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\begin{document}

\title{Maternal health and pregnancy outcome in Marfan syndrome: A
register-based study}



\author[1]{Kristian Groth}%
\author[2]{Birgitte Nielsen}%
\author[3]{Inger Sheyanth }%
\author[1]{Claus Gravholt}%
\author[4]{Niels Andersen}%
\author[1]{Kirstine Stochholm}%
\affil[1]{Aarhus University Hospital}%
\affil[2]{Rigshospitalet}%
\affil[3]{Aalborg Universitetshospital}%
\affil[4]{Odense Universitetshospital}%


\vspace{-1em}



  
  \date{May 07, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective In Marfan syndrome, pregnancy is considered as high-risk due
to connective tissue insufficiency and increased risk of aortic
dissection. The objective was to demonstrate the consequences on
maternal health, including aortic events in women with Marfan syndrome.
Furthermore, to investigate outcome in undiagnosed with Marfan syndrome
at the time of pregnancy. Design Information on aortic operations,
aortic dissections, and pregnancy related outcome, from a national
cohort of women with Marfan syndrome (n=195) were compared to an
age-matched background population (n=19,500). The women with Marfan
syndrome were divided according to whether the Marfan syndrome diagnosis
was known at the time of pregnancy or not. Setting National health care
registers Methods Main outcomes measures Registered events from the
National Patient Registry in Denmark Results Significantly fewer women
with Marfan syndrome gave birth, compared to the background population.
In Marfan syndrome, complications related to cervix were increased (HR:
19.8 (95\% CI: 2.2-177.5)) and the number of caesarean sections was
higher (HR: 2.09 (95\% CI: 1.41-3.08)). No women with known Marfan
syndrome had a pregnancy related aortic dissection and the consequences
of pregnancy and delivery on future aortic events seemed limited. Among
undiagnosed women with Marfan syndrome there were more foetal deaths and
all delivery-related dissections came from this subgroup. Conclusion The
surveillance program for pregnant women with Marfan syndrome seems
appropriate and only women with undiagnosed Marfan syndrome experienced
a pregnancy-related aortic dissection. However, there is still an
increased risk of complications during pregnancy, but the overall
outcome data are quite reassuring.%
\end{abstract}%



\sloppy


\textbf{}

\textbf{Tweetable abstract}

In Marfan syndrome, undiagnosed women have pregnancy-related aortic
disease. Well controlled Marfan syndrome women do not.

\textbf{}

\textbf{Introduction}

Marfan Syndrome (MFS) is an inherited disorder of connective tissue with
multisystem involvement\textsuperscript{1} and a reported prevalence of
6.5 per 100.000.\textsuperscript{2} Mutations in FBN1 are found in more
than 90\% of MFS cases.\textsuperscript{3} FBN1 encodes the
extracellular matrix protein fibrillin-1 which contributes to the
integrity and function of connective tissue.\textsuperscript{4} The
inheritance is autosomal dominant with a high penetrance and great
clinical variability.\textsuperscript{5}

MFS is associated with increased morbidity and mortality primarily due
to progressive aortic dilatation, dissection and
ruptures.\textsuperscript{6, 7}

Pregnancy with the physiological cardiac stress (increased stroke
volume, cardiac output and heart rate) \textsuperscript{8, 9} remains a
controversial topic in MFS. Several studies regarding pregnancy related
cardiovascular complications in MFS have been conducted and data
collated in a systemic review from 2017.\textsuperscript{10} In this
study, aortic dissection rate was 7.9\% and the mortality rate 1.2\%
with a trend towards dissection occurring at pre-pregnancy aortic root
diameter above 40 mm (p=0.0504). Until a recent UK multicentre study
reported an aortic dissection of 1.9\% in 221 live
births,\textsuperscript{11} most studies have been rather small and
mainly case reports indicating possible publication bias.

Besides cardiovascular complications, other birth-related complications
may affect women with Marfan syndrome. However, an overall description
of such pregnancy-related complications still is not clear. Moreover,
most studies are from tertiary centres including only diagnosed Marfan
syndrome women but no controls. A prominent problem related to Marfan
syndrome care is the frequent occurrence of late diagnosis, sometimes
during pregnancy, or outright non-diagnosis, which complicates the
precise description of obstetric complications.

We hypothesized that morbidity in pregnancy is significantly increased
in women with Marfan syndrome, particularly due to cardiac
complications, to uterine, cervical and vaginal complications, as well
as due to preeclampsia and pre-term birth. Thus, our purpose was to
estimate pregnancy outcome, the overall morbidity as well as the risk of
aortic surgery and aortic dissection in relation to pregnancy in a
nationwide MFS cohort, where we included diagnosed as well as
pre-pregnancy in undiagnosed women with Marfan syndrome compared to age
matched controls.

\textbf{Population}

In our previous study\textsuperscript{2} we identified all patients
registered with Marfan syndrome in Denmark in 1977 to 2014; in total 412
patients, whereof 197 were women (183 above 13 years at end of study).
In brief, we verified the Marfan diagnosis after manual evaluation of
their medical records and application of the Ghent-II criteria, and
listed their civil registration number, given to all Danes at
birth\textsuperscript{2}.

\textbf{Methods}

For registrations to all pregnancy related events, we retrieved
information from Statistics Denmark. Statistics Denmark holds copies of
several national registries including the National Patient Registry,
which registers all in- and outpatient contacts in Denmark, including
procedural codes and dates of contact, using International
Classification of Diseases (ICD), 8\textsuperscript{th} or
10\textsuperscript{th} edition. Statistics Denmark utilized the civil
registration number and identified our Marfan syndrome women in the
registries and ensured identification of 100 age matched (year of birth)
female controls as well as accurate linkage of data. For two Marfan
syndrome women, no controls were given, thus, data were obtained for 195
Marfan syndrome women and their 19,500 controls, matched on age and
region.

Statistics Denmark holds no clinical data, for instance on aortic size
and blood pressure.

\textbf{Main outcome measures}

We defined the overall term ``Maternal health'' and divided all relevant
International Classification of Diseases (ICD) codes into four main
groups, namely ``Pregnancy'', ``Delivery'', ``Pregnancy loss'' and
``Death'', and further into subgroups (Figure 1/ Table S1).
Supplementary table 1 shows how we defined the main groups and subgroups
using the ICD 8\textsuperscript{th} and 10\textsuperscript{th} edition.
Unless clearly stated elsewise, the results are only given in those
Marfan syndrome women with at least one pregnancy registration (n=91)
and in their matched controls who all had at least one pregnancy
registration (n=6,801). For each registration within the main groups as
well as the subgroups, we divided the women with Marfan syndrome into
two categories according to whether the Marfan syndrome diagnosis was
known at the time of registration or not. Thus, a woman with Marfan
syndrome could have multiple registrations related to maternal health
before being diagnosed and multiple registrations after being diagnosed
with Marfan syndrome. For all main groups and subgroup registrations, we
only utilized the first registration in each group, regardless of time
of diagnosis.

To report the total number of new-borns, we excluded all registrations
less than 270 days after a delivery registration, as each delivery could
have multiple delivery related registrations within few weeks'
intervals.

In order to study the relationship between maternal health and aortic
disease, we defined aortic dissection and aortic operation as previously
described.\textsuperscript{7} In brief, aortic disease is either a
registration of an aortic dissection, defined as a registration within
the ICD system with a diagnosis of aortic dissection, or a registration
of an aortic operation, defined as a registration in the Nomesco
Classification of Surgical Procedure (NCSP) related to aorta (for
details see Table S2).

The women with Marfan syndrome were diagnosed from 1977 to 2014 and the
registrations of maternal health were from 1977 to 2017. Data were
accessed using a secure remote access to Statistics Denmark. In order to
avoid any possibility of personal identification of cases, Statistics
Denmark prohibits specification of the exact number of cases with a
given condition if less than three, and we therefore report these as
``\textless{}3''.

\emph{Statistics}

Basic epidemiological data are given using median and range. Time to
first registration in all main groups and subgroups was analysed using
stratified Cox regression, where each Marfan syndrome woman and her
matched controls constituting one stratum. For the overall analyses,
time at risk started at birth of the Marfan syndrome woman, and ended at
the date of relevant registration, date of death, end of study, or
emigration, whichever came first. Time at risk \emph{before
diagnosis}started at birth of the Marfan syndrome woman and ended at the
date of relevant registration, date of the Marfan diagnosis, or
emigration, whichever came first. Time at risk \emph{after diagnosis}
started at date of diagnosis and ended at the date of relevant
registration, end of study, date of death or emigration, whichever came
first. Stata 15.1 for Windows (StataCorp LP, College Station, TX, USA)
was used for all calculations.



\textbf{Results}

In total, 91 out of the 195 Danish women with Marfan syndrome (47\%) and
10,188 out of their 19,500 (52\%) controls, had at least one
registration related to ``Maternal health'' and thus a pregnancy (Table
1), corresponding to a significantly decreased hazard ratio (HR) of 0.79
(95\% CI: 0.64-0.97). Seventy-four women with Marfan syndrome (out of
the 91) gave birth to 142 children, and their 6,185 controls gave birth
to 12,088 children.

Fifty women with Marfan syndrome (55 \%) were not diagnosed with Marfan
syndrome at the time of their first registration related to ``Maternal
health'' and 40 of these had one or more registrations of delivery and
thus gave birth to one or more children.

\emph{Maternal health}

Combined, ''Maternal health'' was significantly decreased in women with
Marfan syndrome. This was due to the significantly decreased proportion
of registrations in women diagnosed with Marfan syndrome (HR: 0.68 (95\%
CI: 0.50-0.92)), while among undiagnosed women with Marfan syndrome, the
HR was comparable to controls (Figure 2).

\emph{Complications during pregnancy, pregnancy loss, and delivery}

The following data include all women with Marfan syndrome regardless of
being diagnosed with Marfan syndrome at the time of registration or not
(Figure 3), compared with their controls. In the main group
``Pregnancy'', the only subgroup with a significant finding was
``Complications related to cervix'' (HR: 19.8 (95\% CI: 2.2-177.5)).
There were no significant differences in outcome in ``Pregnancy loss''.
In the main group ``Delivery'', ``Caesarean delivery'' was significantly
increased (HR: 2.09 (95\% CI: 1.41-3.08)) and ``No complications'' was
significantly decreased (HR: 0.52 (95\% CI: 0.37-0.74)), indicating a
somewhat more complicated pregnancy.

\emph{Foetal death}

The HR in ``Foetal death'' was significantly increased in women with
Marfan syndrome (HR: 12.3 (95\% CI: 1.51-99.8)), primarily due to
registrations in women not yet diagnosed with Marfan syndrome, as there
were no registrations of ``Foetal death'' among women already diagnosed
with Marfan syndrome. As there was a limited number of registrations in
``Foetal death'' (MFS: n\textless{}3), no further data can be reported
in this main group.

\emph{Pregnancy complications in relation to having diagnosed or
undiagnosed Marfan syndrome}

Before the Marfan syndrome diagnosis, ``Pregnancy'', ``Pregnancy loss'',
and ``Delivery'' were not affected, whereas after the Marfan syndrome
diagnosis ``Delivery'' was significantly reduced, HR: 0.60 (95\% CI:
0.43-0.85) (Figure 2).

None of the subgroups had significant outcomes both in the undiagnosed
as well as in the diagnosed women with Marfan syndrome.

However, before the Marfan diagnosis, the following subgroups was
significantly increased: In the main group Pregnancy ``Complication
related to vagina'', HR: 27.2 (95\% CI: 2.3-315.0) and ``Preeclampsia''
(HR: 2.25 (95\% CI: 1.11-4.60)), and in the main group Delivery
``Complications, others'' (HR: 1.57 95\% CI: 1.04-2.36)) (Figure 4).

After the Marfan syndrome diagnosis, the main group Pregnancy
``Complication related to cervix'' HR: 17.5 (95\% CI: 1.9-157.7) was
significantly increased, as was in the main group Pregnancy loss ``Late
abortion'' (HR: 3.90 (95\% CI: 1.21-12.56)) and ``Extra uterine
pregnancy'' (HR: 3.90 (95\% CI: 1.58-9.59)), and in main group Delivery
``Infection'' (HR: 25.5 (95\% CI: 2.6-247.1)), and ``Sectio'' (HR: 2.33
(95\% CI: 1.52-3.57)).

\emph{Marfan diagnosis, aortic disease and death}

Combined, 29 women with Marfan syndrome had a pregnancy registration and
at least one registration with aortic disease during the study period.
We did not register any women with known Marfan syndrome with an aortic
dissection in close relation to delivery. Three women diagnosed with
Marfan syndrome had prophylactic aortic surgery prior to a registration
of delivery; none of them were registered with dissection. Twenty
undiagnosed women with Marfan syndrome gave birth to 39 children.

Fifteen (out of the 29 women) had one or more aortic dissections. Their
details are as follows: Nine women suffered from aortic dissection
unrelated to their pregnancy registration, with the event occurring more
than 15 years after the first pregnancy registration and more than 10
years after the last pregnancy registration. Three women with
undiagnosed Marfan syndrome had an aortic dissection in close relation
to delivery. The remaining three women each had a unique order of
events, however, none dissected within 20 years after delivery.

No women with Marfan syndrome and a previous dissection had a pregnancy
registration.

Six of the women with Marfan syndrome and a pregnancy registration and
aortic disease died; all had a registration of an aortic operation and
three had previously had a dissection. Five of these six women died more
than 20 years after their first pregnancy registration. Due to the
prohibited specification of single cases, we cannot report details on
the sixth case. Three controls with a pregnancy registration had aortic
surgery, but no dissections; none of them died.

\textbf{Discussion}

\emph{Main findings}

For the first time, in an unbiased population of women with Marfan
syndrome, including both pre-pregnancy undiagnosed and diagnosed cases,
we show that pregnancy is relatively safe in diagnosed women with Marfan
syndrome. However, undiagnosed Marfan syndrome is associated with
birth-related aortic disease.

We also identified a significantly decreased number of registrations
related to maternal health, indicative of fewer pregnancies, relative to
the background population among diagnosed females with Marfan syndrome,
while women not yet diagnosed with Marfan syndrome had just as many
pregnancies as in the background population. Thus, knowledge of the
diagnosis seems to impact both women with Marfan syndromes decisiveness
and how the health care system advices on pregnancy.

\emph{Strengths and limitations}

Limitations of the current study are the lack of clinical data,
especially cardiac data, including aortic size, in these women. Since
this is a register study we cannot comment on the impact of clinical
surveillance or of medical intervention, such as for example the use of
beta blockers or ACE-inhibitors. Strengths of this study are the
inclusion of diagnosed as well as undiagnosed women with Marfan syndrome
and the nationwide approach with including all diagnosed Marfan syndrome
women. Further, the possibility to utilize the registers with
cross-linkage, which enable identification of the age-matched controls
and the linkage to all hospital contacts, is of paramount importance.

\emph{Interpretation}

It is well known that Marfan syndrome in general is associated with
grossly increased risk of aortic disease\textsuperscript{7}. Prior
studies on Marfan syndrome and pregnancy have primarily been focusing on
aortic events in pregnant women already diagnosed with Marfan syndrome
and cared for in tertiary centres\textsuperscript{12}.

In accordance with previous research, we found an increased risk of
aortic events in Marfan syndrome women, however all dissections during
pregnancy or delivery were in undiagnosed Marfan women.

In the women diagnosed with Marfan syndrome, we identified a
significantly decreased number of registrations of non-complicated
deliveries as well as significantly more extra-uterine pregnancies and
caesarean sections, indicating that a pregnancy in a woman with Marfan
syndrome is indeed more complicated than a normal pregnancy. The
findings related to caesarean section is expected due to the definition
of pregnancy in Marfan syndrome being a high risk pregnancy and the
recommendation of caesarean section at aortic diameter of [?]40
mm.\textsuperscript{13} We consider the findings of a significantly
reduced number of non-complicated deliveries a logic consequence hereof,
as pregnancies and deliveries in women with Marfan syndrome per se are
considered high risk.

Surprisingly, the findings related to the connective tissue component of
the birth canal, here interpreted as findings related to uterine,
cervical, and vaginal complications, were not as frequent as expected.
Although complication related to the cervix was significantly increased,
there was no significantly increased rate of complications related to
the uterine cavity or the vagina. However, in women without a
pre-pregnancy diagnosis of Marfan syndrome there was an increased risk
of vaginal complications, and among women with a pre-pregnancy diagnosis
there were an increased risk of cervical complications.

The significantly increased number of extra uterine pregnancies is an
unexpected finding, not previously reported. Here, we identified an
increased risk in Marfan syndrome women diagnosed at the time of
registration, however the risk in women with Marfan syndrome not yet
diagnosed was not increased. Combined, the association was not
significant.

Preeclampsia was increased in women with Marfan syndrome, however only
significantly in women not yet diagnosed with Marfan syndrome. The
increased risk was also present among women diagnosed with Marfan
syndrome, although this result did not reach significance. Reports of
preeclampsia in a woman diagnosed with Marfan syndrome has been
published previously.\textsuperscript{14}Reassuringly, we found no
association between having Marfan syndrome and experiencing preterm
births. However, this is unexpected since insufficiency of connective
tissue is associated with preterm birth.\textsuperscript{15}

Foetal death was significantly increased among the undiagnosed Marfan
syndrome women, however as none of the registrations were among women
diagnosed with Marfan syndrome, the consequences of this finding in
relation to Marfan syndrome is limited. We could not find any further
information of this result in the registries.

In Denmark, legal abortion is a possibility until 12th week of gestation
on mother's request and after 12th week of gestation if permission is
granted from the regional abortion council. Indications for a late
abortion are for instance mother's health, congenital malformations, and
genetic indications including Marfan syndrome. The significantly
increased proportion of late abortion in the diagnosed Marfan syndrome
women suggests that a diagnosis of MFS in a foetus is followed by
application of legal late abortion in pregnant Marfan women. This could
be a contributing cause of the reduced birth rate among diagnosed Marfan
syndrome women.

The level of cardiac surveillance of the diagnosed Marfan women during
pregnancy in Denmark seems appropriate. It is even likely that some
women with Marfan syndrome, perhaps unnecessarily when scrutinizing the
present data, refrain from becoming pregnant, or choose abortion, due to
careful guidance from the clinical and cardiac Marfan syndrome
centres\textsuperscript{16}. However, we do not have detailed
information concerning the clinical status of the women with diagnosed
Marfan syndrome that chose not to be become pregnant, and it may
therefore be possible that some of these individuals, choosing not to
become pregnant, and then voluntarily infertile, indeed are very high
risk patients\textsuperscript{17}. We anticipate that no cardiac
surveillance program was instituted for the previously undiagnosed women
with Marfan syndrome.

The difference in outcome shows the importance of a pre-pregnancy
diagnosis. Whether some of the associations identified during pregnancy
are driven by historical reports, thus emphasising the clinicians' need
to observe and register the complications, can only be considered among
the women diagnosed with Marfan syndrome, and not among those not yet
diagnosed. However, there is a possibility that the musculo-skeletal
symptoms, known to be present in Marfan syndrome, are already present in
the undiagnosed women, and as such, the clinicians have an increased
awareness and register these complications.

Whether affected connective tissue because of FBN1 mutations in the
uterine system, also can explain the findings with cervical
complications, remains to be determined. The understanding of the
association of an increased risk of preeclampsia in the women not yet
diagnosed, remains to be elucidated, and clinical vigilance is
recommended. It is possible that the pregnant women diagnosed with
Marfan syndrome are treated medically with antihypertensive drugs, thus
reducing the risk of preeclampsia.

\textbf{Conclusions}

We present relatively reassuring data on the aspects of maternal health
in Marfan syndrome and showed that aortic events only appeared in
undiagnosed Marfan syndrome. However, we still consider pregnancy and
delivery in women with Marfan syndrome as high-risk, and close
surveillance during pregnancy and delivery at highly specialised
obstetric centres are a cornerstone in the caretaking of women with
Marfan syndrome.

\textbf{Acknowledgements}

Claus H. Gravholt and Kirstine Stochholm are members of the European
Reference Network on Rare Endocrine Conditions (ENDO-ERN), Project ID
number 739543.

\textbf{Disclosure of interests}

None of the authors have any conflicts of interest to declare

\textbf{Contribution to authorship}

All authors have equally been involved in the conception, planning,
carrying out, analysing and writing up of the work.

\textbf{Details of ethics approval}

The board of the Danish Cytogenetic Central Registry and the Danish Data
Protection Authority approved the project in 2011, with the registration
number 2011-41-6986.

\textbf{Funding}

This study is supported by Department of Clinical Medicine, Aarhus
University Hospital and Aarhus University and the Novo Nordisk
Foundation. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.

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Table 1

Women with Marfan syndrome (n=195) and their controls (n=19,500), and
age at first registration related to maternal health, and the year they
were born.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Number with [?]1 registration\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Median age, years (range)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Year of birth (range)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Marfan syndrome\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Combined\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
91\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
27 (14-40)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1969 (1939-1993)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Not diagnosed with Marfan syndrome at the time of first
registration\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
26 (17-40)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1961 (1939-1989)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Controls\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Combined\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10,188\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (12-48)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1972 (1933-2001)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Matched with a woman with Marfan syndrome\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6,801\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
27 (13-40)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1971 (1939-1993)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Figure 1

\textbf{Maternal health and other groups}

Hierarchal configuration illustrating the combined group maternal
health, the main groups and subgroups. For details, see supplementary
table 1

Figure 2

\textbf{Hazard ratios related to time of the Marfan syndrome diagnosis}

Proportion of all first registrations in maternal health (combined) and
the main groups, Pregnancy, Pregnancy loss, and Delivery. Data are
presented as a) all women with Marfan syndrome b) before the Marfan
syndrome diagnosis, and c) after the Marfan syndrome diagnosis. Data are
presented as women with Marfan syndrome relative to their controls.

Figure 3

\textbf{Hazard ratios in Marfan syndrome compared to controls}

Proportion of all first registrations within the main groups Pregnancy,
Pregnancy loss, and Delivery. Data are presented as women with Marfan
syndrome relative to their controls.

Figure 4

\textbf{Hazard ratios related to time of Marfan syndrome diagnosis,
subgroups}

Proportion of all first registrations in all subgroups in Pregnancy,
Delivery and Pregnancy loss where a) combined data were informative, b)
before the Marfan diagnosis, and c) after the Marfan diagnosis. Data are
presented as women with Marfan syndrome relative to their controls.\selectlanguage{english}
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