980).
Therefore, if Rh HDN is a cause of schizophrenia, Rh incompatible schizophrenics might
be predicted to have poorer premorbid history, earlier age of onset, and a more chronic
form of the illness than do Rh compatible schizophrenics.
1.4 Hypotheses
1. First, the rate of schizophrenia spectrum diagnoses among Rh incompatible
individuals is hypothesized to be significantly higher than the rate of schizophrenia
spectrum diagnoses among Rh compatible individuals. Additionally, no significant
differences in rates of other serious psychiatric illnesses are expected between the Rh
incompatible and compatible individuals.
2. Second, the rate of schizophrenia among Rh incompatible individuals will be
shown to become increasingly elevated with increasing birth order. However, no effect of
birth order will be observed among Rh compatible individuals, and the rate of
schizophrenia among first bom Rh incompatible and compatible individuals will be similar.
3. Third, the clinical features of Rh incompatible and Rh compatible
schizophrenics will be compared. A more chronic course is hypothesized to be more
prevalent among Rh incompatible schizophrenics than among Rh compatible
schizophrenics.
In addition, exploratory analyses will be conducted examining the prevalence of
clinical signs (physiological, physical, and procedural) associated with Rh HDN in Rh
incompatible and Rh compatible individuals, in schizophrenics and nonschizophrenics, and
in Rh incompatible and Rh compatible schizophrenics.
CHAPTER 2
Method
2.1 Sample
The Danish Perinatal Project consists of data collected on the births of 9,182
infants bom to 9,006 women between September, 1959 and December, 1961 at the
University Hospital in Copenhagen. The births of almost all the 9,182 offspring were
observed by senior obstetricians. Extensive data were recorded concerning the pregnancy.
Included in these data were the ABO and the Rhesus blood groups of 8,798 mothers and
3,758 infants. A disproportionate amount of serological data from children of d mothers
was represented (40% versus 17% expected in the normal Danish population). The
selective sampling biased towards offspring of d mothers would be expected since these
infants were at greatest risk for developing HDN. One-hundred-eighty-seven of the 3,758
infants with complete serological data died before they could develop schizophrenia and
an additional 53 subjects were missing data for diagnosis or sex. Therefore, the final
sample with complete serological data was reduced to 3,518 subjects. In addition to birth
and blood data, information collected includes: early neurobehavioral and physical
examinations, birth order, psychiatric diagnoses of the mothers and fathers, and infants
place of residence (Mednick et al, 1971).
In 1992-1993, the National Psychiatric Register of the Institute for Psychiatric
Demography in Risskov, Denmark was accessed to obtain psychiatric hospital diagnoses
of the mothers, fathers, and children in this cohort. This Register had its origin in 1938
when systematic registration of patients admitted to mental hospitals in Denmark was
begun. It was computerized in 1969 and includes information from all 86 psychiatric
institutions in Denmark. The diagnostic system in place at this time was the International
Classification o f Diseases, Eight Revision (ICD-8). As of 1993, 50 of the male and 18 of
the female offspring had developed schizophrenia. The large number of male versus
female schizophrenics may be attributed to the well-established age of onset differences
between males and females (Hafner et al., 1992; Riecher-Rossler et al., 1992; Gureje,
1991)- Rh phenotype is available for 26 of these 68 individuals (21 males and 5 females).
Analyses were limited to male offspring due to the small number of female offspring with
schizophrenia. Therefore, the final sample includes 1,867 male subjects.
2.2 Risk Group Classification
Subjects were separated into Rh incompatible (In) and Rh compatible (Co) groups.
The In group consists of subjects who were In (Rh negative mother/Rh positive offspring-
-conflguration 'd/D') and one-hundred-ten D subjects whose mothers were coded as
"mother with known Rh, ABO or other immunization” (imm/D). In these instances, there
was no way to know with certainty the type of immunization. Since Rh HDN and other
types of fetal HDN are fundamentally similar, it is appropriate to include these subjects in
the In group. Therefore, the In group represents virtually all pregnancies that could give
rise to cases of HDN. The Co group consists of all offspring (d/d; D/D; D/d; imm/d) that
could not have given rise to Rh HDN.
2.3 Psychiatric Diagnoses
Five categories of severe mental disorders were examined in this study. These
categories include ICD-8 diagnoses of: schizophrenia spectrum disorders, affective
psychoses, paranoid psychoses, organic psychoses, and other psychoses. Schizophrenia
spectrum disorders include schizophrenia, schizoaffective psychoses, and
schizophreniform psychoses (ICD-8 diagnoses 295.0-295.9). Affective psychoses include
involutional melancholia, manic depressive psychoses (manic type), manic depressive
psychoses (depressed type), manic and depressive psychoses (circular type) (ICD-8
diagnoses 296.0-296.9). Paranoid psychoses include paranoia, and involutional
paraphrenia (ICD-8 diagnoses 297.0-297.9). Other psychoses include reactive depressive
psychoses, reactive excitation, reactive confusion, acute paranoid reaction, and unspecified
reactive psychoses (ICD-8 diagnoses 298.0-298.9). Organic psychoses include senile and
pre-senile dementia, alcoholic psychoses, psychoses associated with intracranial infections,
psychoses associated with other cerebral conditions, and psychoses associated with other
physical conditions (ICD-8 diagnoses 290-294) (ICD-8, 1974).
2.4 Birth Order
Data on the number of pregnancies prior to the proband was obtained as part of
the original data collection in 1959-1961. The appropriate birth order number was then
assigned to each subject. Subjects in the imm/D and imm/d category were not included in
birth order analyses because the mother's immunization may not be related to birthorder
(the mother may have become immunized from a previous transfusion, abortion, or
miscarriage and not necessarily from a previous birth of a child). Including these subjects
in birth order analyses may confound results. In an effort to obtain maximum power, rate
of schizophrenia was first examined in second bom and later bom In and Co subjects.
Analyses examining rate of schizophrenia in first bom, second bom and third bom In and
Co subjects followed.
2.5 Demographic Features of Individuals with Schizophrenia
Using data obtained through the Psychiatric Register, five variables were
established to assess the chronicity or seriousness of schizophrenia in the two groups.
These variables included: age at first schizophrenia hospitalization; total number of
hospitalizations for schizophrenia; total number of days hospitalized for schizophrenia; and
average number of days per schizophrenia hospitalization. Mean values were examined
for these continuous variables. In addition, the four variables were arbitrarily recoded into
dichotomous variables that included the following: Onset, where age of first
hospitalization is less than 19 or greater than 18; Admit, where number of schizophrenia
hospitalizations is greater than 1 or equal to 1; Stay, where total number of days
hospitalized for schizophrenia is greater than 200 or less than 200; and Avgstav. where
1 7
average number of days per schizophrenia hospitalization is greater than 50 or less than
50. Finally, the schizophrenia subtype classifications were also examined.
2.6 Possible Clinical Signs of HDN
Using data obtained through the Danish Perinatal Cohort, a large number of
variables were established as possible clinical signs of HDN. Subjects were recorded as
normal or abnormal on the following selected variables: bilirubin levels at birth; cord
hemoglobin levels at birth; condition of the blood and endocrine organs; condition of
respiratory organs; peripheral, medial, and universal cyanosis; light, medium and serious
jaundice; and lateral and universal edema. In addition, whether or not an exchange
transfusion occurred was examined. On several variables, only "abnormal" and "no
information" were recorded. Under these circumstances, the "system-missing values"
were substituted with "normal". No differences were observed between the two groups in
amount of missing data.
2.7 Possible Confounds
The In and Co groups were compared on several variables that may have
confounded the findings. These variables included: Paternal and maternal diagnosis of
schizophrenia; maternal age; number of pregnancies; marital status; length of gestation;
and infant mortality. Significant differences were observed on some of these variables and
so a subsample was randomly selected from the Co group that matched the In group on
most all the differentiating variables. Analyses were conducted on the main hypotheses
(psychiatric diagnoses, birthorder, and HDN clinical variables) with the new comparison
group.
2.8 Statistical Procedures
1. Chi-squares' with continuity correction (appropriate when N is greater than 40)
and two-tailed Fisher’ s Exact tests were conducted (appropriate when the minimum
18
expected frequency is less than five)(Siegel, 1956) for hypotheses related to psychiatric
diagnoses and birth order.
2. T-tests for independent samples were conducted to compare In and Co
schizophrenics on demographic features that were coded as continuous variables. Levenes
Test was utilized to assess equality of variance (SPSS, 1993). When variance was
unequal, p-values for unequal variances were used. Fisher's Exact tests were conducted to
compare In and Co schizophrenics on demographic features that were coded as
dichotomous variables.
3. Chi-squares' with continuity correction and Fisher's Exact tests were conducted
for non-hypothesis driven comparisons of the In and Co groups on demographic variables
that might confound findings.
4. Stepwise logistic regression was conducted to control for the possible
confounding influence of sample differences between the In and Co groups.
Schizophrenia outcome was entered into the regression as the dependent variable.
Variables discriminating the two groups were entered (forced entry) in the first step of the
regression and riskgroup classification was entered (forward entry:Wald procedure) in the
second step of the regression.
5. Chi-squares' with continuity correction were conducted comparing the In and
Co groups on variables associated with Rh HDN. Chi-squares' with continuity correction
and Fisher’ s Exact tests were also conducted comparing schizophrenics and
nonschizophrenics on variables associated with Rh HDN.
6. Logistic regression was conducted to test for interactions between risk group
classification, variables associated with Rh HDN, and schizophrenic outcome.
Schizophrenia was entered into the regression as the dependent variable. Clinical variables
were entered (forced entry) in the first step of the regression and an interaction between
riskgroup classification/clinical variable was entered (Forward entry:Wald procedure)
the second step of the regression.
20
CHAPTER 3
Results
3.1 Psychiatric Diagnoses
Hypothesis One: The rate of schizophrenia was found to be significantly higher in
the In group (2.1%) than in the Co group (0.8%) (chi-square(l)=4.73, p=.03). In.
contrast, no significant differences were observed between the In and Co groups for rate
of affective psychoses (Fisher's Exact (two-tail): p=l), organic psychoses (Fisher's Exact
(two-tail): p=.69), other psychoses (Fisher's Exact (two-tail): p=.26), or paranoid
psychoses (Fisher's Exact (two-tail): p=.42). See Table 6.
TABLE 6
Rh Incompatibility and Rate of Psychiatric Diagnoses
In
Schizophrenia 11/535(2.1)
Spectrum
Affective
Psychoses
Organic
Psychoses
2/535(0.4)
3/535(0.6)
Co
10/1332 (0.8)
4/1332(0.3)
4/1332(0.3)
9/1332(0.7)
4/1332(0.3)
Total
21/1867(1.1)
6/1867(0.3)
7/1867(0.4)
16/1867(0.9)
7/1867(0.4)
Significance*
.03
NS
NS
NS
NS
Other Psychoses 7/535( 1.3)
Paranoid 3/535(0.6)
Psychoses
In=Rh Incompatible
Co=Rh Compatible
*p value for chi-square
♦♦Total number of schizophrenics/total sample size (percent with schizophrenia)
3.2 Birth Order and Rate of Schizophrenia
The rate of schizophrenia among second and later-born offspring in the In group
was significantly greater (2.6% vs. 0.8%) than that of second and later-born offspring in
the Co group (Fisher's Exact (two-tail): p=.05). As predicted, In subjects had an
21
increasing risk of schizophrenia with increasing birth order. And, the Co group did not
evidence this pattern of rate of schizophrenia with birth order. However, when rate of
schizophrenia was examined in first, second, and third and later bom groups, no significant
differences were observed between the In and Co groups, probably due to lack of power.
See Table 7.
TABLE 7
Rate of Schizophrenia In Rh Incompatible and Rh Compatible Adult Males by Birth Order
In Co Total Significance*
Second and 7/272(2.6)** 5/634(0.8) 12/906(1.3) .05
Later Born
First Born 2/178(1.1) 5/672 (0.7) 7/850(0.8) £ 4
Second Born 3/134(2.2) 2/328(0.6) 5/462(1.1) .15
Third and Later 4/138(2.9) 3/306(1.0) 7/444(1.6) .21
Born
In=Rh Incompatible
Co=Rh Compatible
*p value for Fisher’ s Exact Test
* T o ta l number of schizophrenics/total sample size (percent with schizophrenia)
3.3 Demographic Features of the In and Co Schizophrenics
The eleven subjects with schizophrenia in the In group were compared to the 10
subjects with schizophrenia in the Co group on variables associated with chronicity of the
illness. Continuous variables included: age of first hospitalization for schizophrenia, total
number of days hospitalized for schizophrenia, total number of separate hospitalizations
for schizophrenia, and length of average hospital stay for schizophrenia. Dichotomous
variables included: Onset, Stay, Admit, and Avgstay. T-tests revealed no significant
differences between the two groups on any of the continuous variables. However, the Co
group appeared more chronic (See Table 8). Comparisons of the dichotomous variables
using Fisher's Exact Tests revealed only one near significant difference which was on
22
Avgstay (Fisher's Exact Test: p=.03, Bonferroni corrected p value=.025) (See Table 9).
No remarkable differences were observed between the In and the Co groups in individual
subtypes of schizophrenia. However, the Co group had a larger number of different
subtypes represented possibly reflecting greater etiological heterogeneity among this
group. Furthermore, In diagnoses included less severe types of schizophrenia (See Table
8).
TABLE 8
Demographic Variables (Continuous and Descriptive) in Rh Incompatible and Rh Compatible
Schizophrenics
Subtype A gelst Hosp Hosp Adm Hosp # Days Avg Hosp Stay
Unspecified 26 8 1188 149
Unspecified 26 1 41 41
Unspecified 25 1 15 15
Unspecified 28 4 37 9
In Latent 24 I 18 18
Group Latent 24 6 278 46
Latent 19 1 14 14
Paranoid 29 3 88 29
Paranoid 15 2 73 37
Mixed 20 2 293 147
Schizoaffective 18 13 517 40
Averages(SD) 23.2(4.2) 3.8(3.8) 232.9(355.2) 49.5(50.0)
Unspecified 18 17 1867 110
Unspecified 26 3 85 28
Unspecified 27 1 143 143
Co Unspecified 29 1 5 5
Group Latent 24 3 346 115
Mixed 19 46 1001 22
Schizoaffective 22 2 221 111
Catatonic 22 15 1268 91
Simple 25 4 771 193
Other 29 4 262
87
Averages(SD) 24.2(3.8) 9.6(14.0) 596.9(613.9)* 90.4(58.2)**
In= Incompatible
Co=Rh Compatible
AgelstHosp=Age at first schizophrenia hospitalization
HospAdm=TotaI number of hospital admissions for schizophrenia
Hosp#Day=Total number of hospital days for schizophrenia
AvgHospDay=Average number o f days in hospital for schizophrenia
*p=0.12 (Levene’s Test for Unequal Variances used)
**p=0.09
23
T A B L E 9
Demographic Variables (Dichotomous) in Rh Incompatible and Rh Compatible Schizophrenics
Onset Admit Stay Avgstay
In Group 2/11(18) 7/11(47) 4/11(36) 2/11(22)
Co Group 1/10(10) 8/10(53) 7/10(64) 7/10(78)
Onset=number of schizophrenics with onset less than 19 years of age/total number in group (percent)
Admit=number of schizophrenics with more than 1 admit/total number in group (percent)
Stay=number of schizophrenics with more hospital days than 200/total number in group (percent)
Avgs(ay=number o f schizophrenics with more hospital days per stay than 50/total number in
group(pcrcent)
3.4 Possible Clinical Signs of HDN
Since no direct measure of Rh HDN (i.e. direct antiglobulin test) in offspring was
available for this sample, variables that may be indicative of Rh HDN were examined.
Comparisons between the In and Co groups, between schizophrenics and
nonschizophrenics, and between In and Co schizophrenics were undertaken on the
following variables: respiratory function, blood organ function, cyanosis, jaundice, edema,
hemoglobin and bilirubin levels, and exchange transfusions. The In group was
significantly more often reported abnormal on the following variables: bilirubin (chi-
squared )=7.49, p=.006), blood organs at day one (chi-square(l)=39.29, pc.00001),
blood organs at day five (chi-square(l)=19.32, p=.00001), universal edema (chi-
square(l)=9.63, p=.002), hemoglobin levels (chi-square( 1 )=7.50, p=.006), and jaundice
at birth (chi-square(l)=25.93, p<.00001). Exchange transfusions were performed
significantly more often on In offspring (chi-square(l)=258, pc.OOOl). The Co group had
significantly more subjects with abnormal reports on: peripheral and medial cyanosis (chi-
square(l)=7.77, p=.005), lateral edema (chi-square(l)=8.83, p=.003), medium jaundice
at day five (chi-square(l)=6.90, p=.009), respiratory organs at day five (chi-
square(l)=4.19, p=.04), and serious jaundice at day five (chi-square(l)=6.39, p=.01).
See Table 10.
TABLE 10
Possible Clinical Signs of HDN in the Rh Incompatible and Rh Compatible Groups
In Co Significance
lateral, day 5 24/507(4.7)* 39/1274(3.1) NS
medial, day 1 50/517(9.7) 122/1296(9.4) NS
cyanosis peripheral, day 1 27/517(5.2) 80/1296(6.2) NS
peri &med,day 1 10/517(1.9) 64/1296(4.9) .005
universal, day 1 2/517(.4) I0/1296{.8) NS
universal, day 5 l/507(.2) 8/1274(.6) NS
at birth 150/517(29) 234/1296(18) .0001
tinge, day S 56/507(11) 161/1274(13) NS
jaundice light, day 5 126/507(25) 234/1296(25) NS
medium, day 5 68/507(13) 239/1274(19) .009
serious, day S 34/507(7) 137/1274(11) .01
lateral, day 1 5/517(1.4) 56/1296(4.3) .003
edema universal, day 1 23/517(4.4) 23/1296(1.8) .002
at day 5 9/507(1.8) 11/1274(.9) NS
blood & at day 1 25/521(4.8) 6/I30K.5) .0001
endocrine al day 5 16/509(3.1) 6/I281C5) .00001
organs
respiratory at day 1 36/521(6.9) 110/1301(8.5) NS
organs at day 5 13/509(2.6) 62/1281(4.8) .04
respiratory at day 1 209/532(39) 501/1313(38) NS
treatment
bilirubin at day 1 86/319(27) 171/881(19) .006
hemoglobin cord 282/531(53) 608/1323(46) .006
exchange post-partum 114/535(21)** 46/1332(3.5) .00001
transfusion
"■number of abnormal reports/total sample (percent)
"""number performed/total sample (percent)
Comparisons between schizophrenics and non-schizophrenics on possible clinical
signs of HDN revealed only one significant difference. Individuals with schizophrenia
were more often reported edemic at day five (Fisher's Exact test: p=.02). Abnormal
reports were more common among schizophrenics on fifteen of the twenty-two clinical
variables examined, although these differences were not significant. See Table 11.
TABLE 11
Possible Clinical Signs of HDN in Schizophrenics and Non Schizophrenics
SZ NoSZ Significance
lateral, day 5 l/20(5)+ 62/1762(3,5) NS
medial, day 1 4/20(20) 168/1794(9.4) .1
cyanosis peripheral, day 1 0 107/1794(6.0) NS
peri &mcd,day 1 0 74/1794(4.1) NS
universal, day 1 0 12/1794(.7) NS
universal, day 5 0 9/1762(.5) NS
al birth 5/20(25) 379/1794(21) NS
tinge, day 5 3/20(15) 214/1762(12) NS
jaundice light, day 5 6/14(30) 443/1319(25) NS
medium, day 5 1/20(5) 306/1456(17) NS
serious, day 5 2/20(10) 169/1762(10) NS
lateral, day 1 0 64/1794(3.6) NS
edema universal, day 1 1/20(5) 45/1794(2.5) NS
at day 5 2/20(10) 18/1762(1) 02+++
blood & at day 1 1/20(5) 30/1803(1.7) NS
endocrine at day 5 1/20(5) 21/1771(1.2) NS
organs
respiratory at day 1 2/20(10) 144/1803(8) NS
organs & at day 5 1/20(5) 74/1771(4.2) NS
respiratory at day 1 9/20(45) 701/1125(38) NS
treatment
bilirubin at day 1 4/13(31) 253/1187(21) NS
hemoglobin cord 11/21(52) 880/1834(48) NS
exchange post-partum 3/21(14)## 157/11846(8.5) NS
transfusion
'•'number of abnormal reports/lolal sample (percent)
♦♦number performed/total sample (percent)
♦♦♦Fisher's Exact test
26
Finally, logistic regressions revealed no significant interaction effects of risk group
classification and clinical variables leading to an outcome of schizophrenia.
3.5 Possible Confounds
Possible confounding variables include: paternal diagnosis, maternal diagnosis, age,
marital status, number of previous pregnancies, length of gestation, and offspring
mortality. No significant differences were observed between the two groups for paternal
or maternal diagnosis of schizophrenia. However, significant differences in the age,
marital status, and number of pregnancies of In and Co mothers were observed.
Significant differences between the In and Co groups were also observed for length of
gestation and death rate of neonates before the age of one year. The significant group
differences can be explained as a recruitment bias affecting the subgroup for whom Rh
blood-group data was available for both mother and offspring. First, In mothers were
significantly more likely to be older (chi-square(l)=7.73, p=.005), to be married (chi-
square(l)=7.35, p=.007), and to have a larger number of previous pregnancies (chi-
square(l)=23.69, p<.0001) than Co mothers. Since HDN is confined almost exclusively
to second and later pregnancies, being most common/severe in third and later incompatible
pregnancies, mothers at risk of giving birth to offspring with Rh HDN are more likely to
be older and married. Second, Co mothers were more likely than In mothers to deliver
prematurely (chi-square(l)=16.78, pc.0001) and to have newborns who died in the first
year of life (chi-square(l)=9.60, p=.002). See Table 12 for a summary of data.
27
TABLE 12
Comparison of Rh Incompatible and Rh Compatible Groups on Demographic Variables
In Co Significance^
M aternal Diagnosis of Schizophrenia .4% .5% NS
Paternal Diagnosis of Schizophrenia .4% .2% NS
M aternal Age >23years* 59% 52% .005
Maternal Marital Status** 15% 68% .007
Parity*** 1st born 39% 51% .0001
2nd born 30% 25%
3rd born 31% 24%
W eeks Gestation <38wks 23% 34% .0001
Infant Mortality 2.9% 6.6% .002
In=Rh Incompatible
Co=Rh Compatible
Ip value for chi-square
•Median split o f total sample.
••Percent who arc currently married or were at one time.
•••Offspring included in study by birth order.
Logistic regression was conducted to control for the possible confounding
influence of these sample differences upon the rate of psychiatric diagnoses. The rate of
schizophrenia in the In group remained significantly higher than that of the Co group when
marital status, age, number of pregnancies and length of gestation were controlled (chi-
square(l)=5.90 p=.02). And, the comparisons of other psychiatric diagnoses, using
logistic regression to control for differences between the two groups, remained
nonsignificant
3.6 Comparisons Using a Subsample of Rh Compatible Subjects
In addition, a subsample was selected from the Co group that matched the In
group on most all the demographic variables related to maternal differences that
distinguished the two groups. See Table 13 and Table 12 for comparison.
28
TABLE 13
Comparison of Rh Incompatible and Rh Compatible Group #2 on Demographic Variables
In 0 .2 Significance
Maternal Diagnosis of Schizophrenia .4% .6% NS
Paternal Diagnosis of Schizophrenia .4% .3% NS
Maternal Age >23years* 59% 61% NS
Maternal Marital Status"" 75% 76% NS
Parity*"* 1st born 39% 46% .02
2nd born 30% 28%
3rd born 31% 26%
W eeks Gestation <38wks 23% 26% NS
Infant Mortality 2.9% 1.6% NS
In=Rh Incompatible
Co=Rh Compatible
* p value for chi-square
"Median split of total sample.
""Percent who are currently married or were at one time.
** "Offspring included in study by birth order.
When the In group was compared to the Co2 group, the findings related to
psychiatric diagnoses remained significant for schizophrenia and non-significant for other
diagnoses. The rate of schizophrenia was found to be significantly higher in the In group
(2.1%) than in the Co2 group (0.6%) (chi-square(l)=4.31, p=.04). In contrast, no
significant differences were observed between the In and Co2 groups for rate of affective
psychoses (Fisher's Exact (two-tail): p=l), organic psychoses (Fisher's Exact (two-tail):
p=.40), other psychoses (chi-square(l)=.511, p=.47), or paranoid psychoses (Fisher's
Exact (two-tail): p=.40). See Table 14 and Table 6 for comparison.
29
TABLE 14
Rate or Psychiatric Diagnoses in theRh Incompatible and Rh Compatible #2 Groups
In
Schizophrenia 11/535 (2.1)
Spectrum
Affective
Psychoses
Organic
Psychoses
2/535(0.4)
3/535(0.6)
Other Psychoses 7/535(1.3)
Co2
5/792 (0.6)
4/792(0.5)
2/792(0.3)
6/792(0.8)
2/792(0.3)
Total
16/1327(1.1)
6/1327(0.5)
5/1327(0.4)
13/1327(1.0)
5/1327(0.4)
Significance*
.04
NS
NS
NS
NS Paranoid 3/535(0.6)
Psychoses
In=Rh Incompatible
Co=Rh Compatible
p value for chi-square (where significance p=,05)
“ "Total number of schizophrenics/total sample size (percent with schizophrenia)
Likewise, when birthorder was considered, the rate of schizophrenia among
second and later bom In subjects was significantly higher than among second and later
bom Co2 subjects, 2.6% versus 0.5%, respectively (Fisher's Exact (two-tail): p=.03).
And, the rate of schizophrenia in the other birth order positions of Co2 subjects remained
similar to the rates observed in Co subjects. See Table 15 and Table 7 for comparison.
TABLE 15
Rate of Schizophrenia in the Rh Incompatible Group and the Rh Compatible #2 Group by Birth
Order
Second and Later
Born
In
7/272 (2.6)**
Co
2/418 (0.5)
Total
9/690(1.3)
Significance*
.03
First Born
Second Born
2/178(1.1)
3/134(2.2)
4/138 (2.9)
3/358 (0.8)
1/217(0.5)
1/201(0.5)
5/536 (0.9)
4/351 (1.1)
5/339 (1.5) Third and Later
Born
In=Rh Incompatible
Co=Rh Compatible
p value for Fisher's Exact Test (where significance p=.05)
**Total number of schizophrenics/total sample size (percent with schizophrenia)
.67
.16
.16
30
When the In group was compared to the Co2 group on clinical signs of HDN,
fewer abnormal findings in the direction of the compatible group were observed. In
addition, abnormal findings in the direction of the In group became more marked. The In
group remained significantly more jaundiced at birth. However, in contrast to the Co
group, the Co2 was not significantly more abnormal than the In group on any of the
jaundice variables. The In group appeared "more" edemic when compared to the Co2
group. Blood and endocrine organs remained significantly more abnormal in the In group.
In general, the In group looks worse when compared to the Co2 group on possible clinical
signs of HDN. See Table 16 and Table 10 for comparison.
TABLE 16
Possible Clinical Signs of HDN In the Rh Incompatible Group and the Rh Compatible Group #2
In Co2 Significance
lateral, day 5 24/507(4.7)* 26/754(3.4) NS
medial, day I 50/517(9.7) 67/775(8.6) NS
cyanosis peripheral, day 1 27/517(5.2) 48/775(6.2) NS
peri &med,day 1 10/517(1.9) 39/775(5.0) .007
universal, day 1 2/517(.4) 2/775(0.3) NS
universal, day 5 l/507(.2) 6/754(0.8) NS
at birth 150/517(29) 152/775(20) .0001
tinge, day 5 56/507(11) 106/754(14) .13
jaundice light, day 5 126/507(25) 187/754(25) NS
medium, day 5 68/507(13) 130/754(17) .08
serious, day 5 34/507(7) 59/754(7.8) NS
lateral, day 1 5/517(1.4) 35/775(4.5) .003
edema universal, day 1 23/517(4.4) 10/775(1.3) .0008
at day 5 9/507(1.8) 3/751(0.4) .02***
blood & at day 1 25/521(4.8) 5/776(0.6) .00001
endocrine at day 5 16/509(3.1) 5/759(0.7) .002
organs
respiratory at day 1 36/521(6.9) 44/776(5.7) NS
organs & at day 5 13/509(2.6) 24/759(3.2) NS
respiratory at day 1 209/532(39) 241/779(31) .002
treatment
b iliru b in at day I 86/319(27) 95/501(19.0)
hemoglobin cord 282/531(53) 340/786(43)
exchange post-partum 114/535(21)** 22/792(2.8)
transfusion
*number of abnormal reports/total sample (percent)
**number performed/total sample (percent)
***Fisher's Exact test
.009
.0006
.00001
CHAPTER 4
Discussion
This study found that Rh incompatibility may be a pre- and perinatal risk factor of
schizophrenia in males. The limitations and advantages of this study are discussed,
followed by a review of the findings and their implications, and suggestions for future
research.
4.1 Limitations
There are several potential limitations to the study presented. These include: the
use of hospital diagnoses rather than interview diagnoses; small number of schizophrenics;
lack of female schizophrenics; a "control" sample which may be at high risk for other
pregnancy and birth complications; and no direct measure of HDN.
The reliability and validity of hospital diagnoses has been questioned. In
argument, some suggest that the Danish Psychiatric Register ICD-8 diagnosis for
schizophrenia is more conservative than the interview-based DSMIII-R diagnosis of
schizophrenia (Jorgensen et al, 1987). This clinical impression is supported by a study
conducted by Munk-Jorgensen and Mortensen (1989). They found that the agreement
was excellent between the Danish National Psychiatric Register diagnoses of
schizophrenia and blind research diagnoses based on structured clinical interviews.
Furthermore, because of the prospective design of this study, it seems extremely unlikely
that, if errors in diagnostic typing occurred, they would be more prevalent among Rh
positive offspring of Rh negative mothers than among other combinations.
The small number of schizophrenics in this study limited the power of comparisons
between In and Co schizophrenics. Likewise, the sample included too few female
schizophrenics to examine the effect of Rh incompatibility. The disproportionate number
of male schizophrenics in this sample can be explained by the age of onset differences
between males and females and the age of the subjects when they were checked in the
33
psychiatric register (32 years) (Hafner et al., 1992; Gureje, 1991; Riecher-Rossler el al.,
1992). In addition to age of onset differences, the sexes may be differentially susceptible
to gestational environmental factors which increase the risk of schizophrenia. Therefore,
analyzing the sexes separately may provide important information regarding Rh HDN as a
risk factor for schizophrenia.
The data provided on subjects in this sample were gathered for research purposes.
However, certain medical procedures (such as taking a blood sample from the neonate)
were not undertaken unless specifically requested. As a result, this study consisted of a
somewhat biased sample towards pregnancies which warranted serological examination.
Therefore, testing for clinical signs of HDN was made more difficult because the
comparison group (Co) had a higher percentage of abnormal findings than might usually
be expected.
Although variables suggesting possible HDN were reported in the clinical
examination of the neonates in this study, no specific instance of HDN was recorded.
Since the severity of HDN varies greatly, examination of the rate of schizophrenia among
infants who had a positive direct antiglobulin test for maternally derived (IgG) erythrocyte
alloantibodies would have resulted in a more sensitive test of the HDN hypothesis.
4.2 Advantages
First, the prospective design of this study is a great advantage. Prospective design
assures that the independent measures (offspring/mother Rh status, birth order, clinical
signs of HDN, etc.) used in this study were assessed long before the development of
schizophrenia and so cannot have been biased by knowledge of the subject's eventual
diagnostic status.
Second, this is the first time Rh incompatibility has been systematically examined
as a risk factor for schizophrenia. Two recent studies exploring the relationship between
OCs and schizophrenia list Rh incompatibility among the numerous items examined
34
(Gunther-Genta et al., 1994; Huen & Maier, 1993). Neither study reported an elevation on
this variable. However, the reliability of reporting is suspect in both studies because the
percent of In pregnancies is much below normal. Approximately 10% of Caucasian
pregnancies are In (Mollison, 1993). Gunther-Genta et al. (1994) reported that 4.8% of
354 subjects were recorded as In. Heun and Maier (1993) reported even less than that,
0.5% of 204 subjects (sample included patients and siblings). Rhesus incompatibility was
not registered until 1954 after the D antigen was first discovered. Both samples include a
large number of subjects who were born before 1954 likely explaining the discrepancy in
the values they obtained for Rh incompatibility.
Third, the Danish Perinatal Cohort has been followed for the past 35 years,
including both comprehensive fetal and neonatal data as well as data on adult psychiatric
diagnoses. And, the Danish population has a sufficiently high prevalence of the d
phenotype in order to obtain a large Rh incompatible group. Blood types were available
for mother and offspring assuring an accurate report of Rh incompatible pregnancies (the
sample actually had a larger proportion of Rh incompatibility than would be expected
because it was a high risk sample). Relying on retrospective or even prospective record of
"Rh incompatible" instead of examining blood types is not recommended because both are
subject to inaccurate or incomplete reporting as was observed in Gunther-Gente et al.
(1994) and Heun and Maier (1993).
Finally, since this is the first time a relationship between Rh incompatibility and
schizophrenia has been explored, a great deal of latitude was available for theoretical
speculation.
4.3 Psychiatric Diagnoses
As hypothesized, the rate of schizophrenia in In male subjects was significantly
greater than the rate of schizophrenia in Co subjects, 2.1% versus 0.8% respectively. In
addition, the rate of other serious mental illnesses (affective psychoses, organic psychoses,
3 5
other psychoses, and paranoid psychoses) was not significantly different in the two
groups. The specificity of Rh incompatibility as a risk factor for schizophrenia but not for
other serious psychiatric disorders strengthens the case of this factor as a possible causal
agent of schizophrenia.
Again, Rh incompatibility is the most serious cause of HDN. What might be the
teratogenic effect of HDN leading to schizophrenia? First, the chronic fetal hypoxia
resulting from hemolysis in Rh HDN may have deleterious effects upon fetal
neurodevelopment, increasing the vulnerability for schizophrenia later in life. As discussed
earlier, McNeil (1988) suggests that pre-, peri- and neonatal oxygen deprivation may
increase the risk for schizophrenia, and one brain region particularly vulnerable to hypoxia
is the hippocampus (Ben An, 1992; Rorke, 1992). Neuropathological studies have
implicated the hippocampus as a brain region frequently found to be abnormal among
schizophrenics (Jeste, 1989). The migration of neurons into the hippocampus is reaching
a peak during the second trimester (Conrad & Scheibel, 1987) at which time the transfer
of maternal antibodies to the fetus is underway (Adinolphi, 1985). And, as discussed
earlier, a study from our laboratory (Mednick et al., 1988), that has been replicated several
times, implicates the second trimester of gestation as critical in the development of
schizophrenia.
Second, it was proposed earlier that kemicterus at birth may be related to the risk
for schizophrenia in adulthood. The hyperbilirubinemic phase of post-partum Rh HDN
can cause damage to the basal ganglia and hippocampus, brain areas associated with
schizophrenia. In addition, some of the clinical manifestations of kernicterus are also
observed in children who later develop schizophrenia and in adults with schizophrenia.
However, given the mounting evidence of second trimester perturbation in schizophrenia,
the fetal phase of Rh HDN rather than the neonatal phase may be the more critical period
of insult. Furthermore, the Co group was significantly more abnormal on two of the three
36
variables that might indicate kemicterus (medium and serious jaundice at day five) and
19% of the Co group evidenced critically elevated bilirubin levels. Although the
percentage was significantly less than the 27% of the In group with critically elevated
bilirubin levels, the disparity is not all that great.
Both neuropathology studies and the second trimester findings are consistent with
the hypothesis that the transfer of anti-D antibodies against a D fetus resulting in HDN
(and the concomitant hypoxia, and hyperbilirubinemia) may damage brain tissues
associated with an increased risk for schizophrenia. The findings reported in this study of
an increase of schizophrenia among the children at greatest risk for Rh mediated HDN
support this hypothesis.
4.4 Birth Order
The rate of schizophrenia was found to be greater in second and later born
offspring from In pregnancies than in parity-matched offspring from Co pregnancies, 2.6%
versus 0.8%, respectively. Moreover, the rate of schizophrenia was higher in third or later
born offspring from In pregnancies (2.9%) than in second born offspring from In
pregnancies (2.2%) in accordance with the fivefold increase of stillbirths attributed to
HDN among second-affected infants. Since some of the offspring preceding In
pregnancies would have been Rh negative (due to paternal Rh heterozygosity-which was
not ascertained), a more-modest (i.e. less than five-fold increase) in rates of schizophrenia
would be expected because only some of the third-born and fewer of the second born of
this group would have suffered from HDN. Also, in-keeping with the widely held notion
that schizophrenia is an etiologically and pathogenetically heterogeneous disorder,
presumably some of the schizophrenics in this cohort will have developed schizophrenia
via means which did not involve Rh immunization of the mothers. Since these cases
would contribute equally, with a certain variance, to both groups they would limit the
37
sensitivity of the tests devised to demonstrate the effects of Rh incompatibility in
pregnancy on subsequent schizophrenia.
4.5 Demographic Features of In and Co Schizophrenics
Interpretation of these data is difficult since the sample size is so small. In
addition, the measures of chronicity used in this study are crude. Consequently, one must
consider these findings extremely preliminary and recognize that all comment is meant to
be speculative. Contrary to the hypothesis, the In schizophrenics appear less chronic than
the Co schizophrenics as shown by their shorter hospital stays and by their smaller number
of total days hospitalized for schizophrenia. However, one could argue that the hospital
findings reflect compliance or stability rather than severity of schizophrenia. In other
words, it is possible that the In schizophrenics are less likely to be in the hospital because
they are out-on-the-streets wandering Europe, while the Co schizophrenics remain with
their families and become hospitalized as their symptoms exacerbate.
However, further suggestive evidence that the In schizophrenics are less chronic is
revealed when subtypes are examined. The In group has among its numbers two paranoid
and three latent schizophrenics, both subtypes that could be considered of the "less
chronic type". In contrast, the Co group has only one latent schizophrenic and no
paranoids. If In schizophrenics are indeed of a less chronic type, an explanation for this
finding might be that this type of schizophrenia has a non-genetic basis (in terms of a
"schizo-gene") and is the consequence of teratogenic effects of the maternal D
alloantibody on fetal development. A similar suggestion has been made with respect to the
influenza findings (Laing et al., 1995). Preliminary reports suggest that the "influenza
schizophrenics" may also have a less severe, paranoid type of schizophrenia (Machon et
al., 1995).
38
4.6 Possible clinical signs of hemolytic disease of the fetus and newborn
None of the variables chosen as pathognomonic of HDN are specific to HDN. For
instance, jaundice and edema can result from any number of prenatal and neonatal
conditions. Therefore, interpretation of these findings is also meant to be undertaken with
caution. Both the In and the Co groups evidenced possible clinical signs of HDN. As
would be expected, the group at risk for HDN (i.e. the In group) evidenced more
abnormal findings on these variables. The significantly lower hemoglobin values and the
significantly higher number of exchange transfusions performed in the In group especially
support the contention that some of the In group suffered from HDN. In addition, the
report of "abnormal blood organs" may indicate hepatosplenomegaly, a sign of severe
HDN, and In subjects were significantly more likely than Co subjects to evidence this
abnormality.
As discussed earlier, blood was not randomly drawn from the newborns. Thus, the
sample used in this study was biased towards neonates who were at risk either because of
Rh incompatibility, prematurity or some other unspecified complication. Therefore, it was
not surprising that the Co group evidenced an assortment of abnormalities on the variables
chosen as representative of HDN. The fact that the Co group had its fair share of clinical
abnormalities at birth yet did not evidence an elevation in rate of schizophrenia is
interesting in that it suggests these neonatal measures in and of themselves did not increase
the risk of schizophrenia.
In general, the clinical signs of HDN became less apparent in the Co2 group,
undoubtedly due to the removal of extremely premature infants from this group. The rate
of schizophrenia dropped slightly in the Co2 group to 0.6% (as compared to 0.8% in the
Co group) raising the question as to whether the presence of obstetric complications does,
in fact, have some effect upon the findings. In other words, perhaps the In group has an
elevated rate of schizophrenia because In pregnancies are more prone to OCs in general,
39
not limited to those associated with HDN. Comparison of general OCs in In and Co
subjects must be undertaken to examine this possibility.
In the introduction, a two-hit model of schizophrenia was discussed in which a
genetic (or a teratogenic) disruption occurs in fetal neurodevelopment (first hit) that
makes the fetus more susceptible to further damage from OCs (second hit). Rh
incompatibility as a risk factor fits this model well. Two possible interpretations are: 1 .
Genetic predisposition for schizophrenia causing initial perturbations in fetal
neurodevelopment (first hit), followed by the development of HDN causing further
neurological impairment (second hit). 2. Teratogenic effects of fetal hemolysis resulting
from Rh incompatibility (first hit), followed by secondary BCs and NCs causing further
neurological impairment.
Earlier it was stated that OCs probably act in interaction with some as yet
unidentified genetic factor or factors. Maybe one genetic factor is susceptibility to
hemolysis. The severity of HDN varies greatly, 50% of newborns will be born with either
mild or no ill effects, 30% will be bom with hepatomegaly and jaundice with the potential
of kernicterus, and the remaining 20% will develop hydrops (Duerbeck & Seeds, 1993).
Perhaps, schizophrenia represents a less serious clinical outcome of the small percentage
of infants who develop moderate to severe HDN.
4.7 Suggestions for future research.
Attempts to replicate these findings must take into account the following :
population prevalence of the d phenotype; information on the hetero- or homozygosity of
the father's blood type; effects of parity; the administration of anti-D prophylaxis.
Population studies of the Rh D antigen find the prevalence of the d phenotype to
range from 0% in a Thai population of Assam, India (Singh & Phookan, 1990) to 20-40%
in the Basque people of the Pyrenees (Mourant et al., 1976). The variance observed in the
prevalence of D and d worldwide raises the question as to whether populations with
40
increased incidence of Rh HDN will also evidence an increased incidence of
schizophrenia? To the author's knowledge, unusual rates of schizophrenia have not been
observed in the above mentioned regions.
The homo- or heterozygosity of the D factor may influence results. For instance,
all offspring of homozygous D (DD) fathers and d (dd) mothers will be D (Dd) which will
increase the probability of anti-D antibody production by the mother's immune system,
thereby increasing the probability of HDN.
Replications must also consider the effect of parity. Non first bom children will
have the greatest probability of suffering from HDN (Mollison, 1993), and according to
the hypothesis presented in this study, these trends will be evident as a correspondingly
increased risk of schizophrenia throughout second and later Rh incompatible pregnancies.
Studies of birth order in schizophrenia have reached no definitive conclusions because of
methodological difficulties (Dalen, 1988). However, studies by Jonsson of large families
in Sweden suggest that increased maternal age is a risk factor (Jonsson, 1993). Since Rh
HDN is correlated with increased maternal age (i.e. mothers most likely to have multiple
offspring), Jonsson's observations of an association between schizophrenia and increased
maternal age could involve HDN as a contributory factor. This would suggest a new
approach to the methodology of birth order studies in schizophrenia-directed at
ascertainment of HDN.
Since the development of anti-D prophylaxis in the late sixties, the occurrence of
Rh HDN has been significantly reduced (Mollison, 1993). If the hypothesis is correct,
that a proportion of schizophrenics develop the illness as a result of Rh HDN, then the
rate of schizophrenia should show a parallel decline. Schizophrenia has been reported to
be on the decline. However, the decline has mainly been attributed to changes in both
diagnostic practices and economic/social forces (Stoll et al., 1993). Attempts to replicate
41
this study must include a sample that predates the administration of anti-D prophylaxis
(late 1960's) since this sample consisted of births occurring between 1959-1961.
Investigators searching for a "schizo-gene" should be aware of these findings. Rh
factor is genetic. The d genotype will "run" in families, therefore, so too, will Rh
incompatible pregnancies. If Rh incompatibility is truly a risk factor for schizophrenia then
schizophrenia would tend to cluster in these families. These families might mistakenly be
identified as having a genetic predisposition for schizophrenia, when in fact what they have
is a genetic predisposition for HDN.
4.8 Conclusion
This study implicates Rh incompatibility as a risk factor for schizophrenia, a risk
factor that involves genetics, maternal immune functioning, OCs and fetal
neurodevelopment. There are numerous ways in which the hypotheses discussed in this
study can be tested. Attempts at replications using other perinatal cohorts are already
underway. In addition, retrospective studies examining the psychiatric outcomes of adult
survivors of HDN and kernicterus can be designed. Studies examining the rate of Rh
incompatibility in large samples of schizophrenics is another possible design. Other forms
of fetal/maternal incompatibilities (i.e. ABO incompatibility— maternal blood type O,
offspring A, B, or AB) and their relationship to schizophrenia can be examined. Studies
can be conducted that examine other human hemolytic conditions such as autoimmune
hemolytic anemia, which incidentally, can be brought on by the influenza virus. Research
using animal models can explore the role of hemolysis, consequent hypoxia and
hyperbilirubinemia on fetal neurodevelopment and aberrant behavior. In future studies,
the limitations discussed earlier can certainly be overcome through research design.
Finally, the observations presented in this study may provide supportive evidence that
maternal antibodies can perturb fetal neurodevelopment either through secondary obstetric
complications or some other unknown mechanism, causing schizophrenia later in life.
Therefore, a wider consideration of the possible role of maternal antibodies, and other
immune factors in the pathogenesis of schizophrenia is indicated.
43
Glossary
alloantibody-antibodies against antigens of the same species.
antibody-complex glycoproteins produced by B lymphocytes in response to antigens,
whose immune function is to combine with antigens to destroy or control them.
antigen-protein marker on cell's surface that identifies the cell as "self' or "non-self,
identifies the type of cell (skin, kidney, etc.), and stimulates the production of antibodies.
autoantibody-anlibodies against "self antigens.
bilirubin-orange or yellowish pigment in bile that is a produced from hemoglobin of red
blood cells.
choreoathetosis-iype of athetosis frequently seen in cerebral palsy, characterized by
extreme range of motion, jerky involuntary movement, and fluctuating muscle tone from
hypotonia to hypertonia.
cyanom-slightly bluish, grayish, or dark purple discoloration of the skin due to reduced
hemoglobin in the blood.
erythrocyte-a mature red blood cell or corpuscle.
erythrolysis-dissoletion of red blood corpuscles.
hydrops fetalis-clinical condition in infants of cardiac decompensation with
hepatosplenomegaly, respiratory distress, and circulatory distress, secondary to HDN or
other conditions.
hyperbilirubinemia-excessive amount of bilirubin in the blood.
icterus gravis neonatorum-hemolytic jaundice of the newborn.
/gG-immunoglobulin G, the principal immunoglobulin in human serum, can move across
the placental barrier; it is the major antibody for antitoxins, viruses, and bacterias.
immunoglobulin-one of a family of closely related though not identical proteins that can
act as antibodies. All antibodies are immunoglobulins but not all immunoglobulins have
antibody functions.
isoimmunization-immunization of an individual against the blood of an individual of the
same species, esp. the development of Rh-negative agglutinins in an Rh-negative mother in
response to agglutinogens present in transfused Rh-positive blood or developed in an Rh-
positive fetus.
/tem/cferus-infiltration of areas of the brain with bilirubin, develops during the second to
eighth day of life and prognosis is poor if untreated.
/ym-destruction of blood cells by a lysin, as when a rabbit's red corpuscles are dissolved
by dog's serum.
Rhesus negative-absence of the D antigen on the surface of the human erythrocyte.
Rhesus positive-presence of the D andgen on the surface of the human erythrocyte.
45
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