International Journal of Clinical Medicine, 2011, 2, 313-317
doi:10.4236/ijcm.2011.23054 Published Online July 2011 (http://www.SciRP.org/journal/ijcm)
Copyright © 2011 SciRes. IJCM
313
Sickle Cell Disease and Pregnancy: Does Outcome
Depend on Genotype or Phenotype?
Catherine Berzolla1, Neil Stuart Seligman1, Aisha Nnoli1, Kevin Dysart2, Jason K. Baxter1,
Samir K. Ballas3
1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Philadelphia, USA; 2Division of Neonatol-
ogy/Nemours Foundation, Department of Pediatrics, Philadelphia, USA; 3Division of Hematology/Cardeza Foundation, Department
of Internal Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, USA.
Email: cberzolla@gmail.com
Received February 25th, 2011; revised May 4th, 2011; accepted June 11th, 2011.
ABSTRACT
Objective: Women with sickle cell disease (SCD) who become pregnant are at risk for serious maternal and fetal com-
plications. Our objective was to determine if pregnancy outcome is dependent on phenotype. Methods: Retrospective
cohort study of pregnant women with SCD, including hemoglobin (Hb) SS, Hb SC and Hb Sβ-thalassemia, between
January 1999 and December 2008. Antenatal and neonatal outcomes were compared between pregnancies with painful
episodes and those without. The primary outcome was preterm birth (PTB) < 37 weeks. Secondary outcomes included
maternal medical complications, antenatal complications, delivery outcomes and neonatal outcomes. Results: 31
women were included (18 (58%) with painful episodes, 13 (42%) without painful episodes). The median number of
painful episodes was 2.5 (1 - 19) and these women required a median of 13 total days (1 - 59) of inpatient treatment. At
delivery, women who had experienced painful episodes had lower Hb levels and were more likely to be taking chronic
narcotic pain medications. The overall incidence of PTB < 37weeks was 55% and was not significantly different be-
tween groups (11 (61%) with painful episodes versus 6 (46%) without painful episodes; p = 0.485). Secondary out-
comes were also not significantly different between groups. There was one maternal death. Conclusion: Adverse ob-
stetrical outcomes were more common among women with sickle cell disease who experienced painful crises however,
in this small sample, the difference were not statistically significant.
Keywords: Pregnancy, Sickle Cell Disease, Painful Vaso-Occlusive Episodes
1. Introduction
Sickle cell disease (SCD) describes hemoglobinopathies
associated with the phenomenon of sickling. These in-
clude sickle cell anemia, or homozygosity for hemoglo-
bin S (Hb SS), Hb SC disease (Hb SC), and Hb S-beta
thalassemia (Hb Sβ). In the United States, the highest
frequency of SCD is in African Americans, with an in-
cidence of 1in 600 births [1,2]. In one study, the inci-
dence of SCD by genotype was found to be 8.5, 4.4, and
2.2 per 100,000 infants screened for Hb SS, Hb SC, and
Hb Sβ respectively [3]. Hispanics are also at a higher
risk for SCD with at least 1 in 180 Hispanic infants hav-
ing sickle cell trait. SCD is not associated with de-
creased fertility in women, but those women who be-
come pregnant are at a higher risk for maternal and fetal
complications than the general population. More than
one-third of pregnancies in women with SCD end in
abortion, stillbirth, or neonatal death [4-6].
Other complications include painful episodes [7],
anemia requiring transfusion [1], infection [1,5], pree-
clampsia [5,6,8], and maternal death [1,8]. Intrauterine
growth restriction [6,8,9], preterm delivery [6,8-10], and
low birth weight [5,6,9] are also more common.
The most common complication of SCD is painful
vaso-occlusive crisis, now referred to as an acute or re-
current painful episode. The frequency of painful epi-
sodes peaks between the ages of 19 and 39 [11], which
coincides with childbearing age. Pregnancy may also
increase the frequency of painful episodes. Up to 55.8%
of women with SCD will have at least one painful epi-
sode during the course of their pregnancy [12]. Physiol-
ogic changes during pregnancy, including hyperco-
aguability, vascular stasis, and increased metabolic de-
mands, predispose women to sickle cell-related compli-
cations and may explain the increased frequency of
Sickle Cell Disease and Pregnancy: Does Outcome Depend on Genotype or Phenotype?
314
painful episodes during pregnancy [7]. The objective of
this study was to estimate the effect of phenotype, spe-
cifically the presence or absence of painful episodes, on
obstetrical and neonatal outcomes of pregnancies in
women with SCD.
2. Materials and Methods
This is a retrospective cohort study evaluating pregnant
women with SCD (Hb SS, Hb SC, Hb Sβ) during a
10-year period. We queried the hospital medical records
database for the ICD-9 codes pertaining to SCD and
pregnancy from January 1, 1999 to December 31, 2008.
Women who experienced painful episodes during preg-
nancy (painful episodes present) were compared to those
who did not (painful episodes absent). Maternal and
neonatal data were obtained from paper charts and the
hospital electronic medical records database; consisting
of labs, radiology reports, and dictations. Painful epi-
sodes were defined as an emergency room discharge or
hospital admission diagnosis of “sickle cell crisis” or
“painful episode”. In general, the clinical diagnosis of a
painful episode was made based on the subjective com-
plaint of pain, overall clinical suspicion, and exclusion
of other etiologies of pain based on associated symptoms.
The decision to admit for painful episodes was deter-
mined by persistent pain after following each woman’s
individualized sickle cell disease Program Treatment
Plan. The number of painful episodes was determined by
counting the number of ER visits in which the woman
was either treated for a painful episode and discharged
or admitted. The length of treatment in days was defined
as the time from admission to discharge. ER visits that
did not result in admission were counted as one day of
treatment. For women who had multiple pregnancies
during the study period, only data from the earliest
pregnancy were analyzed. Women who did not deliver
at Thomas Jefferson University Hospital (TJUH) were
excluded. The primary outcome was preterm birth (PTB)
< 37 weeks. Secondary outcomes included antenatal
maternal medical complications (e.g. acute chest syn-
drome), antenatal complications (e.g. preeclampsia),
delivery outcomes (e.g. cesarean section), and neonatal
outcomes (e.g. birth weight). Transitional nursery ad-
missions were grouped together with term nursery ad-
missions. Transfusion was defined as prophylactic red
cell transfusion or red cell transfusion for treatment of
maternal medical complications (e.g. severe anemia).
Statistical analysis was performed using SPSS 17.0
(SPSS Inc., Chicago, IL). Data are presented as n (%) or
median (range). Fisher’s exact test was used for cate-
gorical variables and the Mann-Whitney U test was used
for non-normally distributed continuous variables. Prior
to data collection, the study received approval by the
hospital institutional review board.
3. Results
Our search identified 52 pregnancies from 47 women
with SCD. Of these, 14 were excluded because they did
not deliver at TJUH. Another pregnancy which resulted
in spontaneous abortion was also excluded. This left 37
pregnancies from 32 women, including one set of twins.
After removing multiple gestations and multiple preg-
nancies by the same woman, there were a total of 31
pregnancies included in the analysis. The rates of Hb SS,
Hb SC, and Hb Sβ in our study population were 19
(61.3%), 11 (35.5%), and 1 (3.2%) respectively. There
were 18 women (58%) who had painful episodes during
pregnancy compared to 13 women (42%) who did not.
The median number of painful episodes was 2.5 (1 - 19)
and the median length of treatment for painful episodes
was 13 days (1 - 59). Of the 18 women that had one or
more painful episodes, 14 (77.8%) and 4 (22.2%) had
Hb SS and Hb SC disease respectively. There were no
women with Hb Sβ in the painful episodes present group.
Demographics are reported in Ta ble 1. For data analysis,
Hb SC and Hb Sβ were grouped as “other”. Women who
had painful episodes were more likely to be Hb SS
(77.8% vs. 38.5%) and had more medical comorbidities;
however, only the incidence of acute chest syndrome
reached statistical significance (p = 0.004). Most women
were African American with the exception of one His-
panic woman. Table 2 compares antenatal complica-
tions between women with and without painful episodes.
Those women with painful episodes had lower hemo-
globin levels on admission and were more likely to have
Table 1. Maternal demographics.
Painful Episodes In Pregnancy
Variable Total
n = 31 Present
n = 18 (58) Absent
n = 13 (42)p
Age (y) 28 (16 - 41)28 (20 - 41) 28 (16 - 35)0.794a
Gravidity 2 (1 - 12) 2 (1 - 7) 3 (1 - 12) 0.436a
Prior Preterm
Birth < 37 wks 5 (16.1) 2 (11.1) 3 (23.1) 0.208b
Hemoglobin
Hb SS
Hb SC
Hb Sβ-thal.
19 (61.2)
11 (35.5)
1 (3.2)
14 (77.8)
4 (22.2)
0
5 (38.5)
7 (53.8)
1 (7.7)
0.067b
Acute Chest
Syndrome 9 (29) 9 (50) 0 0.004b
DVT 2 (6.5) 1(5.6) 1(7.7) >0.99b
Bone Necrosis 3 (9.7) 3 (16.7) 0 0.245b
Splenectomy 3 (9.7) 2 (11.1) 1 (7.7) >0.99b
Narcotic Use
at Deliveryc 13 (41.9) 12 (66.7) 1 (7.7) 0.002b
Smoking 2 (6.5) 1( 5.6) 1 (7.7) >0.99b
Illicit Drug Use2 (6.5) 1( 5.6) 1 (7.7) >0.99b
Hb SS, homozygous disease; a. Mann-Whitney U test; b. Fisher’s exact test;
c. Prescribed narcotics.
Copyright © 2011 SciRes. IJCM
Sickle Cell Disease and Pregnancy: Does Outcome Depend on Genotype or Phenotype?
Copyright © 2011 SciRes. IJCM
315
Table 2. Antenatal complications.
Painful Episodes In Pregnancy
Variable Total
n = 31 Present
n = 18 (58) Absent
n = 13(42) p
Pyelonephritis 2 (6.5) 1 (5.6) 1 (7.7) >0.99a
Transfusion 12 (38.7) 11 (61.1) 1 (7.7) 0.003a
Acute Chest
Syndrome 5 (16.1) 5 (27.8) 0 0.058a
Antenatal
Steroids 6 (19.4) 5 (27.8) 1 (7.7) 0.359a
Preeclampsia 4 (12.9) 3 (16.7) 1 (7.7) 0.621a
Delivery
Hb (g/dL) 9.3(6.6 - 12.4) 8.35(6.6 - 10.9) 9.6(7.1 - 12.4)0.015b
Delivery Hb
<10g/dL 22 (71) 15 (83.3) 7 (53.8) 0.114a
Hb, hemoglobin; a. Fisher’s exact test; b. Mann-Whitney U test.
been transfused during pregnancy (Table 2). There was
a trend towards a higher incidence of acute chest syn-
drome in women with painful episodes. One woman
died at the time of delivery. This woman was admitted
with worsening pulmonary function and acute pain at-
tributed to acute chest syndrome. During an emergency
cesarean section for fetal bradycardia, she became un-
stable and suffered cardio-pulmonary collapse. Autopsy
revealed bone marrow thromboemboli involving the
small pulmonary microcirculation.
A comparison of birth outcomes between groups is
shown in Table 3 . No significant differences were found
in either the primary or secondary outcomes. No term
infants were admitted to the neonatal intensive care unit
(NICU) or the transitional nursery. Birth outcomes for
the subset of women whose genotype was Hb SS are
also shown in Table 3. In this group of women, the
presence of painful episodes was not a significant pre-
dictor of worse birth outcome. The overall prior preterm
birth rate in the study population was 16.1% (Table 1).
None of the women with a prior preterm birth received
progesterone (one woman received progesterone in a
subsequent excluded pregnancy).
Women who experienced painful episodes were ana-
lyzed separately. Using regression analyses, total num-
ber and length of painful episodes were not significantly
associated with either gestational age at delivery (linear
regression; p = 0.955 and p = 0.934, respectively) or
preterm delivery < 37 weeks (logistic regression; p =
0.544 and p = 0.850, respectively). Among women who
were excluded because they did not deliver at TJUH,
there were no fetal demises between 24 and 42 weeks
gestational age and no second trimester losses between
14 and 24 weeks gestational age but other specific in-
formation was unavailable.
4. Discussion
We previously presented outcome data of pregnancies in
women with SCD complicated by painful episodes
compared to historic controls (unselected pregnant
women with SCD) [13]. Our data suggested worse ob-
stetrical and neonatal outcomes in women with SCD
who experienced painful episodes. These included
higher rates of cesarean section, preterm birth < 37
weeks, and low birth weight < 2500 grams. In the pre-
sent study, comparing pregnant women with SCD who
experienced painful episodes to women with SCD who
did not, there were no differences in obstetrical or neo-
natal outcomes. Using controls (women with SCD and
no painful episodes during pregnancy) from our institu-
tion who delivered during the same time period, we were
unable to confirm the hypothesis that phenotype was
associated with worse obstetrical and neonatal out-
comes.
Table 3. Birth outcomes.
All Genotypes Hb SS Onlya
Outcome Total
n = 31
Painful Episodes
Present
n = 18 (58)
Painful Episodes
Absent
n = 13 (42) p Painful Episodes
Present
n = 14 (74)
Painful Episodes
Absent
n = 5 (26) P
Preterm Birth <37wks 18 (54.8) 11 (61.1) 6 (46.2) 0.485a10 (71.4) 3 (60.0) >0.99a
Gestational Age (wk) 36 (24 - 40) 35 (26 - 39) 37 (24 - 40) 0.332b35 (26 - 39) 35 (30 - 38) 0.852b
Birth Weight (g) 2530
(674 - 3677)
2503
(1146 - 3445)
2815
(674 - 3677) 0.401b2503
(1146 - 3060)
2350
(1318 - 3677)>0.99b
Birth Weight <2500g 15 (48.4) 9 (50) 6(46.2) >0.99b7 (50.0) 3 (60.0) >0.99a
Birth Weight <1500g 4 (12.9) 2(11.1) 2(15.4) >0.99a2 (14.3) 1 (20.0) >0.99a
APGAR5 9 (7 - 9) 9 (7 - 9) 9 (8 - 9) 0.851b9 (7 - 9) 9 0.550b
NICU Admission 13 (41.9) 10(55.6) 3(23.1) 0.139a8 (57.1) 2 (40.0) 0.628a
RDS 7 (22.6) 4(22.2) 3(23.1) >0.99a4 (28.6) 2 (40.) >0.99a
Cesarean Section
Repeat
Fetal Indicationc
8 (25.8)
2 (25)
5 (16.1)
7 (38.9)
2 (28.6)
4 (57.1)
1 (7.7)
0
1 (100)
0.095a
>0.99a
>0.99a
4 (28.6)
1 (7.1)
3 (21.4)
1 (20.0)
0
1 (20.0)
>.99a
>0.99a
>0.99a
NICU, neonatal intensive care unit; a. Fisher’s exact test; b. Mann-Whitney U test; c. Abruption or non-reassuring fetal heart rate tracing.
Sickle Cell Disease and Pregnancy: Does Outcome Depend on Genotype or Phenotype?
316
The major strength of our study was the inclusion of
all pregnancies in women with SCD over a 10-year pe-
riod at a single institution. Furthermore, we included
multiple hemoglobinopathies, all defined as SCD, which
have the potential for painful episodes, rather than lim-
iting inclusion to only sickle cell anemia (Hb SS). De-
spite the extensive time period and inclusion of multiple
hemoglobinopathies, the final sample was still small in
size. Exclusion of multiple pregnancies by the same
woman during the study period decreased the sample
size even further. We analyzed data from the earlier of
the two pregnancies in the five cases of multiple preg-
nancies by a single woman on the assumption that the
natural progression of SCD is stable or worsens over
time. This decision was a balance between study power
and confounding by disease progression and clustering
of outcomes (e.g. higher chance of recurrence of preterm
birth < 37 weeks).
Our study is unique in that we discriminated between
pregnancies complicated by painful episodes and those
that were not. Several previous studies of pregnancy in
women with SCD compare outcomes by genotype but
not phenotype (e.g. Hb SS vs Hb SC) [4,10,12,14].
Compared to Hb SC, Hb SS is associated with worse
obstetrical and neonatal outcomes, including earlier
gestational age at delivery [14], lower mean birth weight
[10,14], and a higher incidence of low birth < 2500 g
[10], preterm birth < 37 weeks [10], and intrauterine
fetal demise [12]. Only one cohort study analyzed preg-
nancy outcomes in women with Hb Sβ [4]. In this study,
the authors discriminated between Hb Sβ+ and Sβo. Hb
Sβ+ is a more mild disease in which there is a small
amount of normal Hb A (genotype Sβ/SA). Contrary to
expected, women with Hb Sβ+ had pregnancy outcomes
that were worse than Sβo and comparable to women
with Hb SS. In our study there was only one woman
with Hb Sβ and the exact genotype was unavailable.
These retrospective studies did not control for painful
episodes. Epigenetic factors, such as psychosocial back-
ground, education, employment, family structure, and
adherence to medical treatment, affect the phenotypic
manifestations of the genotype. It is therefore unclear
whether worse outcomes were due to factors intrinsic to
the hemoglobinopathy or whether painful episodes,
which are more common in women with Hb SS, are a
marker for more severe disease.
Women in our study who experienced painful epi-
sodes had more antenatal complications, including a
higher rate of transfusions, lower hemoglobin at delivery,
and a trend towards a higher incidence of acute chest
syndrome. We did not differentiate between prophylac-
tic red cell transfusion and red cell transfusion for
treatment of maternal medical conditions; however,
prophylactic transfusion is not an independent predictor
of neonatal outcome. Prophylactic red cell transfusion
decreases the incidence of painful episodes but has not
been shown to improve neonatal outcome [15]. The
higher incidence of acute chest syndrome among women
who experienced painful episodes is consistent with the
finding that nearly half of the time, acute chest syn-
drome occurs in the setting of an acute painful episode
[16]. Additional data that may have been helpful in in-
terpreting the results, such as Hb level, white blood cell
count, and Hb F levels, were not available. Similarly,
preconception information, such as medication use (e.g.
hydroxyurea) and the frequency of painful episodes,
were not available.
Despite a trend toward worse obstetrical and neonatal
outcomes in women who experienced painful episodes,
these differences did not reach statistical significance in
our study. We used a post-hoc power calculation to de-
termine the sample size necessary to detect a difference
in the primary outcome. Based on a 21% higher rate of
preterm birth < 37 weeks in women who experienced
painful episodes, 87 women per group would be re-
quired to reach a power of 80% with an alpha of 0.05. A
study of this size at our institution would not be feasible
at a rate of approximately 3 eligible deliveries per year.
Extending the study period by an additional 10 years
would be unlikely to yield enough women and would
introduce confounding by changes in obstetrical practice
and medical management of women with SCD.
Defining our cohorts by the presence of painful epi-
sodes as opposed to genotype limited the ability to
compare our results with those of other studies. To ad-
dress this limitation, we estimated the external validity
by examining the rate of painful episodes between ours
and other studies. The overall rate of painful episodes in
our study population was 58.0% which was higher than
the 21.8% to 43.7% rate of painful episodes in prior
studies [5,6,10,14,17]. The rates of cesarean section, low
birth weight, and preterm birth in our study are compa-
rable to rates obtained from previous studies (Figure 1).
Adverse obstetrical outcomes were more common
among women with sickle cell disease who experienced
painful crises; however, in this small sample, the differ-
ences were not statistically significant. Given that the
frequency of painful episodes may increase during
pregnancy, women with SCD who have previously ex-
perienced painful episodes may benefit from the coun-
seling provided as a result of this study. These findings
should be confirmed by a larger, multi-center prospec-
tive study. Nevertheless, the outcome in both groups is
worse than the outcome of pregnancy in African Ameri-
can women without SCD based on historical data. Fu-
ture research is needed to determine if poor pregnancy
Copyright © 2011 SciRes. IJCM
Sickle Cell Disease and Pregnancy: Does Outcome Depend on Genotype or Phenotype?
Copyright © 2011 SciRes. IJCM
317
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