Alloimmunization of Pregnancy (by Naira Matevosyan)

Isoimmunization in Pregnancy
Naira Roland Matevosyan, MD, MSJ, PhD
Copyright © 2022. All rights reserved.

Table of Contents
Immunology of Gestation (4)
Innate and adaptive immune responses (5)
The allograft paradigm: Transplantation v. implantation (11)
Development of the fetal immune system (15)
Fetal inflammatory response syndrome (FIRS) (23)
Sensitized Pregnancy with & without Hemolytic Disease (26)
Nine mandatory conditions for Rh-immunization (26)
Alloimmune thrombocytopenia (28)
Nonimmune hydrops fetalis (35)
Management of Rh-sensitized Pregnancy (42)
Schedule of prophylaxis with RhIg (43)
Measuring fetus-to-mother hemorrhage (45)
Intrauterine blood transfusion to the fetus (46)
Algorithm of management of Rh-sensitized pregnancy (50)
Management in undercapacity rural settings (61)
Prognosis
Prognosis (62)

Table of Contents (continued)
Malpractice Law: Case Analysis (63)
Price v. Neyland (DC) (64)
Schnebly v. Baker (IA) (66)
Renslow v. Mennonite Hospital et al (IL) (68)
Empire Cas. v. St. Paul Fire & Marine (en banc) (CO) (69)
Graham v. Keuchel (OK) (73)
Lynch v. Scheininger (NJ) (75)
Review Questions & Answers (78)
Medical (79)
Legal (86)
Answer keys (85, 93)
Notice of Non-Affiliation & Disclaimer (94)

A Related Publication by This Author
ISBN: 9781541356900
Publication year: 2016
Pages: 216 4

Innate and Adaptive Immune Responses
The hemochorial placentation in mammal pregnancies introduces a
complex battle or tolerance with the maternal innate and adaptive
immune systems that operate, on one hand, to repel invaders carrying
foreign DNA and RNA, and on the other, to bear fetus and prevent aseptic
endometritis.
Mammals that gestate with hemochorial or discoid placentation (enclosed
in the brackets are diploid numbers of chromosomes for each):
• rodents – capybara (66), chinchilla (64), chipmunk (38), coypu or
nutria (42), gerbil (36-50), guinea pig (64), lemming (38-64), marmot (38),
megabat (38-62), mouse (40), pocket gopher (40), rat (42), squirrel (40), tuco-
tuco (46); exceptions are cavy (64), hutia (88), octodon (38-102) whose
placentation type is somewhat between endotheliochorial and hemochorial
• lagomorphs – hare (48), pika (38-62), rabbit (44)
• higher order primates – ape (48), human (46), monkey (48).
In early pregnancy, the maternal immune system reassembles to
adjust for decidualization, early embryo development, and tolerance
of the semiallogeneic conceptus. 5

Innate v. Adaptive
INNATE (inborn, pathogen-nonspecific, rapid)
Three pathways: classical, lectin, alternative.
ADAPTIVE (acquired, pathogen-specific)
Humoral - protects against extracellular pathogens; mediated
by antibodies produced by B- lymphocytes and the growth factor.
Cellular - protects against intracellular pathogens; mediated
by T-lymphocytes that kill infected cells by apoptosis.
DEFENSE ORGANS/TISSUES: thymus, spleen, bone marrow,
lymph nodes (tonsils, adenoids, axillary nodes, cervical nodes,
inguinal nodes, mediastinal nodes, pelvic nodes, retroperitoneal
nodes, etc), lymph vessels, hair, eyelashes, mucous membranes
of intestines, nasopharynx, cilia, etc.
6

Defense Workhorses
●
Peptides - Defensins, Formylmethionine, Major Histocompatibility Complex
(MHC), APK-2, Complement system of 20 soluble proteins. Act as modulators.
●
Cytokines - Chemokines, Interferons, Tumor Necrosis Factor Alpha (TNF��
),
Lymphokines, Interleukins. Acute innate cytokines (IL-1, TNF-α, IL-6, IL-12, CXCL8
or IL-18, G-CSF, GM-CSF) locally activate endothelial cells, tissue leukocytes (mast
cells, dendritic cells, γδ T cells) and neurons, generating endothelial cell adhesion,
triggering humoral defense proteins, complement, Ig, leukocytes (innate
lymphocytes, γδ T cells, natural killer (NNK) cells, NK-T cells). The result is
inflammation. A cohort of cytokines (IL-1, IL-6, TNF-α) concurrently prepare
microbial defense by antigen-presenting cells (APC) for adaptive immunity.
●
Lysosomes - are terminal catabolic command stations in eukaryote cells that
discard the waste, scavenge metabolic building blocks to sustain biosynthetic
reactions during starvation, breakdown and digest macromolecules, repair cell
membranes, respond to the foreign invaders.
●
Neutrophil leukocytes - phagocytize and kill bacteria.
●
Macrophages – infiltrate innate immune cells for homeostasis, normal tissue
development, and damage repair.
●
Lymphocytes - T-cells, B-cells, Natural killers (NK) such as CD56 dim
, CD,16 bright.
Produce antibodies, direct the killing of virus-infected and tumor cells.
●
Toll-like receptors (TLR) - link innate and adaptive immunity. 7

Anatomy of Battle
Immune responses are mediated by leukocytes derived from precursors in the bone
marrow. A pluripotent hematopoietic stem cell gives rise to lymphocytes responsible for
adaptive immunity, and to myeloid lineages involved in both innate and adaptive
responses. Granulocytes (neutrophils, eosinophils, basophils) circulate in blood unless
recruited to act as effector cells at sites of infection and inflammation. Macrophages and
mast cells differentiate in tissues for their role as effector cells in the frontline of
inflammation. Macrophages phagocytose bacteria and recruit other phagocytic cells,
neutrophils, from the blood. Mast cells are exocytic: they orchestrate defense against
parasites, trigger allergic inflammation, recruit eosinophils and basophils (also exocytic).
Dendritic cells enter the tissues as immature phagocytes to specialize in ingesting
antigens. These antigen-presenting cells (APC) then migrate into lymphoid tissues.
There are two major types of lymphocytes: B-cells that mature in bone marrow and T-
cells that mature in the thymus. Most adaptive immune responses are triggered when a
recirculating T-cell recognizes its specific antigen on the surface of a dendritic cell.
Mature lymphocytes circulate from the bloodstream through the peripheral or
secondary lymphoid organs, returning to the blood through lymphatic vessels. The three
major peripheral lymphoid tissues are spleen (collects antigens from the blood), lymph
nodes (collect antigen from the infected tissues), mucosal-associated lymphoid tissues
(MALT) (collect antigens from the body's epithelial surfaces). Adaptive immune
response is initiated by peripheral lymphoid tissues: T-cells that encounter antigen
proliferate and differentiate into antigen-specific effector cells, while B-cells proliferate
and differentiate into antibody-secreting cells. 8

Innate v. Adaptive: Basic Differences
continued
9

The Allograft Paradigm: Transplantation v. Implantation
●
Maternal-fetal immune interaction should not be viewed as a transplanted
allograft. Maternal immune system is a reinforced network of recognition,
trafficking and repair, able to raise the alarm to maintain the well-being of
both mother and fetus. Whereas, fetal immune system modifies the way
mother responds to the environment.
●
FIRST TRIMESTER: Following fertilization, the blastocyst breaks
through the endometrium. Endometrial epithelium is gradually replaced
by trophoblastic cells. The trophoblast initiates an immune response by
producing anti-microbial peptides as well as secretory leukocyte protease
inhibitor (SLPI) – an inducer of bacterial lysis.
●
Without NK cells and dendritic cells, trophoblast is unable to develop
endometrial vasculature and pregnancy is terminated. The period of
implantation and placentation, until the 16th
week, resembles ‘an open
wound’ (the trophoblastic seat) that requires a strong inflammatory
response. The human decidua contains a higher number of macrophages,
NK-cells and regulatory T-cells (T-reg). Seventy percent (70%) of the
decidual leukocytes are NK cells, 20–25% are macrophages, and 1.7% are
dendritic cells. From the adaptive battery, B-cells are absent but T-cells
constitute the 3–10% of cellular defense. 11

First Trimester Immunology (continued):
●
By the 4th
gestation week, the conceptus is less than 2cm in diameter
but the basic structure of the mature placenta is laid out: a fetal
circulation terminates in capillary loops within chorionic villi which
penetrate the maternal space supplied by spiral arteries and drained by
uterine veins – like ocean water circulating around the sea anemone.
●
The TNF-related apoptosis, inducing ligand/Apo-2L (TRAIL) protein is
prominent in syncytiotrophoblast (the uninterrupted layer) as well as in
macrophage-like placental mesenchymal cells (Hofbauer cells). Numerous
study results are consistent with the role of TRAIL/TRAIL-R system in
establishing placental immune privilege.
12
Interactions between the
TRAIL and receptors kill
the activated lymphocytes.
Expressions of toll-like
receptors (TLR) such as
TLR-3, TLR-7, TLR-8 and
TLR-9 by trophoblast cells
may explain how the
placenta regulates anti-
microbial factors and
maternal interface.

First Trimester (continued): Immunology of Hyperemesis
Stimulation of the trophoblast cells through TLR-3 promotes the production
and secretion of secretory leukocyte protease inhibitor (SLPI) and interferon-
beta (IFN-β) – two important anti-viral factors. Therefore, the early trophoblast
is already an active immunological organ, capable of recognizing and
responding to pathogens. The described inflammatory environment, deemed
necessary to secure an adequate repair of the uterine epithelium and removal of
the cellular debris, is a type of innate immune activation involving NK cells,
neutrophils, macrophages, and toll-like receptors (TLR).
Studies suggest that women suffering hyperemesis gravidarum (“morning
sickness”) have significantly higher neutrophil/lymphocyte ratio (NLR) and C-
reactive protein (CRP) levels compared to the control (r= 0.703). If a higher
adaptive immune response (due to the decreased NLR) lowers the risk of
hyperemesis gravidarum, then given the main quality of adaptive immunity (i.e.
memory) one would assume that parity should negatively correlate to the
morning sickness. Yet, studies show that nulliparity is significantly associated
with hyperemesis, along with other confounders (ethnicity, genetics, obesity,
number of the conceptus, embryonal anomalies). While the morning sickness is
largely viewed as linked to hyperthyroidism, some authors (Matevosyan, 1999)
find that the first pregnancies have a state of sub-clinical hypothyroidism (with
decreased T3, increased T4 in 9-13 weeks which then drops from the 21st
week,
and TSH mirroring the T4 curve). 13

Second & Third Trimesters
SECOND TRIMESTER: Weeks 13-28 are somewhat the 'optimal'
period, where the mother, placenta, and fetus are the most symbiotic
and the predominant immunological mode is anti-inflammatory. A
pregnant woman no longer suffers from nausea or fever, in part
because the immune response is no longer the leading endocrine
power.
THIRD TRIMESTER: The fetal organogenesis is complete and the
only need for renewed inflammation is the preparation for labor.
Parturition is characterized by an influx of immune cells into the
myometrium to promote recrudescence of the inflammatory process.
Such a pro-inflammatory environment promotes the contraction of
the uterus, expulsion of the fetus, and spontaneous detachment of the
placenta.
Romero R (2005). Novel aspects of neutrophil biology in human pregnancy. The American
Journal of Reproductive Immunology; 53:275
Mor G (2008). Inflammation and pregnancy: The role of toll-like receptors in trophoblast-
immune interaction. Annuals of New York Academy of Sciences; 1127:121–128 14

Development of the Fetal Immune System
●
Relative to adults, the human fetus has limited ability to mount an immune
response in both quantitative and qualitative terms. This can be conditioned
with the mounting of effective host defense. This issue is unsettled because –
due to ethiical reasons - most of the studies of a human fetal immune system
rely on the umbilical cord blood sampling at term (>37 weeks) labors.
●
Weeks 2-10: Fetal hemopoiesis starts at week-2 in mesoderm of the yolk sac
and extraembryonic mesenchymal tissue. Pluripotent erythroid and
granulomacrophage progenitors are detected in the yolk sac at weeks 3-4. At
weeks 4-6, these primitive cells migrate to the liver. At weeks 5-10, the liver
dramatically shrinks as the number of nucleated cells increases. A discrete
granulocyte/macrophage population emerges at this time. At weeks 4-6, there
are two populations of cells with dendritic/macrophage structure in the yolk
sac and mesenchyme, and in the prehaematopoietic liver at week-5. The
majority of yolk sac macrophages are MHC class II-negative and the minority
is MHC class II-positive. MHC -negatives appear in the thymic cortex,
marginal zones of lymph nodes, splenic red pulp, and erythopoietic activity in
the bone marrow. A few MHC-positives are seen in the liver at weeks 7-8 and
thymic epithelium at weeks 8–9. By week 6, the blood flow to the liver passes
through the left umbilical vein, directly from the placenta, providing rich
nutrients to Kupffer cells.
15

Fetal Immunopoiesis (continued)
●
T-lymphocytes: Putative prothymocytes are identified in the fetal liver
from the 7th
week of gestation as highly proliferative cells positive for
CD7, CD45, and cytoplasmic CD3 but which do not express membrane
CD3, TCR-b chain or TdT (terminal deoxynucleotidyl transferase) involved
in the diversification of Ig heavy chain and T-cell receptors. Membrane
CD3 is evident after the week-10 at which time the cells are less
proliferative. CD7+ T-cell precursors from the fetal liver seed the thymus
at 8–9 weeks; 60% of these are CD2+ (cytoplasmic), only 4% are CD3+
(cytoplasmic), and none are TCR-d or b-positive. From 9.5 weeks to birth,
TCR b+ cells increase to form over 90% of the CD7+ population. CD7 is
an early T-lineage marker in the fetus.
●
Weeks 11-16: Thymus and spleen are seeded from the liver and stem
cells are detectable in the bone marrow at weeks 11–12. The culture of
fetal blood collected by fetoscopy at 12–16 weeks yields high levels of
both erythroid and granulocytic/monocytic progenitor cells – with
monocytes comprising 42–68%, neutrophils 27–41%, and eosinophils 5–
30%. An MHC class II-positive cells are found in the lymph nodes at 11–13th
weeks of gestation and in T-cell areas of developing thymic medulla by
the 16
16th
th
week.
week. 16

Fetal Immunopoiesis (continued)
●
SECOND TRIMESTER: From 18–24 weeks, the mesenteric lymph
nodes have a high percentage of CD45RA+ T-cells but very few B-
cells or monocytes. The fetal spleen at this time has equal numbers
of T-cells, B-cells, and monocytes/macrophages. Lymph-node and
thymus T-cells at this point do not proliferate in response to the
mitogen PHA or upon anti-CD3 stimulation, although expression
of CD69 as an activation marker does increase. Yet, splenic T-cells
do proliferate to PHA and anti-CD3. Also, CD4+/CD45RO+
population is frequently expressed as CD25 and can proliferate in
response to L-2, but not anti-CD2 or anti-CD3.
●
Fetal splenic T-cells have adult levels of CD3, CD4, CD8, and also
expressed CD2 and CD11a. By the 18th
week, the spleen is already
fully immunocompetent with sufficient accessory cells to ensure
T-cell activation, whereas the mesenteric lymph nodes are deficient
in accessory cells – both numerically and functionally.
●
The next slide illustrates the fetal lymphocyte differentiation in
the 2nd
trimester. 17

Fetal Lymphocyte Differentiation in Second Trimester
18

Fetal T-cells (continued)
T-cells of the fetal intestinal mucosa are detectable in lamina propria and
epithelium from 12–14 weeks. T-cells in the fetal ileal epithelium are mostly
CD8+ – expressing CD8αα, especially in the Peyer's patches. These thymus-
independent cells develop in the solar plexus (the gut). CD3+ T-cells are
detectable in fetal blood or the omentum at weeks 15-19, expressing CD2 and
CD5. There is no overlap between the gut and blood origins in the rearranged
TCR b transcripts. Proliferation in response to PHA is first seen at 17 weeks.
The majority of lamina propria lymphocytes express CD7 in the absence of CD3
and proliferate by Ki67 expression. T-cells in the fetal intestine express
activation markers (HLA-DR, CD25, CD69, low CD62L and CD45RO) – with
the latter also reflecting a thymus leakage because thymic development is
complete when these cells appear in the omentum.
The thymic and omental γ/δ T-cell repertoires overlap early in development but
diverge during the second trimester. However, these cells are distinctly not of
thymic origin in the fetal liver and the liver may be a site of γ/δ T-cell
development. At 20–22 weeks of gestation, 63% of the liver CD3+ cells are TCR
α/β and 32% are TCR γ/δ. The latter has a CD4+ phenotype.
Fetal (or neonatal) T-cells have poorer capacity (compared to that of adults) to
produce Th1 cytokines, due to the secretory function of the placenta. Lower IFN-
γ production reduces the cellular cytotoxicity of NK cells. 19

Fetal B-cells
●
Pro- (CD24+/surface IgM-negative) and pre-B cells (cytoplasmic
IgM+/surface IgM-negative) are detected in the fetal liver and omentum
as early as 8 weeks of gestation. Their number decreases in the
omentum at 13-23 weeks and remains the same in the liver. Thus, B-cell
development in the omentum is transitory. B-cells are detectable in the
spleen at 13–23 weeks, and CD5+ B cells can be found in the peritoneal
and pleural cavities at 15 weeks. Liver B cells also express CD20 but are
negative for CD21 and CD22.
●
B-cells emerge into the peripheral circulation at 12 weeks and show
positivity for CD19, CD20, CD21, CD22, HLA-DR, IgM, and IgD. The
percentage of CD5+ B cells (B-1 B cells) is higher in the fetal circulation
than that in adults, and declines with progressing pregnancy CD5+ B
cells are largely T-independent and produce polyreactive antibodies of
the primary immune response.
● Bofill M, Janossy G, Janossa M, et al (1985). Human B cell development. II. Subpopulations in
the human fetus. Journal of Immunology; 134:15311538
●
Hofman FM, Danilovs J, Husmann L, Taylor CR (1984). Ontogeny of B cell markers in the
human fetal liver. Journal of Immunology; 133:1197-1201
● Namikawa R, Mizuno T, Matsuoka H, et al (1986). Ontogenic development of T- and B-cells
and non-lymphoid cells in the white pulp of human spleen. Immunology; 57:6169 20

●
FETAL IMMUNOGLOBULINS: The IgG and IgM syntheses occur primarily
in the spleen as early as 10 weeks of gestation, with maximal levels reached at
17–18 weeks. Serum IgG levels slowly grow between 5.5 and 22 weeks, with a
sharp increase at 26 weeks and one more peak at birth. IgG of a haplotype,
distinct from the mother, is detected in fetal circulation as early as 17 weeks,
although most of the IgG is of maternal origin. IgG traverses the placenta
throughout pregnancy with a marked transfer control occurring from 20
weeks and reaching its maximal power at 32 weeks. IgE synthesis is observed
at 11 weeks in fetal liver and lung, and by 21 weeks in the fetal spleen.
●
MUCOUS BARRIERS: IgM- and IgA-producing cells are observed in the fetal
parotid gland at 20–40 weeks, with the predominating IgA1 subclass. Amylase,
lysozyme, and lactoferrin are detectable and most prominent in early fetal life,
whereas only small amounts of the secretory component are seen. Duodenal
expression of secretory components (classes I and II) is seen and IgA-, IgM-,
and IgG-producing cells from 24–32 weeks. From the second postnatal week,
intense expressions of epithelial HLA-DR (the secretory component) and IgA
are observed, reflecting on modulation by the environmental factors.
●
Brugnoni D, Airo P, Graf D, et al (1994). Ineffective expression of CD40 ligand on cord
blood T cells may contribute to poor immunoglobulin production in the newborn.
European Journal of Immunology; 24:1919-1924
●
Macardle PJ, Weedon H, Fusco M, et al (1997). The antigen receptor complex on cord B
lymphocytes. Immunology; 90:376-382
21

FETAL EOSINOPHILS
Granulopoiesis takes place
in the fetal liver.
Eosinophilic granulocytes
are evident at 5 weeks in
the hepatic laminae. With
progressing pregnancy,
their numbers grow in the
liver, and after 20 weeks
they appear in the porta.
Neonatal eosinophils have
less L-selectin than those of
adults; yet, at 23-24 weeks,
fetal eosinophils have adult
levels of L-selectin.
Figure:
Expression of Progenitors of B-1 cells & Eosinophils
22
Rognum TO, Thrane PS, Stotlenberg L, et al (1992). Development of intestinal mucous
immunity in fetal life and the first postnatal months. Pediatric Research; 32:145-149

Fetal Inflammatory Response Syndrome
Fetal inflammatory response syndrome (FIRS) is a condition where,
despite the absence of cultivable microorganisms, a newborn has high
circulating levels of inflammatory cytokines: IL-1, IL-6, IL-8, and TNF-α.
Studies on the animal models suggest that viral infection of the placenta
triggers a fetal inflammatory response similar to the FIRS, even though
the virus cannot reach the fetus. Such neonates have ventriculomegaly
and hemorrhages which may be caused by fetal pro-inflammatory
cytokines: Il-1, TNFα, MCP-1, MIP1-β, and INF-γ.
Compelling evidence suggests that the FIRS may predispose to diseases
in adulthood, increasing the risk of autism, schizophrenia, neurosensorial
deficits, and psychosis. Surviving infants with placental malaria may
suffer adverse neurodevelopmental sequelae and have abnormal
responses to a later parasitic infection where the parasite does not even
reach the placenta. In any event, the inflammatory response in placenta
affects the fetal development.
●
Desai M, ter Kuile FO, Nosten F, McGready R, et al. (2007). Epidemiology and burden of
malaria in pregnancy. Lancet Infectious Diseases; 7:93–104
●
Jamieson DJ, Theiler RN, Rasmussen SA (2006). Emerging infections and pregnancy.
Emergency Infectious Diseases; 12:1638–1643
23

Maternal Anti-Fetal Rejection Syndrome
●
Maternal anti-fetal rejection syndrome (MAFRS) is the derangement of
systemic fetal chemokine milieu (typically, CXCL10) and elevation of fetal
plasma IL-6, a condition similar to allograft rejection. CXCL10 is a ligand of
CXCR3 - chemotactic for the activated T-cells, macrophages, and NK cells.
●
Mechanism of fetal tolerance is orchestrated by the calming autoreactive T-
cell precursors combative against MHC or crucial proteins (insulin, relaxin,
collagen) during their differentiation in the thymus. To prevent an auto-
conflict, immature thymocytes traffic through the thymic medulla where
they encounter antigens and undergo apoptosis. This process, known as
clonal deletion, is also complemented by other mechanisms such as clonal
diversion, TCR editing, and induction of anergy.
●
To deal with autoreactive cells, there is peripheral tolerance enforced by
regulatory cells - with the most studied, CD4+CD25+FoxP3+Treg.
●
Gomez R, Romero R, Ghezzi F, et al (1998). The fetal inflammatory response syndrome.
American Journal of Obstetrics and Gynecology; 179(1):194-202
● Lee JH, Romero R, Chaiworapongsa T, et al (2013). Characterization of the fetal blood
transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel
type of human fetal systemic inflammatory response. American Journal of Reproductive
Immunology; 70(4): 265–284 24

Sensitization
A small amount of fetal blood may cross the placenta due to the:
●
Abdominal compression syndrome
●
Amniocentesis
●
Bleeding in pregnancy
●
Blunt trauma to the abdomen during pregnancy
●
Chorionic villus sampling (CVS)
●
Cordocentesis
●
Ectopic pregnancy (including abdominal pregnancy)
●
Elective abortion after 6 weeks of gestation
●
External cephalic version of a fetus in transverse lie
●
Fetal-maternal hemorrhage (occurs in 30% of uneventful pregnancies and
the Rh conflicts are weak). Known as “grandma's syndrome,” it concerns the
birth of Rh-negative female to Rh-positive mother.
●
Internal cephalic version in management of breech labor
●
Intrauterine death of the fetus
●
Placenta previa
●
Polyhydramnios
●
Pregnancy combined with trophoblastic disease.
25

Nine Mandatory Conditions for Rh-immunization
(1) Rh antigen (from three genetic loci) on the short arm of fetal chromosome 1,
with the following possible alleles:
●
Fisher-Race coding (used in obstetrics): CDE, cde, CDe, Cde, cDE, cdE, CdE;
●
Du
antigen (incomplete D antigen): Mother with a pure Du
phenotype does
not need RhIg administration (exception, a mixed-field Du
positivity caused by
hemorrhage from Rh+ fetus into Rh-negative mother).
(2) Molecular weight of the Rh antigen: 7 x 103 - 10 x 103
(3) Functionality of the Rh antigen: Unlike the A and B blood groups, the Rh
antigen is confined to erythrocytes; the majority of Rh isoimmunization is caused
by the D antigen (the Cc and Ee antigens are minor antigens).
Heterozygous Rh + males (Dd) contribute in 60% of cases.
Homozygous Rh + males (DD) contribute in 40% of cases.
A homozygous Rh-negative woman (dd) has a 50% Rh-incompatible risk if
she mates with a heterozygous Rh+ male and a 100% risk if she mates with a
homozygous Rh+ male (Rh- men excluded).
26

Nine Mandatory Conditions (continued)
(4) The chance of incompatibility is 60% in the white population: (0.85)
(0.70) = 0.6
(5) With no prophylaxis, the 20 % of white Rh-negative pregnant women
become sensitized: (0.6) (0.2) = 0.12. Ergo, the 12% are practically
sensitized as opposed to the theoretical 20% indicator.
(6) The critical volume of fetal blood volume required for sensitization is as
low as 0.1ml. There is great individual variability though, as even larger
volumes may be non-immunogenic.
(7) The fetus must be Rh+ and the mother must be Rh-negative.
(8) A sufficient number of fetal erythrocytes must enter the maternal
circulation, or prior exposure to the Rh antigen must have occurred. The
antigen load for inducing an immune response varies. Without prophylaxis,
the rates of sensitization are 1% - 2% before delivery, and 15% - 20%
intrapartum.
(9) The maternal ability to produce an anti-D antibody is necessary.
Iams JD, Zuspan FP, Qulligan EJ (1990). Manual of obstetrics and gynecology. C.V. Mosby Co.
27

Alloimmune Thrombocytopenia
Cause:
1. Platelet antigen PIA1 in 90% of
cases.
Platelet antigen incompatibility (PAI):
2. Incidence – 1: 5000 births.
3. Mechanism is analogous to Rh
sensitization, i.e. placental transfer
of the maternal immunoglobulin
(IgG) antibodies against fetal platelet antigens inherited from the father.
4. Symptoms vary from mild petechiae to severe intracranial hemorrhage and long-
term disabilities.
5. Immunofluorescence platelet suspension is 90% positive for platelet antibodies.
6. Is distinct from idiopathic thrombocytopenic purpura (ITP) by the presence of
platelet-associated antibodies in platelet isoimmunization.
7. May affect the first pregnancy.
8. Recurrence is 75%.
9. Perinatal management - avoiding nonsteroid anti-inflammatory drugs or aspirin.
10. Antenatal management - mother receives intravenous immunoglobulin, steroids,
and intrauterine platelet transfusions.
28

Feto-maternal alloimmune thrombocytopenia (FMAIT)
1. A relatively uncommon disease, FMAIT is
the leading cause of severe
thrombocytopenia (< 150,000
platelets/μL) and intra-cranial
hemorrhage in newborns, with far-term
impairments in adulthood.
2. FMAIT occurs when a woman is
alloimmunized against fetal platelet
antigens inherited from the father.
Disseminated Petechiae
3. Prevalence ranges between 1:5000 to 1:350 live births.
4. Causality: In the white population, the most common antibody is anti-HPA-1a
(75%–80%) which targets the polymorphic Leu/Pro residue of glycoprotein IIIa
(GPIIIa) on the platelet membrane. The second common is anti-HPA-5b (10%–
15%). Yet, only 10% of the general (mixed-ethnic) population develops anti-
HPA-1 antibodies. An association is found between the HLA II group (HLA
DRB3*0101) and the immunogenicity of the HPA-1 antigen. The latter is
expressed not only on the surface of platelets but also on other fetal cells, as the
number of fetal platelets transferred across the placenta is not sufficient to
produce immunization and anti-HPA antibodies are rarely produced after an
allogeneic transfusion (continued). 29

FMAIT (continued)
Causality (continued): GPIIIa, a platelet glycoprotein that carries the HPA-1a/1b
polymorphism, is identified on the surface of villous syncytiotrophoblast in the
first-trimester and term placentas, and its interaction with the maternal
immunity through subcellular villous syncytiotrophoblast microparticles is one of
the clues. This also explains why FMAIT is clinically present in the 1st
trimester.
5. Clinics: Symptoms vary depending on the FMAIT onset or severity, and range
from subdermal petechiae (47%) and ecchymoses to hematomas and internal
hemorrhages (7-26%). Forty-two percent of symptoms occur by 30 weeks.
6. Diagnosis is based on the presence of circulating maternal alloantibodies
against fetal platelet antigens. Thereafter, both parents and the newborn are
genotyped for HPA antigen. Specific antiplatelet antibodies are detected by
indirect platelet immunofluorescence or monoclonal antibody immobilization
platelet antigen (MAIPA) tests. There are two problems in diagnosing FMAIT:
(A) Patients with uncommon antiplatelet antibodies. If the initial HPA test is
negative, MAIPA should be performed and repeated with increasing amounts of
maternal serum. Once the common antibodies are excluded, a cross-match should
be performed between the maternal serum and paternal platelets to detect low-
frequency or private (“unique”) incompatible antigens.
(B) False-negative results. In <30% of cases, maternal anti-HPA-1a may not be
instantly detectable but can become positive weeks or months after childbirth. 30

FMAIT (continued)
7. Cost-Effectiveness of Mandatory Antenatal Screening: The aim of the
FMAIT route screening is to prevent or reduce intracranial hemorrhage.
There is no standardized testing strategy and trends must consider these:
(A) Prevalence of HPA-1a phenotype in the general population is low (1%–2%);
(B) Only 10% of the patients develop anti-HPA-1a antibodies and the 30% of their
neonates only develop thrombocytopenia (which is severe in 20% cases);
(C) Anti-HPA1 are good predictors only at 22-34 gestation weeks as the test lacks
accuracy/precision if performed in the 1st
trimester and thus isn't cost-effective.
Simple cell-free DNA screening for noninvasive fetal HPA-1a is inconsistently
reported for compelling sensitivity or specificity. An alternative strategy is a
screening of circulating anti-HPA antibodies; however, this test can only
recognize certain antibody types. HLA DRB3*0101 genotyping has not been
tested in large populations, either. In 2007, a three-tiered (cost-effective)
screening module was introduced:
(1) initial measurement of circulating anti-HPA antibodies and fetal ultrasound
(2) followed by a serial antibody titer and fetal testing if in either, the -HPA1 is
> 100 arbitrary units/mL;
(3) and testing regardless of the anti-HPA1 level if the woman has anti-HPA-1bb
antibodies and is HLA DRB3*0101 genotype positive. 31

FMAIT (continued)
8. Differential Diagnosis: FMAIT is often confused with neonatal autoimmune
thrombocytopenia (NAT). In FMAIT, only fetal platelets are affected. Whereas,
NAT is featured by the presence of maternal autoantibodies due to a maternal
disease (idiopathic thrombocytopenic purpura, systemic lupus erythematosus,
hyperthyroidism) in which antibodies affect both maternal and fetal platelets.
Other causes of neonatal thrombocytopenia are excluded after a careful
examination of the newborn and maternal history. The main causes other
than FMAIT are infections, drug-related destruction of platelets, disseminated
intravascular coagulation, necrotizing enterocolitis, hypersplenism, Kasabach-
Merritt syndrome, and thrombosis. Less common causes include genetic
abnormalities (congenital amegakaryocytic thrombocytopenia, congenital
platelet disorder), bone marrow infiltrative disease (bone marrow metastases,
neonatal leukemia), or toxic megakaryocyte injury. The rarest causes are
preeclampsia, hypoxic-ischemic injury, and neonatal cold injury.
The disease severity is typically greater in FMAIT because the
thrombocytopenia is associated with a decrease of platelet count as well as
platelet dysfunction (because the alloantibodies are capable of binding both
glycoproteins IIb and IIIa). The NAT symptoms are milder and present with
petechial purpura several days after delivery.
32

FMAIT (continued)
9. Management of pregnancies at risk for FMAIT includes planned delivery and
avoiding nonsteroidal anti-inflammatory drugs and aspirin. The aim is to prevent or
reduce intracranial hemorrhage (ICH). Below is the general protocol:
33
Maternal intravenous
immunoglobulin (IVIG)
injection and intrauterine
platelet transfusion (IUPT)
may prevent severe
thrombocytopenia in fetus;
given the IUPT complications
(fetal hemorrhage, death),
non-invasive treatment with
close monitoring is the best
strategy. IVIG is given
0.5g/kg - 1.0g/kg, starting
from 12-20 weeks. In 67% of
cases, it greatly increases the
fetal platelet counts (>
50,000/mL). In case of failed
response, the IVIG dose is
doubled, corticosteroids are added, and fetal blood is sampled in 2-4 weeks. Of the antenatal
corticosteroids, prednisolone (0.5 mg/kg) is preferred, as dexamethasone is associated with
oligohydramnios. Adverse maternal effects from corticosteroids are hypertension, osteoporosis.

FMAIT (concluding)
10. Prognosis: There is no maternal laboratory marker to precisely predict the
severity of FMAIT. History of a previously affected child, especially with ICH, is
the strongest predictor. The determination of maternal HPA alloantibody
should be considered if there is a history of a previously affected newborn.
However, the HPA antibody titer itself does not correlate with clinical severity;
a severe disease can occur even with low antibody titers. Besides, the
antibody titer can fluctuate over time, which limits its clinical value.
Fetal HPA group can be obtained by amniocentesis, and should be indicated
only if there is a previously affected child with FMAIT from a heterozygous
partner. Fetal genotyping using cell-free fetal DNA is becoming popular.
11. Recurrence depends on zygosity of father for the relevant antigen. In
general, the severity of FMAIT and fetal thrombocytopenia are lesser than that
in previous pregnancies.
12. Mortality rates vary from 1% to 10% and far-term complications (mental
retardation, cerebral palsy, cortical blindness, seizures) may occur in as many
as 14% to 26% of cases. Thrombocytopenia resulting from anti-HPA-1a
immunization is usually more severe than that from anti-HPA-5b, which
commonly produces moderate thrombocytopenia and few clinical
manifestations. However, the ICH can be observed in both cases. 34

Nonimmune Hydrops Fetalis
Hydrops fetalis (HF) is severe oedema in multiple
body areas of a fetus or neonate.
Overwhelmingly, the onset is the second
trimester (13-28 weeks). HF can be immune
(IHF) or non-immune (NIHF), coded ICD-9 and
ICD-10, correspondingly. IHF is the outcome of
RH, HLA, or ABO incompatibility between
mother and fetus. Causes will be provided.
Non-immune hydrops in 15 weeks
35
Prevalence of NIHF ranges from 1/1500 to 1/3800 births. The widespread use
of Rh(D) immune globulin has dramatically decreased the prevalence of the
Rh(D) alloimmunization and associated hydrops. Ergo, NIHF now accounts for ~
90 % of hydrops cases.
Pathogenesis is understudied. Fluid homeostasis within vascular and interstitial
compartments is controlled by hydrostatic and osmotic pressure differences that
move the fluid, as measured by the Starling equation, Q = k(Pcap − Pint) −
σ(pcap − pint). Cellular mechanisms also regulate fluid movement and contribute
to the Starling forces. Dysregulation of net fluid movement between the vascular
and interstitial spaces - leading to NIHF - can be caused by fetal disorders with
obstructed lymphatic drainage in the thoracic and abdominal cavities.

NIHF Etiology
Complex causality includes fetal, maternal, mixed (i.e. placental), and idiopathic
factors.
●
FETAL FACTORS:
1. Hematological (10-27% cases) - Chronic maternal-fetal transfusion,
Homozygous α – thalassemia, Hypophrome anemia, Impaired RBC
production, Multiple gestation with parasitic fetus, Twin-to-twin transfusion,
Pregnancy concurrent to trophoblastic disease.
2. Cardiovascular (40% cases) - Bradyarrhythmia (heart block), Congenital
cardiac anomalies (atrial septum defect, ventricular septum defect, hypoplastic
left heart, pulmonary valve failure, Ebstein's disease, sub-aortic stenosis),
Fibroelastosis, Large A-V malformation, Myocarditis, Paroxysmal
supraventricular tachycardia, Premature closure of foramen ovale,
Tachyarrhythmia (atrial flutter, supraventricular tachycardia).
3. Chromosomal (10% cases) - Deficiency of beta-glucuronidase (a
lysosomal storage disease, a type-7 mucopolysaccharidosis), Disorders of
glycosylation, Mosaicism, Noonan syndrome (mutation of chromosome 12),
Thalassemia, Triploidy, Trisomy (10, 13, 15, 18, 21), Turner syndrome (45,
XO), Type-C Niemann-Pick disease (NPC), Type-2 Gaucher disease, and other
metabolic-genetic disorders (continued). 36

NIHF Etiology: Fetal Factors (continued)
4. Pulmonary (4-7% cases) - Congenital chylothorax, Cystic
adenomatoid malformation of lungs, Pulmonary hypoplasia,
Pulmonary lymphangiectasia.
5. Urological (5% cases) - Congenital nephrosis, Renal vein thrombosis,
Posterior urethral valves, Spontaneous bladder perforation.
6. Intrauterine infections (8- 35% cases) - Chagas' disease,
Cytomegalovirus (CMV), Hepatitis C, Herpes simplex, Leptospirosis,
Parvovirus B-19, Rubella, Syphilis, Toxoplasmosis, Zika virus.
7. Congenital anomalies ( < 2% cases) - Achondroplasia (short-limb
dwarfism), Diaphragmatic hernia, Polycystic kidneys, Thanatophoric
dwarfism.
8. Tumors (< 10% cases) - Cystic adenomatoid malformation, Cystic
hygroma, Sacrococcygeal teratoma.
9. Miscellaneous - Fetal neuroblastomatosis, Meconium peritonitis,
Small-bower volvulus, Tuberous sclerosis. 37

NIHF Etiology (concluding)
●
MATERNAL FACTORS: Diabetes mellitus, Hypothyroidism, Lupus
erythematosus, Mirror syndrome (preeclampsia with maternal oedema
and diastolic hypertension), Severe anemia, Toxemia.
●
PLACENTAL FACTORS: Chorioangioma, True cord knots, Umbilical vein
thrombosis.
●
IDIOPATHIC: Cardiomyopathy, Chylothorax.
38
NIHF Symptoms
●
FETAL: Abnormal fluid accumulation in the abdomen; Enlarged heart,
liver or spleen; Polyhydramnios (sonographically, the largest amniotic
pocket between the fetal echo-positive structures is > 8 cm in two
perpendicular planes); Thickened placenta.
●
NEONATAL: Anemia, Cardiac failure, Difficulty of breathing, Enlarged
liver and spleen, Jaundice, Pallor (pale skin coloring), Severe oedema
(especially on the abdomen).

NIHF
Differe
ntial
Diagn
ostics
39

NIHF Management
40
(1) Amniocentesis
●
Amniotic fluid sampling - αFP, karyotype, ΔOD 450 for Liley's chart,
Fetal blood film and indices, Fetal plasma albumin and total protein,
Specific IgM is a new infection is in question, TORCH titers, Viral cultures.
●
Fetal blood sampling – Albumin, Albumin-corrected calcium (for
thalassemia), Alpha smooth muscle actin (SMA), Blood group and Rh
factor, Electrolytes , Glucose-6-phosphate dehydrogenase, Hemoglobin-A
and F chain analysis, Liver battery (blood urea nitrogen -BUN,
aminotransferase), Serum alkaline phosphatase (for thalassemia)
(2) Maternal blood sampling
●
Alpha feto protein (αFP), Antibody screening, Blood group and Rh factor,
HLA type (if recurrent or idiopathic), Kleihauer–Betke acid elution test for
the amount of fetal hemoglobin transferred to mother's bloodstream;
Toxoplasmosis, Rubella, CMV, Herpes simplex (TORCH) titers; VDRL
(venereal disease research lab) for syphilis.
(3) Urological tests
●
CMV culture, Urine analysis. (continued)

NIHF Management (continued)
(4) Ultrasound exam
●
Diameter of the major fetal vessels; Fetal cardiac evaluation (rhythm and
the chamber size); Fetal skin thickness; Free fluid in the fetal abdominal,
thoracic, pleural cavities; Full fetal growth; Irregular amniotic fluid
accumulation (polyhydramnios, oligohydramnios); Morphological survey
of the fetal organs and anomalies; Placental thickness.
(5) At delivery
●
Autopsy, Forensic X-ray, Karyotype (if not checked before), Taking
photographs, Viral studies.
41
NIHF Treatment
●
During pregnancy: Anti-arrhythmic medications (digoxin) to mother to
correct fetal arrhythmia; Early induction of labor; Early C- section in case of a
rapid decline of fetal condition; Fetal surgery (removal of a damaged gland or
organ, thoracocentesis, paracentesis); Intrauterine blood transfusion to fetus.
●
Postnatal: Breathing support (ventilator or NCPAP); Cardiac medications;
Direct intravascular transfusion of packed and compatible RBC to the
newborn along with exchange transfusion for eliminating antibodies;
Diuretics; Needle aspiration of fluid from the newborn's abdomen or pleura;
Oxygen therapy; Surfactant replacement therapy.

Management of RH-sensitized Pregnancy
Rh incompatibility is diagnosed during pregnancy and treated with Rh
immunoglobulin (RhIg) injections.
●
During pregnancy: RhIg is administered by intramuscular injection,
typically at 28 weeks of gestation. The chances of sensitization before
28 weeks are too small (< 1%) and are higher (2%) after 28 weeks.
Postulated duration of protection after the RhIg injection is about 12
weeks.
●
Intrapartum: Sensitization rate with RhIg is low, 0.2%.
●
Postpartum: If given within 72 hours of delivery, the rate of
sensitization is decreased to 1%. 300g of RhIg reliably prevents
sensitization with 30 ml of Rh+ blood (nearly 20 μg per cc fetal cells).
RhIg must be given at the correct times to work properly.
Note: Half-life of RhIg is 25 days. Administration of 20 μg of RhIg
consistently prevents sensitization with 1cc of fetal cells. Note, 1cc of
fetal cells equals approximately 2cc fetal blood, as hematocrit index in
the fetus is commonly 50%. 42

Schedule of Prophylaxis with RhIg
OBJECTIVES:
1) To increase the clearance of antibody-coated cells.
2) To mask the Rh antigens by exogenous antibodies.
3) To suppress B-lymphocytes by mediator substances produced by T-cells.
Production of mediator substances is in turn stimulated by the T-cell
recognition of antibody-coated Rh antigens.
The table below presents a schedule of RhIg administration and the fetal
fetal
cell coverage. Note, that the total number of days is 100 (~ 14 weeks):
weeks):
43

Dose-specific Rules of Prophylaxis
44
The standard is, that in 28 weeks, the RhIg should be sufficient to
prevent the majority of fetal-maternal hemorrhages.
1) Administering 300 μg RhIg is indicated for:
• pregnancy that terminates at 12 gestation weeks
• pregnancy that terminates and the gestation age is unknown
• during amniocentesis or CVS.
2) Administering 50 μg RhIg is required for pregnancy that
terminates before 12 weeks.
3) More than 300 μg RhIg is indicated for fetal-maternal
hemorrhage that is larger than usual. In such an instance, the
estimation of the amount of fetal blood should be
be made with
made with the
help of the Kleihauer-Betke test.

Measuring Fetus-to-
Mother Hemorrhage
More than 50% of fetus-to-
mother bleeding at
delivery is less than 1cc.
Only the 1/300 of fetal-
maternal hemorrhage
(FMH) cases exceeds the
capacity of one vial (300
μg) of RhIg.
There are two main arrays
of quantifying FMH:
(1) directly conjugated
monoclonal anti-D labeling
(2) anti-fetal hemoglobin
(HbF) labeling.
To the left is the sensitivity
of various tests for FMH.
45

Intrauterine Blood Transfusion to the Fetus
If a positive FMH test confirms the cause of fetal death, the % of the total
fetal blood volume lost should be calculated, considering the following:
The size of the fetal red blood cells is 1.22 times that of adult red
blood cells;
Kleihauer-Betke (KB) stain has a 92% mean success rate in detecting
fetal red blood cells;
At term, the mean volume of maternal red blood cells is ~ 1800 ml;
Mean fetal hematocrit is 50%;
At stillbirth, the main fetal blood volume is 150 ml/kg.
These constraints can then be applied to yield the KB formula -
PFB = (3,200)( FC) /(FW) (MC) where
PFB is the percentage of fetal blood lost;
FC is the observed number of fetal erythrocytes;
MC is the observed number of maternal erythrocytes, quantified by
MC = TC-FC where TC is the total # of erythrocytes (mother+ fetus);
FW is the weight of the stillborn fetus in kilograms. 46

Trying the KB Formula
Suppose, Kleihauer-Betke (KB) stain is performed and the total
erythrocytes TC = 4,000, of which
fetal erythrocytes FC = 180
the stillborn's weight (FW) = 2.4kg.
The KB formula will quantify the total percentage of the fetal
blood loss like this:
PBF = (3,200)(FC) / (FW)(MC) =
(3,200)(180) / (2.4)(3,820) = 62.827225
The final estimate must be rounded to five digits: 62.827.
Answer: The fetus, under consideration, has lost 62.827%
(almost 2/3) of his/her blood due to the fetus-to-mother
hemorrhage.
47

Recommended Volumes of Intrauterine Blood Transfusion
From the last example, if the
fetus abruptly loses 2/3 of
his blood, stillbirth is highly
likely. However, the KB stain
results shall not serve as a
conclusive diagnosis. A fetus
may lose large quantities of
blood over extensive periods
and compensate for the
losses slowly. The KB stain
cannot inform a high PFB
with stillbirth. Yet, when
adjusted for the known
hereditary complications of
pregnancy, significant
correlations (r > 875)
between FMH and stillbirth
are found. 48

Required Volumes for Direct Intrauterine Blood Transfusion
49
The ways of estimating
intervals between
transfusions are subjects
of endless controversy.
The quantitative
accuracy is diminished
by the varying rates of
destruction of the
erythrocytes not only in
different patients but
also in the same patient
at different times.
Typically, it is a 1%
hematocrit drop per day.
Iams JD, Zuspan FP, Qulligan
EJ (1990). Manual of
obstetrics and gynecology.
Mosby Co.

Algorithm for Managing Rh-sensitized Pregnancy
50
Similar to managing non-immune hydrops, there are six default
strategies for managing Rh-immunized pregnancy:
(1) Serology; (2) Amniocentesis; (3) Blood transfusion; (4) Fetal
heart monitoring; (5) Prenatal ultrasound; (6) Doppler.
I. SEROLOGY
1. First-sensitized pregnancy:
✔ If the titer is less than the critical value (usually, 1:16 - 1:31) –
the serum test must be repeated every 4 weeks.
✔ If the titer exceeds the critical value – amniocentesis or
cordocentesis is required at 22-24 weeks of pregnancy.
2. Subsequent-sensitized pregnancy:
✔ Amniocentesis or cordocentesis are required at 22 to 24
weeks.
✔ The protocol for managing first-sensitized pregnancy is in the
next slide.

Management of the First
Rh-sensitized Pregnancy
51

Management of Rh-
sensitized Pregnancy
with Critical Titer
52

II. AMNIOCENTESIS To the left is the Liley curve,
the delta (difference) between
predicted and expected optical
density of the amniotic fluid at
450 nm – per gestation week,
where
➢Zone-I is consistent with an
unaffected or mildly affected
fetus;
➢Zone-IIA is consistent with
moderately affected fetus
(decreasing values, mild
disorder)
➢Zone-IIB is consistent with
moderately to severely affected
fetus (increasing values –
severe condition, the degree of
which is shown by steepness);
➢Zone-III is consistent with a
severely affected fetus.
53

Protocol of Action
Following Amniocentesis:
➢Zone -I: Repeat amniocentesis every 3 -4 weeks.
➢Zone-II (A and B): Repeat amniocentesis every 1- 2
weeks.
➢Zone-III: Immediate intrauterine blood transfusion or
termination of pregnancy by C-section or induction of
labor – according to the gestation age and other
indicators (biophysical profile, fetal heart rates, maternal
comorbidity).
* See descriptions of Zones in the former slide.
54

III. Intrauterine Blood Transfusion
●
Performed either via cordocentesis or intraperitoneally. The timing
in both is similar. Conventionally, the intraperitoneal transfusion is
not performed beyond 32 gestation weeks. The success and safety of
both techniques depend on the skills of the surgeon. The blood used
for transfusion is washed group 0/Rh-negative. Both intraperitoneal
and intravascular transfusions are performed under the ultrasound
monitor. The formula for quantifying the necessary volume of blood
to be transfused per gestation week is discussed in slides 47, 48.
IV. Fetal Heart Monitoring
●
Lacks sensitivity as the fetus has to suffer a significant degree of
anemia before the appreciable changes are reflected in the fetal heart.
●
Normal fetal heart rate (FHR) is 120-160 beats per minute. Baseline
rate is the rate over time. Changes in FHR that last less than 2 minutes
are periodic (normal) changes. Baseline FHR abnormalities include:
tachycardia (moderate 160 – 180/min; severe > 180/min), and
bradycardia (moderate 100 - 200, severe < 100/min). The next slide
shows the details.
55

Periodic v. Variable Changes of FHR
Periodic changes refer to healthy accelerations (increase in FHR of 15
beats/min lasting 15-120 seconds) and decelerations (variable, early, late, or
prolonged):
56
Variable decelerations vary in
shape, degree, and time relative
to contractions. Those are
common, occurring in 70% of
labors, with rapid return to
baseline. Patterns remind "W" or
"V" shapes (continued).

Distinction between the Common and Warning Decelerations
Decelerations start with the onset of
contractions and include: acceleration at the
start of the pattern (a good sign), smooth
acceleration at the end, and slow return to
baseline (a bad sign of fetal distress).
Variable decelerations are caused by the
compression of the umbilical cord. They can
be mild (last < 30 seconds with FHR > 80
beats/min), moderate (FHR < 80 beats/min
regardless of the duration of deceleration),
severe (last 60 seconds with FHR < 70
beats/min). Administering 100% oxygen is
required if the severe variable deceleration
is prolonged. Even minutes before the
urgent C-section, the patient's position
needs to be changed to relieve the pressure
on the cord.
Early decelerations are non-pathological,
caused by the fetal head compression with
vagal stimulation. No treatment is required.
Continued.
57
Severe Variable Decelerations
Early Decelerations

Warning Decelerations (continued)
Late decelerations are caused by fetal and/or
maternal hypoxia, interference with IV blood flow,
hyperstimulated uterus, maternal hypotension, Rh-
isoimmunisation with fetal anemia, premature
detachment of the placenta, and placental infarction.
They can be mild (15-60 sec), moderate (30-90 sec),
and severe (30-90 sec, with FHR < 100 beats/min, or
a decrease by 45 beats/min). Treatment includes
100% oxygen to the mother, improving maternal
uterine blood flow, correcting hypotension, turning
pregnant to the left side, intrauterine blood
transfusion, injection of dexamethasone to mother if
fetal anemia is confirmed. During the Rh-sensitized
pregnancy, the FHR is predominantly in sinusal
pattern. If FHR accelerates in response to scalp or
acoustic stimulation, the fetal scalp blood PH must be
reassessed. Urgent C-section is required (depending
on gestation age) if the late deceleration links to a flat
baseline FHR.
58
Late Deceleration w/ Variability Loss
Prolonged Decelerations
Prolonged decelerations are when the drop in FHR is rapid and lasts > 2 minutes. Etiology
is uncertain and may include Rh- sensitization of pregnancy. Recovery is fast. Treatment
constitutes of immediate C-section if decelerations are prolonged > 10 minutes.

V. Prenatal Ultrasound
The degree of fetal anemia cannot be determined by an ultrasound exam
unless hydrops fetalis is present. And hydrops becomes sonographically
identifiable only when a tiny amount of fetal hemoglobulin ( < 4 mg/dL)
enters the maternal bloodstream. The ultrasound markers of hydrops
fetalis are abnormal collection of fluid in at least two different fetal organ
spaces (ascites of the abdomen, pericardial effusion, pleural effusion, skin
edema in the subcutaneous area, etc).
To the left is an 18-
week-old fetus with
non-immune
hydrops manifested
by ascites and
cystic hygroma (a
soft bulge under
the skin).
59

VI. Doppler
Non-invasive Doppler ultrasound is
capable to reveal correlations
between the velocity and volume of
the fetal blood flow and fetal
hemoglobin level. An increased peak
velocity of systolic blood flow in the
fetal middle cerebral artery (MCA)
can predict anemia (with 90.5%
sensitivity* and 78.6% specificity *)
and with that, postpone unnecessary
invasive interventions until the blood
transfusion is performed (if
necessary). The diagnostic errors are
explained by the negative
correlations between the gestational
age and multiple of median (MOM)
of fetal hemoglobin (r=−0.358, P <
0.028), and between the gestational
age and MCA (r=−0.525, P<0.014).
High Doppler imaging of the middle cerebral artery
(MCA) peak systolic velocity (68.5) in anemic fetus
with fetal Hb 7.5 at 30 weeks gestation
* Shourbagya S.E., Elsakhawya M. (2012).
Prediction of fetal anemia by middle cerebral
artery Doppler. Middle East Fertility Society
Journal; 17(4): 275-282 60

Management of Erythroblastosis Fetalis in Undercapacity Rural Settings
61
In rural areas, the incidence of erythroblastosis fetalis is usually 1:200 pregnancies and
an affected fetus has < 50 % chance to survive without treatment.* In such conditions,
two tests still can be arranged: Typing for Rh factor and Coombs test. Must-do list:
1. A thorough reproductive and transfusion history.
2. Pregnant women should be referred to the labs for Rh typing and routine blood
screening. Mailing containers must be used for sending the blood samples to
advanced laboratories.
3. If the maternal blood is Rh-negative, antibody screening is required. Antibodies in
early pregnancy indicate sensitization with carry-over from previous exposures.
4. Titration tests must be repeated at the 7th
month of pregnancy. If results are
negative, no more tests are required. If the results are positive, titrations should be
repeated in the 8th
month. A rise in titer may be significant.
5. The umbilical blood should be sampled for the Coombs test.
6. Irrespective of the antenatal anti-D Ig dosage, postpartum prophylaxis is required
and the peurperiae must be screened for FMH for additional Ig. (Note, that anti-D
Ig is not required in women with threatened miscarriage with a viable fetus and
cessation of bleeding before 12 weeks).
7. At least 500 IU of anti-D immunoglobulin should be given to non-sensitized Rh-
negative women at 28 weeks and 34 weeks of pregnancy.
*Dennis J.L. (1951). The Rh factor in rural practice: Responsibility of the general practitioner. The 80th Annual Session
of the California Medical Association, Los Angeles
* Kumar S. (2005). Management of pregnancies with RhD alloimmunization. BMJ; 330(7502): 1255-58.

PROGNOSIS
●
In summary, maternal-fetal Rh incompatibility can lead to alloimmunization,
transplacental transfer of maternal immunoglobulin, and hemolytic disease of the
fetus and newborn (HDFN). The use of routine antenatal anti-D prophylaxis
(RAADP) has sharply decreased the HDFN incidence and mortality rate.
●
The ability to identify high-risk pregnancies for HDFN has improved due to the
paternal molecular RHD zygosity testing, and non-invasive fetal molecular
diagnostics for detecting putative antigens (notably RhD) in fetuses utilizing cf-DNA
in maternal plasma.
●
Fetal RHD genotyping using cf-DNA has become increasingly accurate for fetal RHD
detection, prompting to implement of targeted RAADP through mass screening
programs of RhD-negative pregnant women. Along with middle cerebral artery
Doppler ultrasonography for predicting fetal anemia, non-invasive fetal molecular
diagnostics have greatly decreased the need for invasive screening procedures in
pregnancies at risk for severe HDFN.
●
Erythroblastosis fetalis is a grave condition with 15% stillbirth and perinatal
mortality.* Surviving newborns may develop kernicterus, which can lead to
deafness, speech pathology, cerebral palsy, or mental retardation. Extended
hydrops fetalis can inhibit lung growth and contribute to heart failure.
Erythroblastosis fetalis may be prevented with a careful blood monitor. Treatment
of minor symptoms is typically successful.
* Fasano R.M. (2016). Hemolytic disease of the fetus and newborn in the molecular era. Seminars in Fetal and
Neonatal Medicine; 21(1):28-34
62

MALPRACTICE LAW
Price v. Neyland (DC, 1963)
Schnebly v. Baker (IA, 1974)
Renslow v. Mennonite Hospital et al (IL, 1977)
Empire Cas. v. St. Paul Fire and Marine (en banc) (CO, 1988)
Graham v. Keuchel (OK, 1993)
Lynch v. Scheininger (NJ, 2000)
Note: The cases are visited in chronological order.
63

Price v. Neyland, 320 F. 2d 674 (D.C. Circuit 1963)
●
FACTUAL NARRATIVE: Plaintiff (Neyland) is the mother of an injured Rh+ positive child
born to Rh+ positive homozygous father and Rh-negative mother. The child was born
with erythroblastosis fetalis and kernicterus because of her mother's Rh-sensitized
pregnancy. Defendant (Dr. Price) had diagnosed her jaundice as physiological, based on
primary laboratory tests, including the Coombs test indicative of the absence of
antibodies. In fact, these tests were wrong. Neither a Vandenberg test was performed, nor
a follow-up Hemoglobin (Hb) test was ordered - in spite of the diagnostic evidence of
erythroblastosis fetalis. Prior to the birth, plaintiff had a positive Coombs test. Her
condition worsened and preterm labor was induced. The premature newborn developed
jaundice within the first 50 hours of life. Yet, Dr. Price ignored thejaundice. Within a
week, the newborn developed convulsions due to the brain damage. Three weeks after,
she was seen by defendant (Dr. Price). Two months later, during the follow-up visti, Dr.
Price was informed about the additive seizures. At six months of age, the infant had a
seizure right in Dr. Price's office. At nine months of plaintiff's age, her mother informed
Dr. Price that she was going to change the pediatrician. Instead, Dr. Price recommended a
neurological exam. The neurologist confirmed the brain damage. The expert opinion
suggested that if proper tests were timely performed, the pathologic jaundice would be
timely diagnosed and managed. Due to the diagnostic disadvantage, the exchange
transfusion was not performed in the newborn.
●
PROCEDURAL HISTORY: Ten years after, in 1963, plaintiff brought a malpractice action
against Dr. Price and her claim was partially favored. Defendant appealed contending an
error in the admission of evidence, and improper jury instructions (continued).
64

Price v. Neyland
●
PROCEDURAL HISTORY (continued). Defendant (Price) claimed that the obstetrician
(co-defendant) was called by the plaintiff adversely under Rule 43(b), F.R.Civ.P, and that
he was asked, inter alia, whether a second Coombs test should be performed while she
was still in the hospital. The obstetrician confirmed it at the deposition. Dr. Price also
argued that the appellant did not and could not challenge the propriety of adverse
questioning and the use of deposition against the obstetrician pursuant to the Rules
43(b) and 26(d)(2), F.R.Civ.P. He also alleged that the Trial Court failed to give three
requested charges, particularly one containing appellant's version of malpractice law.
●
ISSUES: Whether the co-defendant (obstetrician) was adversely questioned at trial, and
whether an en banc hearing was necessary to revisit the co-defendant's testimony.
●
HOLDING: Defendant cannot challenge the propriety of adverse questioning and the use
of deposition against co-defendants.
●
AUTHORITIES: Rules 43(b) and 26(d) (2), F.R.Civ.P; and Davis v. Virginian R. Co (1960)
●
APPELLATE JUDGMENT: Affirm. Petition for hearing en banc is denied.
●
REASONING: The charge of malpractice - as given by the Trial Court - was more
favorable to the defendant than his requested charge. “If the proof leaves it equally
probable that a bad result may have been due to a cause for which the defendant was not
responsible as to a cause for which he was responsible, the plaintiff cannot recover." In
order to fasten liability in a malpractice case, a plaintiff must prove, by a preponderance
of the evidence: (1) a recognized standard of care in the community exercised by
physicians of the same specialty under similar circumstances, and (2) the defendant's
departure from that standard. Here, there was substantial evidence to support the
plaintiff's theory of the case, and the jury accepted that theory. 65

Schnebly v. Baker, 217 N.W.2d 708 (Iowa 1974)
●
FACTS: The Rh-negative plaintiff (Schnebly) carried the third pregnancy with a
Rh+ fetus. The former two pregnancies were with Rh+ and Rh- babies. Her
husband was Rh+. During the third pregnancy, the plaintiff's GP (Dr. Irish)
ordered an X-ray, ran lab tests, and informed the patient about the “virulent level”
of her Rh antibodies. He engaged his brother-in-law (pediatrician Baker) for a
joint monitor. Nearing the term, Rh antibodies increased and labor was induced.
At birth, the newborn's bilirubin was 1.48 mg %, next day - 9.4 mg %, and grew
rapidly while jaundice developed. GP alerted that if bilirubin increases to 20 mg
%, blood transfusions will be necessary. Plaintiff asked for a retest in another
location (due to the absence of a pathology lab). The test results from two places
were striking inconsistent. Dr Baker chose to rely on the test with lower results
(11.3mg %), ignoring the 25mg % on the child's third day of life. On day 4, the
Mason City results were 37 mg % and the Forest City's 9.9 mg %. Bilirubinuria
was diagnosed. Still, Dr. Baker relied on the Forest City's results. When the
bilirubin raised to 39.8 mg %, Dr Irish (the GP) panicked and arranged the
newborn's hospitalization for blood transfusion. Aftermath, the bilirubin
effectively dropped but the child had already sustained severe brain damage and
deafness – further requiring expensive specialized care and schooling.
●
PROCEDURAL HISTORY: In 1966, the plaintiff (with her husband, on behalf of
the injured child) brought malpractice actions against the hospital (continued).
66

Schnebly v. Baker
●
PROCEDURAL HISTORY (continued): Next year (1967), the plaintiff filed an
amended complaint, this time against Dr. Baker (pediatrician) and two other
providers. Parallel to answering, the defendants filed cross-petitions against each
other. The two providers settled the case. Dr. Baker remained to face the jury.
After he argued that the case publicity would improperly influence the jury, the
case was heard before the bench and $912,124.00 +$132,674.00+$300,000.00
damages were sought. Baker appealed. The Appellate Court underlined
differences between “personal injury” and “bodily injury” in assessing discovery
rule, comparative negligence, overlapping damages, or time bar points.
●
HOLDING: There was insufficient evidence to support Trial Court's factual
finding that the intervening act was a superseding cause.
●
AUTHORITIES: Emmert v. Grill, 39 Iowa, 690. Paragraph 3, § 3447, of the Code §
614.1(2); numerous common-law; Restatement, Torts 2d, § 453.
●
APPEALS JUDGMENT: Affirming in part (child's damages), reversing in part
(plaintiff's damages), and remanding for entry of judgment by District Court.
●
REASONING: The hospital and the pathologists are liable for one-half damages.
Dr. Baker bears the other half under the contribution rules.* Subsequently, the
Appeals Court relied on O'Banion that "relative rights cover consequential
damages to a plaintiff arising from injuries to another.” Chase v. Winterset, 203
Iowa 1361, 1363, 214 N.W. 591, 592
●
*Note: The language is imprecise, as Iowa is a modified comparative fault state. 67

Renslow v. Mennonite Hospital, 367 NE 2d 1250 - Ill: Supreme Court (1977)
●
FACTS: In 1965, Renslow was 13 y/o when the hospital (defendant), on two occasions,
negligently transfused her 500 cc Rh + positive blood and did not notify her. In 1973,
Renslow discovered her RhD sensitized condition during the routine screening in her first
pregnancy. Her sensitization from 1965 allegedly caused prenatal damage (hemolytic
disease) to her fetus (L.A) that necessitated an induction of premature birth. L.A. was born
preterm in 1974, with hyperbilirubinemia and jaundice requiring immediate blood
transfusion. L.A. suffered permanent damages to various organs, including the brain.
●
PROCEDURAL HISTORY: A six-count malpractice tort brought by the plaintiff (Renslow)
individually and on behalf of her suffered child (L.A.) was dismissed. The Trial Court
determined that “the child wasn't conceived yet at the time of the alleged infliction of injury."
The “defendants could not reasonably have foreseen that the teenage girl would later marry
and bear a child and that the child would be injured as the result of an improper blood
transfusion." The appeal followed.
●
ISSUE: Does a child, not conceived at the time of negligent act against her mother, have
standing against the tortfeasors for her perinatal injuries resulting from negligent conduct
prior to her mother's pregnancy?
●
APPEAL JUDGMENT: Affirm. The sub judice claim contains no allegation that plaintiff was
viable when her injuries were sustained. It is not appropriate to manifest sympathies for the
injured parties by permitting compensation through the extension and distortion of the ideas
of duty and foreseeability beyond the bounds of reason.
●
AUTHORITY: Supreme Court Rule 304(a); Dietrich v.Inhabitants of Northhampton (1884).
●
REASONING: Neither causation nor foreseeability standing alone are adequate standards
upon which to predicate liability. 68

Empire Cas. v. St. Paul Fire and Marine,
764 P.2d 1191 (Colo. Supreme Court 1988)
●
FACTS: Baby Pete's mother was Rh-negative and father was Rh+
homozygous. Their first child was born unaffected, although the mother
received suboptimal prenatal care where her blood type was misrecorded
as RH+ and she didn't receive RhoGAM during the 1st pregnancy. The 2nd
pregnancy ended with stillbirth. During the 3rd pregnancy, Pete's mother
chose another hospital where the blood type was finally established as RH-
negative. Subsequent tests determined that the fetus had developed severe
erythroblastosis and attempts were made to treat the disease by
intrauterine transfusions. In 1976, Pete was delivered by induced preterm
birth at 30-31 weeks. Severely injured by erythroblastosis fetalis, Pete
became mentally and physically handicapped.
●
PROCEDURAL HISTORY: In 1988, 12-year after Pete was diagnosed with
disabilities, the parents filed a malpractice action against the physician who
attended the first and second pregnancies of Pete's mother. The advisory
jury found that plaintiff was sensitized immediately after the birth of her
first son in 1972, and that the defendant (Dr. Lockwood) had committed
four separate acts of negligence through the two pregnancies where each
act was a proximate cause of injuries sustained by Pete (continued). 69

Empire Cas. v. St. Paul Fire and Marine (continued)
●
PROCEDURAL HISTORY: Defendant's negligence constituted in: (1)
misrecording the blood type in 1972; (2) failing to retype the mother's
blood for RH factor during the second pregnancy and labor; (3) failing to
investigate adequately the cause of death of Pete's stillborn sibling; and (4)
affirmatively advising the mother to have additional children, without
establishing the cause of death of the second child. The Trial Court adopted
the findings of the jury, with some modifications. Defendant claimed
malpractice insurance coverage by three providers: Empire, Continental,
and Chicago. The case grew into a dispute among three insurance providers
as to the share each had to pay from the total $575,000.00 damages entered
against the defendant. The Trial Court rejected the Empire and Chicago
argument that “the mistyping of mother's blood was the only proximate
cause of the injury sustained by Pete,” and that “an apportionment of damage
award based upon any of defendant's subsequent acts of negligence could
only be accomplished by recognizing a claim for wrongful life.” The Trial
ruled that the doctrine of “continuing negligence” was inapplicable to this
case, and implicitly held that Continental had waived the threshold limit of
its umbrella insurance policy. The Court entered judgment against Empire
for $200,000 on each policy (a total of $400,000) and against two excess
carriers, Continental and Chicago ($87,500.00 from each) (continued).
70

Empire Cas. v. St. Paul
●
LEGAL PROCEDURES (continued): Defendants appealed. The CO Court of
Appeals agreed with Empire and Chicago insurances in that “allocating the
damage award based upon defendant's subsequent acts of negligence was
tantamount to allowing recovery for wrongful life.” Despite, recognizing the claim
for relief, it ruled that Continental could not waive the threshold limit on its
umbrella policy and reallocated damages accordingly. The Court of Appeals
affirmed the $400,000.00 award against Empire, vacated the award against
Continental and ordered the Trial Court to enter judgment against Chicago for
$175,000.00. Defendants appealed to CO Supreme Court.
●
ISSUES: (1)Whether a legally cognizable cause of action exists in Colorado for the
tort of "wrongful life;" (2) Whether the doctrine of continuing negligence should be
applied to the facts of the case; (3) Whether, as a matter of law, Continental did
waive the threshold limit on its umbrella policy; (4)Whether the Court of Appeals
failed to conclude that a portion of malpractice judgment exceeded Continental's
limit of coverage even when Continental did not waive that limit.
●
HOLDING: The CO Supreme Court rejected the tort of wrongful life claim and
overruled pursuant to the continuing negligence doctrine. It affirmed the Appellate
Court's decision that the Trial court erred in imposing liability upon Continental
below the threshold amount. Each insurance company was responsible for the
remaining $75,000. Chicago and Continental were liable for $37,500 each (of the
total $75,000); Chicago was liable for $137,500 of the excess amount (continued). 71

Empire Cas. v. St. Paul (continued)
AUTHORITIES: Lininger v. Eisenbaum (1988); Procanik v. Cillo (1984); Wilson v.
Prasse (1972), Johnson v. Winthrop Laboratories Div. (1971); St. Paul Fire & Marine
Ins. Co. v. Hawaiian Ins. & Guaranty Co (1981), etc.
DISPOSITION: The CO Supreme Court affirmed in part and reversed in part the
judgment of the Appellate Court, and the case was remanded to the Trial Court for
entry of judgment accordingly.
REASONING: (1) This case didn't fit the wrongful life definition because Pete's
condition was not genetically preordained and the subsequent negligent acts of the
defendant were proximate causes of injuries sustained by Pete. (2) The doctrine of
continuing negligence did apply to this case because three separate negligent acts
against Pete occurred during a 2-3 year period and each of them implicated all
insurance policies in force during the time of negligence. (3) The application of the
doctrine of implied estoppel is to be distinguished from the asserted grounds of
forfeiture. Continental is responsible only for its portion of the judgment ( >
$500,000). (4) Continental provided defendant with broad professional liability
coverage which was triggered by any one of the three following events: (a) a
negligent act, error, or omission which occurred during the policy period which
caused the insured an "ultimate net loss"; (b) "following form" coverage, and (c)
"claims made" coverage. Thus, the Appeals Court erred by considering only the
"following form" coverage and failing to recognize the "ultimate net loss" coverage.
72

Graham v. Keuchel,
847 P. 2d 342 - Okla: Supreme Court (1993)
●
FACTUAL NARRATIVE: Baby Donald was born in 1983 with erythroblastosis
fetalis and died four days later. His mother's Rh sensitization could be prevented
by administering Rho-GAM during all pregnancies (after each miscarriage,
abortion, or birth of RH-positive fetus or child).
●
PROCEDURAL HISTORY: Donald's parents brought malpractice action. The
defendants (prenatal, postnatal care providers) denied any negligence on their
part, arguing that (1) the statute of limitations barred the claims, (2) the mother's
sensitization wasn't caused by her 1982 miscarriage, (3) the mother was
negligent (contributory fault) for failing to tell them that she was Rh-negative and
had received Rho-GAM before, and (4) a superseding cause cut off their liability
because the mother had willfully conceived Donald with full knowledge of her
sensitization and the serious risks posed to herself and her fetus. The jury found
for defendants on all claims. Plaintiffs appealed. Defendants counter-appealed.
●
ISSUES ON APPEAL: (1) Was the supervening cause instruction in wrongful death
claim fatally or reversibly flawed? (2) Did the Trial Court commit reversible error
by instructing on "mistake of judgment" when this jury charge was unwarranted
by the evidence adduced in the trial of both claims?
●
ISSUES ON COUNTER-APPEAL: (1) Did the Trial Court err by failing to direct a
verdict for defendants on wrongful death claim? (2) Should the Trial Court have
held that the mother's bodily injury claim was time-barred?
73

Graham v. Keuchel (continued)
●
HOLDING: The Appeals Court sided with the plaintiffs on all claims.
●
JURISDICTION: Strong v. Allen (1989); Unah v. Martin (1984); Sixkiller v.
Summers (1984); Haws v. Luethje (1972); and Paul v. N.L. Industries (1981).
●
JUDGMENT: Trial Court judgment was reversed and remanded for a new trial.
●
REASONING: (1) The mother's negligence in becoming pregnant did not legally
support a supervening cause instruction. No parent's act or omission is available
as a supervening cause if it is rested on ordinary negligence. With narrow
exceptions permitting filial recovery for insured losses from vehicular
negligence, a child cannot recover from a parent for the latter's ordinary
negligence that causes or contributes to the child's injury or death. These
principles combine to prevent the doctors from directly or obliquely shifting to
the mother their own tort liability. As the lower court concluded, there was no
direct evidence of the mother's intent to get pregnant at the time she conceived
Donald. (2) The predictable failure of birth control methods resultant in
pregnancy would not be a supervening cause. (3) It is a judicial error to treat a
controverted fact as a question of law and withhold the issue from the jury,
while the trial court did with the foreseeability issue. (4) Since the trial judge
had included mistakes of judgment in his instructions, the jury wasn't misled.
Hence, there was a strong probability that the jury reached a result different
from that which it would have reached but for the flawed jury charge. 74

Lynch v. Scheininger,
744 A.2d 113, 162 N.J. 209 (2000)
●
FACTS: Defendants (obstetricians) rendered negligent services to the
plaintiff, resulting in stillbirth from erythroblastosis fetalis, in 1984. Plaintiff
(Lynch) had delivered two healthy children before. In 1984, during her third
pregnancy, her obstetrician (Dr. Finkel) died. Dr. Scheininger assumed duties
for her prenatal care. After the pregnancy loss, Dr. Scheininger confessed that
he didn't diagnose Mrs. Lynch's Rh isoimmunization during the third
pregnancy and that failure to treat resulted in stillbirth of the fetus (Brian).
●
PROCEDURAL HISTORY: In 1986, Lynch and her husband filed a malpractice
suit against Dr. Scheininger and others, to recover damages associated with
stillbirth. While the action was pending, Mrs. Lynch gave birth to plaintiff
Joseph Lynch in 1987. Joseph was born with permanent neurological
disabilities, caused by erythroblastosis fetalis, the same condition that had
taken the fetus Brian's life in 1984. In January 1990, the plaintiffs moved to
amend their complaint to assert damage related to Joseph's birth. The motion
was denied and plaintiffs instituted another action against Dr. Scheininger
and others, alleging that the defendants' failure to diagnose and treat Lynch's
Rh- conflict in 1984 increased the risk of harm to children subsequently
conceived. In the second suit, plaintiffs asserted a claim of wrongful birth on
their behalf, and a claim of "wrongful life" on Joseph's behalf (continued). 75

Lynch v. Scheininger (continued)
●
PROCEDURAL HISTORY (continued): In 1992, while this action was
pending, the earlier suit for 1984's stillbirth was settled but the release
expressly excluded the claims against Dr. Scheininger in the second action. A
settlement was also reached with the co-defendant, Dr. Grochmal, against who
Scheininger had filed a third-party complaint. Pursuant to Lopez v. Swyer
jurisdiction, the claims of “wrongful life” and “wrongful birth” were tried. The
complaint was seen as time-barred and the plaintiff's discovery rule theory
failed. After a 23-day trial, the court submitted the case to the jury, reserving a
decision on defendants' motions to dismiss Joseph's malpractice claims. The
jury, however, was unable to reach a verdict. In the unpublished opinion on
reserved motions, the Trial Court presumed that New Jersey courts would
recognize a cause of action for a "preconception tort." The appeal followed. The
Appellate Court affirmed the Trial Court's dismissal of Lynches' wrongful birth
claim on statute of limitations grounds and affirmed the dismissal of Joseph's
"wrongful life" claim as well as other claims due to the lack of proof. It
reversed, however, the judgment dismissing Joseph's case against Dr.
Scheininger. The Appeals concluded that the finding was not subject to
collateral estoppel on the motion to dismiss Joseph's claims because it was not
necessary to support the court's determination to dismiss the wrongful birth
claim. The appeal followed (continued). 76

Lynch v. Scheininger (continued)
●
HOLDING: The parent's "voluntary decision to conceive another child did not
constitute a supervening cause" that precluded the child from maintaining a
malpractice claim to recover damages for irremediable birth defects allegedly
caused in part by the preconception negligence of the mother's physician during a
prior pregnancy.
●
JUDGMENT: The NJ Supreme Court affirmed the Appeals judgment and remanded
the case for further proceedings consistent with its opinion.
●
JURISPRUDENCE: People Express Airlines, Inc. v. Consolidated Rail Corp (1985);
Ayers v. Jackson Township (1987); Ostrowski v. Azzara (1988), etc.
●
REASONING: Related to the doctrine of contributory negligence is the doctrine
of avoidable consequences rooted in the law of contracts and torts. Avoidable
consequences come into action when the injured party's carelessness occurs
[after] a defendant's wrongful act. Contributory negligence comes into action
when the injured party's carelessness occurs [before] (or concurrent to) the
defendant's wrongful act. The doctrine of superseding cause focuses on whether
events or conducts that intervene subsequently to a defendant's negligence are
sufficiently unrelated to the negligent act to warrant termination of the
defendant's responsibility. A related doctrine of avoidable consequences focuses
on the diminution of damages on a basis of plaintiff's failure to avoid the
consequences of defendant's tortious conduct. In this case, neither collateral
estoppel nor the law of prima facie case was applicable.
77

REVIEW QUESTIONS & ANSWERS
●
Medical survey: Slides 79 - 84
●
Legal survey: Slides 86 - 92
●
Answer keys: Slides 85, 93
78

Medical Survey
Question 1:
True or false?
E,e; C,c are part of the rhesus antigen.
Question 2:
True or false?
E,e; C,c are considered minor antigens.
Question 3:
Select the best answer. The rate of sensitization in a
rhesus-incompatible pregnancy after delivery without
RhIg administration is:
(a) 15% - 20%; (b) 10%; (c) 1% - 2%; (d) 0.2%.
79

Medical Survey
Question 4:
Select the best answer. The rate of sensitization in a
rhesus-incompatible pregnancy with RhIg
administration after delivery is:
(a) 15% - 20%; (b) 10%; (c) 1% - 2%; (d) 0.2%.
Question 5:
Choose the correct answer. The rate of sensitization in a
rhesus-incompatible pregnancy with antepartum and
postpartum RhIg administration is:
(a) 15% - 20%; (b) 10%; (c) 1% - 2%; (d) 0.2%.
0.2%.
Question 6:
Choose the correct answer. Half-life of RhIg is:
(a) 100 days; (b) 50 days; (c) 25 days; (d) 10 days. 80

Medical Survey
Question 7:
The definitive quantitative test for estimating the volume of
fetus-to-mother hemorrhage is:
(a) Rosette method; (b)DU
method; (c) ELISA;
(d) Kleihauer-Betke method.
Question 8:
The ABO incompatibility is a common cause of:
(a) Hydrops fetalis; (b) Neonatal hyperbilirubinemia;
(c) Platelet antigen incompatibility; (d) Lupus erythematosus.
Question 9:
The hemolytic disease of the fetus or newborn (HDFN) is also
known as:
(a) Erythroblastosis fetalis; (b) Pernicious anemia; (c) Sickle-
cell anemia; (d) None of the above. 81

Medical Survey
Question 10:
In erythroblastosis fetalis:
(a) Fetal body attempts to produce increased numbers of
erythrocytes to replace the destroyed ones.
(b) The immature red cells (erythroblasts) deposited into the
fetal bloodstream cannot carry adequate oxygen, causing
anemia.
(c) Hemoglobin freed from the destroyed RBCs can cause
kidney damage and failure.
(d) All above.
82

Medical Survey
Question 11:
The purpose of RhIG injection is to reduce pregnancy-
associated ______ formation:
(a) Anti-D; (b) Anti-K; (c) Neither; (d) Both A and B.
Question 12:
One "dose" or vial of RhIG is able to protect the mother
from stimulating ________ in response to 15 mL Rh-positive
cells of 30 mL positive whole blood:
(a) Rh o-D; (b) Anti-K; (c) Anti-k; (d) Anti-H.
Question 13:
A grave condition resultant from the passing of
unconjugated bilirubin into the fetal lipid tissues like brain
or spinal cord, and causing CNS/PNS damage:
(a) Hyperchrome anemia; (b) Kernicterus;
(c) Hyperbilirubinemia; (d) Neither. 83

Medical Survey
Question 14:
Blood banks determine their own critical levels of titers but
usually a titer of ______ or ______ is considered significant in
detecting INCREASED severity of the hemolytic disease of
the newborn (HDN):
(a) 16, 32 (two-fold)
(b) 32, 64 (two-fold)
(c) 16, 64 (four-fold)
(d) None of the above.
84

Medical Survey
1. True
2. True
3. a
4. c
5. d
6. c
7. d
85
ANSWER KEY
8. b
9. a
10. d
11. a
12. a
13. b
14. c

Question 1:
______ allows the defendant (healthcare provider, hospital, or
biopharma agency) to present evidence that the patient's condition
resulted from factors other than the defendant's negligence:
(a) Promissory estoppel
(b) Contributory fault doctrine
(c) Comparative fault doctrine
(d) Affirmative defense.
Question 2:
Replace the vacant spaces with the correct order of terms:
_______ is performing a wrong and illegal act
_______ is improperly performing a proper or lawful act
_______ is the failure to perform the necessary act.
(a) Misfeasance, Nonfeasance, Malfeasance
(b) Malfeasance, Misfeasance, Nonfeasance
(c) Nonfeasance, Malfeasance, Misfeasance. 86
Legal Survey

Legal Survey
Question 3:
A defense strategy that prevents the plaintiff from recovering
damages if the plaintiff voluntarily accepts a risk associated
with his/her conduct:
(a) Contributory fault; (b) Assumption of risk;
(c) Mirror image rule; (d) Affirmative defense.
Question 4:
A special application of respondent superior in which an
employer lends an employee to someone else:
(a) “Standing in the shoes” doctrine
(b) No-fault doctrine
(c) Borrowed servant doctrine
(d) Plaintiff's reasonableness doctrine. 87

Legal Survey
Question 5:
Ordering more tests or procedures than necessary in
order to protect oneself from lawsuits or prosecutions:
(a) Net economic loss doctrine
(b) Medical error
(c) Risk foreseeability
(d) Defensive practice.
Question 6:
A proportionate responsibility or a 50% bar rule, whereby
plaintiff's negligence will offset defendant's liability but
plaintiff may not recover if s/he is found 50% or more at fault.
Applied in these jurisdictions: AR, AS, CO, GA, GU, ID, KS, ME,
NE, ND, PR, TN, U.S.V.I, UT.
(a) Modified comparative fault; (b) Modified
contributory fault; (c) Joint liability; (d) Pure
comparative fault.
88

Legal Survey
Question 7:
A fault system whereby a plaintiff may not recover if s/he
contributed to injury in any way. The following jurisdictions
follow that doctrine: AL, CNMI, DC, MD, NC, VA.
(a) Modified comparative negligence
(b) Contributory negligence
(c) Calculus of negligence
(d) Canterbury standard.
Question 8:
The only state in the Union where a party's negligence is
measured by a hybrid of comparative and contributory
negligence laws, known as the “slight/gross negligence
comparative” law. A plaintiff may only recover if s/he was
“slightly” faulty and the other party displayed “gross”
negligence:
(a) Hawaii; (b) Maine; (c) South Dakota; (d) Vermont. 89

Legal Survey
Question 9:
A fault system where a plaintiff’s recovery will be reduced by
his/her share of fault. Practiced in AK, AZ, CA, FL, KY, LA, MO,
MS, NM, NY, RI, WA:
(a) Hand's formula
(b) Straight liability
(c) Modified contributory
(d) Pure comparative fault.
Question 10:
A fault system where plaintiffs cannot recover
compensation if s/he is found 51% or more at fault. Applied
in those jurisdictions: CT, DE, HI, IL, IA, IN, MA, MI, MN, MT,
NE, NH, NJ,OH, OK, OR, PA, SC, TX, VT, WI, WV, WY:
(a) Joint liability; (b) Canterbury standard;
(c) Modified comparative fault; (d) Modified
contributory fault. 90

Legal Survey
Question 11:
Improper termination of a patient care by a physician:
(a) Discharge; (b) Disengagement
(c) Abandonment; (d) Referral.
Question 12:
The _____________ is an event that operates independently and
becomes the proximate cause of an accident. For an event to fall
within the doctrine of _____________, also known as Last Clear
Chance, four conditions must be satisfied: (I) The injured party
has to be in a perilous position; (II) the tortfeasor in the
exercise of ordinary prudence must be aware that the party in
peril cannot safely avoid injury; (III) the tortfeasor has the
opportunity to save the other person; and (IV) the tortfeasor
fails to exercise such care.
(a) Strict liability; (b) Supervening cause;
(c) EMTALA; (d) Good Samaritan law. 91

Legal Survey
Question 13:
In Lynch v. Scheininger (2000), the NJ Appellate Court affirmed
the Trial Court's dismissal of the plaintiff's “wrongful birth” claim
and "wrongful life" claim (as to baby Joseph) for all reasons below
except for:
(a) Doctrine of superseding cause
(b) Contributory negligence doctrine
(c) Statute of limitations
(d) Collateral estoppel.
Question 14:
In Lynch v. Scheininger (2000), how did the NJ Appellate Court
define the differences between “avoidable consequences” and
“contributory negligence”?
(a) Avoidable consequences are when the injured party's negligence
occurs after defendant's wrongful act, and contributory negligence
is when the injured party's negligence occurs before defendant's
wrongful act; (b) Vice versa; (c) Either; (d) Neither. 92

Legal Survey
93
ANSWER KEY
1. a
2. b
3. b
4. c
5. d
6. a
7. b
8. c
9. d
10. c
11. c
12. b
13. d
14. a

NOTICE OF NON-AFFILIATION & DISCLAIMER
This presentation is rather arbitrary. It shan't be utilized as
medical or legal advice.
The author maintains neither commercial, fiduciary,
strategic interests nor conflicts of interests with the names,
entities, or published respective sources mentioned or
omitted herein.
Presented is knowledge cultivated from the author's own
experiences as an ob/gyn doctor managing high-risk
pregnancies, as well as from the review of 359 publications
(books, articles, case studies). As crediting all 359 sources
on limited-space slides was a technical challenge, the
author has unbiasedly cited only some. The complete list of
references used for this presentation is published in her
216-page book (ISBN 9781541356900), as shown in slide 4.
94

Alloimmunization of Pregnancy (by Naira Matevosyan)

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