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\begin{document}

\title{Influence of cancer in pregnancy on obstetric and neonatal outcomes: An
observational retrospective cohort study}



\author[1]{Xuan Huang}%
\author[1]{Chen Zhang}%
\author[1]{Jialei Zhu}%
\author[1]{Yueyan Li}%
\author[1]{Jing Tang}%
\affil[1]{Obstetrics and Gynecology Hospital of Fudan University}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: Determine the effects of cancer treatment in pregnancy.
Design: Observational retrospective cohort study. Setting: 7 Chinese
tertiary A hospitals during 2003--2021. Population: Pregnant patients
with cancer. Methods: We conducted multiple logistic regression to
determine the influence of various factors on preterm birth and
small-for-gestational-age infants, log-binomial regression to analyze
temporal changes, and chi-square tests to explore the effects of cancer
type/treatment. Main outcome measures: Obstetric outcomes; Neonatal
outcomes. Results: Of 204 women, 17\% terminated pregnancies; 59\%
received pre-delivery treatment. Rates of pregnancy termination
({[}RR{]}: 0.48, 95\% confidence interval {[}CI{]}: 0.35--0.67) and
iatrogenic preterm births (RR: 0.73, 95\% CI: 0.54--0.98) reduced, and
that of pre-delivery treatment increased, mainly due to increased rates
of surgery (RR: 1.87, 95\% CI: 1.31--2.67). Maternal systemic diseases
were related to a higher risk of small-for-gestational-age infants
({[}OR{]}: 12.02, 95\% CI: 1.82--79.43). Chemotherapy with taxanes plus
platinum-based agents was related to adverse obstetric outcomes (OR:
1.87, 95\% CI: 1.42--2.46, P \textless{} 0.05). Thyroid (OR: 0.36, 95\%
CI: 0.22--0.57) and ovarian cancer (OR: 0.70, 95\% CI: 0.50--0.98) were
associated with fewer cesarean sections. Thyroid cancer was associated
with fetal growth restriction (OR: 5.21, 95\% CI: 1.21--22.55).
Conclusions: Rates of pregnancy termination in cancer have declined.
Taxane plus platinum-based chemotherapy was associated with adverse
obstetric outcomes. Cancer type influenced outcomes. Funding: Special
Project for clinical Research in health industry of Shanghai Municipal
Health Commission; Shanghai Science and Technology Commission. Tweetable
abstract: Cancer in pregnancy on obstetric and neonatal outcomes: higher
risks of adverse obstetric and neonatal outcomes.%
\end{abstract}%



\sloppy


\textbf{Influence of cancer in pregnancy on obstetric and neonatal
outcomes: An observational retrospective cohort study}

Xuan Huang\textsuperscript{1}, Chen Zhang\textsuperscript{1}, Jialei
Zhu\textsuperscript{1}, Yueyan Li\textsuperscript{1}, Jing
Tang\textsuperscript{1,*}

\textsuperscript{1}Department of Pharmacy, Obstetrics \& Gynecology
Hospital of Fudan University, Shanghai 200090, P. R. China

\textbf{Running Title:} Cancer in pregnancy

\textbf{*Correspondence:}

Jing Tang, PhD, Department of Pharmacy, Obstetrics \& Gynecology
Hospital of Fudan University, 128 Shenyang Road, Shanghai 200090, P. R.
China; Tel: +86-021-33189900; Email: 1817@fckyy.org.cn

\textbf{Conflict of interest:} The authors declare no potential
conflicts of interest.

\section*{Abstract}

{\label{abstract}}

\textbf{Objective:} Determine the effects of cancer treatment in
pregnancy.

\textbf{Design:} Observational retrospective cohort study.

\textbf{Setting:} 7 Chinese tertiary A hospitals during 2003--2021.

\textbf{Population:} Pregnant patients with cancer.

\textbf{Methods:} We conducted multiple logistic regression to determine
the influence of various factors on preterm birth and
small-for-gestational-age infants, log-binomial regression to analyze
temporal changes, and chi-square tests to explore the effects of cancer
type/treatment.

\textbf{Main outcome measures:} Obstetric outcomes; Neonatal outcomes.

\textbf{Results:} Of 204 women, 17\% terminated their pregnancies; 59\%
received pre-delivery treatment. Every 6 years, the rates of pregnancy
termination ({[}RR{]}: 0.48, 95\% confidence interval {[}CI{]}:
0.35--0.67) and iatrogenic preterm births (RR: 0.73, 95\% CI:
0.54--0.98) reduced, and that of pre-delivery treatment increased,
mainly due to increased rates of surgery (RR: 1.87, 95\% CI:
1.31--2.67). Maternal systemic diseases were related to a higher risk of
small-for-gestational-age infants ({[}OR{]}: 12.02, 95\% CI:
1.82--79.43). Chemotherapy with taxanes plus platinum-based agents was
related to adverse obstetric outcomes (OR: 1.87, 95\% CI:
1.42--2.46,\emph{P} \textless{} 0.05). Thyroid (OR: 0.36, 95\% CI:
0.22--0.57) and ovarian cancer (OR: 0.70, 95\% CI: 0.50--0.98) were
associated with fewer cesarean sections. Thyroid cancer was associated
with fetal growth restriction (OR: 5.21, 95\% CI: 1.21--22.55).

\textbf{Conclusions:} Rates of pregnancy termination in cancer have
declined. Taxane plus platinum-based chemotherapy was associated with
adverse obstetric outcomes. Cancer type influenced outcomes.

\textbf{Funding:} Special Project for clinical Research in health
industry of Shanghai Municipal Health Commission; Shanghai Science and
Technology Commission.

\textbf{Keywords:} Retrospective Studies; Cohort Studies; Premature
Birth; Pregnancy Complications; Neoplastic; Antineoplastic Agents

\textbf{Tweetable abstract:} Cancer in pregnancy on obstetric and
neonatal outcomes: a higher risk of adverse obstetric and neonatal
outcomes.



\section*{Introduction}

{\label{introduction}}

It has been estimated that one in every one thousand women will be
diagnosed with cancer during pregnancy (1). In recent years, with the
postponement of childbirth to later ages, the adjustment of the
fertility policy in China, and the onset of cancer at younger ages, the
incidence of cancer during pregnancy has increased (2). The diagnostic
work-up for cancer, such as the detection of tumor markers, may be
affected by the physiology of pregnancy (3). Furthermore, the
implementation of diagnostic surgical procedures during pregnancy is
often rendered challenging due to safety concerns. Approximately
20\%--30\% of cancer cases in women occur prior to the age of 45, which
has a severe impact on future fertility and pregnancy management (4).
The most common malignant tumors during pregnancy are breast cancer,
melanoma, hematological cancers, and cervical cancer (1); among these,
breast cancer has the highest incidence (5), and accounts for 39\% of
all malignant tumors during pregnancy. The type of cancer can also have
an impact on obstetric and neonatal outcomes; for example, patients
diagnosed with melanoma have a significantly increased risk of death
during pregnancy, while patients diagnosed with breast or ovarian cancer
have a significantly increased risk of death during lactation (6-8).

The treatment of cancer in pregnancy complicates clinical
decision-making (2). For instance, pregnant women with cancer may need
to choose between continuing or terminating the pregnancy. In general,
cancer and its treatment are considered to have adverse effects on
women's fertility. Current medical practice attempts, where possible, to
retain reproductive function (9). Fortunately, the oncological and
obstetric prognoses of patients who receive cancer treatment during
pregnancy are relatively good, though termination of pregnancy is
usually recommended for such patients. Up to 44\% of gynecologists tend
to terminate the pregnancy, and 37\% of women do not undergo chemo- or
radiotherapy during pregnancy (10). Therefore, iatrogenic preterm birth
is the most common obstetric complication of cancer in pregnancy
(11,12).

With advances in research and the optimization of therapeutic regimens
for cancer, it is increasingly becoming possible to treat cancer during
pregnancy as well as protect the fetus and the mother from adverse
effects as much as possible. Although life-saving cancer treatments for
pregnant women seem to conflict with the interests of the developing
fetus, termination of pregnancy has not been shown to improve the
prognosis of pregnant women in any type of cancer (13). Several recent
studies have recommended that cancer treatment during pregnancy should
be as similar as possible to the treatment of non-pregnant women and
that preterm birth should be avoided; however, radiotherapy is still
recommended to be postponed until after delivery, and chemotherapy
should be postponed until the second trimester (14). With the continual
improvements in cancer therapy during pregnancy, the rates of survival
and iatrogenic premature births have been observed to improve every 5
years (15). Currently, it is accepted that surgery and chemotherapy are
relatively safe during pregnancy, while radiotherapy is relatively
contraindicated. The existing research shows that chemotherapy from the
second trimester does not impact the growth and development of newborns
or cause obvious long-term complications (13,16,17). However, other
studies have reported that chemotherapy during pregnancy is associated
with fetal adverse events (15).

Many organizations have provided recommendations on conception for women
with cancer, but warn that more evidence is needed (17), as the precise
impact of different tumors and anti-tumor treatment regimens on the
mother and fetus remains to be elucidated. Due to this gap in clinical
evidence, oncological management during pregnancy remains challenging
for both patients as well as gynecologists, oncologists, and
obstetricians. Thus far, no large-scale clinical study on pregnancy with
cancer has been conducted in China. Therefore, the present study aimed
to review the oncological characteristics and treatment of
pregnancy-associated cancers, and analyze the obstetric and neonatal
outcomes to provide evidence-based recommendations for reproductive
function preservation, oncological treatment, and obstetric management
in pregnancy-associated cancer.

\section*{Patients and Methods}

{\label{patients-and-methods}}

\textbf{Study design and participants}

This descriptive retrospective cohort study analyzed data from pregnant
women who were diagnosed with cancer and registered in 11 centers from 7
provinces of China. The core study was registered with the Chinese
Clinical Trial Registry (registration number: ChiCTR2100044292;
ongoing), and approved by the ethics committee of the Obstetrics \&
Gynecology Hospital of Fudan University (approval number: 2020-130). The
inclusion criteria were pregnant patients aged 18--45 years with primary
invasive cancer or borderline ovarian cancer who were admitted to one of
the 11 centers between 1\textsuperscript{st} January 2003 and
2\textsuperscript{nd} February 2021. All subjects voluntarily
participated in the study and provided written informed consent. All
participants were diagnosed on the basis of pathological evidence.
Patients with pre-invasive disease or postpartum diagnosis, those with
primary invasive cancer or borderline ovarian cancer diagnosed after
delivery, and those who had received high-dose scatter radiation to the
pelvis or brain before delivery were excluded. We designed a
questionnaire to collect detailed oncological, obstetric, and neonatal
data. All participating centers received an online electronic
questionnaire, and each center collected the required data from its
electronic medical record system. The data from all centers were then
consolidated and aggregated by the authors.

\textbf{Definitions}

Systemic disease was defined as maternal hypertensive disorders, cardiac
disease, hypothyroidism, gestational diabetes, and gestational anemia.
Pre-delivery surgery was defined as any therapeutic or palliative
surgical procedure for cancer performed after the diagnosis of cancer
and prior to delivery (or termination of pregnancy). Similarly,
pre-delivery chemotherapy was defined as chemotherapy administered at
any time from the cancer diagnosis to the delivery (or termination of
pregnancy). Miscarriage was defined as the loss of a baby before the
20\textsuperscript{th} week of gestation, while stillbirth was defined
as the loss of a baby at or after 20 weeks of gestation. Preterm
pre-labor rupture of membranes (PPROM) was defined as the preterm
rupture of membranes without contractions, and was diagnosed by the
local centers. Small for gestational age (SGA) was defined as a birth
weight less than the 10\textsuperscript{th} percentile, as calculated
according to the Chinese neonatal birth weight curve for different
gestational ages (18). Preterm birth was defined as delivery before 37
completed weeks of gestation. Iatrogenic preterm birth was defined as
preterm cesarean delivery without labor. Low birth weight (LBW) and
fetal macrosomia were defined as birth weights of \textless{}2500 g or
\textgreater{}4000 g, respectively.

\textbf{Statistical analysis}

We aggregated the oncological, obstetric, and neonatal data, and
provided descriptive statistics for these data. Age at pregnancy was
grouped into 8-year intervals as follows: 21--28, 29--36, and 37--45
years. Multiple logistic regression models were used to analyze the
effects of the following factors on premature birth and birth of SGA
infants: maternal age, year of last menstrual period (LMP), gestational
period (in terms of trimesters) at the time of cancer diagnosis, cancer
type, treatment method, and maternal complications during pregnancy. The
results were reported as adjusted odds ratios (ORs) with 95\% confidence
intervals (CIs). \emph{P} values were used to measure the strength of
the evidence against the null hypothesis of no relationship. The study
data spanned an 18-year period, and were divided into the following
three 6-year intervals according to the year in which the LMP occurred:
2003--2008, 2009--2014, and 2015--2020. Log-binomial regression models
were used to analyze the average changes in patient characteristics,
tumor types, treatment before delivery, and maternal complications, with
year of diagnosis as a continuous predictor. The results were presented
as relative risks (RRs) and 95\% CIs. Considering the limited sample
size, the number of independent variables, and the limited correlation
between independent variables, we chose to use chi-square tests to
directly study the relationship between two variables. Chi-square tests
(one-tailed) were performed to assess the influence of cancer type and
pre-delivery chemotherapy on maternal complications, and obstetric and
neonatal outcomes. All statistical analyses were performed using IBM
SPSS Statistics for Windows, version 26.0 (IBM, Armonk, NY,
USA).\emph{P} values of less than 0.05 were considered statistically
significant.

\section*{Results}

{\label{results}}

\textbf{General information}

In all, 204 women (Figure 1) registered in 7 tertiary A hospitals were
eligible for this study. A tertiary A hospital is the highest
classification grade for hospitals in mainland China and represents a
large general hospital. Some tertiary A hospitals have more than 20,000
outpatient visits per day (19). Of these, 35 (17\%) women chose to
terminate their pregnancies by surgery or drugs, and 119 (59\%) women
received antenatal treatment for cancer.

The baseline characteristics of the patients are shown in S31, and the
distribution of cancer types is shown in Figure 2. Patient
characteristics stratified by cancer type are shown in Supplementary
Table S1.

\textbf{Obstetric and neonatal complications and neonatal outcomes}

Of the 204 eligible women, 201 patients had records of pregnancy-related
complications. In total, 118 (59\%) women developed pregnancy-related
complications. The most common complications were gestational diabetes
(9\%), gestational maternal infection (9\%), and PPROM (9\%). The most
common obstetric outcome was preterm birth (39\%), and the most common
neonatal comorbidity was neonatal hyperbilirubinemia (19\%). Congenital
defects were observed in 6 (4\%) newborns or aborted fetuses
(Supplementary Table S2).

Of the 204 patients included in the study, the majority (147, 72\%) were
from the Obstetrics \& Gynecology Hospital of Fudan University. We
recorded the total number of pregnant women who received antenatal care
at this hospital between January 1, 2003 and December 31, 2021. We also
noted the incidence of pregnancy-related complications, neonatal
complications, and obstetric events, such as caesarean section, among
these patients, as provided by the Information Department of the
hospital (Supplementary Tables S3 and S4). We performed chi-square
analyses (one-tailed) of the data of all 204 pregnant women with cancer
included in this study and the data of all pregnant women from the
Obstetrics \& Gynecology Hospital of Fudan University.

All pregnant women from the Obstetrics \& Gynecology Hospital of Fudan
University during the study period were taken as the reference group.
Compared with all pregnant women, pregnant women with cancer had a
significantly higher risk of maternal hypertension (OR: 2.18, 95\% CI:
1.37--3.46, \emph{P} \textless{} 0.05), heart disease (OR: 35.72, 95\%
CI: 14.87--85.81, \emph{P} \textless{} 0.05), intestinal obstruction
(OR: 105.68, 95\% CI: 32.56--342.99, \emph{P} \textless{} 0.001), and
liver damage (OR: 4.19, 95\% CI: 1.77--9.92, \emph{P} \textless{} 0.05)
during pregnancy as well as fetal intrauterine growth restriction (OR:
17.23, 95\% CI: 8.31--35.71, \emph{P} \textless{} 0.001). Compared to
women without cancer, those with cancer had with a significantly higher
incidence of cesarean section (OR: 4.54, 95\% CI: 4.02--5.12,
\emph{P}\textless{} 0.001), preterm birth (OR: 8.28, 95\% CI:
6.75--10.18,\emph{P} \textless{} 0.001), LBW (OR: 6.39, 95\% CI:
4.98--8.19,\emph{P} \textless{} 0.001), and fetal macrosomia (OR: 5.2,
95\% CI: 2.54--10.64, \emph{P} \textless{} 0.001). Cancer in pregnancy
was also associated with a significantly increased likelihood of
neonatal acidosis (OR: 2.85, 95\% CI: 1.57--5.18, \emph{P} \textless{}
0.05), birth defects (OR: 3.83, 95\% CI: 1.75--8.4, \emph{P} \textless{}
0.01), and neonatal respiratory distress (OR: 10.26, 95\% CI:
7.29--14.45,\emph{P} \textless{} 0.001). The results of this chi-square
analysis are shown in Table 2. Since only the pregnancy data from the
Obstetrics \& Gynecology Hospital of Fudan University were used instead
of data from all centers, these results are for reference only.

\textbf{Cancer treatments}

Of the 204 women, 119 (59\%) women received treatment for cancer before
the termination of pregnancy, and of these 121 women, 73 (60\%) women
were treated using a single treatment modality, 53 (42\%) women
underwent surgery alone, and 5 (2\%) women were treated using
chemotherapy alone (Table 3). Among the 28 patients who received a
combination of different treatment modalities, 19 (9\%) patients
received a combination of surgery and chemotherapy, and 2 (1\%) received
a combination of surgery, chemotherapy, and targeted therapy. Twelve
patients received paclitaxel plus platinum-based chemotherapy (TP
regimen), and seven patients received epirubicin plus cyclophosphamide
chemotherapy (EC regimen).

\par\null

\textbf{Obstetric outcomes}

Among the 35 women who chose to undergo termination of pregnancy, 19
(53\%) terminated their pregnancy in the first trimester, 12 (34\%)
terminated it in the second trimester, and 2 (6\%) terminated in the
third trimester; the time of termination of pregnancy was unknown in 2
cases. All 35 women who chose to terminate the pregnancy were between
the ages of 24 and 43 years, and 31 of these women were aged 28 years or
above. In total, 8 of these women had had a previous pregnancy, and 6 of
these 8 had had a previous live birth. Among the 169 women who chose to
continue the pregnancy, the pregnancy outcomes of 13 patients were
missing. Among the 156 patients with recorded pregnancy outcomes, 144
live births were reported, of which 3 cases (2\%) were twin pregnancies,
and the others were singleton pregnancies. Among these 156 patients, 10
(6\%) had a miscarriage before 20 weeks of gestation, and 2 (1\%)
patients had a stillbirth after 20 weeks of gestation. The obstetric
outcomes stratified by cancer type are shown in Table 4.

\textbf{Impact of cancer type on complications and outcomes}

Univariate analysis using chi-square tests revealed that cancer type
significantly affected the obstetric outcome (Table 5). Compared with
pregnant women with cervical cancer, pregnant women with thyroid cancer
(OR: 0.16, 95\% CI: 0.06--0.42, \emph{P} \textless{} 0.001), breast
cancer (OR: 0.3, 95\% CI: 0.13--0.68, \emph{P} \textless{} 0.05), or
other cancer types (OR: 0.64, 95\% CI: 0.41--1, \emph{P} \textless{}
0.05) had a significantly lower probability of premature delivery of the
fetus. No significant relationship was found between cancer type and the
occurrence of other obstetric complications. Taking the patients with
cervical cancer as the reference group, we found that significantly
fewer proportions of patients with thyroid cancer (OR: 0.36, 95\% CI:
0.22--0.57, \emph{P} \textless{} 0.001) or ovarian cancer (OR: 0.70,
95\% CI: 0.50--0.98, \emph{P} \textless{} 0.05) underwent cesarean
section. Among pregnant women with thyroid cancer, the proportion of
those who chose fetal preservation was significantly increased relative
to the reference group (OR: 1.28, 95\% CI: 1.03--1.58,
\emph{P}\textless{} 0.05), but the risk of fetal intrauterine growth
restriction was also significantly increased (OR: 5.21, 95\% CI:
1.21--22.55,\emph{P} \textless{} 0.05). Pregnancy with thyroid cancer
(OR: 0.25, 95\% CI: 0.09--0.68, \emph{P} \textless{} 0.05), ovarian
cancer (OR: 0.33, 95\% CI: 0.11--1.02, \emph{P} \textless{} 0.05), or
breast cancer (OR: 0.28, 95\% CI: 0.09--0.87, P \textless{} 0.05) was
associated with a lower risk of neonatal respiratory distress syndrome
than pregnancy with cervical cancer (Supplementary Table S5).

\textbf{Impact of chemotherapy}

According to the use of chemotherapy drugs before the end of pregnancy
(including delivery, miscarriage, and stillbirth), the patients were
divided into those who did not receive chemotherapy, those who received
treatment with the TP regimen, and those who received treatment with the
EC regimen (Table 6). Chi-square analyses showed that compared with no
chemotherapy before delivery (or miscarriage or stillbirth), the use of
the TP regimen during pregnancy was associated with adverse pregnancy
outcomes (i.e., preterm birth, miscarriage, stillbirth, and SGA; OR:
1.87, 95\% CI: 1.42--2.46, \emph{P} \textless{} 0.05).

\textbf{Factors influencing obstetric outcomes}

The results of the multiple logistic regression models are shown in
Table 7. Both the outcome variables and the covariates in these models
were prespecified. The key covariates in the models were as follows:
patient's age at admission (stratified into three 8-year ranges), timing
of cancer diagnosis (relative to the pregnancy), cancer type,
pre-delivery surgery or chemotherapy, year in which the LMP occurred,
maternal reproductive system complications (including uterine, placenta,
and umbilical cord problems), maternal digestive system complications,
and maternal systemic disease. The regression coefficients and standard
errors determined using this analysis can be found in Supplementary
Table S6. Pregnant women with cancer as well as systemic diseases (such
as hypertension, hyperlipidemia, diabetes, heart disease, and anemia)
were more likely to give birth to SGA infants (OR: 12.02, 95\% CI:
1.82--79.43).

\textbf{Changes in cancer treatments and obstetric outcomes over the
study period}

This study reviewed data collected over an 18-year period. We divided
the patients into the following 3 subgroups according to the year in
which they had their LMP: 2003--2008, 2009--2014, and 2015--2020. The
LMP was used as a continuous predictor in the log-binomial regression
model. The results are shown in Table 8. Every 6 years, we observed a
decrease in the proportion of patients choosing to terminate the
pregnancy (RR: 0.48, 95\% CI: 0.35--0.67). The proportions of patients
who chose termination of pregnancy stratified by cancer type are shown
in Supplementary Table S7. Every 6 years, the likelihood of receiving
cancer treatment before delivery was found to increase, mainly due to
the increase in the rate of surgery (RR: 1.87, 95\% CI: 1.31--2.67).
Every 6 years, we observed fewer iatrogenic preterm births on average
(RR: 0.73, 95\% CI: 0.54--0.98) and more term births (RR: 1.46, 95\% CI:
1.00--2.13).

\section*{Discussion}

{\label{discussion}}

Of the 204 pregnant women with cancer who were eligible for the present
study, 35 women decided to terminate their pregnancy. These 35 women
were aged between 24 and 43 years, and 31 (89\%) of them were aged 28
years or older; in addition, 77\% of these women had previously been
pregnant and given birth to a live infant. A Chinese population study
has reported that the age of Chinese women at first childbirth has
gradually increased from 24 years to nearly 28 years between 2006 and
2017 (20). Therefore, it can be inferred that the age of the patients
and the previous live birth were important reasons driving the decision
to terminate the pregnancy.

Preterm birth was the most common obstetric outcome for pregnant women
with cancer. Moreover, of the 56 (30\%) women who gave birth prematurely
in our study, only 7 (12\%) gave birth vaginally; the remaining 49
(88\%) women underwent cesarean section. This shows that in addition to
spontaneous preterm delivery, iatrogenic preterm delivery and artificial
early termination of pregnancy are common outcomes among pregnant women
with cancer. Nevertheless, it remains to be determined whether the
artificial shortening of pregnancy benefits pregnant women or affects
the health of their newborns. The timing and specific conditions under
which early termination of pregnancy is maximally beneficial to the
pregnant woman and her newborn remain a thorny problem of clinical
decision-making.

In the present study, the incidence of congenital defects among cases of
abortions, stillbirths, and live births was approximately 4\%, and among
live births, the incidence of congenital malformations was 3.5\%.
According to the China Birth Defect Prevention Report (2012) issued by
the National Health Commission of the People's Republic of China, the
incidence of birth defects is significantly higher in rural and remote
areas than in urban areas. Compared with the 2012 national report, the
present study did not find a high proportion of birth defects among
babies born to women with cancer; this is probably because our patients
were all from tertiary A hospitals in capital cities, while the national
report included women from across the country. We used the birth defect
data obtained from all cases of pregnancy in the Obstetrics \&
Gynecology Hospital of Fudan University as a reference, and found that
pregnant women with cancer were more likely to have babies with birth
defects (OR: 3.83, 95\% CI: 1.75--8.4,\emph{P} \textless{} 0.01). These
data may put greater pressure on women with cancer to continue their
pregnancies. Further research is required to determine whether it is the
physiological changes caused by the cancer itself or the treatments that
affect the rate of birth defects.

Every 6 years, the proportion of pregnant women with cancer who choose
to continue their pregnancy increased. More patients chose to undergo
treatment for cancer before delivery, but this was mainly attributable
to an increase in pre-delivery surgery rather than pre-delivery
chemotherapy, which is not consistent with the results of a European
study (8). The majority of our patients (86\%) did not receive
chemotherapy prenatally. This indicates that currently, Chinese
clinicians may be relatively conservative in regards to chemotherapy
during pregnancy.

In this study, all of the 10 cervical cancer patients who received
chemotherapy before delivery were treated with the TP regimen. In
addition, 63\% of the 11 breast cancer patients who received
chemotherapy before delivery were treated with the EC regimen. This
suggests that multidrug regimens are used in the majority of pregnant
patients with cancer. However, current studies on the toxicity of
chemotherapeutic drugs during pregnancy focus on single-drug
chemotherapy. Thus, more research is required to investigate the effects
of multi-drug chemotherapeutic regimens during pregnancy.

Our study supports the findings that adriamycin, cyclophosphamide, and
5-fluorouracil are relatively safe for fetuses and newborns (21). We did
not find any significant impact of the EC regimen on obstetric outcomes.
In previous studies, platinum-based therapy with or without taxanes was
recommended for advanced or high-risk cancer during pregnancy (22).
Taxanes have a low potential for placental transfer (21) and low
toxicity, and their use is considered feasible in the second and third
trimesters (23). This may partially explain the high proportion of
patients treated with the TP regimen before delivery in this study. Our
data in this cohort study suggested a relationship between the TP
regimen and adverse obstetric outcomes. Another study has also shown
that the use of platinum-based chemotherapy drugs is statistically
associated with the birth of SGA babies, and taxane chemotherapy is
associated with NICU admission (15). In future studies, increased
monitoring may be needed during the use of the TP regimen during
pregnancy, especially monitoring for long-term developmental defects in
newborns. Our results showed that cisplatin is more widely used than
carboplatin in China. However, carboplatin is recommended as a priority
drug when using the TP regimen, considering the safety issues (23,24).

A few studies have provided theoretical suggestions for oncological
management during pregnancy, especially for cancer treatment and
termination of pregnancy (25,26). In clinical practice, however, whether
to terminate the pregnancy, when to terminate the pregnancy, whether to
carry out surgery and drug treatment, and which drug to administer at
what dosage remain perplexing questions. The existing research is
insufficient for the formulation of comprehensive oncological management
guidelines for cancer during pregnancy (27). We suggest strengthening
the clinical research and conducting follow-up assessments of pregnant
patients with cancer; we also recommend coordination among the
obstetrics, oncology, neonatology, and clinical pharmacy departments in
clinical practice to balance maternal benefits, fetal benefits, and
possible risks for the offspring (28). Careful multidisciplinary
management is required for pregnant women with cancer.

\section*{Acknowledgements}

{\label{acknowledgements}}

This work was supported by grants from the Special Project for clinical
Research in health industry of Shanghai Municipal Health Commission
(201940153) and Shanghai Science and Technology Commission (19401900900)
to Jing Tang.

\textbf{Author Roles}

X H: study design, data analysis and interpretation, manuscript writing

C Z: critical manuscript revision

JL Z: manuscript writing

YY L: data abstraction

J T: study design, critical manuscript revision

\section*{References}

{\label{references}}

1. Berends C, Maggen C, Lok CAR, van Gerwen M, Boere IA, Wolters
V\emph{, et al.} Maternal and Neonatal Outcome after the Use of G-CSF
for Cancer Treatment during Pregnancy. \emph{Cancers}2021;\textbf{13}
(6):1214 doi 10.3390/cancers13061214.

2. McCormick A, Peterson E. Cancer in Pregnancy. \emph{Obstetrics and
Gynecology Clinics of North America} 2018;\textbf{45} (2):187-200 doi
https://doi.org/10.1016/j.ogc.2018.01.009.

3. Botha MH, Rajaram S, Karunaratne K. Cancer in
pregnancy.\emph{International Journal of Gynecology \&
Obstetrics}2018;\textbf{143} (S2):137-42 doi
https://doi.org/10.1002/ijgo.12621.

4. Puzzi-Fernandes C, Surita FG, Schettini CS, Parpinelli MA, Guida JP,
Costa ML. Awareness towards an increasing concern during pregnancy:
maternal and perinatal outcomes of women with cancer. \emph{American
journal of obstetrics \& gynecology MFM} 2020;\textbf{2} (3):100168 doi
10.1016/j.ajogmf.2020.100168.

5. Becker S. Breast cancer in pregnancy: A brief clinical
review.\emph{Best practice \& research Clinical obstetrics \&
gynaecology}2016;\textbf{33} :79-85 doi 10.1016/j.bpobgyn.2015.10.013.

6. Stensheim H, M\selectlanguage{ngerman}øller B, van Dijk T, Fosså SD. Cause-Specific Survival
for Women Diagnosed With Cancer During Pregnancy or Lactation: A
Registry-Based Cohort Study. \emph{Journal of Clinical
Oncology}2009;\textbf{27} (1):45-51 doi 10.1200/JCO.2008.17.4110.

7. Cottreau CM, Dashevsky I, Andrade SE, Li DK, Nekhlyudov L, Raebel
MA\emph{, et al.} Pregnancy-Associated Cancer: A U.S. Population-Based
Study. \emph{Journal of women's health (2002)} 2019;\textbf{28}
(2):250-7 doi 10.1089/jwh.2018.6962.

8. Metcalfe A, Cairncross ZF, Friedenreich CM, Ray JG, Nelson G, Fell
DB\emph{, et al.} Incidence of Pregnancy-Associated Cancer in Two
Canadian Provinces: A Population-Based Study. \emph{International
journal of environmental research and public health}2021;\textbf{18}
(6):3100 doi 10.3390/ijerph18063100.

9. Wolters V, Heimovaara J, Maggen C, Cardonick E, Boere I, Lenaerts
L\emph{, et al.} Management of pregnancy in women with
cancer.\emph{International journal of gynecological cancer : official
journal of the International Gynecological Cancer
Society}2021;\textbf{31} (3):314-22 doi 10.1136/ijgc-2020-001776.

10. Cordeiro CN, Gemignani ML. Gynecologic Malignancies in Pregnancy:
Balancing Fetal Risks With Oncologic Safety. \emph{Obstetrical \&
gynecological survey} 2017;\textbf{72} (3):184-93 doi
10.1097/ogx.0000000000000407.

11. Barrois M, Anselem O, Pierga JY, Goldwasser F, Bouscary D,
Alessandrini V\emph{, et al.} Cancer during pregnancy: Factors
associated with termination of pregnancy and perinatal
outcomes.\emph{European journal of obstetrics, gynecology, and
reproductive biology} 2021;\textbf{261} :110-5 doi
10.1016/j.ejogrb.2021.04.020.

12. Albright CM, Wenstrom KD. Malignancies in pregnancy. \emph{Best
practice \& research Clinical obstetrics \& gynaecology}2016;\textbf{33}
:2-18 doi 10.1016/j.bpobgyn.2015.10.004.

13. Cardonick EH, Gringlas MB, Hunter K, Greenspan J. Development of
children born to mothers with cancer during pregnancy: comparing in
utero chemotherapy-exposed children with nonexposed
controls.\emph{American journal of obstetrics and
gynecology}2015;\textbf{212} (5):658.e1-8 doi
10.1016/j.ajog.2014.11.032.

14. Loibl S, Schmidt A, Gentilini O, Kaufman B, Kuhl C, Denkert C\emph{,
et al.} Breast Cancer Diagnosed During Pregnancy: Adapting Recent
Advances in Breast Cancer Care for Pregnant Patients. \emph{JAMA
Oncology} 2015;\textbf{1} (8):1145-53 doi 10.1001/jamaoncol.2015.2413
\%J JAMA Oncology.

15. de Haan J, Verheecke M, Van Calsteren K, Van Calster B, Shmakov RG,
Mhallem Gziri M\emph{, et al.} Oncological management and obstetric and
neonatal outcomes for women diagnosed with cancer during pregnancy: a
20-year international cohort study of 1170 patients. \emph{The Lancet
Oncology} 2018;\textbf{19} (3):337-46 doi
https://doi.org/10.1016/S1470-2045(18)30059-7.

16. Korakiti AM, Zografos E, van Gerwen M, Amant F, Dimopoulos MA,
Zagouri F. Long-Term Neurodevelopmental Outcome of Children after in
Utero Exposure to Chemotherapy. \emph{Cancers} 2020;\textbf{12}
(12):3623 doi 10.3390/cancers12123623.

17. Hartnett KP, Mertens AC, Kramer MR, Lash TL, Spencer JB, Ward
KC\emph{, et al.} Pregnancy after cancer: Does timing of conception
affect infant health? \emph{Cancer} 2018;\textbf{124} (22):4401-7 doi
10.1002/cncr.31732.

18. Zhu L, Zhang R, Zhang S, Shi W, Yan W, Wang X\emph{, et
al.}{[}Chinese neonatal birth weight curve for different gestational
age{]}.\emph{Zhonghua er ke za zhi = Chinese journal of
pediatrics}2015;\textbf{53} (2):97-103.

19. Li Y, Gong W, Kong X, Mueller O, Lu G. Factors Associated with
Outpatient Satisfaction in Tertiary Hospitals in China: A Systematic
Review. \emph{International journal of environmental research and public
health} 2020;\textbf{17} (19):7070 doi 10.3390/ijerph17197070.

20. Chen W, Duan YY. Recent Levels and Trends of Fertility in
China.\emph{Population Research} 2019;\textbf{43} (01):3-17.

21. Oliveira MMS, Salgado CM, Viana LR, Gomes-Marcondes MCC. Pregnancy
and Cancer: Cellular Biology and Mechanisms Affecting the
Placenta.\emph{Cancers} 2021;\textbf{13} (7):1667 doi
10.3390/cancers13071667.

22. Peccatori FA, Azim HA, Jr., Orecchia R, Hoekstra HJ, Pavlidis N,
Kesic V\emph{, et al.} Cancer, pregnancy and fertility: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up. \emph{Annals
of oncology : official journal of the European Society for Medical
Oncology} 2013;\textbf{24 Suppl 6} :vi160-70 doi 10.1093/annonc/mdt199.

23. Benoit L, Mir O, Vialard F, Berveiller P. Cancer during Pregnancy: A
Review of Preclinical and Clinical Transplacental Transfer of Anticancer
Agents. \emph{Cancers} 2021;\textbf{13} (6):1238 doi
10.3390/cancers13061238.

24. Eliesen GAM, van Hove H, Meijer MH, van den Broek PHH, Pertijs J,
Roeleveld N\emph{, et al.} Toxicity of anticancer drugs in human
placental tissue explants and trophoblast cell lines. \emph{Archives of
toxicology} 2021;\textbf{95} (2):557-71 doi 10.1007/s00204-020-02925-w.

25. Kim Y, Kang M, Jung J, Cho EK, Park HK, Chun Y-S. Subsequent
pregnancy and long-term safety from breast cancer patients.\emph{Journal
of Clinical Oncology} 2020;\textbf{38} (15\_suppl):e13575-e doi
10.1200/JCO.2020.38.15\_suppl.e13575.

26. Maggen C, Wolters V, Cardonick E, Fumagalli M, Halaska MJ, Lok
CAR\emph{, et al.} Pregnancy and Cancer: the INCIP Project.\emph{Current
oncology reports} 2020;\textbf{22} (2):17 doi 10.1007/s11912-020-0862-7.

27. Michalczyk K, Cymbaluk-P\selectlanguage{polish}ł\selectlanguage{english}oska A. Fertility Preservation and
Long-Term Monitoring of Gonadotoxicity in Girls, Adolescents and Young
Adults Undergoing Cancer Treatment. \emph{Cancers}2021;\textbf{13}
(2):202 doi 10.3390/cancers13020202.

28. Linkeviciute A, Buonomo B, Fazio N, Spada F, Peccatori FA.
Discussing motherhood when the oncological prognosis is dire: ethical
considerations for physicians. \emph{ESMO open}2020;\textbf{5}
(6):e000956 doi 10.1136/esmoopen-2020-000956.

\textbf{Figure Legend}

\textbf{Figure 1.} Patients included in this study

\textbf{Figure 2.} Distribution of cancers during pregnancy

*Ovarian cancers include borderline ovarian tumors. +Other cancers
consisted of 6 different cancer types.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

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\textbf{Hosted file}

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